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FTR #1121 More than One “Flu” Over the Cuckoo’s Nest, Part 2

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FTR #1121 This pro­gram was record­ed in one, 60-minute seg­ment

Intro­duc­tion: Oya­Gen, Inc. has used a drug devel­oped, test­ed and FDA-approved that suc­cess­ful­ly treats and–apparently–cures Covid-19. Inter­est­ing­ly and, per­haps, sig­nif­i­cant­ly, the tri­als were con­duct­ed at Fort Det­rick. As seen in FTR #‘s 1119 and 1120, the mil­i­tary has been heav­i­ly involved in research­ing virus­es of this type.

There con­tin­ues to be enor­mous empha­sis on Gilead Sci­ences by hedge funds includ­ing Renais­sance Tech­nolo­gies. Robert Mer­cer stepped down as CEO of the firm at the end of 2017, as pub­lic­i­ty around Cam­bridge Ana­lyt­i­ca and the fall­out from the Char­lottesville march made him some­thing of a PR lia­bil­i­ty. Usu­al­ly in such sit­u­a­tions, peo­ple like Mer­cer remain as key investors.

In FTR #1118, we not­ed that the Board of Direc­tors of the firm is “inter­est­ing.” The “dis­ap­point­ing” per­for­mance of Gilead Sci­ences changed dra­mat­i­cal­ly with the Covid-19 out­break. ” . . . . Until Mon­day, when it fell in a bru­tal mar­ket rout, Gilead’s stock price had defied the over­all mar­ket decline of recent weeks, ris­ing almost 20 per­cent from Feb. 21 to March 6, on hopes that the drug could pro­vide the first treat­ment for covid-19. The lack of treat­ment helps explain why. The stock price increased 5 per­cent on Feb. 24 alone when a top offi­cial of the World Health Orga­ni­za­tion pinned much of the world’s hopes for a treat­ment on the drug. . . .”

Again, in FTR #‘s 1119 and 1120 we looked at the pro­found involve­ment of the Pen­ta­gon in research­ing coro­n­avirus­es like Covid-19, as well as DARPA’s deep involve­ment with com­pa­nies approved to begin work­ing on vac­cines. Now, Med­ica­go, anoth­er DARPA-fund­ed com­pa­ny, claims to have a vac­cine ready for tri­al. . . . . Using plants and genet­i­cal­ly engi­neered agrobac­te­ria works faster than eggs also makes the vac­cine much eas­i­er to pro­duce at scale, which, in part, is why the U.S. mil­i­tary has invest­ed in the com­pa­ny. In 2010, the Defense Advanced Research Projects Agency, or DARPA, put togeth­er a $100 mil­lion pro­gram dubbed Blue Angel to look into new forms of vac­cine dis­cov­ery and pro­duc­tion. A big chunk of that mon­ey went to Med­ica­go to build a facil­i­ty in North Car­oli­na, where they showed that they could find a vac­cine in just 20 days, then rapid­ly scale up pro­duc­tion. . . .”

Next, we turn to an arti­cle not­ing that the char­ac­ter­is­tics of the COVID-19 dis­ease has remark­able over­lap with a hypo­thet­i­cal dis­ease, dubbed “Dis­ease X.” In 2018, the World Health Orga­ni­za­tion empha­sized an alarm­ing char­ac­ter­is­tic of “hypo­thet­i­cal” “Dis­ease X” that appears to be shared with SARS-CoV­‑2: the abil­i­ty to rapid­ly morph from a mild to dead­ly dis­ease. The sud­den turn towards a dead­ly dis­ease appears to be due, in part, to an over­ly aggres­sive immune response that ends up rav­aging the lungs. As one expert points out, this is the same pat­tern seen in the 1918 “Span­ish flu” pan­dem­ic.

In FTR #1117, we reviewed the fact that mil­i­tary researchers had suc­cess­ful­ly recov­ered DNA from that infa­mous 1918 flu virus. as will be seen below, that virus was re-cre­at­ed in a lab­o­ra­to­ry in 2005.

So the WHO warned a cou­ple years ago about a hypo­thet­i­cal “Dis­ease X” dis­ease that was high­ly con­ta­gious with the abil­i­ty to spread with asymp­to­mati­cal­ly, is mild in most cas­es but with the abil­i­ty to sud­den­ly turn dead­ly. And here we are two years lat­er with a dis­ease that fits that pro­file. It was a pret­ty pre­scient pre­dic­tion.

Note, also, that Mar­i­on Koopmans–head of viro­science at Eras­mus Med­ical Cen­ter in Rot­ter­dam and one of the WHO per­son­nel who opined that Covid-19 was “Dis­ease X” worked at the same insti­tu­tion as the researchers who per­formed gain-of-func­tion exper­i­ments on the HN51 Avian Bird Flu virus, adapt­ing to fer­rets and mak­ing it com­mu­ni­ca­ble through casu­al res­pi­ra­to­ry activ­i­ty. Those GOF experiements were also dis­cussed in FTR #1117.

” . . . . From recent reports about the stealthy ways the so-called Covid-19 virus spreads and maims, a pic­ture is emerg­ing of an enig­mat­ic pathogen whose effects are main­ly mild, but which occa­sion­al­ly — and unpre­dictably — turns dead­ly in the sec­ond week. . . . The doc­tor [Li Wen­liang], who was in good health pri­or to his infec­tion, appeared to have a rel­a­tive­ly mild case until his lungs became inflamed, lead­ing to the man’s death two days lat­er, said Lin­fa Wang, who heads the emerg­ing infec­tious dis­ease pro­gram at Duke-Nation­al Uni­ver­si­ty of Sin­ga­pore Med­ical School. A sim­i­lar pat­tern of inflam­ma­tion not­ed among Covid-19 patients was observed in those who suc­cumbed to the 1918 ‘Span­ish flu’ pan­dem­ic . . .”

We won­der if vari­ants of the Covid-19 may have been mod­i­fied to infect the upper res­pi­ra­to­ry tract and/or mod­i­fied with DNA from the res­ur­rect­ed 1918 “Span­ish Flu”?

Peter Daszak of the WHO once again, voiced the (self-ful­fill­ing?) opinion/prophecy that Covid-19 is indeed “Dis­ease X.”

A key fac­tor spurring our sus­pi­cion con­cern­ing genet­ic-engi­neer­ing of one or more vari­ant of the Covid-19 virus con­cerns a 2015 Gain-of-Func­tion exper­i­ment: “Ralph Bar­ic, an infec­tious-dis­ease researcher at the Uni­ver­si­ty of North Car­oli­na at Chapel Hill, last week (Novem­ber 9) pub­lished a study on his team’s efforts to engi­neer a virus with the sur­face pro­tein of the SHC014 coro­n­avirus, found in horse­shoe bats in Chi­na, and the back­bone of one that caus­es human-like severe acute res­pi­ra­to­ry syn­drome (SARS) in mice. The hybrid virus could infect human air­way cells and caused dis­ease in mice. . . . The results demon­strate the abil­i­ty of the SHC014 sur­face pro­tein to bind and infect human cells, val­i­dat­ing con­cerns that this virus—or oth­er coro­n­avirus­es found in bat species—may be capa­ble of mak­ing the leap to peo­ple with­out first evolv­ing in an inter­me­di­ate host, Nature report­ed. They also reignite a debate about whether that infor­ma­tion jus­ti­fies the risk of such work, known as gain-of-func­tion research. ‘If the [new] virus escaped, nobody could pre­dict the tra­jec­to­ry,’ Simon Wain-Hob­son, a virol­o­gist at the Pas­teur Insti­tute in Paris, told Nature. . . .”

The above-men­tioned Ralph Bar­ic–who did the gain-of-func­tion mod­i­fi­ca­tion on the Horse­shoe Bat coro­n­avirus, has been select­ed to engi­neer the Covid-19.

Note what might be termed a “viro­log­ic Juras­sic Park” man­i­fes­ta­tion: ” . . . . . . . . The tech­nol­o­gy imme­di­ate­ly cre­at­ed bio-weapon wor­ries. . . . Researchers at the US Cen­ters for Dis­ease Con­trol and Pre­ven­tion (CDC) drove that point home in 2005 when they res­ur­rect­ed the influen­za virus that killed tens of mil­lions in 1918–1919. . . .

1a. Oya­Gen, Inc. has used a drug devel­oped, test­ed and FDA-approved that suc­cess­ful­ly treats and–apparently–cures Covid-19. Inter­est­ing­ly and, per­haps, sig­nif­i­cant­ly, the tri­als were con­duct­ed at Fort Det­rick. As seen in FTR #‘s 1119 and 1120, the mil­i­tary has been heav­i­ly involved in research­ing virus­es of this type.

“ROC biotech com­pa­ny says lab tests of for­mer can­cer drug con­firm it stops COVID-19” by Jane Flasch; 13WHAM News; 03/11/2020

A vac­cine for COVID-19 is like­ly years away. Yet a drug test­ed in a lab three weeks ago has been found to stop the virus from spread­ing from cell to cell.

The stun­ning announce­ment comes from a Rochester biotech com­pa­ny called Oya­Gen, Inc. The com­pa­ny is seek­ing to fast-track the for­mu­la to treat peo­ple who become infect­ed.

“A treat­ment right now is the pri­or­i­ty,” said Dr. Harold Smith of Oya­Gen. He added the drug already has FDA approval for anoth­er use.

The tests were con­duct­ed at the fed­er­al government’s inte­grat­ed research facil­i­ty in Fort Det­rick, Md. A drug called Oya 1 had already been proven in lab tests there to be effec­tive against Ebo­la.

“If it worked for Ebo­la, is it absolute­ly unique to Ebo­la, or would it work on oth­er virus­es?” asked Dr. Smith – though he said an actu­al drug for human con­sump­tion was nev­er pur­sued.

The coro­n­avirus was still new and con­tained to Wuhan, Chi­na when a sam­ple of the live virus was shipped to the gov­ern­ment lab for test­ing with Oya 1. Test sam­ples viewed under a micro­scope show a clear “before” and “after” that indi­cates prop­er­ties that allowed the virus to grow and spread were neu­tral­ized.

“The drug was so effec­tive that, even though we got through our dose-test­ing, we had lit­er­al­ly ster­il­ized the cul­ture of the virus, so we knew this was a pow­er­ful thing,” said Dr. Smith.

Under a dif­fer­ent name, Oya‑1 was first devel­oped in the 1960s as a treat­ment for can­cer. It was lat­er shelved as inef­fec­tive, but not before it received approval from the Food and Drug Admin­is­tra­tion. Safe dosage lev­els were deter­mined for men, women and chil­dren.

“Clin­i­cal tri­als have already been done on this com­pound and, if safe­ty is a main issue, we feel safe­ty has been addressed years ago,” said Dr. Smith.

He said pre­lim­i­nary research indi­cates a sin­gle dose of the med­i­cine stops the pro­gres­sion of COVID-19 for eight days and con­tin­ues to work at half-strength for anoth­er four days.

The ques­tion is whether the drug will react to the virus the same way in the body as it has in the lab. When an approved drug is pro­posed for a new use, the FDA usu­al­ly requires new clin­i­cal tri­als.

Oya­Gen says the live virus tests were con­duct­ed and val­i­dat­ed by a third par­ty – the U‑S gov­ern­ment, and argue that is also a rea­son the drug should be fast-tracked.

“You’ve got this com­pound that’s absolute­ly lethal to the virus, and we know it has a mar­gin of safe­ty in peo­ple,” said Dr. Smith. “What are we wait­ing for?”

1b. There con­tin­ues to be enor­mous empha­sis on Gilead Sci­ences by hedge funds includ­ing Renais­sance Tech­nolo­gies. Robert Mer­cer stepped down as CEO of the firm at the end of 2017, as pub­lic­i­ty around Cam­bridge Ana­lyt­i­ca and the fall­out from the Char­lottesville march made him some­thing of a PR lia­bil­i­ty. Usu­al­ly in such sit­u­a­tions, peo­ple like Mer­cer remain as key investors.

In FTR #1118, we not­ed that the Board of Direc­tors of the firm is “inter­est­ing.”

“2019 Review: Most Favored Hedge Fund Stocks vs. Gilead Sci­ences, Inc. (GILD)” by Asma UL Hus­na in Hedge Funds; Insid­er Mon­key; 12/29/2019

It has been a fan­tas­tic year for equi­ty investors as Don­ald Trump pres­sured Fed­er­al Reserve to reduce inter­est rates and final­ized the first leg of a trade deal with Chi­na. If you were a pas­sive index fund investor, you had seen gains of 31% in your equi­ty port­fo­lio in 2019. How­ev­er, if you were an active investor putting your mon­ey into hedge funds’ favorite stocks, you had seen gains of more than 41%. In this arti­cle we are going to take a look at how hedge funds feel about a stock like Gilead Sci­ences, Inc. (NASDAQ:GILD) and com­pare its per­for­mance against hedge funds’ favorite stocks.

Gilead Sci­ences, Inc. (NASDAQ:GILD) was in 58 hedge funds’ port­fo­lios at the end of the third quar­ter of 2019. GILD has seen an increase in hedge fund inter­est recent­ly. . . .

. . . . The largest stake in Gilead Sci­ences, Inc. (NASDAQ:GILD) was held by Renais­sance Tech­nolo­gies, which report­ed hold­ing $933.9 mil­lion worth of stock at the end of Sep­tem­ber. It was fol­lowed by D E Shaw with a $349.9 mil­lion posi­tion. . . . Oth­er investors bull­ish on the com­pa­ny includ­ed Two Sig­ma Advi­sors, AQR Cap­i­tal Man­age­ment, and GLG Part­ners. In terms of the port­fo­lio weights assigned to each posi­tion Coper­ni­cus Cap­i­tal Man­age­ment allo­cat­ed the biggest weight to Gilead Sci­ences, Inc. (NASDAQ:GILD), around 11.67% of its 13F port­fo­lio. Health­care Val­ue Cap­i­tal is also rel­a­tive­ly very bull­ish on the stock, ear­mark­ing 8.01 per­cent of its 13F equi­ty port­fo­lio to GILD.

. . . . Our cal­cu­la­tions showed that top 20 most pop­u­lar stocks among hedge funds returned 41.1% in 2019 through Decem­ber 23rd and out­per­formed the S&P 500 ETF (SPY) by 10.1 per­cent­age points. Unfor­tu­nate­ly GILD wasn’t near­ly as pop­u­lar as these 20 stocks and hedge funds that were bet­ting on GILD were dis­ap­point­ed as the stock returned 10.8% so far in 2019 (through 12/23) and trailed the mar­ket. . . . .

1c. The “dis­ap­point­ing” per­for­mance of Gilead Sci­ences changed dra­mat­i­cal­ly with the Covid-19 out­break. ” . . . . Until Mon­day, when it fell in a bru­tal mar­ket rout, Gilead’s stock price had defied the over­all mar­ket decline of recent weeks, ris­ing almost 20 per­cent from Feb. 21 to March 6, on hopes that the drug could pro­vide the first treat­ment for covid-19. The lack of treat­ment helps explain why. The stock price increased 5 per­cent on Feb. 24 alone when a top offi­cial of the World Health Orga­ni­za­tion pinned much of the world’s hopes for a treat­ment on the drug. . . .”

“The best hope for coro­n­avirus treat­ment is an exper­i­men­tal drug that fiz­zled against Ebo­la” by Christo­pher Row­land; The Wash­ing­ton Post; 03/11/2020

. . . . Now the drug, [remde­sivir] cre­at­ed by phar­ma­ceu­ti­cal giant Gilead Sci­ences, is being test­ed in new clin­i­cal tri­alsand glob­al health author­i­ties deem it the most promis­ing of pos­si­ble treat­ments for peo­ple who are severe­ly ill with the nov­el coro­n­avirus, which caus­es the covid-19 dis­ease. Because it is a “broad spec­trum’’ drug that has been effec­tive against mul­ti­ple viral tar­gets in the lab and in ani­mals, the strat­e­gy could work, experts said. . . .

Gilead, the Nation­al Insti­tutes of Health and Chi­nese health author­i­ties are rac­ing to test it on hun­dreds of peo­ple in con­trolled clin­i­cal tri­als, includ­ing a patient who was quar­an­tined in Nebras­ka after being removed from the Dia­mond Princess cruise ship. Axios report­ed this month that Gilead act­ed so quick­ly that it did not even wait for required approval by the Food and Drug Admin­is­tra­tion before it shipped dos­es to Chi­na. Asked to respond, Gilead said it thinks its “lim­it­ed ship­ments’’ were made in com­pli­ance with U.S. law.

. . . . Until Mon­day, when it fell in a bru­tal mar­ket rout, Gilead’s stock price had defied the over­all mar­ket decline of recent weeks, ris­ing almost 20 per­cent from Feb. 21 to March 6, on hopes that the drug could pro­vide the first treat­ment for covid-19.

The lack of treat­ment helps explain why. The stock price increased 5 per­cent on Feb. 24 alone when a top offi­cial of the World Health Orga­ni­za­tion pinned much of the world’s hopes for a treat­ment on the drug.

“There is only one drug right now that we think may have real effi­ca­cy, and that’s remde­sivir,” said Bruce Ayl­ward, WHO’s assis­tant direc­tor gen­er­al. Ten days lat­er, RBC Cap­i­tal Mar­kets gave it only a 50 per­cent chance of suc­ceed­ing as a treat­ment.

The mixed sig­nals have done lit­tle to damp­en inter­est. There have been des­per­ate pleas for sup­plies to treat patients on a ‘com­pas­sion­ate use’ basis.

. . . . But drug com­pa­nies also have been accused of not pur­su­ing vac­cines and antivi­ral treat­ments aggres­sive­ly because the com­mer­cial mar­kets for such drugs are weak. . . .

. . . . Giv­en the large degree of pub­lic finan­cial sup­port, debates are already flar­ing about how much Gilead should charge for its treat­ment if it ever makes it to mar­ket.

Con­gress and Pres­i­dent Trump autho­rized up to $3 bil­lion last week for efforts by aca­d­e­m­ic researchers and drug com­pa­nies to devel­op vac­cines and treat­ments for coro­n­avirus, part of an $8.3 bil­lion emer­gency spend­ing bill. The indus­try suc­cess­ful­ly opposed efforts by some House Democ­rats to attach guar­an­tees for afford­able prices for vac­cines or treat­ments that result. . . .”

1d. Again, in FTR #‘s 1119 and 1120 we looked at the pro­found involve­ment of the Pen­ta­gon in research­ing coro­n­avirus­es like Covid-19, as well as DARPA’s deep involve­ment with com­pa­nies approved to begin work­ing on vac­cines. Now, Med­ica­go, anoth­er DARPA-fund­ed com­pa­ny, claims to have a vac­cine ready for tri­al. . . . . Using plants and genet­i­cal­ly engi­neered agrobac­te­ria works faster than eggs also makes the vac­cine much eas­i­er to pro­duce at scale, which, in part, is why the U.S. mil­i­tary has invest­ed in the com­pa­ny. In 2010, the Defense Advanced Research Projects Agency, or DARPA, put togeth­er a $100 mil­lion pro­gram dubbed Blue Angel to look into new forms of vac­cine dis­cov­ery and pro­duc­tion. A big chunk of that mon­ey went to Med­ica­go to build a facil­i­ty in North Car­oli­na, where they showed that they could find a vac­cine in just 20 days, then rapid­ly scale up pro­duc­tion. . . .”

“We’ve Got the Vac­cine, Says Pen­ta­gon-Fund­ed Com­pa­ny” by Patrick Tuck­er; Defense One; 3/12/2020.

A Cana­di­an com­pa­ny says that it haspro­duced a COVID-19 vac­cine just 20 days after receiv­ing the coronavirus’s genet­ic sequence, using a unique tech­nol­o­gy that they soon hope to sub­mit for FDA approval.

Med­ica­go CEO Bruce Clark said his com­pa­ny could pro­duce as many as 10 mil­lion dos­es a month. If reg­u­la­to­ry hur­dles can be cleared, he said in a Thurs­day inter­view, the vac­cine could start to become avail­able in Novem­ber 2021. . . .

. . . . Using plants and genet­i­cal­ly engi­neered agrobac­te­ria works faster than eggs also makes the vac­cine much eas­i­er to pro­duce at scale, which, in part, is why the U.S. mil­i­tary has invest­ed in the com­pa­ny. 

In 2010, the Defense Advanced Research Projects Agency, or DARPA, put togeth­er a $100 mil­lion pro­gram dubbed Blue Angel to look into new forms of vac­cine dis­cov­ery and pro­duc­tion. A big chunk of that mon­ey went to Med­ica­go to build a facil­i­ty in North Car­oli­na, where they showed that they could find a vac­cine in just 20 days, then rapid­ly scale up pro­duc­tion. . . .

1d. Next, we turn to an arti­cle not­ing that the char­ac­ter­is­tics of the COVID-19 dis­ease has remark­able over­lap with a hypo­thet­i­cal dis­ease, dubbed “Dis­ease X.” In 2018, the World Health Orga­ni­za­tion empha­sized an alarm­ing char­ac­ter­is­tic of “hypo­thet­i­cal” “Dis­ease X” that appears to be shared with SARS-CoV­‑2: the abil­i­ty to rapid­ly morph from a mild to dead­ly dis­ease. The sud­den turn towards a dead­ly dis­ease appears to be due, in part, to an over­ly aggres­sive immune response that ends up rav­aging the lungs. As one expert points out, this is the same pat­tern seen in the 1918 “Span­ish flu” pan­dem­ic.

In FTR #1117, we reviewed the fact that mil­i­tary researchers had suc­cess­ful­ly recov­ered DNA from that infa­mous 1918 flu virus. as will be seen below, that virus was re-cre­at­ed in a lab­o­ra­to­ry in 2005.

So the WHO warned a cou­ple years ago about a hypo­thet­i­cal “Dis­ease X” dis­ease that was high­ly con­ta­gious with the abil­i­ty to spread with asymp­to­mati­cal­ly, is mild in most cas­es but with the abil­i­ty to sud­den­ly turn dead­ly. And here we are two years lat­er with a dis­ease that fits that pro­file. It was a pret­ty pre­scient pre­dic­tion.

Note, also, that Mar­i­on Koopmans–head of viro­science at Eras­mus Med­ical Cen­ter in Rot­ter­dam and one of the WHO per­son­nel who opined that Covid-19 was “Dis­ease X” worked at the same insti­tu­tion as the researchers who per­formed gain-of-func­tion exper­i­ments on the HN51 Avian Bird Flu virus, adapt­ing to fer­rets and mak­ing it com­mu­ni­ca­ble through casu­al res­pi­ra­to­ry activ­i­ty. Those GOF experiements were also dis­cussed in FTR #1117.

” . . . . From recent reports about the stealthy ways the so-called Covid-19 virus spreads and maims, a pic­ture is emerg­ing of an enig­mat­ic pathogen whose effects are main­ly mild, but which occa­sion­al­ly — and unpre­dictably — turns dead­ly in the sec­ond week. . . . The doc­tor [Li Wen­liang], who was in good health pri­or to his infec­tion, appeared to have a rel­a­tive­ly mild case until his lungs became inflamed, lead­ing to the man’s death two days lat­er, said Lin­fa Wang, who heads the emerg­ing infec­tious dis­ease pro­gram at Duke-Nation­al Uni­ver­si­ty of Sin­ga­pore Med­ical School. A sim­i­lar pat­tern of inflam­ma­tion not­ed among Covid-19 patients was observed in those who suc­cumbed to the 1918 ‘Span­ish flu’ pan­dem­ic . . .”

We won­der if vari­ants of the Covid-19 may have been mod­i­fied to infect the upper res­pi­ra­to­ry tract and/or mod­i­fied with DNA from the res­ur­rect­ed 1918 “Span­ish Flu”?

“Coro­n­avirus May Be ‘Dis­ease X’ Health Experts Warned About” By Jason Gale; Bloomberg; 02/22/2020

* Pic­ture is emerg­ing of an unpre­dictable, enig­mat­ic pathogen
* SARS-like lung inflam­ma­tion seen in severe Covid-19 cas­es

The World Health Orga­ni­za­tion cau­tioned years ago that a mys­te­ri­ous “dis­ease X” could spark an inter­na­tion­al con­ta­gion. The new coro­n­avirus ill­ness, with its abil­i­ty to quick­ly morph from mild to dead­ly, is emerg­ing as a con­tender.

From recent reports about the stealthy ways the so-called Covid-19 virus spreads and maims, a pic­ture is emerg­ing of an enig­mat­ic pathogen whose effects are main­ly mild, but which occa­sion­al­ly — and unpre­dictably — turns dead­ly in the sec­ond week. In less than three months, it’s infect­ed almost 78,000 peo­ple, most­ly in Chi­na, and killed more than 2,300. Emerg­ing hot spots in South Korea, Iran and Italy have stoked fur­ther alarm.

“Whether it will be con­tained or not, this out­break is rapid­ly becom­ing the first true pan­dem­ic chal­lenge that fits the dis­ease X cat­e­go­ry,” Mar­i­on Koop­mans, head of viro­science at Eras­mus Uni­ver­si­ty Med­ical Cen­ter in Rot­ter­dam, and a mem­ber of the WHO’s emer­gency com­mit­tee, wrote Wednes­day in the jour­nal Cell.

The dis­ease has now spread to more than two dozen coun­tries and ter­ri­to­ries. Some of those infect­ed caught the virus in their local com­mu­ni­ty and have no known link to Chi­na, the U.S. Cen­ters for Dis­ease Con­trol and Pre­ven­tion said.

“We are not see­ing com­mu­ni­ty spread here in the Unit­ed States yet, but it’s very pos­si­ble — even like­ly — that it may even­tu­al­ly hap­pen,” Nan­cy Mes­son­nier, direc­tor of the CDC’s Nation­al Cen­ter for Immu­niza­tion and Res­pi­ra­to­ry Dis­eases, told reporters Fri­day.

Unlike SARS, its viral cousin, the Covid-19 virus repli­cates at high con­cen­tra­tions in the nose and throat akin to the com­mon cold, and appears capa­ble of spread­ing from those who show no, or mild, symp­toms. That makes it impos­si­ble to con­trol using the fever-check­ing mea­sures that helped stop SARS 17 years ago.

Spread­ing Sur­rep­ti­tious­ly

A clus­ter of cas­es with­in a fam­i­ly liv­ing in the Chi­nese city of Anyang is pre­sumed to have begun when a 20-year-old woman car­ried the virus from Wuhan, the outbreak’s epi­cen­ter, on Jan. 10 and spread it while expe­ri­enc­ing no ill­ness, researchers said Fri­day in the Jour­nal of the Amer­i­can Med­ical Asso­ci­a­tion.

Five rel­a­tives sub­se­quent­ly devel­oped fever and res­pi­ra­to­ry symp­toms. Covid-19 is less dead­ly than SARS, which had a case fatal­i­ty rate of 9.5%, but appears more con­ta­gious. Both virus­es attack the res­pi­ra­to­ry and gas­troin­testi­nal tracts, via which they can poten­tial­ly spread.

While more than 80% of patients are report­ed to have a mild ver­sion of the dis­ease and will recov­er, about one in sev­en devel­ops pneu­mo­nia, dif­fi­cul­ty breath­ing and oth­er severe symp­toms. About 5% of patients have crit­i­cal ill­ness, includ­ing res­pi­ra­to­ry fail­ure, sep­tic shock and mul­ti-organ fail­ure.

“Unlike SARS, Covid-19 infec­tion has a broad­er spec­trum of sever­i­ty rang­ing from asymp­to­matic to mild­ly symp­to­matic to severe ill­ness that requires mechan­i­cal ven­ti­la­tion,” doc­tors in Sin­ga­pore said in a paper in the same med­ical jour­nal Thurs­day. “Clin­i­cal pro­gres­sion of the ill­ness appears sim­i­lar to SARS: patients devel­oped pneu­mo­nia around the end of the first week to the begin­ning of the sec­ond week of ill­ness.”

Unpre­dictable Ill­ness

Old­er adults, espe­cial­ly those with chron­ic con­di­tions, such as hyper­ten­sion and dia­betes, have been found to have a high­er risk of severe ill­ness. Still, “the expe­ri­ence to date in Sin­ga­pore is that patients with­out sig­nif­i­cant co-mor­bid con­di­tions can also devel­op severe ill­ness,” they said.

Li Wen­liang, the 34-year-old oph­thal­mol­o­gist who was one of the first to warn about the coro­n­avirus in Wuhan, died ear­li­er this month after receiv­ing anti­bod­ies, antivi­rals, antibi­otics, oxy­gen and hav­ing his blood pumped through an arti­fi­cial lung.

Update: Li Wen­liang is cur­rent­ly in crit­i­cal con­di­tion. His heart report­ed­ly stopped beat­ing at around 21:30. He was then giv­en treat­ment with ECMO(extra-corporeal mem­brane oxy­gena­tion). https://t.co/ljhMSwHBXB
— Glob­al Times (@globaltimesnews) Feb­ru­ary 6, 2020

The doc­tor, who was in good health pri­or to his infec­tion, appeared to have a rel­a­tive­ly mild case until his lungs became inflamed, lead­ing to the man’s death two days lat­er, said Lin­fa Wang, who heads the emerg­ing infec­tious dis­ease pro­gram at Duke-Nation­al Uni­ver­si­ty of Sin­ga­pore Med­ical School.

A sim­i­lar pat­tern of inflam­ma­tion not­ed among Covid-19 patients was observed in those who suc­cumbed to the 1918 “Span­ish flu” pan­dem­ic, said Gre­go­ry A. Poland, the Mary Low­ell Leary emer­i­tus pro­fes­sor of med­i­cine, infec­tious dis­eases, and mol­e­c­u­lar phar­ma­col­o­gy and exper­i­men­tal ther­a­peu­tics at the Mayo Clin­ic in Rochester, Min­neso­ta.

“When­ev­er, you have an infec­tion, you have a bat­tle going on,” Poland said in a phone inter­view Thurs­day. “And that bat­tle is a bat­tle between the dam­age that the virus is doing, and the dam­age the body can do when it tries to fight it off.” . . . .

2. Peter Daszak of the WHO once again, voiced the (self-ful­fill­ing?) opinion/prophecy that Covid-19 is indeed “Dis­ease X.”

“We Knew Dis­ease X Was Com­ing. It’s Here Now.” by Peter Daszak; The New York Times; 02/27/2020

In ear­ly 2018, dur­ing a meet­ing at the World Health Orga­ni­za­tion in Gene­va, a group of experts I belong to (the R&D Blue­print) coined the term “Dis­ease X”: We were refer­ring to the next pan­dem­ic, which would be caused by an unknown, nov­el pathogen that hadn’t yet entered the human pop­u­la­tion. As the world stands today on the edge of the pan­dem­ic precipice, it’s worth tak­ing a moment to con­sid­er whether Covid-19 is the dis­ease our group was warn­ing about.

Dis­ease X, we said back then, would like­ly result from a virus orig­i­nat­ing in ani­mals and would emerge some­where on the plan­et where eco­nom­ic devel­op­ment dri­ves peo­ple and wildlife togeth­er. Dis­ease X would prob­a­bly be con­fused with oth­er dis­eases ear­ly in the out­break and would spread quick­ly and silent­ly; exploit­ing net­works of human trav­el and trade, it would reach mul­ti­ple coun­tries and thwart con­tain­ment. Dis­ease X would have a mor­tal­i­ty rate high­er than a sea­son­al flu but would spread as eas­i­ly as the flu. It would shake finan­cial mar­kets even before it achieved pan­dem­ic sta­tus.

In a nut­shell, Covid-19 is Dis­ease X. . . .

3. A key fac­tor spurring our sus­pi­cion con­cern­ing genet­ic-engi­neer­ing of one or more vari­ant of the Covid-19 virus con­cerns a 2015 Gain-of-Func­tion exper­i­ment: “Ralph Bar­ic, an infec­tious-dis­ease researcher at the Uni­ver­si­ty of North Car­oli­na at Chapel Hill, last week (Novem­ber 9) pub­lished a study on his team’s efforts to engi­neer a virus with the sur­face pro­tein of the SHC014 coro­n­avirus, found in horse­shoe bats in Chi­na, and the back­bone of one that caus­es human-like severe acute res­pi­ra­to­ry syn­drome (SARS) in mice. The hybrid virus could infect human air­way cells and caused dis­ease in mice. . . . The results demon­strate the abil­i­ty of the SHC014 sur­face pro­tein to bind and infect human cells, val­i­dat­ing con­cerns that this virus—or oth­er coro­n­avirus­es found in bat species—may be capa­ble of mak­ing the leap to peo­ple with­out first evolv­ing in an inter­me­di­ate host, Nature report­ed. They also reignite a debate about whether that infor­ma­tion jus­ti­fies the risk of such work, known as gain-of-func­tion research. ‘If the [new] virus escaped, nobody could pre­dict the tra­jec­to­ry,’ Simon Wain-Hob­son, a virol­o­gist at the Pas­teur Insti­tute in Paris, told Nature. . . .”

“Lab-Made Coro­n­avirus Trig­gers Debate” by Jef Akst; The Sci­en­tist; 11/16/2015

Ralph Bar­ic, an infec­tious-dis­ease researcher at the Uni­ver­si­ty of North Car­oli­na at Chapel Hill, last week (Novem­ber 9) pub­lished a study on his team’s efforts to engi­neer a virus with the sur­face pro­tein of the SHC014 coro­n­avirus, found in horse­shoe bats in Chi­na, and the back­bone of one that caus­es human-like severe acute res­pi­ra­to­ry syn­drome (SARS) in mice. The hybrid virus could infect human air­way cells and caused dis­ease in mice, accord­ing to the team’s results, which were pub­lished in Nature Med­i­cine.

The results demon­strate the abil­i­ty of the SHC014 sur­face pro­tein to bind and infect human cells, val­i­dat­ing con­cerns that this virus—or oth­er coro­n­avirus­es found in bat species—may be capa­ble of mak­ing the leap to peo­ple with­out first evolv­ing in an inter­me­di­ate host, Nature report­ed. They also reignite a debate about whether that infor­ma­tion jus­ti­fies the risk of such work, known as gain-of-func­tion research. “If the [new] virus escaped, nobody could pre­dict the tra­jec­to­ry,” Simon Wain-Hob­son, a virol­o­gist at the Pas­teur Insti­tute in Paris, told Nature.

In Octo­ber 2013, the US gov­ern­ment put a stop to all fed­er­al fund­ing for gain-of-func­tion stud­ies, with par­tic­u­lar con­cern ris­ing about influen­za, SARS, and Mid­dle East res­pi­ra­to­ry syn­drome (MERS). “NIH [Nation­al Insti­tutes of Health] has fund­ed such stud­ies because they help define the fun­da­men­tal nature of human-pathogen inter­ac­tions, enable the assess­ment of the pan­dem­ic poten­tial of emerg­ing infec­tious agents, and inform pub­lic health and pre­pared­ness efforts,” NIH Direc­tor Fran­cis Collins said in a state­ment at the time. “These stud­ies, how­ev­er, also entail biosafe­ty and biose­cu­ri­ty risks, which need to be under­stood bet­ter.”

Baric’s study on the SHC014-chimeric coro­n­avirus began before the mora­to­ri­um was announced, and the NIH allowed it to pro­ceed dur­ing a review process, which even­tu­al­ly led to the con­clu­sion that the work did not fall under the new restric­tions, Bar­ic told Nature. But some researchers, like Wain-Hob­son, dis­agree with that deci­sion.

The debate comes down to how infor­ma­tive the results are. “The only impact of this work is the cre­ation, in a lab, of a new, non-nat­ur­al risk,” Richard Ebright, a mol­e­c­u­lar biol­o­gist and biode­fence expert at Rut­gers Uni­ver­si­ty, told Nature.

But Bar­ic and oth­ers argued the study’s impor­tance. “[The results] move this virus from a can­di­date emerg­ing pathogen to a clear and present dan­ger,” Peter Daszak, pres­i­dent of the Eco­Health Alliance, which sam­ples virus­es from ani­mals and peo­ple in emerg­ing-dis­eases hotspots across the globe, told Nature.

4. The above-men­tioned Ralph Baric–who did the gain-of-func­tion mod­i­fi­ca­tion on the Horse­shoe Bat coro­n­avirus, has been select­ed to engi­neer the Covid-19.

Note what might be termed a “viro­log­ic Juras­sic Park” man­i­fes­ta­tion: ” . . . . . . . . The tech­nol­o­gy imme­di­ate­ly cre­at­ed bio-weapon wor­ries. . . . Researchers at the US Cen­ters for Dis­ease Con­trol and Pre­ven­tion (CDC) drove that point home in 2005 when they res­ur­rect­ed the influen­za virus that killed tens of mil­lions in 1918–1919. . . .

“Biol­o­gists rush to re-cre­ate the Chi­na coro­n­avirus from its DNA code” by Anto­nio Regal­a­do; MIT Tech­nol­o­gy Review; 02/15/2020

The world is watch­ing with alarm as Chi­na strug­gles to con­tain a dan­ger­ous new virus, now being called SARS-CoV­‑2. It has quar­an­tined entire cities, and the US has put a blan­ket ban on trav­ellers who’ve been there. Health offi­cials are scram­bling to under­stand how the virus is trans­mit­ted and how to treat patients.

But in one Uni­ver­si­ty of North Car­oli­na lab, there’s a dif­fer­ent race. Researchers are try­ing to cre­ate a copy of the virus. From scratch.

Led by Ralph Bar­ic, an expert in coronaviruses—which get their name from the crown-shaped spike they use to enter human cells—the North Car­oli­na team expects to recre­ate the virus start­ing only from com­put­er read­outs of its genet­ic sequence post­ed online by Chi­nese labs last month.

The remark­able abil­i­ty to “boot up” virus­es from genet­ic instruc­tions is made pos­si­ble by com­pa­nies that man­u­fac­ture cus­tom DNA mol­e­cules, such as Inte­grat­ed DNA Tech­nol­o­gy, Twist Bio­science, and Atum. By order­ing the right genes, which cost a few thou­sand dol­lars, and then stitch­ing them togeth­er to cre­ate a copy of the coro­n­avirus genome, it’s pos­si­ble to inject the genet­ic mate­r­i­al into cells and jump-start the virus to life.

The abil­i­ty to make a lethal virus from mail-order DNA was first demon­strat­ed 20 years ago. It’s enough of a bioter­ror­ism con­cern that com­pa­nies care­ful­ly mon­i­tor who is order­ing which genes. But it’s also an impor­tant way to respond to a sud­den out­break, since syn­thet­ic virus recipes give researchers pow­er­ful ways to study treat­ments, vac­cines, and how muta­tions could make it more dan­ger­ous.

When a syn­thet­ic virus is bet­ter than the real thing

Baric’s North Car­oli­na lab, which spe­cial­izes in engi­neer­ing virus­es, has pre­vi­ous­ly butted heads with Wash­ing­ton agen­cies over the work, which has includ­ed syn­the­siz­ing new, nev­er before seen coro­n­avirus­es that can infect mice. In 2014, the Nation­al Insti­tutes of Health froze fund­ing to sev­er­al labs, includ­ing Baric’s, over con­cerns that such research was too risky. The fund­ing was lat­er rein­stat­ed.

For the Chi­na virus, Bar­ic said in a tele­phone inter­view, his team placed an order for match­ing DNA from a man­u­fac­tur­er last month. Their first step was to go online and look at genet­ic sequences of the virus. They then com­pared sev­er­al avail­able sequences, which dif­fer slight­ly, and picked a “con­sen­sus” ver­sion to have man­u­fac­tured. . . .

. . . . The tech­nol­o­gy imme­di­ate­ly cre­at­ed bio-weapon wor­ries. What if ter­ror­ists used the tech­nique to res­ur­rect small­pox? That hasn’t hap­pened, but it does mean that scourges like polio, smallpox—and now the Chi­nese coronavirus—cannot now ever be tru­ly wiped out. Researchers at the US Cen­ters for Dis­ease Con­trol and Pre­ven­tion (CDC) drove that point home in 2005 when they res­ur­rect­ed the influen­za virus that killed tens of mil­lions in 1918–1919. . . .

To keep the tech­nol­o­gy out of the hands of evil-doers, com­pa­nies that man­u­fac­ture DNA band­ed togeth­er a few years ago to lim­it access to dan­ger­ous genes. The big US play­ers have all agreed to com­pare incom­ing DNA orders to a data­base of about 60 lethal germs and tox­ins called “select agents” so that only autho­rized labs can ever obtain the DNA need­ed to res­ur­rect them. . . .

 

Discussion

16 comments for “FTR #1121 More than One “Flu” Over the Cuckoo’s Nest, Part 2”

  1. Well, looks like ol’ Dov “Project For A New Amer­i­can Cen­tu­ry” Zakheim is advis­ing Herr Trump on invok­ing the Cold-War mon­stros­i­ty that is the “Defense Pro­duc­tion Act” on order to “aug­ment” civil­ian hos­pi­tal’s abil­i­ty to cope with the com­ing pan­dem­ic:

    https://news.yahoo.com/pressure-grows-on-trump-to-invoke-defense-production-act-for-coronavirus-response-004710535.html

    Posted by Booji Boy | March 18, 2020, 1:42 am
  2. Here’s an inter­est­ing piece in the Atlantic describ­ing some of what’s been learned about what makes the SARS-CoV­‑2 virus that caus­es COVID-19 dif­fer­ent from oth­er coro­n­avirus­es known to infect humans. The arti­cle men­tions some of what we’ve already heard, like how this virus unusu­al­ly infects both the upper and low­er res­pi­ra­to­ry tracts and describes the biol­o­gy of why that hap­pens. It turns out the ‘spike’ part of the SARS-CoV­‑2 virus is unusu­al­ly good at latch­ing into a pro­tein called ACE2 which is found on the exte­ri­or of the cells in human air­ways. This abil­i­ty to latch onto ACE2 is like­ly a big fac­tor in what has allowed the virus to infect upper air­ways. It’s thought that the virus like­ly infects the upper air­ways first and then, as cells in the air­way die and are sloughed off, the virus makes its way down to the low­er res­pi­ra­to­ry tract and lungs where the dead­ly infec­tions might occur. It’s this pat­tern of first infect­ing the upper res­pi­ra­to­ry tract before mak­ing its way down to the lungs that has giv­en the virus the abil­i­ty to silent­ly spread while it’s in a rel­a­tive­ly asymp­to­matic ini­tial phase before it sud­den­ly turns much more vicious and dead­ly.

    But that abil­i­ty to latch strong­ly on the ACE2 pro­tein in human air­ways is just one of the muta­tions that has made this virus excep­tion­al at spread­ing among humans. Anoth­er key fea­ture has to do with a pro­tein bridge that con­nects two halves of the virus’s spike. When the spike gets acti­vate the virus injects its pay­load into the cell. Acti­vat­ing the spike requires the cleav­age of a pro­tein bridge con­nect­ing the two halves of the spike and it turns out this pro­tein bridge is cleav­able by the enzyme furin which is ubiq­ui­tous in human cells. This was­n’t the case for SARS, which had a pro­tein bridge that was less like­ly to be cleaved. So SARS-CoV­‑2 can first latch onto to human upper air­way cells more effec­tive­ly than SARS and once there is read­i­ly acti­vat­ed much more eas­i­ly than SARS.

    But here is per­haps the most notable obser­va­tion made about this virus thus far: it does­n’t appear to be muta­tion in any mean­ing­ful ways. Out of the 100-plus muta­tions that have been observed in wild so far, none of those viral strains has emerged as a dom­i­nant strain. That’s unusu­al­ly for a virus that appar­ent­ly only recent­ly jumped to humans and has been spread­ing at a wild rate. It’s as if the virus is already evo­lu­tion­ar­i­ly opti­mized for spread­ing among humans and there are no ‘gain-of-fuc­tion’ muta­tions left for it acquire. As Lisa Gralin­s­ki, a coro­n­avirus expert at the Uni­ver­si­ty of North Car­oli­na Chapel Hill, described it, “The virus has been remark­ably sta­ble giv­en how much trans­mis­sion we’ve seen...That makes sense, because there’s no evo­lu­tion­ary pres­sure on the virus to trans­mit bet­ter. It’s doing a great job of spread­ing around the world right now.” Note that Gralin­sky works close­ly with Ralph Bar­ic’s lab. Recall that Bar­ic is the researcher who con­struct­ed a chimeric virus out of a SARS virus and horse­shoe bat coro­n­avirus in 2015, so Bar­ic and Gralin­s­ki are going to be world lead­ing experts on coro­n­avirus­es. They lit­er­al­ly build news ones. So when some­one like Gralin­s­ki observes that the it makes sense that the virus would­n’t feel any evo­lu­tion­ary pres­sure to spread more read­i­ly because it’s already doing such a good job that’s quite a state­ment. Evo­lu­tion does­n’t stop just because it’s already doing a real­ly good job. If there was a muta­tion that would allow the virus to spread even more read­i­ly that would hap­pen. And nor­mal­ly does hap­pen. But it has­n’t hap­pened so for SARS-CoV­‑2 because it’s appar­ent­ly already at some sort of coro­n­avirus evo­lu­tion­ary peak:

    The Atlantic

    Why the Coro­n­avirus Has Been So Suc­cess­ful

    We’ve known about SARS-CoV­‑2 for only three months, but sci­en­tists can make some edu­cat­ed guess­es about where it came from and why it’s behav­ing in such an extreme way.

    Ed Yong
    March 20, 2020

    One of the few mer­cies dur­ing this cri­sis is that, by their nature, indi­vid­ual coro­n­avirus­es are eas­i­ly destroyed. Each virus par­ti­cle con­sists of a small set of genes, enclosed by a sphere of fat­ty lipid mol­e­cules, and because lipid shells are eas­i­ly torn apart by soap, 20 sec­onds of thor­ough hand-wash­ing can take one down. Lipid shells are also vul­ner­a­ble to the ele­ments; a recent study shows that the new coro­n­avirus, SARS-CoV­‑2, sur­vives for no more than a day on card­board, and about two to three days on steel and plas­tic. These virus­es don’t endure in the world. They need bod­ies.

    But much about coro­n­avirus­es is still unclear. Susan Weiss, of the Uni­ver­si­ty of Penn­syl­va­nia, has been study­ing them for about 40 years. She says that in the ear­ly days, only a few dozen sci­en­tists shared her interest—and those num­bers swelled only slight­ly after the SARS epi­dem­ic of 2002. “Until then peo­ple looked at us as a back­ward field with not a lot of impor­tance to human health,” she says. But with the emer­gence of SARS-CoV‑2—the cause of the COVID-19 disease—no one is like­ly to repeat that mis­take again.

    To be clear, SARS-CoV­‑2 is not the flu. It caus­es a dis­ease with dif­fer­ent symp­toms, spreads and kills more read­i­ly, and belongs to a com­plete­ly dif­fer­ent fam­i­ly of virus­es. This fam­i­ly, the coro­n­avirus­es, includes just six oth­er mem­bers that infect humans. Four of them—OC43, HKU1, NL63, and 229E—have been gen­tly annoy­ing humans for more than a cen­tu­ry, caus­ing a third of com­mon colds. The oth­er two—MERS and SARS (or “SARS-clas­sic,” as some virol­o­gists have start­ed call­ing it)—both cause far more severe dis­ease. Why was this sev­enth coro­n­avirus the one to go pan­dem­ic? Sud­den­ly, what we do know about coro­n­avirus­es becomes a mat­ter of inter­na­tion­al con­cern.

    The struc­ture of the virus pro­vides some clues about its suc­cess. In shape, it’s essen­tial­ly a spiky ball. Those spikes rec­og­nize and stick to a pro­tein called ACE2, which is found on the sur­face of our cells: This is the first step to an infec­tion. The exact con­tours of SARS-CoV‑2’s spikes allow it to stick far more strong­ly to ACE2 than SARS-clas­sic did, and “it’s like­ly that this is real­ly cru­cial for per­son-to-per­son trans­mis­sion,” says Angela Ras­mussen of Colum­bia Uni­ver­si­ty. In gen­er­al terms, the tighter the bond, the less virus required to start an infec­tion.

    There’s anoth­er impor­tant fea­ture. Coro­n­avirus spikes con­sist of two con­nect­ed halves, and the spike acti­vates when those halves are sep­a­rat­ed; only then can the virus enter a host cell. In SARS-clas­sic, this sep­a­ra­tion hap­pens with some dif­fi­cul­ty. But in SARS-CoV­‑2, the bridge that con­nects the two halves can be eas­i­ly cut by an enzyme called furin, which is made by human cells and—crucially—is found across many tis­sues. “This is prob­a­bly impor­tant for some of the real­ly unusu­al things we see in this virus,” says Kris­t­ian Ander­sen of Scripps Research Trans­la­tion­al Insti­tute.

    For exam­ple, most res­pi­ra­to­ry virus­es tend to infect either the upper or low­er air­ways. In gen­er­al, an upper-res­pi­ra­to­ry infec­tion spreads more eas­i­ly, but tends to be milder, while a low­er-res­pi­ra­to­ry infec­tion is hard­er to trans­mit, but is more severe. SARS-CoV­‑2 seems to infect both upper and low­er air­ways, per­haps because it can exploit the ubiq­ui­tous furin. This dou­ble wham­my could also con­ceiv­ably explain why the virus can spread between peo­ple before symp­toms show up—a trait that has made it so dif­fi­cult to con­trol. Per­haps it trans­mits while still con­fined to the upper air­ways, before mak­ing its way deep­er and caus­ing severe symp­toms. All of this is plau­si­ble but total­ly hypo­thet­i­cal; the virus was only dis­cov­ered in Jan­u­ary, and most of its biol­o­gy is still a mys­tery.

    The new virus cer­tain­ly seems to be effec­tive at infect­ing humans, despite its ani­mal ori­gins. The clos­est wild rel­a­tive of SARS-CoV­‑2 is found in bats, which sug­gests it orig­i­nat­ed in a bat, then jumped to humans either direct­ly or through anoth­er species. (Anoth­er coro­n­avirus found in wild pan­golins also resem­bles SARS-CoV­‑2, but only in the small part of the spike that rec­og­nizes ACE2; the two virus­es are oth­er­wise dis­sim­i­lar, and pan­golins are unlike­ly to be the orig­i­nal reser­voir of the new virus.) When SARS-clas­sic first made this leap, a brief peri­od of muta­tion was nec­es­sary for it to rec­og­nize ACE2 well. But SARS-CoV­‑2 could do that from day one. “It had already found its best way of being a [human] virus,” says Matthew Frie­man of the Uni­ver­si­ty of Mary­land School of Med­i­cine.

    This uncan­ny fit will doubtless­ly encour­age con­spir­a­cy the­o­rists: What are the odds that a ran­dom bat virus had exact­ly the right com­bi­na­tion of traits to effec­tive­ly infect human cells from the get-go, and then jump into an unsus­pect­ing per­son? “Very low,” Ander­sen says, “but there are mil­lions or bil­lions of these virus­es out there. These virus­es are so preva­lent that things that are real­ly unlike­ly to hap­pen some­times do.”

    Since the start of the pan­dem­ic, the virus hasn’t changed in any obvi­ous­ly impor­tant ways. It’s mutat­ing in the way that all virus­es do. But of the 100-plus muta­tions that have been doc­u­ment­ed, none has risen to dom­i­nance, which sug­gests that none is espe­cial­ly impor­tant. “The virus has been remark­ably sta­ble giv­en how much trans­mis­sion we’ve seen,” says Lisa Gralin­s­ki of the Uni­ver­si­ty of North Car­oli­na. “That makes sense, because there’s no evo­lu­tion­ary pres­sure on the virus to trans­mit bet­ter. It’s doing a great job of spread­ing around the world right now.”

    There’s one pos­si­ble excep­tion. A few SARS-CoV­‑2 virus­es that were iso­lat­ed from Sin­ga­pore­an COVID-19 patients are miss­ing a stretch of genes that also dis­ap­peared from SARS-clas­sic dur­ing the late stages of its epi­dem­ic. This change was thought to make the orig­i­nal virus less vir­u­lent, but it’s far too ear­ly to know whether the same applies to the new one. Indeed, why some coro­n­avirus­es are dead­ly and some are not is unclear. “There’s real­ly no under­stand­ing at all of why SARS or SARS-CoV­‑2 are so bad but OC43 just gives you a run­ny nose,” Frie­man says.

    Researchers can, how­ev­er, offer a pre­lim­i­nary account of what the new coro­n­avirus does to the peo­ple it infects. Once in the body, it like­ly attacks the ACE2-bear­ing cells that line our air­ways. Dying cells slough away, fill­ing the air­ways with junk and car­ry­ing the virus deep­er into the body, down toward the lungs. As the infec­tion pro­gress­es, the lungs clog with dead cells and flu­id, mak­ing breath­ing more dif­fi­cult. (The virus might also be able to infect ACE2-bear­ing cells in oth­er organs, includ­ing the gut and blood ves­sels.)

    The immune sys­tem fights back and attacks the virus; this is what caus­es inflam­ma­tion and fever. But in extreme cas­es, the immune sys­tem goes berserk, caus­ing more dam­age than the actu­al virus. For exam­ple, blood ves­sels might open up to allow defen­sive cells to reach the site of an infec­tion; that’s great, but if the ves­sels become too leaky, the lungs fill even more with flu­id. These dam­ag­ing over­re­ac­tions are called cytokine storms. They were his­tor­i­cal­ly respon­si­ble for many deaths dur­ing the 1918 flu pan­dem­ic, H5N1 bird flu out­breaks, and the 2003 SARS out­break. And they’re prob­a­bly behind the most severe cas­es of COVID-19. “These virus­es need time to adapt to a human host,” says Akiko Iwasa­ki of the Yale School of Med­i­cine. “When they’re first try­ing us out, they don’t know what they’re doing, and they tend to elic­it these respons­es.”

    Dur­ing a cytokine storm, the immune sys­tem isn’t just going berserk but is also gen­er­al­ly off its game, attack­ing at will with­out hit­ting the right tar­gets. When this hap­pens, peo­ple become more sus­cep­ti­ble to infec­tious bac­te­ria. The storms can also affect oth­er organs besides the lungs, espe­cial­ly if peo­ple already have chron­ic dis­eases. This might explain why some COVID-19 patients end up with com­pli­ca­tions such as heart prob­lems and sec­ondary infec­tions.

    But why do some peo­ple with COVID-19 get incred­i­bly sick, while oth­ers escape with mild or nonex­is­tent symp­toms? Age is a fac­tor. Elder­ly peo­ple are at risk of more severe infec­tions pos­si­bly because their immune sys­tem can’t mount an effec­tive ini­tial defense, while chil­dren are less affect­ed because their immune sys­tem is less like­ly to progress to a cytokine storm. But oth­er factors—a person’s genes, the vagaries of their immune sys­tem, the amount of virus they’re exposed to, the oth­er microbes in their bodies—might play a role too. In gen­er­al, “it’s a mys­tery why some peo­ple have mild dis­ease, even with­in the same age group,” Iwasa­ki says.

    Coro­n­avirus­es, much like influen­za, tend to be win­ter virus­es. In cold and dry air, the thin lay­ers of liq­uid that coat our lungs and air­ways become even thin­ner, and the beat­ing hairs that rest in those lay­ers strug­gle to evict virus­es and oth­er for­eign par­ti­cles. Dry air also seems to damp­en some aspects of the immune response to those trapped virus­es. In the heat and humid­i­ty of sum­mer, both trends reverse, and res­pi­ra­to­ry virus­es strug­gle to get a foothold.

    Unfor­tu­nate­ly, that might not mat­ter for the COVID-19 pan­dem­ic. At the moment, the virus is tear­ing through a world of immuno­log­i­cal­ly naive peo­ple, and that vul­ner­a­bil­i­ty is like­ly to swamp any sea­son­al vari­a­tions. After all, the new virus is trans­mit­ting read­i­ly in coun­tries like Sin­ga­pore (which is in the trop­ics) and Aus­tralia (which is still in sum­mer). And one recent mod­el­ing study con­clud­ed that “SARS-CoV­‑2 can pro­lif­er­ate at any time of year.” “I don’t have an immense amount of con­fi­dence that the weath­er is going to have the effect that peo­ple hope it will,” Gralin­s­ki says. “It may knock things down a lit­tle, but there’s so much per­son-to-per­son trans­mis­sion going on that it may take more than that.” Unless peo­ple can slow the spread of the virus by stick­ing to phys­i­cal-dis­tanc­ing rec­om­men­da­tions, the sum­mer alone won’t save us.

    ...

    ———–

    “Why the Coro­n­avirus Has Been So Suc­cess­ful” Ed Yong; The Atlantic; 03/20/2020

    “Since the start of the pan­dem­ic, the virus hasn’t changed in any obvi­ous­ly impor­tant ways. It’s mutat­ing in the way that all virus­es do. But of the 100-plus muta­tions that have been doc­u­ment­ed, none has risen to dom­i­nance, which sug­gests that none is espe­cial­ly impor­tant. “The virus has been remark­ably sta­ble giv­en how much trans­mis­sion we’ve seen,” says Lisa Gralin­s­ki of the Uni­ver­si­ty of North Car­oli­na. “That makes sense, because there’s no evo­lu­tion­ary pres­sure on the virus to trans­mit bet­ter. It’s doing a great job of spread­ing around the world right now.”

    No evo­lu­tion­ary pres­sure to trans­mit bet­ter. It’s already evolved the abil­i­ty to latch onto ACE2 far more strong­ly than SARS. And once it latch­es onto those ACE2 pro­teins in the upper res­pi­ra­to­ry tract, the virus is able to acti­vate itself more eas­i­ly than SARS with the help of a ubiq­ui­tous human pro­tein furin that will come along and cleave the spike pro­tein bridge required to acti­vate the virus. Those two evo­lu­tion­ary fea­tures appear to be crit­i­cal for giv­ing this virus its remark­ably high lev­els of infec­tious­ness.

    ...
    The struc­ture of the virus pro­vides some clues about its suc­cess. In shape, it’s essen­tial­ly a spiky ball. Those spikes rec­og­nize and stick to a pro­tein called ACE2, which is found on the sur­face of our cells: This is the first step to an infec­tion. The exact con­tours of SARS-CoV‑2’s spikes allow it to stick far more strong­ly to ACE2 than SARS-clas­sic did, and “it’s like­ly that this is real­ly cru­cial for per­son-to-per­son trans­mis­sion,” says Angela Ras­mussen of Colum­bia Uni­ver­si­ty. In gen­er­al terms, the tighter the bond, the less virus required to start an infec­tion.

    There’s anoth­er impor­tant fea­ture. Coro­n­avirus spikes con­sist of two con­nect­ed halves, and the spike acti­vates when those halves are sep­a­rat­ed; only then can the virus enter a host cell. In SARS-clas­sic, this sep­a­ra­tion hap­pens with some dif­fi­cul­ty. But in SARS-CoV­‑2, the bridge that con­nects the two halves can be eas­i­ly cut by an enzyme called furin, which is made by human cells and—crucially—is found across many tis­sues. “This is prob­a­bly impor­tant for some of the real­ly unusu­al things we see in this virus,” says Kris­t­ian Ander­sen of Scripps Research Trans­la­tion­al Insti­tute.

    For exam­ple, most res­pi­ra­to­ry virus­es tend to infect either the upper or low­er air­ways. In gen­er­al, an upper-res­pi­ra­to­ry infec­tion spreads more eas­i­ly, but tends to be milder, while a low­er-res­pi­ra­to­ry infec­tion is hard­er to trans­mit, but is more severe. SARS-CoV­‑2 seems to infect both upper and low­er air­ways, per­haps because it can exploit the ubiq­ui­tous furin. This dou­ble wham­my could also con­ceiv­ably explain why the virus can spread between peo­ple before symp­toms show up—a trait that has made it so dif­fi­cult to con­trol. Per­haps it trans­mits while still con­fined to the upper air­ways, before mak­ing its way deep­er and caus­ing severe symp­toms. All of this is plau­si­ble but total­ly hypo­thet­i­cal; the virus was only dis­cov­ered in Jan­u­ary, and most of its biol­o­gy is still a mys­tery.
    ...

    And then we have the oblig­a­tory assur­ances that, despite the seem­ing improb­a­bil­i­ty of a virus jump­ing from ani­mals to humans already hav­ing the key fea­tures that make it seem­ing­ly opti­mized for spread­ing between peo­ple, we should­n’t jump to con­clu­sions like the obvi­ous pos­si­bil­i­ty that the virus was man-made. Instead, we’re remind­ed that while the odds of an indi­vid­ual virus acquir­ing these muta­tions and then jump­ing to humans is “very low”, ran­dom low prob­a­bil­i­ty events do hap­pen. That’s the assur­ance. A reminder that even the improb­a­ble is pos­si­ble:

    ...
    The new virus cer­tain­ly seems to be effec­tive at infect­ing humans, despite its ani­mal ori­gins. The clos­est wild rel­a­tive of SARS-CoV­‑2 is found in bats, which sug­gests it orig­i­nat­ed in a bat, then jumped to humans either direct­ly or through anoth­er species. (Anoth­er coro­n­avirus found in wild pan­golins also resem­bles SARS-CoV­‑2, but only in the small part of the spike that rec­og­nizes ACE2; the two virus­es are oth­er­wise dis­sim­i­lar, and pan­golins are unlike­ly to be the orig­i­nal reser­voir of the new virus.) When SARS-clas­sic first made this leap, a brief peri­od of muta­tion was nec­es­sary for it to rec­og­nize ACE2 well. But SARS-CoV­‑2 could do that from day one. “It had already found its best way of being a [human] virus,” says Matthew Frie­man of the Uni­ver­si­ty of Mary­land School of Med­i­cine.

    This uncan­ny fit will doubtless­ly encour­age con­spir­a­cy the­o­rists: What are the odds that a ran­dom bat virus had exact­ly the right com­bi­na­tion of traits to effec­tive­ly infect human cells from the get-go, and then jump into an unsus­pect­ing per­son? “Very low,” Ander­sen says, “but there are mil­lions or bil­lions of these virus­es out there. These virus­es are so preva­lent that things that are real­ly unlike­ly to hap­pen some­times do.”
    ...

    And while that’s cer­tain­ly true that low prob­a­bil­i­ty events can indeed hap­pen, that’s not exact­ly a com­pelling counter argu­ment to sus­pi­cious that the virus was man-made. After all, what’s more improb­a­ble: that an incred­i­bly low-prob­a­bly event hap­pened where this virus just hap­pened to have all of these opti­mized fea­tures for humans when it jumped from anoth­er ani­mal vs the prob­a­bly that it was made in a lab. Which sce­nario is less like­ly?

    Also keep in mind that, while the large num­ber of virus­es that get pro­duced means high­ly improb­a­bly events can real­is­ti­cal­ly hap­pen, let’s not for­get that the same prin­ci­ple should apply when it comes to new vari­ants of the virus emerg­ing with new func­tion­al muta­tions. Like a new dom­i­nant strain with a muta­tion that allows it to spread more quick­ly and become a dom­i­nant strain. That’s not hap­pen­ing. Why aren’t those low prob­a­bly events dri­ving the evo­lu­tion of this virus? Might the virus already have had its evo­lu­tion sped up? Don’t for­get that the noto­ri­ous “gain-of-func­tion” exper­i­ments involv­ing H5N1 were exper­i­ments that sped up the evo­lu­tion of the virus. That’s how the gain of func­tion was hap­pen­ing. Sped up evo­lu­tion exper­i­ments. So if you just sped a virus’s evo­lu­tion up long enough with these kinds of exper­i­ments would you hit a point where the virus does­n’t evolve any­more and is basi­cal­ly already opti­mized? Might a lack of viral evo­lu­tion be an indi­rect sign that it’s already man-made? Who knows, but it’s worth not­ing the one sil­ver lin­ing in all this: at least it does­n’t sound like the virus itself will get much worse. Because it can’t get any bet­ter.

    Posted by Pterrafractyl | March 23, 2020, 2:12 pm
  3. Here’s a pair of research pub­li­ca­tions that are just get­ting released that expand on the obser­va­tion that SARS-CoV­‑2 virus has two key fea­tures that caus­es COVID-19 to be much more infec­tious in humans than the SARS-CoV virus that cause the SARS out­break in 2003:

    First, recall how SARS-CoV­‑2 appears to stick to the ACE2 recep­tors on the cell walls of human air­ways much more effec­tive­ly than SARS-CoV. This helps the virus infect the upper res­pi­ra­to­ry tract unlike SARS. Also recall how SARS-CoV­‑2 has a cleav­age site on its spike pro­tein that can be cleaved by the human pro­tein furin. This is seen as cru­cial for its infec­tious­ness because cleav­age of the spike pro­tein is required for the virus to inject its pay­load into the cell and furin is ubiq­ui­tous on the sur­face of human air­way cells. The orig­i­nal SARS-CoV virus from 2003 does­n’t have that furin cleav­age site. These are two key fea­tures that have made COVID-19 much more infec­tious than SARS.

    So the first pub­li­ca­tion below expands on how anom­alous it is for the SARS-CoV­‑2 to pos­sess that furin cleav­age site on the spike pro­tein when you look at the entire fam­i­ly of known coro­n­avirus­es and the sub­group that SARS-CoV­‑2 falls into. The paper uses the label 2019-nCoV for the SARS-CoV­‑2 virus (which is the more wide­ly used label), so the nam­ing can get a lit­tle con­fus­ing.

    There are dif­fer­ent gen­eras (fam­i­lies) of coro­n­avirus­es. SARS-CoV­‑2 (2019-nCoV) belongs to the Beta­coro­n­avirus fam­i­ly which has dif­fer­ent lin­eages. Click here to see a visu­al­iza­tion from the paper of the phy­lo­ge­net­ic coro­n­avirus fam­i­ly tree for dif­fer­ent coro­n­avirus­es in the Alpha­coro­n­avirus and Beta­coro­n­avirus fam­i­lies. You can see that the Beta­coro­n­avirus fam­i­ly has four dif­fer­ence lin­eages (a, b, c, d). SARS-CoV­‑2 belongs to the b lin­eage, which includes the SARS-CoV virus from 2003. The b lin­eage also includes the CoV ZXC21 bat virus, which is one of the virus­es most close­ly relat­ed to SARS-CoV­‑2 which is the major rea­son for the ini­tial sus­pi­cions that the virus jumped from bats to humans.

    Now, one would expect SARS-CoV­‑2 to be more sim­i­lar to oth­er virus­es in that same lin­eage than it is to the virus­es in oth­er lin­eages or gen­eras since it’s assumed they emerged from a com­mon ances­tor. And for the most part that’s true, with the major excep­tion of that cleav­age site on SARS-CoV­‑2. It turns out that no oth­er known virus­es in that b lin­eage of Beta­coro­n­avirus­es pos­sess the furin cleav­age site. There are Beta­coro­n­avirus­es in dif­fer­ent lin­eages that do poss­es the furin cleav­age site, but none in the b lin­eage. It’s pret­ty odd.

    The authors in the paper spec­u­late that this addi­tion of the furin cleav­age site in SARS-CoV­‑2 rep­re­sents a gain-of-func­tion muta­tion for the virus that allows it to infect humans more effi­cient­ly. So why is it that no oth­er coro­n­avirus­es in the b lin­eage of Beta­coro­n­avirus­es have the furin cleav­age site? Well, the authors spec­u­late that this might be an exam­ple of con­ver­gent evo­lu­tion tak­ing place between SARS-CoV­‑2 and oth­er coro­n­avirus­es out­side of the b lin­eage that also pos­sess the furin cleav­age sites. Con­ver­gent evo­lu­tion is a well known phe­nom­e­na in nature where dif­fer­ent organ­isms inde­pen­dent­ly evolve to pos­sess sim­i­lar fea­tures. And if we assume that SARS-CoV­‑2 isn’t a man-made virus then con­ver­gent evo­lu­tion is a rea­son­able sus­pi­cion. Of course, in the era of syn­thet­ic biol­o­gy and ‘gain-of-func­tion’ tech­niques in the lab, that assump­tion that this isn’t man-made is becom­ing an increas­ing­ly ten­u­ous assump­tion. More gen­er­al­ly, when we have to fall back on assump­tions of con­ver­gent evo­lu­tion to explain an appar­ent gain-of-func­tion adap­ta­tion it high­lights how unusu­al SARS-CoV­‑2 is com­pared to its clos­est viral cousins.

    Now, in the sec­ond pub­li­ca­tion below, the authors sug­gest a dif­fer­ent nat­ur­al mech­a­nism that could have result­ed in the evo­lu­tion­ar­i­ly unusu­al SARS-CoV­‑2 virus: recom­bi­na­tion. That’s a process that can hap­pen in the same ani­mal gets infect­ed by two RNA dif­fer­ent virus­es at the same time, result­ing a new chimeri­ca virus that a com­bi­na­tion of the two viral genomes. The authors observe that the genet­ic sequence of the Pan­golin-CoV virus — the coro­n­avirus that infects Pan­golins — is the sec­ond most sim­i­lar so SARS-CoV­‑2 after the horse­shoe bat ver­sion. But one part of the the S‑protein (the pro­tein with the furin cleav­age site) in SARS-CoV­‑2 is actu­al­ly much more close­ly relat­ed to the S‑protein in Pan­golin-CoV than to the horse­shoe bat ver­sion of the virus. The S‑protein con­sists of two sub­units (S1 and S2) that are gen­er­at­ed when the pro­tein is cleaved. The S1 sub­unit con­tains the part of the pro­tein that rec­og­nizes the ACE2 recep­tor on mam­malian cells. The S1 sub­unit also con­tains the furin cleav­age site in SARS-CoV­‑2, but not Pan­golin-CoV. Recall how Pan­golins have been sus­pect­ed to be an inter­me­di­ate host between bats and humans if we assume this real­ly did jump to humans from the wild. And yet even Pan­golin-CoV virus’s S‑protein does­n’t have the furin cleav­age site.

    The authors try to explain the sud­den emer­gence of the furin cleav­age site by sug­gest­ing that anoth­er coro­n­avirus with a furin cleav­age site infect­ed an ani­mal (a Pan­golin or bat) at the same time it was infect­ed with the Pan­golin or bat coro­n­avirus and that result­ed in a recom­bi­na­tion even and the inser­tion of that cleav­age site in Pan­golin-CoV, result­ing in SARS-CoV­‑2 (or an inter­me­di­ate) emerg­ing. And while it’s pos­si­ble recom­bi­na­tion was what led to the sud­den addi­tion of pre­cise­ly the adap­ta­tion that allows the virus to infect humans high­ly effi­cient­ly, it’s still a low prob­a­bil­i­ty event that we’re talk­ing about. After all, that furin cleav­age site is in an S‑protein that’s almost iden­ti­cal between SARS-CoV­‑2 and Pan­golin-CoV, imply­ing that if a recom­bi­na­tion event took place it did­n’t change the Pan­golin-CoV S‑protein very much. So what are the odds that the change just hap­pened to include this cru­cial furin cleav­age site? That seems like awful luck. Now, if we lat­er dis­cov­er a coro­n­avirus that has an S‑protein genet­ic sequence that’s an even clos­er match to the SARS-CoV­‑2 S‑protein sequence and con­tains that furin cleav­age site, well that would make a recom­bi­na­tion event sce­nario more plau­si­ble. But unless we find an exam­ple of an exist­ing virus with a close S‑protein match it seems like just hor­ri­ble luck that the furin cleav­age site just hap­pened to be part of the mys­tery coro­n­avirus that got recom­bined into the bat or Pan­golin ver­sions.

    Also note that falling back on the recom­bi­na­tion expla­na­tion is part­ly appeal­ing in this case between that furin cleav­age site is can­non­i­cal accord­ing to the first arti­cle below. It’s like exact­ly what you would need for furin to latch onto the spike pro­tein and not a less potent vari­ant. We would expect a can­non­i­cal cleav­age site in a virus that’s had a long time to evolve with­in a human host. That’s just evo­lu­tion in action. But in this case it’s like the virus had that evo­lu­tion­ar­i­ly opti­mized site right away, which is why it’s tempt­ing to assume it acquired it from a dif­fer­ent virus that already had an evo­lu­tion­ar­i­ly opti­mized site. It’s pos­si­ble, but real­ly bad luck.

    And that appears to be the gen­er­al theme for explain­ing the unex­pect­ed genet­ic char­ac­ter­is­tics of the SARS-CoV­‑2 virus caus­ing the COVID-19 pan­dem­ic: if this hap­pened nat­u­ral­ly, it was a very unlucky turn of events both because of the extreme neg­a­tive con­se­quences and because of how improb­a­ble it was to hap­pen in the first place. That’s not to say that viral pan­demics of this nature were improb­a­ble. On the con­trary, future pan­demics are a cer­tain­ty. It was just a mat­ter of when and how. But hav­ing this virus emerge with seem­ing­ly opti­mized genet­ics for infect­ing humans with­out first going through an ear­li­er, less infec­tious strain, is just hor­ri­ble luck if that’s what hap­pened.

    Now, it’s also pos­si­ble there was an evo­lu­tion­ary inter­me­di­ary we just haven’t found yet. For exam­ple, let’s say SARS-CoV­‑2 real­ly did emerge from Pan­golin-CoV. There could have been an ear­li­er ver­sion we nev­er detect­ed that had non-can­non­i­cal furin cleav­age sites that furin could only weak­ly act upon. Per­haps this hypo­thet­i­cal ear­li­er ver­sion of the virus has been infect­ing peo­ple for a while with­out caus­ing sig­nif­i­cant symp­toms and allow­ing evo­lu­tion to play out in the human host. This would be the con­ver­gent evo­lu­tion sce­nario involv­ing an unknown inter­me­di­ary. It’s a pos­si­ble sce­nario, espe­cial­ly if the weak­er ver­sion of the virus did­n’t real­ly cause sig­nif­i­cant dis­ease. In that case there would­n’t have been any rea­son for doc­tors to zero in on it and sequence its genome. But so far we have no evi­dence of that ear­li­er ver­sion of this virus float­ing around. It’s still just a hypo­thet­i­cal.

    So when it comes to the ques­tion of whether or not this is a man-made virus, we appear to be a sit­u­a­tion where we’re forced to gues­ti­mate the rel­a­tive like­li­hood that this virus could have emerged nat­u­ral­ly vs being made in a lab. We know it could emerge nat­u­ral­ly. There are known mech­a­nisms for doing that. We also know it could obvi­ous­ly have been built in a lab, which would cer­tain­ly explain the unex­pect­ed char­ac­ter­is­tics of this virus. Which of those sce­nar­ios is most like­ly?

    Ok, here’s the first arti­cle in Antivi­ral Research that describes how the SARS-CoV­‑2 virus (2019-nCov) is the only virus in the b lin­eage of the Beta­coro­n­avirus gen­era with that furin cleav­age site. A furin cleav­age site that hap­pens to be a can­non­i­cal site which means its basi­cal­ly evo­lu­tion­ar­i­ly opti­mized for furin to latch onto. As the authors put it, this rep­re­sents a gain-of-func­tion for SARS-CoV­‑2 (2019-nCov) and since sim­i­lar furin cleav­age sites have been observed in dif­fer­ent lin­eages of Beta­coro­n­avirus this may be an exam­ple of con­ver­gent evo­lu­tion in action:

    Antivi­ral Research

    The spike gly­co­pro­tein of the new coro­n­avirus 2019-nCoV con­tains a furin-like cleav­age site absent in CoV of the same clade

    B.Coutard, C.Valle, X.de Lam­bal­lerie, B.Canard, N.G.Seidah, E.Decroly
    Vol­ume 176, April 2020

    High­lights

    • The genom­ic sequence of 2019-nCoV indi­cates that the virus clus­ters with beta­coro­n­avirus­es of lin­eage b.
    • 2019-nCoV S‑protein sequence has a spe­cif­ic furin-like cleav­age site absent in lin­eage b CoV includ­ing SARS-CoV sequences.
    • The furin-like cleav­age site in the S‑protein of 2019-nCoV may have impli­ca­tions for the viral life cycle and path­o­genic­i­ty.
    • Cam­paigns to devel­op anti-2019-nCoV ther­a­peu­tics should include the eval­u­a­tion of furin inhibitors.

    Abstract

    In 2019, a new coro­n­avirus (2019-nCoV) infect­ing Humans has emerged in Wuhan, Chi­na. Its genome has been sequenced and the genom­ic infor­ma­tion prompt­ly released. Despite a high sim­i­lar­i­ty with the genome sequence of SARS-CoV and SARS-like CoVs, we iden­ti­fied a pecu­liar furin-like cleav­age site in the Spike pro­tein of the 2019-nCoV, lack­ing in the oth­er SARS-like CoVs. In this arti­cle, we dis­cuss the pos­si­ble func­tion­al con­se­quences of this cleav­age site in the viral cycle, path­o­genic­i­ty and its poten­tial impli­ca­tion in the devel­op­ment of antivi­rals.

    Human coro­n­avirus­es (CoV) are enveloped pos­i­tive-strand­ed RNA virus­es belong­ing to the order Nidovi­rales, and are most­ly respon­si­ble for upper res­pi­ra­to­ry and diges­tive tract infec­tions. Among them SARS-CoV and MERS-CoV that spread in 2002 and 2013 respec­tive­ly, have been asso­ci­at­ed with severe human ill­ness­es, such as severe pneu­mo­nia and bron­chi­oli­tis, and even menin­gi­tis in more vul­ner­a­ble pop­u­la­tions (de Wit et al., 2016). In Decem­ber 2019, a new CoV (2019-nCoV) has been detect­ed in the city of Wuhan, and this emerg­ing viral infec­tion was asso­ci­at­ed with severe human res­pi­ra­to­ry dis­ease with a ~2–3% fatal­i­ty rate (Li et al., 2020). The virus that was pre­sumed to have ini­tial­ly been trans­mit­ted from an ani­mal reser­voir to humans pos­si­bly via an ampli­fy­ing host. How­ev­er human-to-human trans­mis­sion has been report­ed, lead­ing to a sus­tained epi­dem­ic spread with >31,000 con­firmed human infec­tions, includ­ing >640 deaths, report­ed by the WHO in ear­ly Feb­ru­ary 2020. The esti­mat­ed effec­tive repro­duc­tive num­ber ® val­ue of ~2.90 (95%: 2.32–3.63) at the begin­ning of the out­break rais­es the pos­si­bil­i­ty of a pan­demics (Zhao et al., 2020). This prompt­ed WHO to declare it as a Pub­lic Health Emer­gency of Inter­na­tion­al Con­cern. This is espe­cial­ly rel­e­vant because so far there are no spe­cif­ic antivi­ral treat­ments avail­able or vac­cine. Based on its genome sequence, 2019-nCoV belongs to lin­eage b of Beta­coro­n­avirus (Fig. 1A), which also includes the SARS-CoV and bat CoV ZXC21, the lat­ter and CoV ZC45 being the clos­est to 2019-nCoV. 2019-nCoV shares ~76% amino acid sequence iden­ti­ty in the Spike (S)-protein sequence with SARS-CoV and 80% with CoV ZXC21 (Chan et al., 2020). In this arti­cle, we focus on a spe­cif­ic furin-like pro­tease recog­ni­tion pat­tern present in the vicin­i­ty of one of the mat­u­ra­tion sites of the S pro­tein (Fig. 1B) that may have sig­nif­i­cant func­tion­al impli­ca­tions for virus entry.

    The pro­pro­tein con­ver­tases (PCs; genes PCSKs) con­sti­tute a fam­i­ly of nine ser­ine secre­to­ry pro­teas­es that reg­u­late var­i­ous bio­log­i­cal process­es in both healthy and dis­ease states (Sei­dah and Prat, 2012). By pro­te­ol­y­sis, PCs are respon­si­ble for the acti­va­tion of a wide vari­ety of pre­cur­sor pro­teins, such as growth fac­tors, hor­mones, recep­tors and adhe­sion mol­e­cules, as well as cell sur­face gly­co­pro­teins of infec­tious virus­es (Sei­dah and Chre­tien, 1999) (Table 1). Sev­en PCs cleave pre­cur­sor pro­teins at spe­cif­ic sin­gle or paired basic amino acids (aa) with­in the motif (R/K)-(2X)n-(R/K)↓, where n = 0, 1, 2, or 3 spac­er aa (Sei­dah and Chre­tien, 1999). Because of their role in the pro­cess­ing of many crit­i­cal cell sur­face pro­teins PCs, espe­cial­ly furin, have been impli­cat­ed in viral infec­tions. They have the poten­tial to cleave specif­i­cal­ly viral enve­lope gly­co­pro­teins, there­by enhanc­ing viral fusion with host cell mem­branes (Iza­guirre, 2019; Moulard and Decroly, 2000). In the case of human-infect­ing coro­n­avirus­es such as HCoV-OC43 (Le Coupanec et al., 2015), MERS-CoV (Mil­let and Whit­tak­er, 2014), and HKU1 (Chan et al., 2008) the spike pro­tein has been demon­strat­ed to be cleaved at an S1/S2 cleav­age site (Fig. 2) gen­er­at­ing the S1 and S2 sub­units. The above three virus­es dis­play the canon­i­cal (R/K)-(2X)n-(R/K)↓ motif (Table 1). Addi­tion­al­ly, it has been demon­strat­ed that vari­a­tion around the viral enve­lope gly­co­pro­tein cleav­age site plays a role in cel­lu­lar tro­pism and patho­gen­e­sis. For instance, the patho­gen­e­sis of some CoV has been pre­vi­ous­ly relat­ed to the pres­ence of a furin-like cleav­age site in the S‑protein sequence. For exam­ple, the inser­tion of a sim­i­lar cleav­age site in the infec­tious bron­chi­tis virus (IBV) S‑protein results in high­er path­o­genic­i­ty, pro­nounced neur­al symp­toms and neu­rotro­pism in infect­ed chick­ens (Cheng et al., 2019).

    Sim­i­lar­ly, in the case of influen­za virus, low-path­o­genic­i­ty forms of influen­za virus con­tain a sin­gle basic residue at the cleav­age site, which is cleaved by trypsin-like pro­teas­es and the tis­sue dis­tri­b­u­tion of the acti­vat­ing protease(s) typ­i­cal­ly restricts infec­tions to the res­pi­ra­to­ry and/or intesti­nal organs (Sun et al., 2010). Con­verse­ly, the high­ly path­o­gen­ic forms of influen­za have a furin-like cleav­age site cleaved by dif­fer­ent cel­lu­lar pro­teas­es, includ­ing furin, which are expressed in a wide vari­ety of cell types allow­ing a widen­ing of the cell tro­pism of the virus (Kido et al., 2012). Fur­ther­more the inser­tion of a multi­ba­sic motif RERRRKKR↓GL at the H5N1 hemag­glu­tinin HA cleav­age site was like­ly asso­ci­at­ed with the hyper-vir­u­lence of the virus dur­ing the Hong Kong 1997 out­break Claas et al., 1998). This motif exhibits the crit­i­cal Arg at P1 and basic residues at P2 and P4, as well as P6 and P8 and an aliphat­ic Leu at P2’ posi­tions (Table 1) (Schechter and Berg­er nomen­cla­ture (Schechter and Berg­er, 1968)), typ­i­cal of a furin-like cleav­age speci­fici­ty (Braun and Sauter, 2019; Iza­guirre, 2019; Sei­dah and Prat, 2012).

    The coro­n­avirus S‑protein is the struc­tur­al pro­tein respon­si­ble for the crown-like shape of the CoV viral par­ti­cles, from which the orig­i­nal name “coro­n­avirus” was coined. The ~1200 aa long S‑protein belongs to class‑I viral fusion pro­teins and con­tributes to the cell recep­tor bind­ing, tis­sue tro­pism and patho­gen­e­sis (Lu et al., 2015; Mil­let and Whit­tak­er, 2014). It con­tains sev­er­al con­served domains and motifs (Fig. 2). The tri­met­ric S‑protein is processed at the S1/S2 cleav­age site by host cell pro­teas­es, dur­ing infec­tion. Fol­low­ing cleav­age, also known as prim­ing, the pro­tein is divid­ed into an N‑terminal S1-ectodomain that recog­nis­es a cog­nate cell sur­face recep­tor and a C‑terminal S2-mem­brane-anchored pro­tein involved in viral entry. The SARS-CoV S1-pro­tein con­tains a con­served Recep­tor Bind­ing Domain (RBD), which recog­nis­es the angiotensin-con­vert­ing enzyme 2 (ACE2) (Li et al., 2003). The SARS-CoV binds to both bat and human cells, and the virus can infect both organ­isms (Ge et al., 2013; Kuhn et al., 2004). The RBD sur­face of S1/ACE2 impli­cates 14 aa in the S1 of SARS-CoV (Li et al., 2005). Among them, 8 residues are strict­ly con­served in 2019-nCoV, sup­port­ing the hypoth­e­sis that ACE2 is also the recep­tor of the new­ly emerged nCoV (Wan et al., 2020). The S2-pro­tein con­tains the fusion pep­tide (FP), a sec­ond pro­te­olyt­ic site (S2’), fol­lowed by an inter­nal fusion pep­tide (IFP) and two hep­tad-repeat domains pre­ced­ing the trans­mem­brane domain ™ (Fig. 2). Notably, the IFPs of the 2019-nCoV and SARS-CoV are iden­ti­cal, dis­play­ing char­ac­ter­is­tics of viral fusion pep­tides (Fig. 2). While the mol­e­c­u­lar mech­a­nism involved in cell entry is not yet ful­ly under­stood, it is like­ly that both FP and IFP par­tic­i­pate in the viral entry process (Lu et al., 2015) and thus the S‑protein must like­ly be cleaved at both S1/S2 and S2’ cleav­age sites for virus entry. The furin-like S2’ cleav­age site at KR↓SF with P1 and P2 basic residues and a P2’ hydropho­bic Phe (Sei­dah and Prat, 2012), down­stream of the IFP is iden­ti­cal between the 2019-nCoV and SARS-CoV (Fig. 2). In the MERS-CoV and HCoV-OC43 the S1/S2 site is replaced by RXXR↓SA, with P1 and P4 basic residues, and an Ala (not aliphat­ic) at P2’, sug­gest­ing a some­what less favourable cleav­age by furin. How­ev­er, in the oth­er less path­o­gen­ic cir­cu­lat­ing human CoV, the S2’ cleav­age site only exhibits a monoba­sic R↓S sequence (Fig. 2) with no basic residues at either P2 and/or P4 need­ed to allow furin cleav­age, sug­gest­ing a less effi­cient cleav­age or high­er restric­tion at the entry step depend­ing on the cog­nate pro­teas­es expressed by tar­get cells. Even though pro­cess­ing at S2’ in 2019-nCoV is expect­ed to be a key event for the final acti­va­tion of the S‑protein, the protease(s) involved in this process have not yet been con­clu­sive­ly iden­ti­fied. Based on the 2019-nCoV S2’ sequence and the above argu­ments, we pro­pose that one or more furin-like enzymes would cleave the S2’ site at KR↓SF. In con­trast to the S2’, the first cleav­age between the RBD and the FP (S1/S2 cleav­age site, Fig. 2) has been exten­sive­ly stud­ied for many CoVs (Lu et al., 2015). Inter­est­ing­ly the S1/S2 pro­cess­ing site exhibits dif­fer­ent motifs among coro­n­avirus­es (Fig. 2, site 1 & site 2), with many of them dis­play­ing cleav­age after a basic residue. It is thus like­ly that the prim­ing process is ensured by dif­fer­ent host cell pro­teas­es depend­ing on the sequence of the S1/S2 cleav­age site. Accord­ing­ly the MERS-CoV S‑protein, which con­tains a RSVR↓SV motif is cleaved dur­ing virus egress, prob­a­bly by furin (Mille and Whit­tak­er, 2014). Con­verse­ly the S‑protein of SARS-CoV remains large­ly uncleaved after biosyn­the­sis, pos­si­bly due to the lack of a favourable furin-like cleav­age site (SLLR-ST). In this case, it was report­ed that fol­low­ing recep­tor bind­ing the S‑protein is cleaved at a con­served sequence AYT↓M (locat­ed 10 aa down­stream of SLLR-ST) by tar­get cells’ pro­teas­es such as elas­tase, cathep­sin L or TMPRSS2 (Bosch et al., 2008; Mat­suya­ma et al., 2010, 2005; Mil­let and Whit­tak­er, 2015). As the prim­ing event is essen­tial for virus entry, the effi­ca­cy and extent of this acti­va­tion step by the pro­teas­es of the tar­get cells should reg­u­late cel­lu­lar tro­pism and viral patho­gen­e­sis. In the case of the 2019-nCoV S‑protein, the con­served site 2 sequence AYT↓M may still be cleaved, pos­si­bly after the pre­ferred furin-cleav­age at the site 1 (Fig. 2).

    Since furin is high­ly expressed in lungs, an enveloped virus that infects the res­pi­ra­to­ry tract may suc­cess­ful­ly exploit this con­ver­tase to acti­vate its sur­face gly­co­pro­tein (Bassi et al., 2017; Mbikay et al., 1997). Before the emer­gence of the 2019-nCoV, this impor­tant fea­ture was not observed in the lin­eage b of beta­coro­n­avirus­es. How­ev­er, it is shared by oth­er CoV (HCoV-OC43, MERS-CoV, MHV-A59) har­bour­ing furin-like cleav­age sites in their S‑protein (Fig. 2; Table 1), which were shown to be processed by furin exper­i­men­tal­ly (Le Coupanec et al., 2015; Mille and Whit­tak­er, 2014). Strik­ing­ly, the 2019-nCoV S‑protein sequence con­tains 12 addi­tion­al nucleotides upstream of the sin­gle Arg↓ cleav­age site 1 (Fig. 1, Fig. 2) lead­ing to a pre­dic­tive­ly sol­vent-exposed PRRAR↓SV sequence, which cor­re­sponds to a canon­i­cal furin-like cleav­age site (Braun and Sauter, 2019; Iza­guirre, 2019; Sei­dah and Prat, 2012). This furin-like cleav­age site, is sup­posed to be cleaved dur­ing virus egress (Mille and Whit­tak­er, 2014) for S‑protein “prim­ing” and may pro­vide a gain-of-func­tion to the 2019-nCoV for effi­cient spread­ing in the human pop­u­la­tion com­pared to oth­er lin­eage b beta­coro­n­avirus­es. This pos­si­bly illus­trates a con­ver­gent evo­lu­tion path­way between unre­lat­ed CoVs. Inter­est­ing­ly, if this site is not processed, the S‑protein is expect­ed to be cleaved at site 2 dur­ing virus endo­cy­to­sis, as observed for the SARS-CoV.

    Obvi­ous­ly much more work is need­ed to demon­strate exper­i­men­tal­ly our asser­tion, but the inhi­bi­tion of such pro­cess­ing enzyme(s) may rep­re­sent a poten­tial antivi­ral strat­e­gy. Indeed, it was recent­ly shown that in an effort to lim­it viral infec­tions, host cells that are infect­ed by a num­ber of virus­es pro­voke an inter­fer­on response to inhib­it the enzy­mat­ic activ­i­ty of furin-like enzymes. It was also demon­strat­ed that HIV infec­tion induces the expres­sion of either the pro­tease acti­vat­ed recep­tor 1 (PAR1) (Kim et al., 2015) or guany­late bind­ing pro­teins 2 and 5 (GBP2,5) (Braun and Sauter, 2019) that restrict the traf­fick­ing of furin to the trans Gol­gi net­work (PAR1) or to ear­ly Gol­gi com­part­ments (GBP2,5) where the pro­pro­tein con­ver­tase remains inac­tive. Alto­geth­er, these obser­va­tions sug­gest that inhibitors of furin-like enzymes may con­tribute to inhibit­ing virus prop­a­ga­tion.

    ...

    ————

    “The spike gly­co­pro­tein of the new coro­n­avirus 2019-nCoV con­tains a furin-like cleav­age site absent in CoV of the same clade” by B.Coutard, C.Valle, X.de Lam­bal­lerie, B.Canard, N.G.Seidah, E.Decroly; Antivi­ral Research; April 2020

    “Since furin is high­ly expressed in lungs, an enveloped virus that infects the res­pi­ra­to­ry tract may suc­cess­ful­ly exploit this con­ver­tase to acti­vate its sur­face gly­co­pro­tein (Bassi et al., 2017; Mbikay et al., 1997). Before the emer­gence of the 2019-nCoV, this impor­tant fea­ture was not observed in the lin­eage b of beta­coro­n­avirus­es. How­ev­er, it is shared by oth­er CoV (HCoV-OC43, MERS-CoV, MHV-A59) har­bour­ing furin-like cleav­age sites in their S‑protein (Fig. 2; Table 1), which were shown to be processed by furin exper­i­men­tal­ly (Le Coupanec et al., 2015; Mille and Whit­tak­er, 2014). Strik­ing­ly, the 2019-nCoV S‑protein sequence con­tains 12 addi­tion­al nucleotides upstream of the sin­gle Arg↓ cleav­age site 1 (Fig. 1, Fig. 2) lead­ing to a pre­dic­tive­ly sol­vent-exposed PRRAR↓SV sequence, which cor­re­sponds to a canon­i­cal furin-like cleav­age site (Braun and Sauter, 2019; Iza­guirre, 2019; Sei­dah and Prat, 2012). This furin-like cleav­age site, is sup­posed to be cleaved dur­ing virus egress (Mille and Whit­tak­er, 2014) for S‑protein “prim­ing” and may pro­vide a gain-of-func­tion to the 2019-nCoV for effi­cient spread­ing in the human pop­u­la­tion com­pared to oth­er lin­eage b beta­coro­n­avirus­es. This pos­si­bly illus­trates a con­ver­gent evo­lu­tion path­way between unre­lat­ed CoVs. Inter­est­ing­ly, if this site is not processed, the S‑protein is expect­ed to be cleaved at site 2 dur­ing virus endo­cy­to­sis, as observed for the SARS-CoV.”

    As the authors put it, the obser­va­tion of the of an addi­tion­al 12 nucleotides (encod­ing for four addi­tion­al amino acids) that hap­pens to encode for a furin cleav­age site right in the S‑protein (the pro­tein that needs to be cleaved for the virus to inject its pay­load) is strik­ing. It’s strik­ing, in part because it’s not found in the close­ly relat­ed bat coro­n­avirus or any oth­er virus­es in the b lin­eage of Beta­coro­n­avirus­es. And strik­ing because the furin cleav­age site encod­ed by these 12 nucleotides is the can­non­i­cal site. That’s why con­ver­gent evo­lu­tion is pro­posed as an expla­na­tion: it’s one of the nat­ur­al process­es that could explain this strik­ing obser­va­tion that SARS-CoV­‑2 some­how acquired a can­non­i­cal furin cleav­age site despite the sites’s absence in all of the virus­es in the b lin­eage that the virus is assumed to have evolved from.

    But as the sec­ond paper below indi­cates, coevo­lu­tion isn’t the only pos­si­ble nat­ur­al expla­na­tion for this strik­ing obser­va­tion. It’s pos­si­ble there was a recom­bi­na­tion event. That’s what they spec­u­lat­ed when observ­ing that the S‑protein of SARS-CoV­‑2 — the pro­tein that con­tains this furin cleav­age site — is even more close­ly relat­ed to the S‑protein found in the Pan­golin-CoV than the bat ver­sion. The Recep­tor Bind­ing Domain (RBD) of SARS-CoV­‑2 and Pan­golin-CoV — the parts of the virus that rec­og­nize and stick to the ACE2 recep­tor on human cells — are almost iden­ti­cal. All indi­ca­tion from the genet­ics make Pan­golin-CoV the like­li­est known pre­cur­sor to SARS-CoV­‑2. But even with Pan­golin-CoV the S‑protein does­n’t have that furin cleav­age site. But instead of sug­gest­ing the seem­ing­ly sud­den addi­tion to the furin cleav­age site may have arisen through evo­lu­tion (con­ver­gent evo­lu­tion in this case), the authors spec­u­late that per­haps a recom­bi­na­tion even took place where a Pan­golin, or some oth­er inter­me­di­ate host, got infect­ed with both Pan­golin-CoV and a dif­fer­ent virus with does have the furin cleav­age site and SARS-CoV­‑2 emerged:

    Cur­rent Biol­o­gy
    Issue 30, pages 1–6

    Prob­a­ble Pan­golin Ori­gin of SARS-CoV­‑2 Asso­ci­at­ed with the COVID-19 Out­break

    Tao Zhang, Qun­fu Wu, Zhi­gang Zhang
    April 6, 2020

    High­lights

    • Pan­golin-CoV is 91.02% iden­ti­cal to SARS-CoV­‑2 at the whole-genome lev­el
    • Pan­golin-CoV is the sec­ond clos­est rel­a­tive of SARS-CoV­‑2 behind RaTG13
    • Five key amino acids in the RBD are con­sis­tent between Pan­golin-CoV and SARS-CoV­‑2
    • Only SARS-CoV­‑2 con­tains a poten­tial cleav­age site for furin pro­teas­es

    Sum­ma­ry

    An out­break of coro­n­avirus dis­ease 2019 (COVID-19) caused by the 2019 nov­el coro­n­avirus (SARS-CoV­‑2) began in the city of Wuhan in Chi­na and has wide­ly spread world­wide. Cur­rent­ly, it is vital to explore poten­tial inter­me­di­ate hosts of SARS-CoV­‑2 to con­trol COVID-19 spread. There­fore, we rein­ves­ti­gat­ed pub­lished data from pan­golin lung sam­ples from which SARS-CoV-like CoVs were detect­ed by Liu et al. [1]. We found genom­ic and evo­lu­tion­ary evi­dence of the occur­rence of a SARS-CoV-2-like CoV (named Pan­golin-CoV) in dead Malayan pan­golins. Pan­golin-CoV is 91.02% and 90.55% iden­ti­cal to SARS-CoV­‑2 and Bat­CoV RaTG13, respec­tive­ly, at the whole-genome lev­el. Aside from RaTG13, Pan­golin-CoV is the most close­ly relat­ed CoV to SARS-CoV­‑2. The S1 pro­tein of Pan­golin-CoV is much more close­ly relat­ed to SARS-CoV­‑2 than to RaTG13. Five key amino acid residues involved in the inter­ac­tion with human ACE2 are com­plete­ly con­sis­tent between Pan­golin-CoV and SARS-CoV­‑2, but four amino acid muta­tions are present in RaTG13. Both Pan­golin-CoV and RaTG13 lost the puta­tive furin recog­ni­tion sequence motif at S1/S2 cleav­age site that can be observed in the SARS-CoV­‑2. Con­clu­sive­ly, this study sug­gests that pan­golin species are a nat­ur­al reser­voir of SARS-CoV-2-like CoVs.

    Results and Dis­cus­sion

    Sim­i­lar to the case for SARS-CoV and MERS-CoV [2], the bat is still a prob­a­ble species of ori­gin for 2019 nov­el coro­n­avirus (SARS-CoV­‑2) because SARS-CoV­‑2 shares 96% whole-genome iden­ti­ty with a bat CoV, Bat­CoV RaTG13, from Rhi­nolo­phus affi­nis from Yun­nan Province [3]. How­ev­er, SARS-CoV and MERS-CoV usu­al­ly pass into inter­me­di­ate hosts, such as civets or camels, before leap­ing to humans [4]. This fact indi­cates that SARS-CoV­‑2 was prob­a­bly trans­mit­ted to humans by oth­er ani­mals. Con­sid­er­ing that the ear­li­est coro­n­avirus dis­ease 2019 (COVID-19) patient report­ed no expo­sure at the seafood mar­ket [5], it is vital to find the inter­me­di­ate SARS-CoV­‑2 host to block inter­species trans­mis­sion. On 24 Octo­ber 2019, Liu and his col­leagues from the Guang­dong Wildlife Res­cue Cen­ter of Chi­na [1] first detect­ed the exis­tence of a SARS-CoV-like CoV from lung sam­ples of two dead Malayan pan­golins with a frothy liq­uid in their lungs and pul­monary fibro­sis, and this fact was dis­cov­ered close to when the COVID-19 out­break occurred. Using their pub­lished results, we showed that all virus con­tigs assem­bled from two lung sam­ples (lung07 and lung08) exhib­it­ed low iden­ti­ties, rang­ing from 80.24% to 88.93%, with known SARSr-CoVs. Hence, we con­jec­tured that the dead Malayan pan­golins may car­ry a new CoV close­ly relat­ed to SARS-CoV­‑2.

    Assess­ing the Prob­a­bil­i­ty of SARS-CoV-2-like CoV Pres­ence in Pan­golin Species

    To con­firm our assump­tion, we down­loaded raw RNA sequenc­ing (RNA-seq) data (SRA: PRJNA573298) for those two lung sam­ples from the SRA and con­duct­ed con­sis­tent qual­i­ty con­trol and con­t­a­m­i­nant removal, as described by Liu’s study [1]. We found 1,882 clean reads from the lung08 sam­ple that mapped to the SARS-CoV­‑2 ref­er­ence genome (Gen­Bank: MN908947) [6] and cov­ered 76.02% of the SARS-CoV­‑2 genome. We per­formed de novo assem­bly of those reads and obtained 36 con­tigs with lengths rang­ing from 287 bp to 2,187 bp, with a mean length of 700 bp. Via Blast analy­sis against pro­teins from 2,845 CoV ref­er­ence genomes, includ­ing RaTG13, SARS-CoV-2s, and oth­er known CoVs, we found that 22 con­tigs were best matched to SARS-CoV-2s (70.6%–100% amino acid iden­ti­ty; aver­age: 95.41%) and that 12 con­tigs matched to bat SARS-CoV-like CoV (92.7%–100% amino acid iden­ti­ty; aver­age: 97.48%) (Table S1). These results indi­cate that the Malayan pan­golin might car­ry a nov­el CoV (here named Pan­golin-CoV) that is sim­i­lar to SARS-CoV­‑2.

    Draft Genome of Pan­golin-CoV and Its Genom­ic Char­ac­ter­is­tics

    Using a ref­er­ence-guid­ed scaf­fold­ing approach, we cre­at­ed a Pan­golin-CoV draft genome (19,587 bp) based on the above 34 con­tigs. To reduce the effect of raw read errors on scaf­fold­ing qual­i­ty, small frag­ments that aligned against the ref­er­ence genome with a length less than 25 bp were man­u­al­ly dis­card­ed if they were unable to be cov­ered by any large frag­ments or ref­er­ence genome. Remap­ping 1,882 reads against the draft genome result­ed in 99.99% genome cov­er­age (cov­er­age depth range: 1X–47X) (Fig­ure 1A). The mean cov­er­age depth was 7.71X across the whole genome, which was two times high­er than the low­est com­mon 3X read cov­er­age depth for SNP call­ing based on low-cov­er­age sequenc­ing in the 1000 Genomes Project pilot phase [7]. Sim­i­lar cov­er­age lev­els are also suf­fi­cient to detect rare or low-abun­dance micro­bial species from metage­nom­ic datasets [8], indi­cat­ing that our assem­bled Pan­golin-CoV draft genome is reli­able for fur­ther analy­ses. Based on Sim­plot analy­sis [9], Pan­golin-CoV showed high over­all genome sequence iden­ti­ty to RaTG13 (90.55%) and SARS-CoV­‑2 (91.02%) through­out the genome (Fig­ure 1B), although there was a high­er iden­ti­ty (96.2%) between SARS-CoV­‑2 and RaTG13 [3]. Oth­er SARS-CoV-like CoVs sim­i­lar to Pan­golin-CoV were bat SARSr-CoV ZXC21 (85.65%) and bat SARSr-CoV ZC45 (85.01%). While this man­u­script was under review, two sim­i­lar preprint stud­ies found that CoVs in pan­golins shared 90.3% [10] and 92.4% [11] DNA iden­ti­ty with SARS-CoV­‑2, approx­i­mat­ing the 91.02% iden­ti­ty to SARS-CoV­‑2 observed here and sup­port­ing our find­ings. Tak­en togeth­er, these results indi­cate that Pan­golin-CoV might be the com­mon ori­gin of SARS-CoV­‑2 and RaTG13.

    The Pan­golin-CoV genome orga­ni­za­tion was char­ac­ter­ized by sequence align­ment against SARS-CoV­‑2 (Gen­Bank: MN908947) and RaTG13. The Pan­golin-CoV genome con­sists of six major open read­ing frames (ORFs) com­mon to CoVs and four oth­er acces­so­ry genes (Fig­ure 1C; Table S2). Fur­ther analy­sis indi­cat­ed that Pan­golin-CoV genes aligned to SARS-CoV­‑2 genes with cov­er­age rang­ing from 45.8% to 100% (aver­age cov­er­age 76.9%). Pan­golin-CoV genes shared high aver­age nucleotide and amino acid iden­ti­ty with both SARS-CoV­‑2 (Gen­Bank: MN908947) (93.2% nucleotide/94.1% amino acid iden­ti­ty) and RaTG13 (92.8% nucleotide/93.5% amino acid iden­ti­ty) genes (Fig­ure 1C; Table S2). Sur­pris­ing­ly, some Pan­golin-CoV genes showed high­er amino acid sequence iden­ti­ty to SARS-CoV­‑2 genes than to RaTG13 genes, includ­ing orf1b (73.4%/72.8%), the spike (S) pro­tein (97.5%/95.4%), orf7a (96.9%/93.6%), and orf10 (97.3%/94.6%). The high S pro­tein amino acid iden­ti­ty implies func­tion­al sim­i­lar­i­ty between Pan­golin-CoV and SARS-CoV­‑2.

    Phy­lo­ge­net­ic Rela­tion­ships among Pan­golin-CoV, RaTG13, and SARS-CoV­‑2

    To deter­mine the evo­lu­tion­ary rela­tion­ships among Pan­golin-CoV, SARS-CoV­‑2, and pre­vi­ous­ly iden­ti­fied CoVs, we esti­mat­ed phy­lo­ge­net­ic trees based on the nucleotide sequences of the whole-genome sequence, RNA-depen­dent RNA poly­merase gene (RdRp), non-struc­tur­al pro­tein genes ORF1a and ORF1b, and main struc­tur­al pro­teins encod­ed by the S and M genes. In all phy­lo­ge­nies, Pan­golin-CoV, RaTG13, and SARS-CoV­‑2 were clus­tered into a well-sup­port­ed group, here named the “SARS-CoV­‑2 group” (Fig­ures 2, S1, and S2). This group rep­re­sents a nov­el Beta­coro­n­avirus group. With­in this group, RaTG13 and SARS-CoV­‑2 were grouped togeth­er, and Pan­golin-CoV was their clos­est com­mon ances­tor. How­ev­er, whether the basal posi­tion of the SARS-CoV­‑2 group is SARSr-CoV ZXC21 and/or SARSr-CoV ZC45 is still under debate. Such debate also occurred in both the Wu et al. [6] and Zhou et al. [3] stud­ies. A pos­si­ble expla­na­tion is a past his­to­ry of recom­bi­na­tion in the Beta­coro­n­avirus group [6]. It is note­wor­thy that the dis­cov­ered evo­lu­tion­ary rela­tion­ships of CoVs shown by the whole genome, RdRp gene, and S gene were high­ly con­sis­tent with those exhib­it­ed by com­plete genome infor­ma­tion in the Zhou et al. study [3]. This cor­re­spon­dence indi­cates that our Pan­golin-CoV draft genome has enough genom­ic infor­ma­tion to trace the true evo­lu­tion­ary posi­tion of Pan­golin-CoV in CoVs.

    Dual­ism of the S Pro­tein of Pan­golin-CoV

    The CoV S pro­tein con­sists of two sub­units (S1 and S2), medi­ates infec­tion of recep­tor-express­ing host cells, and is a crit­i­cal tar­get for antivi­ral neu­tral­iz­ing anti­bod­ies [12]. S1 con­tains a recep­tor-bind­ing domain (RBD) that con­sists of an approx­i­mate­ly 193 amino acid frag­ment, which is respon­si­ble for rec­og­niz­ing and bind­ing the cell sur­face recep­tor [13, 14]. Zhou et al. exper­i­men­tal­ly con­firmed that SARS-CoV­‑2 is able to use human, Chi­nese horse­shoe bat, civet, and pig ACE2 pro­teins as an entry recep­tor in ACE2-express­ing cells [3], sug­gest­ing that the RBD of SARS-CoV­‑2 medi­ates infec­tion in humans and oth­er ani­mals. To gain sequence-lev­el insight into the path­o­gen­ic poten­tial of Pan­golin-CoV, we first inves­ti­gat­ed the amino acid vari­a­tion pat­tern of the S1 pro­teins from Pan­golin-CoV, SARS-CoV­‑2, RaTG13, and oth­er rep­re­sen­ta­tive SARS/SARSr-CoVs. The amino acid phy­lo­ge­net­ic tree showed that the S1 pro­tein of Pan­golin-CoV is more close­ly relat­ed to that of 2019-CoV than to that of RaTG13. With­in the RBD, we fur­ther found that Pan­golin-CoV and SARS-CoV­‑2 were high­ly con­served, with only one amino acid change (500H/500Q) (Fig­ure 3), which is not one of the five key residues involved in the inter­ac­tion with human ACE2 [3, 14]. These results indi­cate that Pan­golin-CoV could have path­o­gen­ic poten­tial sim­i­lar to that of SARS-CoV­‑2. In con­trast, RaTG13 has changes in 17 amino acid residues, 4 of which are among the key amino acid residues (Fig­ure 3). There are evi­dences sug­gest­ing that the change of 472L (SARS-CoV) to 486F (SARS-CoV­‑2) (cor­re­spond­ing to the sec­ond key amino acid residue change in Fig­ure 3) may make stronger van der Waals con­tact with M82 (ACE2) [15]. Besides, the major sub­sti­tu­tion of 404V in the SARS-CoV-RBD with 417K in the SARS-CoV-2-RBD (see 420 align­ment posi­tion in Fig­ure 3 and with­out amino acid change between the SARS-CoV­‑2 and RaTG13) may result in tighter asso­ci­a­tion because of the salt bridge for­ma­tion between 417K and 30D of ACE2 [15]. Nev­er­the­less, fur­ther inves­ti­ga­tion is still need­ed about whether those muta­tions affect the affin­i­ty for ACE2. Whether the Pan­golin-CoV or RaTG13 are poten­tial infec­tious agents to humans remains to be deter­mined.

    The S1/S2 cleav­age site in the S pro­tein is also an impor­tant deter­mi­nant of the trans­mis­si­bil­i­ty and path­o­genic­i­ty of SARS-CoV­/SARS-CoVr virus­es [16]. The tri­met­ric S pro­tein is processed at the S1/S2 cleav­age site by host cell pro­teas­es dur­ing infec­tion. Fol­low­ing cleav­age, also known as prim­ing, the pro­tein is divid­ed into an N‑terminal S1-ectodomain that rec­og­nizes a cog­nate cell sur­face recep­tor and a C‑terminal S2-mem­brane anchored pro­tein that dri­ves fusion of the viral enve­lope with a cel­lu­lar mem­brane. We found that the SARS-CoV­‑2 S pro­tein con­tains a puta­tive furin recog­ni­tion motif (PRRARSV) (Fig­ure 4) sim­i­lar to that of MERS-CoV, which has a PRSVRSV motif that is like­ly cleaved by furin [16, 17] dur­ing virus egress. Con­verse­ly, the furin sequence motif at the S1/S2 site is miss­ing in the S pro­tein of Pan­golin-CoV and all oth­er SARS/SARSr-CoVs. This dif­fer­ence indi­cates the SARS-CoV­‑2 might gain a dis­tinct mech­a­nism to pro­mote its entry into host cells [18]. Inter­est­ing­ly, aside from MERS-CoV, sim­i­lar sequence pat­terns to the SARS-CoV­‑2 were also pre­sent­ed in some mem­bers of Alpha­coro­n­avirus, Beta­coro­n­avirus, and Gamm­coro­n­avirus [19], rais­ing an inter­est­ing ques­tion regard­ing whether this furin sequence motif in SARS-CoV­‑2 might be derived from those exist­ing S pro­teins of oth­er coro­n­avirus­es or alter­na­tive­ly if the SARS-CoV­‑2 might be the recom­bi­nant of Pan­golin-CoV or RaTG13 and oth­er coro­n­avirus­es with a sim­i­lar furin recog­ni­tion motif in the unknown inter­me­di­ate host.

    ...

    Con­clu­sion

    Based on pub­lished metage­nom­ic data, this study pro­vides the first report on a poten­tial close­ly relat­ed kin (Pan­golin-CoV) of SARS-CoV­‑2, which was dis­cov­ered from dead Malayan pan­golins after exten­sive res­cue efforts. Aside from RaTG13, the Pan­golin-CoV is the CoV most close­ly relat­ed to SARS-CoV­‑2. Due to unavail­abil­i­ty of the orig­i­nal sam­ple, we did not per­form fur­ther exper­i­ments to con­firm our find­ings, includ­ing PCR val­i­da­tion, sero­log­i­cal detec­tion, or even iso­la­tion of the virus par­ti­cles. Our dis­cov­ered Pan­golin-CoV genome showed 91.02% nucleotide iden­ti­ty with the SARS-CoV­‑2 genome. How­ev­er, whether pan­golin species are good can­di­dates for SARS-CoV­‑2 ori­gin is still under debate. Con­sid­er­ing the wide spread of SARSr-CoVs in nat­ur­al reser­voirs, such as bats, camels, and pan­golins, our find­ings would be mean­ing­ful for find­ing nov­el inter­me­di­ate SARS-CoV­‑2 hosts to block inter­species trans­mis­sion.

    ————

    “Prob­a­ble Pan­golin Ori­gin of SARS-CoV­‑2 Asso­ci­at­ed with the COVID-19 Out­break” by Tao Zhang, Qun­fu Wu, Zhi­gang Zhang; Cur­rent Biol­o­gy issue 30, pages 1–6; 04/06/2020

    “The CoV S pro­tein con­sists of two sub­units (S1 and S2), medi­ates infec­tion of recep­tor-express­ing host cells, and is a crit­i­cal tar­get for antivi­ral neu­tral­iz­ing anti­bod­ies [12]. S1 con­tains a recep­tor-bind­ing domain (RBD) that con­sists of an approx­i­mate­ly 193 amino acid frag­ment, which is respon­si­ble for rec­og­niz­ing and bind­ing the cell sur­face recep­tor [13, 14]. Zhou et al. exper­i­men­tal­ly con­firmed that SARS-CoV­‑2 is able to use human, Chi­nese horse­shoe bat, civet, and pig ACE2 pro­teins as an entry recep­tor in ACE2-express­ing cells [3], sug­gest­ing that the RBD of SARS-CoV­‑2 medi­ates infec­tion in humans and oth­er ani­mals. To gain sequence-lev­el insight into the path­o­gen­ic poten­tial of Pan­golin-CoV, we first inves­ti­gat­ed the amino acid vari­a­tion pat­tern of the S1 pro­teins from Pan­golin-CoV, SARS-CoV­‑2, RaTG13, and oth­er rep­re­sen­ta­tive SARS/SARSr-CoVs. The amino acid phy­lo­ge­net­ic tree showed that the S1 pro­tein of Pan­golin-CoV is more close­ly relat­ed to that of 2019-CoV than to that of RaTG13. With­in the RBD, we fur­ther found that Pan­golin-CoV and SARS-CoV­‑2 were high­ly con­served, with only one amino acid change (500H/500Q) (Fig­ure 3), which is not one of the five key residues involved in the inter­ac­tion with human ACE2 [3, 14]. These results indi­cate that Pan­golin-CoV could have path­o­gen­ic poten­tial sim­i­lar to that of SARS-CoV­‑2. In con­trast, RaTG13 has changes in 17 amino acid residues, 4 of which are among the key amino acid residues (Fig­ure 3). There are evi­dences sug­gest­ing that the change of 472L (SARS-CoV) to 486F (SARS-CoV­‑2) (cor­re­spond­ing to the sec­ond key amino acid residue change in Fig­ure 3) may make stronger van der Waals con­tact with M82 (ACE2) [15]. Besides, the major sub­sti­tu­tion of 404V in the SARS-CoV-RBD with 417K in the SARS-CoV-2-RBD (see 420 align­ment posi­tion in Fig­ure 3 and with­out amino acid change between the SARS-CoV­‑2 and RaTG13) may result in tighter asso­ci­a­tion because of the salt bridge for­ma­tion between 417K and 30D of ACE2 [15]. Nev­er­the­less, fur­ther inves­ti­ga­tion is still need­ed about whether those muta­tions affect the affin­i­ty for ACE2. Whether the Pan­golin-CoV or RaTG13 are poten­tial infec­tious agents to humans remains to be deter­mined.”

    So Pan­golin-CoV­’s S1 sub­unit is the most close­ly relat­ed to SARS-CoV-2’s S1 sub­unit. And that’s the part of the S‑protein that con­tains the furin cleav­age site in SARS-CoV­‑2 but not in any oth­er b lin­eage Beta­coro­n­avirus­es. But the furin cleav­age site is found in more dis­tant­ly relat­ed coro­n­avirus­es. That’s why the authors sug­gest SARS-CoV­‑2 may have arisen from a recom­bi­na­tion event:

    ...
    The S1/S2 cleav­age site in the S pro­tein is also an impor­tant deter­mi­nant of the trans­mis­si­bil­i­ty and path­o­genic­i­ty of SARS-CoV­/SARS-CoVr virus­es [16]. The tri­met­ric S pro­tein is processed at the S1/S2 cleav­age site by host cell pro­teas­es dur­ing infec­tion. Fol­low­ing cleav­age, also known as prim­ing, the pro­tein is divid­ed into an N‑terminal S1-ectodomain that rec­og­nizes a cog­nate cell sur­face recep­tor and a C‑terminal S2-mem­brane anchored pro­tein that dri­ves fusion of the viral enve­lope with a cel­lu­lar mem­brane. We found that the SARS-CoV­‑2 S pro­tein con­tains a puta­tive furin recog­ni­tion motif (PRRARSV) (Fig­ure 4) sim­i­lar to that of MERS-CoV, which has a PRSVRSV motif that is like­ly cleaved by furin [16, 17] dur­ing virus egress. Con­verse­ly, the furin sequence motif at the S1/S2 site is miss­ing in the S pro­tein of Pan­golin-CoV and all oth­er SARS/SARSr-CoVs. This dif­fer­ence indi­cates the SARS-CoV­‑2 might gain a dis­tinct mech­a­nism to pro­mote its entry into host cells [18]. Inter­est­ing­ly, aside from MERS-CoV, sim­i­lar sequence pat­terns to the SARS-CoV­‑2 were also pre­sent­ed in some mem­bers of Alpha­coro­n­avirus, Beta­coro­n­avirus, and Gamm­coro­n­avirus [19], rais­ing an inter­est­ing ques­tion regard­ing whether this furin sequence motif in SARS-CoV­‑2 might be derived from those exist­ing S pro­teins of oth­er coro­n­avirus­es or alter­na­tive­ly if the SARS-CoV­‑2 might be the recom­bi­nant of Pan­golin-CoV or RaTG13 and oth­er coro­n­avirus­es with a sim­i­lar furin recog­ni­tion motif in the unknown inter­me­di­ate host.
    ...

    Might we be deal­ing with a virus that’s a con­se­quence of real­ly bad evo­lu­tion­ary luck? If we assume this virus arose nat­u­ral­ly then those are the kinds of sce­nar­ios we need to assumed hap­pened. Real­ly bad luck sce­nar­ios.

    A man-made virus could also be seen as a dif­fer­nt kind of real­ly bad luck sce­nario although that’s not real­ly luck. It’s just real­ly bad. Luck does­n’t have that much to do with it. So what’s more like­ly: a real­ly bad luck nat­ur­al sce­nario or a real­ly bad no-luck-involved man-made sce­nario? That’s kind of the meta ques­tion involved year. Grant, if this is a man-made sce­nario we have got­ten very lucky so far in that that virus has­n’t mutat­ed into some­thing worse as it blows up and spreads across the globe. Although that lack of observed evo­lu­tion appears to have more to do with the virus already being opti­mized for spread­ing among humans, which is pret­ty bad as far good luck goes.

    Posted by Pterrafractyl | March 26, 2020, 2:49 pm
  4. @Pterrafractyl–

    It is impor­tant to remem­ber that this did NOT occur in a vac­u­um, but in the con­text of a full-court press desta­bi­liza­tion effort against Chi­na, head­ed by white nation­al­ist Steve Ban­non, whose pri­ma­ry political/philosophical ref­er­ence is Julius Evola. Evola orig­i­nal­ly liked Mus­soli­ni, but thought he was too soft and grav­i­tat­ed to the Nazi SS, who financed his work by the end of the war. https://spitfirelist.com/for-the-record/ftr-947-evola-on-our-minds/

    In July of last year, Ban­non said ” . . . . ‘These are two sys­tems that are incom­pat­i­ble,’ Mr. Ban­non said of the Unit­ed States and Chi­na. ‘One side is going to win, and one side is going to lose.’ . . . .”

    https://www.nytimes.com/2019/07/20/us/politics/china-red-scare-washington.html

    That is a dec­la­ra­tion of totaler krieg–total war!

    The “bad luck” hypoth­e­sis reminds me of “The New York Times’s” reac­tion to the Dal­las Police Depart­ment dictabelt record­ing that indi­cat­ed at least four shots fired in Dealy Plaza on 11/22/1963, there­by dis­prov­ing the War­ren Com­mis­sion’s hypoth­e­sis.

    They opined that this sim­ply meant that there were two, appar­ent­ly uncon­nect­ed “lone nuts” at work in Dal­las on that day.

    Now that is REALLY bad luck, indeed!

    In the age of gene edit­ing, “bad luck” does­n’t cut it.

    Using recom­bi­nant DNA in an inter­me­di­ate host could very eas­i­ly be engi­neered as well.

    More on that in a minute.

    Best,

    Dave

    Posted by Dave Emory | March 27, 2020, 5:02 pm
  5. @Pterrafractyl–

    Note that the “pan­golin-host research” falls in line with some of the DARPA-fund­ed research Whit­ney Webb dis­cuss­es:

    https://spitfirelist.com/news/disturbing-article-about-darpa-and-bat-borne-coronaviruses/

    ” . . . . .For instance, DARPA spent $10 mil­lion on one project in 2018 ‘to unrav­el the com­plex caus­es of bat-borne virus­es that have recent­ly made the jump to humans, caus­ing con­cern among glob­al health offi­cials.” Anoth­er research project backed by both DARPA and NIH saw researchers at Col­orado State Uni­ver­si­ty exam­ine the coro­n­avirus that caus­es Mid­dle East Res­pi­ra­to­ry Syn­drome (MERS) in bats and camels ‘to under­stand the role of these hosts in trans­mit­ting dis­ease to humans.’  . . . For instance, one study con­duct­ed in South­ern Chi­na in 2018 result­ed in the dis­cov­ery of 89 new “nov­el bat coro­n­avirus” strains that use the same recep­tor as the coro­n­avirus known as Mid­dle East Res­pi­ra­to­ry Syn­drome (MERS). That study was joint­ly fund­ed by the Chi­nese government’s Min­istry of Sci­ence and Tech­nol­o­gy, USAID — an orga­ni­za­tion long alleged to be a front for U.S. intel­li­gence, and the U.S. Nation­al Insti­tute of Health — which has col­lab­o­rat­ed with both the CIA and the Pen­ta­gon on infec­tious dis­ease and bioweapons research.. . . .”

    Damn, what bad luck!

    Posted by Dave Emory | March 27, 2020, 5:31 pm
  6. There’s an analy­sis of the SARS-CoV­‑2 virus pub­lished a Nature Med­i­cine a cou­ple weeks ago that claimed to have con­clu­sive­ly proven that the virus could­n’t have emerged from a lab. It did­n’t actu­al­ly remote­ly prove that but the let­ter is still note­wor­thy for a num­ber of very inter­est­ing obser­va­tion about the nature of the virus and its ori­gins. In par­tic­u­lar, the authors note the two key fea­tures of the virus that oth­ers have observed that make it so unusu­al­ly infec­tious: 1. The high affin­i­ty the virus’s Recep­tor Bind­ing Domain (RBD) has for the human ACE2 recep­tors found in the res­pi­ra­to­ry tracts of humans are oth­er mam­mals (like fer­rets). And 2. The cleav­age site in the S‑protein of the virus that allow the human pro­tein furin to cleave the virus which trig­gers the release of its viral pay­load into the cell.

    As we’ve seen and as the authors note, that cleav­age furin site is a canon­i­cal human furin cleav­age site — so human furin is very good at cleav­ing it — and has­n’t been found in any oth­er virus­es in the “b lin­eage” of the beta­coro­n­avirus fam­i­ly so from an evo­lu­tion­ary per­spec­tive it’s a sur­prise to see it in this virus. But SARS-CoV­‑2 RBD that binds to ACE2 is not, how­ev­er, and that’s what the authors are rely­ing on to make their claim that it could­n’t pos­si­bly have been cre­at­ed in a lab. As the authors note, the mod­els researchers use to pre­dict whether or not a viral RBD would be effec­tive at allow­ing it to bind to the ACE2 recep­tor actu­al­ly pre­dict that the RBD in SARS-CoV­‑2 would­n’t be effec­tive at bind­ing ACE2 and that’s the basis for their con­clu­sive claim that it could­n’t have been devel­oped in a lab.

    That is, of course, a non­sense form of analy­sis because it assumes the only tech­niques used in labs to cre­ate more potent forms of virus­es rely on first deduc­ing what an opti­mal viral pro­tein sequence would be an direct­ly cre­at­ing a viral genome to encode for that sequence. And as we saw, most notably in the ‘gain-of-func­tion’ exper­i­ments involv­ing H5N1 avian flu in fer­rets, those researchers did­n’t need to have a par­tic­u­lar viral sequence in mind when cre­at­ing their improved form of the virus. They sped up evo­lu­tion and let evo­lu­tion take care of com­ing up with the opti­mal sequence. Specif­i­cal­ly, in that now-noto­ri­ous exper­i­ment, they used three strains of H5N1: one unmod­i­fied native strain and two strains that had mod­i­fi­ca­tions known to make influen­za more vir­u­lent. They then took those strains and suc­ces­sive­ly passed the virus from fer­ret to fer­ret. After ten pas­sages, the strains that start­ed off with the mod­i­fi­ca­tions had acquired the abil­i­ty to be passed from fer­ret to fer­ret through the air, although the native unmod­i­fied H5N1 strain had­n’t acquired that abil­i­ty. But, cru­cial­ly, all three strains — mod­i­fied and unmod­i­fied — acquired a par­tic­u­lar nov­el muta­tion that the researchers had­n’t known about and it was pre­sumed that this muta­tion was was allowed the mod­i­fied strains to now spread in the air. It was an exam­ple of sim­ple exper­i­ment that allowed researchers to cre­ate a new strain in the lab with new abil­i­ties with­out know­ing in advance the pro­tein sequence required to con­fer those abil­i­ties.

    So when the researchers in the fol­low­ing Nature Med­i­cine let­ter con­clu­sive­ly con­clude that there’s no way the SARS-CoV­‑2 virus could have been devel­oped in a lab because the SARS-CoV­‑2 RBD that has an unusu­al­ly high affin­i­ty for ACE2 would­n’t have been pre­dict­ed by exist­ing mod­els, that’s a con­clu­sion that appears to com­plete­ly ignore the exis­tence of these ‘gain-of-func­tion’ exper­i­ments involv­ing the pas­sage of virus­es from ani­mal to ani­mal. And yet they actu­al­ly refer to such exper­i­ments in the let­ter and point out that we can’t con­clude that the virus did­n’t emerge from a lab pre­cise­ly between there are so many doc­u­ment­ed cas­es of SARS-CoV-like virus­es get­ting worked on in biosafe­ty labs around the world in cell cul­ture and/or ani­mal mod­els and acci­den­tal­ly escap­ing. Yep. In the very piece that claims to con­clu­sive­ly con­clude that the virus could­n’t have been engi­neered, they point out that SARS-CoV-like virus­es have been worked on in cell cul­tures and ani­mal mod­els in labs around the world for years. So it’s a very con­fus­ing let­ter in that respect. They appear to have argued that the virus could­n’t have been engi­neered but may have orig­i­nat­ed from a lab.

    There’s anoth­er fea­ture of the virus they point to as evi­dence that it could­n’t have been devel­oped in a lab that also com­plete­ly ignores these ani­mal pas­sage exper­i­ments. They point out the furin cleav­age site is pre­ced­ed by a pro­line amino acid. And that pro­line — which cre­ates a strong twist in the pro­tein — pre­dicts the exis­tence of O‑linked gly­cans around the cleav­age site which is exact­ly what is found. The authors point out that O‑linked gly­cans are only going to be devel­oped in the pres­ence of an immune sys­tem and there­fore the virus could­n’t have evolved from a cell cul­ture envi­ron­ment. And while that may be true, it com­plete­ly ignores ani­mal pas­sage exper­i­ments where the ani­mals’ immune sys­tems would obvi­ous­ly be involved in the evo­lu­tion of the virus. It’s also worth point out that ani­mal pas­sage exper­i­ments would explain the furin cleav­age site that isn’t found in any of the oth­er b lin­eage beta­coro­n­avirus­es. At least if the exper­i­ments were done in an ani­mal with a human-like furin. Some­thing put that furin cleav­age site there. The authors specif­i­cal­ly raise the pos­si­bil­i­ty of ani­mal pas­sage exper­i­ments being used but assert that it would have required a prog­en­i­tor virus with a very high sequence sim­i­lar­i­ty to SARS-CoV­‑2 and no such prog­en­i­tor virus has been observed. This, again, ignores how that land­mark 2011 ‘gain-of-func­tion’ exper­i­ment with H5N1 in fer­rets “includ­ed the use of man-made virus­es as a start­ing point. In some exper­i­ments they used native H5N1 and in oth­ers they used man-made virus­es with mod­i­fi­ca­tions known to make influen­za more vir­u­lent. So the lack of any known prog­en­i­tor virus­es as a start­ing point for an ani­mal pas­sage exper­i­ment as some sort of proof that the the virus could­n’t have been made in a lab com­plete­ly ignore that the prog­en­i­tor virus could also have been made in a lab.

    After con­clud­ing that the virus could­n’t pos­si­bly have been gen­er­at­ed in a lab, the authors spec­u­late about two pos­si­ble sce­nar­ios for a nat­ur­al ori­gin of the virus: that the virus evolved these unusu­al char­ac­ter­is­tics before it jump to humans or after it jumped to humans. If we con­sid­er the first sce­nario — that the virus acquired these unusu­al char­ac­ter­is­tics that make it opti­mal for spread­ing between humans in an ani­mal before jump­ing to humans — the authors sim­ply point out that the full range of vir­sues in bats and pan­golins is very under­sam­pled and so while we don’t know of any bat or pan­golin coro­n­avirus­es with furin cleav­age sites we don’t know they don’t exist. And then they point out that the virus would have had to evolve in an ani­mal with an ACE2 recep­tor sim­i­lar to humans. So the authors are basi­cal­ly say­ing it’s pos­si­ble that the virus could have acquired the char­ac­ter­is­tics that make it high­ly infec­tious in humans before it actu­al­ly made the jump.

    The authors’ con­clu­sion about sec­ond sce­nario — that it evolved these char­ac­ter­is­tics after jump­ing to humans — is where they make an impor­tant point about the pos­si­ble ori­gins of this virus: it’s very pos­si­ble the prog­en­i­tors to SARS-CoV­‑2 had already been cir­cu­lat­ing in humans and that’s how a virus opti­mized for spread­ing to humans sud­den­ly emerged. It’s a very fea­si­ble sce­nario and it does­n’t involve the virus being devel­oped in the lab at all. It’s also worth not­ing that this would be con­sis­tent with the the­o­ry put forth by some Chi­nese researchers that there are two dis­tinct strains — the ‘L‑type’ and ‘S‑Type’ strain — where the ‘S‑type’ strain was an old­er but less vir­u­lent strain that had been cir­cu­lat­ing for a while before an ‘L‑type’ strain emerged near Wuhan that caused the spike in deaths. One of the authors of the fol­low­ing Nature Med­i­cine let­ter, Andrew Ram­baut, is one of the peo­ple who took strong issue with the analy­sis by those Chi­nese researchers. Ram­baut now appears to be very open to the idea that there was some sort of much less vir­u­lent ear­ly ver­sion of SARS-CoV­‑2 that would cir­cu­lat­ing between humans for years, giv­ing the virus time to devel­op the fea­tures that allow it to spread so effec­tive­ly.

    In the fol­low­ing Sci­ence Alert arti­cle that describes this research, it includes a blog post by Fran­cis Collins, the head of the US Nation­al Insti­tutes of Health (NIH), high­light­ing the Nature Med­i­cine let­ter. In that post, Collins points out that the prog­en­i­tor virus could have been cir­cu­lat­ing for years or decades in humans, giv­ing it time to evolve these char­ac­ter­is­tics for bet­ter human trans­mis­sion. But it’s worth not­ing the remark­able coin­ci­dence if its the case that a less vir­u­lent form of the virus has been spread­ing around for years: if it’s been spread­ing for years or decades, the present day super ver­sion could have pre­sum­ably spread around the world and there­fore emerged any­where in the world. And yet it just hap­pened to emerge in Chi­na, the coun­try where the ini­tial ani­mal-to-human jump could would most like­ly have tak­en place. Right at this time when there’s a big Chi­nese desta­bi­liza­tion cam­paign tak­ing place. That’s some inter­est­ing luck.

    Ok, here’s a piece about that Nature Med­i­cine let­ter that includ­ed an inter­view of some of the authors. And its in that inter­view where the authors point out that the sce­nario that assumes the virus first jumped from ani­mal to human before acquir­ing all of these fea­tures makes it pos­si­ble that ear­li­er weak­er forms of the virus have been float­ing around for years or decades:

    Sci­ence Alert

    The COVID-19 Virus May Have Been in Humans For Years, Study Sug­gests

    JACINTA BOWLER
    30 MARCH 2020

    As COVID-19 has hitch­hiked around the globe, caus­ing lock­downs, pneu­mo­nia and fear, sci­en­tists have been rac­ing to deter­mine where the SARS-CoV­‑2 coro­n­avirus has come from.

    While we don’t have all the answers yet — includ­ing whether it came from an ani­mal reser­voira new analy­sis has defin­i­tive­ly put to rest the con­spir­a­cies that claim it’s a lab-made dis­ease.

    The study rais­es some inter­est­ing pos­si­bil­i­ties regard­ing the ori­gin of the new coro­n­avirus. One of the sce­nar­ios sug­gests the virus may have been cir­cu­lat­ing harm­less­ly in human pop­u­la­tions for quite a while before it became the pan­dem­ic that’s now stopped the world in its tracks.

    “It is pos­si­ble that a prog­en­i­tor of SARS-CoV­‑2 jumped into humans, acquir­ing [new genom­ic fea­tures] through adap­ta­tion dur­ing unde­tect­ed human-to-human trans­mis­sion,” the team from the US, UK and Aus­tralia writes in the study.

    “Once acquired, these adap­ta­tions would enable the pan­dem­ic to take off and pro­duce a suf­fi­cient­ly large clus­ter of cas­es.”

    The researchers analysed genom­ic data avail­able from SARS-CoV­‑2 and oth­er sim­i­lar coro­n­avirus­es, show­ing that the recep­tor-bind­ing domain (RBD) sec­tions of SARS-CoV­‑2 spike pro­teins were so effec­tive at bind­ing to human cells, they had to be caused by nat­ur­al selec­tion.

    “By com­par­ing the avail­able genome sequence data for known coro­n­avirus strains, we can firm­ly deter­mine that SARS-CoV­‑2 orig­i­nat­ed through nat­ur­al process­es,” said one of the researchers, immu­nol­o­gist Kris­t­ian Ander­sen at Scripps Research.

    “Two fea­tures of the virus, the muta­tions in the RBD por­tion of the spike pro­tein and its dis­tinct back­bone, rules out lab­o­ra­to­ry manip­u­la­tion as a poten­tial ori­gin for SARS-CoV­‑2.”

    With ‘lab­o­ra­to­ry exper­i­ment gone wrong’ out of the way, the team explored two viable hypothe­ses. First, that the nat­ur­al selec­tion occurred in an ani­mal host before the virus was trans­mit­ted to humans. The team explains that although sam­ples of coro­n­avirus­es in bats and pan­golins have shown sim­i­lar genomes, none of them fit per­fect­ly just yet.

    “Although no ani­mal coro­n­avirus has been iden­ti­fied that is suf­fi­cient­ly sim­i­lar to have served as the direct prog­en­i­tor of SARS-CoV­‑2, the diver­si­ty of coro­n­avirus­es in bats and oth­er species is mas­sive­ly under­sam­pled,” the researchers write.

    The sec­ond hypoth­e­sis is that the nat­ur­al selec­tion hap­pened in humans — after the virus was trans­mit­ted from an ani­mal host.

    “The sec­ond sce­nario is that the new coro­n­avirus crossed from ani­mals into humans before it became capa­ble of caus­ing human dis­ease,” direc­tor of the Nation­al Insti­tute of Health, Fran­cis Collins explains on the NIH blog.

    “Then, as a result of grad­ual evo­lu­tion­ary changes over years or per­haps decades, the virus even­tu­al­ly gained the abil­i­ty to spread from human-to-human and cause seri­ous, often life-threat­en­ing dis­ease.”

    Although we don’t yet know which of the two hypothe­ses is cor­rect, the researchers think that more evi­dence might tip the scales in favour of one or the oth­er — but we’ll have to wait for that research to be done.

    ...

    The cor­re­spon­dence has been pub­lished in Nature Med­i­cine.

    ———-

    “The COVID-19 Virus May Have Been in Humans For Years, Study Sug­gests” by JACINTA BOWLER; Sci­ence Alert; 03/30/2020

    ““By com­par­ing the avail­able genome sequence data for known coro­n­avirus strains, we can firm­ly deter­mine that SARS-CoV­‑2 orig­i­nat­ed through nat­ur­al process­es,” said one of the researchers, immu­nol­o­gist Kris­t­ian Ander­sen at Scripps Research.”

    By com­par­ing the avail­able genome sequence data for known coro­n­avirus strains, we can firm­ly deter­mine that SARS-CoV­‑2 orig­i­nat­ed through nat­ur­al process­es. That was the con­clu­sion of this let­ter. As we’ll see, that’s a high­ly sus­pect con­clu­sion that com­plete­ly ignores ani­mal-pas­sage exper­i­ments. But if we assume it was­n’t cre­at­ed in a lab, that leaves two gen­er­al sce­nar­ios: it either evolved these char­ac­ter­is­tics before jump­ing to humans or after humans. If that hap­pened before jump­ing to humans it would assume the exis­tence of a virus that’s nev­er been observed. And it’s entire­ly pos­si­ble there’s a virus in ani­mals with these remark­able char­ac­ter­is­tics that have nev­er been observed since the diver­si­ty of coro­n­avirus­es in ani­mals is very under­sam­pled. But if we assume this came from bats or pan­golins, it’s notable that none of the known coro­n­avirus­es in those ani­mals have these char­ac­ter­is­tics because such char­ac­ter­is­tics would­n’t actu­al­ly help the virus spread in those ani­mals:

    ...
    With ‘lab­o­ra­to­ry exper­i­ment gone wrong’ out of the way, the team explored two viable hypothe­ses. First, that the nat­ur­al selec­tion occurred in an ani­mal host before the virus was trans­mit­ted to humans. The team explains that although sam­ples of coro­n­avirus­es in bats and pan­golins have shown sim­i­lar genomes, none of them fit per­fect­ly just yet.

    “Although no ani­mal coro­n­avirus has been iden­ti­fied that is suf­fi­cient­ly sim­i­lar to have served as the direct prog­en­i­tor of SARS-CoV­‑2, the diver­si­ty of coro­n­avirus­es in bats and oth­er species is mas­sive­ly under­sam­pled,” the researchers write.
    ...

    Then there’s the hypoth­e­sis that it jumped to humans, per­haps years or decades ago, and evolved his char­ac­ter­is­tics at that point with­in human hosts. That seems like a much more plau­si­ble sce­nario. But it’s a sce­nario that sug­gests this vir­u­lent human-opti­mized form of the virus could have erupt­ed any­where. And yet it hap­pened in Chi­na, the loca­tion that would have been the pri­ma­ry sus­pect for a recent ani­mal-to-human jump. What are the odds of that?

    ..
    The sec­ond hypoth­e­sis is that the nat­ur­al selec­tion hap­pened in humans — after the virus was trans­mit­ted from an ani­mal host.

    “The sec­ond sce­nario is that the new coro­n­avirus crossed from ani­mals into humans before it became capa­ble of caus­ing human dis­ease,” direc­tor of the Nation­al Insti­tute of Health, Fran­cis Collins explains on the NIH blog.

    “Then, as a result of grad­ual evo­lu­tion­ary changes over years or per­haps decades, the virus even­tu­al­ly gained the abil­i­ty to spread from human-to-human and cause seri­ous, often life-threat­en­ing dis­ease.”
    ...

    Ok, now here’s the actu­al Nature Med­i­cine let­ter:

    Nature Med­i­cine

    The prox­i­mal ori­gin of SARS-CoV­‑2

    Kris­t­ian G. Ander­sen, Andrew Ram­baut, W. Ian Lip­kin, Edward C. Holmes & Robert F. Gar­ry

    Nature Med­i­cine (2020)
    Pub­lished 17 March 2020

    To the Edi­tor — Since the first reports of nov­el pneu­mo­nia (COVID-19) in Wuhan, Hubei province, Chi­na1,2, there has been con­sid­er­able dis­cus­sion on the ori­gin of the causative virus, SARS-CoV­‑23 (also referred to as HCoV-19)4. Infec­tions with SARS-CoV­‑2 are now wide­spread, and as of 11 March 2020, 121,564 cas­es have been con­firmed in more than 110 coun­tries, with 4,373 deaths5.

    SARS-CoV­‑2 is the sev­enth coro­n­avirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV­‑2 can cause severe dis­ease, where­as HKU1, NL63, OC43 and 229E are asso­ci­at­ed with mild symp­toms6. Here we review what can be deduced about the ori­gin of SARS-CoV­‑2 from com­par­a­tive analy­sis of genom­ic data. We offer a per­spec­tive on the notable fea­tures of the SARS-CoV­‑2 genome and dis­cuss sce­nar­ios by which they could have arisen. Our analy­ses clear­ly show that SARS-CoV­‑2 is not a lab­o­ra­to­ry con­struct or a pur­pose­ful­ly manip­u­lat­ed virus.

    Notable fea­tures of the SARS-CoV­‑2 genome

    Our com­par­i­son of alpha- and beta­coro­n­avirus­es iden­ti­fies two notable genom­ic fea­tures of SARS-CoV­‑2: (i) on the basis of struc­tur­al stud­ies7,8,9 and bio­chem­i­cal exper­i­ments1,9,10, SARS-CoV­‑2 appears to be opti­mized for bind­ing to the human recep­tor ACE2; and (ii) the spike pro­tein of SARS-CoV­‑2 has a func­tion­al poly­ba­sic (furin) cleav­age site at the S1–S2 bound­ary through the inser­tion of 12 nucleotides8, which addi­tion­al­ly led to the pre­dict­ed acqui­si­tion of three O‑linked gly­cans around the site.

    1. Muta­tions in the recep­tor-bind­ing domain of SARS-CoV­‑2

    The recep­tor-bind­ing domain (RBD) in the spike pro­tein is the most vari­able part of the coro­n­avirus genome1,2. Six RBD amino acids have been shown to be crit­i­cal for bind­ing to ACE2 recep­tors and for deter­min­ing the host range of SARS-CoV-like virus­es7. With coor­di­nates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which cor­re­spond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-27. Five of these six residues dif­fer between SARS-CoV­‑2 and SARS-CoV (Fig. 1a). On the basis of struc­tur­al stud­ies7,8,9 and bio­chem­i­cal exper­i­ments1,9,10, SARS-CoV­‑2 seems to have an RBD that binds with high affin­i­ty to ACE2 from humans, fer­rets, cats and oth­er species with high recep­tor homology77

    While the analy­ses above sug­gest that SARS-CoV­‑2 may bind human ACE2 with high affin­i­ty, com­pu­ta­tion­al analy­ses pre­dict that the inter­ac­tion is not ide­al7 and that the RBD sequence is dif­fer­ent from those shown in SARS-CoV to be opti­mal for recep­tor bind­ing7,11. Thus, the high-affin­i­ty bind­ing of the SARS-CoV­‑2 spike pro­tein to human ACE2 is most like­ly the result of nat­ur­al selec­tion on a human or human-like ACE2 that per­mits anoth­er opti­mal bind­ing solu­tion to arise. This is strong evi­dence that SARS-CoV­‑2 is not the prod­uct of pur­pose­ful manip­u­la­tion.

    2. Poly­ba­sic furin cleav­age site and O‑linked gly­cans

    The sec­ond notable fea­ture of SARS-CoV­‑2 is a poly­ba­sic cleav­age site (RRAR) at the junc­tion of S1 and S2, the two sub­units of the spike8 (Fig. 1b). This allows effec­tive cleav­age by furin and oth­er pro­teas­es and has a role in deter­min­ing viral infec­tiv­i­ty and host range12. In addi­tion, a lead­ing pro­line is also insert­ed at this site in SARS-CoV­‑2; thus, the insert­ed sequence is PRRA (Fig. 1b). The turn cre­at­ed by the pro­line is pre­dict­ed to result in the addi­tion of O‑linked gly­cans to S673, T678 and S686, which flank the cleav­age site and are unique to SARS-CoV­‑2 (Fig. 1b). Poly­ba­sic cleav­age sites have not been observed in relat­ed ‘lin­eage B’ beta­coro­n­avirus­es, although oth­er human beta­coro­n­avirus­es, includ­ing HKU1 (lin­eage A), have those sites and pre­dict­ed O‑linked gly­cans13. Giv­en the lev­el of genet­ic vari­a­tion in the spike, it is like­ly that SARS-CoV-2-like virus­es with par­tial or full poly­ba­sic cleav­age sites will be dis­cov­ered in oth­er species.

    The func­tion­al con­se­quence of the poly­ba­sic cleav­age site in SARS-CoV­‑2 is unknown, and it will be impor­tant to deter­mine its impact on trans­mis­si­bil­i­ty and patho­gen­e­sis in ani­mal mod­els. Exper­i­ments with SARS-CoV have shown that inser­tion of a furin cleav­age site at the S1–S2 junc­tion enhances cell–cell fusion with­out affect­ing viral entry14. In addi­tion, effi­cient cleav­age of the MERS-CoV spike enables MERS-like coro­n­avirus­es from bats to infect human cells15. In avian influen­za virus­es, rapid repli­ca­tion and trans­mis­sion in high­ly dense chick­en pop­u­la­tions selects for the acqui­si­tion of poly­ba­sic cleav­age sites in the hemag­glu­tinin (HA) pro­tein16, which serves a func­tion sim­i­lar to that of the coro­n­avirus spike pro­tein. Acqui­si­tion of poly­ba­sic cleav­age sites in HA, by inser­tion or recom­bi­na­tion, con­verts low-path­o­genic­i­ty avian influen­za virus­es into high­ly path­o­gen­ic forms1616. The acqui­si­tion of poly­ba­sic cleav­age sites by HA has also been observed after repeat­ed pas­sage in cell cul­ture or through ani­mals17.

    The func­tion of the pre­dict­ed O‑linked gly­cans is unclear, but they could cre­ate a ‘mucin-like domain’ that shields epi­topes or key residues on the SARS-CoV­‑2 spike pro­tein18. Sev­er­al virus­es uti­lize mucin-like domains as gly­can shields involved immu­no­eva­sion18. Although pre­dic­tion of O‑linked gly­co­sy­la­tion is robust, exper­i­men­tal stud­ies are need­ed to deter­mine if these sites are used in SARS-CoV­‑2.

    The­o­ries of SARS-CoV­‑2 ori­gins

    It is improb­a­ble that SARS-CoV­‑2 emerged through lab­o­ra­to­ry manip­u­la­tion of a relat­ed SARS-CoV-like coro­n­avirus. As not­ed above, the RBD of SARS-CoV­‑2 is opti­mized for bind­ing to human ACE2 with an effi­cient solu­tion dif­fer­ent from those pre­vi­ous­ly pre­dict­ed7,11. Fur­ther­more, if genet­ic manip­u­la­tion had been per­formed, one of the sev­er­al reverse-genet­ic sys­tems avail­able for beta­coro­n­avirus­es would prob­a­bly have been used19. How­ev­er, the genet­ic data irrefutably show that SARS-CoV­‑2 is not derived from any pre­vi­ous­ly used virus back­bone20. Instead, we pro­pose two sce­nar­ios that can plau­si­bly explain the ori­gin of SARS-CoV­‑2: (i) nat­ur­al selec­tion in an ani­mal host before zoonot­ic trans­fer; and (ii) nat­ur­al selec­tion in humans fol­low­ing zoonot­ic trans­fer. We also dis­cuss whether selec­tion dur­ing pas­sage could have giv­en rise to SARS-CoV­‑2.

    1. Nat­ur­al selec­tion in an ani­mal host before zoonot­ic trans­fer

    As many ear­ly cas­es of COVID-19 were linked to the Hua­nan mar­ket in Wuhan1,2, it is pos­si­ble that an ani­mal source was present at this loca­tion. Giv­en the sim­i­lar­i­ty of SARS-CoV­‑2 to bat SARS-CoV-like coro­n­avirus­es2, it is like­ly that bats serve as reser­voir hosts for its prog­en­i­tor. Although RaTG13, sam­pled from a Rhi­nolo­phus affi­nis bat1, is ~96% iden­ti­cal over­all to SARS-CoV­‑2, its spike diverges in the RBD, which sug­gests that it may not bind effi­cient­ly to human ACE27 (Fig. 1a).

    Malayan pan­golins (Man­is javan­i­ca) ille­gal­ly import­ed into Guang­dong province con­tain coro­n­avirus­es sim­i­lar to SARS-CoV­‑221. Although the RaTG13 bat virus remains the clos­est to SARS-CoV­‑2 across the genome1, some pan­golin coro­n­avirus­es exhib­it strong sim­i­lar­i­ty to SARS-CoV­‑2 in the RBD, includ­ing all six key RBD residues21 (Fig. 1). This clear­ly shows that the SARS-CoV­‑2 spike pro­tein opti­mized for bind­ing to human-like ACE2 is the result of nat­ur­al selec­tion.

    Nei­ther the bat beta­coro­n­avirus­es nor the pan­golin beta­coro­n­avirus­es sam­pled thus far have poly­ba­sic cleav­age sites. Although no ani­mal coro­n­avirus has been iden­ti­fied that is suf­fi­cient­ly sim­i­lar to have served as the direct prog­en­i­tor of SARS-CoV­‑2, the diver­si­ty of coro­n­avirus­es in bats and oth­er species is mas­sive­ly under­sam­pled. Muta­tions, inser­tions and dele­tions can occur near the S1–S2 junc­tion of coro­n­avirus­es22, which shows that the poly­ba­sic cleav­age site can arise by a nat­ur­al evo­lu­tion­ary process. For a pre­cur­sor virus to acquire both the poly­ba­sic cleav­age site and muta­tions in the spike pro­tein suit­able for bind­ing to human ACE2, an ani­mal host would prob­a­bly have to have a high pop­u­la­tion den­si­ty (to allow nat­ur­al selec­tion to pro­ceed effi­cient­ly) and an ACE2-encod­ing gene that is sim­i­lar to the human ortholog.

    2. Nat­ur­al selec­tion in humans fol­low­ing zoonot­ic trans­fer

    It is pos­si­ble that a prog­en­i­tor of SARS-CoV­‑2 jumped into humans, acquir­ing the genom­ic fea­tures described above through adap­ta­tion dur­ing unde­tect­ed human-to-human trans­mis­sion. Once acquired, these adap­ta­tions would enable the pan­dem­ic to take off and pro­duce a suf­fi­cient­ly large clus­ter of cas­es to trig­ger the sur­veil­lance sys­tem that detect­ed it1,2.

    All SARS-CoV­‑2 genomes sequenced so far have the genom­ic fea­tures described above and are thus derived from a com­mon ances­tor that had them too. The pres­ence in pan­golins of an RBD very sim­i­lar to that of SARS-CoV­‑2 means that we can infer this was also prob­a­bly in the virus that jumped to humans. This leaves the inser­tion of poly­ba­sic cleav­age site to occur dur­ing human-to-human trans­mis­sion.

    Esti­mates of the tim­ing of the most recent com­mon ances­tor of SARS-CoV­‑2 made with cur­rent sequence data point to emer­gence of the virus in late Novem­ber 2019 to ear­ly Decem­ber 201923, com­pat­i­ble with the ear­li­est ret­ro­spec­tive­ly con­firmed cas­es24. Hence, this sce­nario pre­sumes a peri­od of unrec­og­nized trans­mis­sion in humans between the ini­tial zoonot­ic event and the acqui­si­tion of the poly­ba­sic cleav­age site. Suf­fi­cient oppor­tu­ni­ty could have arisen if there had been many pri­or zoonot­ic events that pro­duced short chains of human-to-human trans­mis­sion over an extend­ed peri­od. This is essen­tial­ly the sit­u­a­tion for MERS-CoV, for which all human cas­es are the result of repeat­ed jumps of the virus from drom­e­dary camels, pro­duc­ing sin­gle infec­tions or short trans­mis­sion chains that even­tu­al­ly resolve, with no adap­ta­tion to sus­tained trans­mis­sion25.

    Stud­ies of banked human sam­ples could pro­vide infor­ma­tion on whether such cryp­tic spread has occurred. Ret­ro­spec­tive sero­log­i­cal stud­ies could also be infor­ma­tive, and a few such stud­ies have been con­duct­ed show­ing low-lev­el expo­sures to SARS-CoV-like coro­n­avirus­es in cer­tain areas of Chi­na26. Crit­i­cal­ly, how­ev­er, these stud­ies could not have dis­tin­guished whether expo­sures were due to pri­or infec­tions with SARS-CoV, SARS-CoV­‑2 or oth­er SARS-CoV-like coro­n­avirus­es. Fur­ther sero­log­i­cal stud­ies should be con­duct­ed to deter­mine the extent of pri­or human expo­sure to SARS-CoV­‑2.

    3. Selec­tion dur­ing pas­sage

    Basic research involv­ing pas­sage of bat SARS-CoV-like coro­n­avirus­es in cell cul­ture and/or ani­mal mod­els has been ongo­ing for many years in biosafe­ty lev­el 2 lab­o­ra­to­ries across the world27, and there are doc­u­ment­ed instances of lab­o­ra­to­ry escapes of SARS-CoV28. We must there­fore exam­ine the pos­si­bil­i­ty of an inad­ver­tent lab­o­ra­to­ry release of SARS-CoV­‑2.

    In the­o­ry, it is pos­si­ble that SARS-CoV­‑2 acquired RBD muta­tions (Fig. 1a) dur­ing adap­ta­tion to pas­sage in cell cul­ture, as has been observed in stud­ies of SARS-CoV11. The find­ing of SARS-CoV-like coro­n­avirus­es from pan­golins with near­ly iden­ti­cal RBDs, how­ev­er, pro­vides a much stronger and more par­si­mo­nious expla­na­tion of how SARS-CoV­‑2 acquired these via recom­bi­na­tion or muta­tion19.

    The acqui­si­tion of both the poly­ba­sic cleav­age site and pre­dict­ed O‑linked gly­cans also argues against cul­ture-based sce­nar­ios. New poly­ba­sic cleav­age sites have been observed only after pro­longed pas­sage of low-path­o­genic­i­ty avian influen­za virus in vit­ro or in vivo17. Fur­ther­more, a hypo­thet­i­cal gen­er­a­tion of SARS-CoV­‑2 by cell cul­ture or ani­mal pas­sage would have required pri­or iso­la­tion of a prog­en­i­tor virus with very high genet­ic sim­i­lar­i­ty, which has not been described. Sub­se­quent gen­er­a­tion of a poly­ba­sic cleav­age site would have then required repeat­ed pas­sage in cell cul­ture or ani­mals with ACE2 recep­tors sim­i­lar to those of humans, but such work has also not pre­vi­ous­ly been described. Final­ly, the gen­er­a­tion of the pre­dict­ed O‑linked gly­cans is also unlike­ly to have occurred due to cell-cul­ture pas­sage, as such fea­tures sug­gest the involve­ment of an immune sys­tem18.

    Con­clu­sions

    In the midst of the glob­al COVID-19 pub­lic-health emer­gency, it is rea­son­able to won­der why the ori­gins of the pan­dem­ic mat­ter. Detailed under­stand­ing of how an ani­mal virus jumped species bound­aries to infect humans so pro­duc­tive­ly will help in the pre­ven­tion of future zoonot­ic events. For exam­ple, if SARS-CoV­‑2 pre-adapt­ed in anoth­er ani­mal species, then there is the risk of future re-emer­gence events. In con­trast, if the adap­tive process occurred in humans, then even if repeat­ed zoonot­ic trans­fers occur, they are unlike­ly to take off with­out the same series of muta­tions. In addi­tion, iden­ti­fy­ing the clos­est viral rel­a­tives of SARS-CoV­‑2 cir­cu­lat­ing in ani­mals will great­ly assist stud­ies of viral func­tion. Indeed, the avail­abil­i­ty of the RaTG13 bat sequence helped reveal key RBD muta­tions and the poly­ba­sic cleav­age site.

    The genom­ic fea­tures described here may explain in part the infec­tious­ness and trans­mis­si­bil­i­ty of SARS-CoV­‑2 in humans. Although the evi­dence shows that SARS-CoV­‑2 is not a pur­pose­ful­ly manip­u­lat­ed virus, it is cur­rent­ly impos­si­ble to prove or dis­prove the oth­er the­o­ries of its ori­gin described here. How­ev­er, since we observed all notable SARS-CoV­‑2 fea­tures, includ­ing the opti­mized RBD and poly­ba­sic cleav­age site, in relat­ed coro­n­avirus­es in nature, we do not believe that any type of lab­o­ra­to­ry-based sce­nario is plau­si­ble.

    ...

    ————

    “The prox­i­mal ori­gin of SARS-CoV­‑2” by Kris­t­ian G. Ander­sen, Andrew Ram­baut, W. Ian Lip­kin, Edward C. Holmes & Robert F. Gar­ry; Nature Med­i­cine; 03/17/2020

    “The genom­ic fea­tures described here may explain in part the infec­tious­ness and trans­mis­si­bil­i­ty of SARS-CoV­‑2 in humans. Although the evi­dence shows that SARS-CoV­‑2 is not a pur­pose­ful­ly manip­u­lat­ed virus, it is cur­rent­ly impos­si­ble to prove or dis­prove the oth­er the­o­ries of its ori­gin described here. How­ev­er, since we observed all notable SARS-CoV­‑2 fea­tures, includ­ing the opti­mized RBD and poly­ba­sic cleav­age site, in relat­ed coro­n­avirus­es in nature, we do not believe that any type of lab­o­ra­to­ry-based sce­nario is plau­si­ble.”

    They just don’t see any type of lab­o­ra­to­ry-based sce­nario as plau­si­ble. That’s what they con­clud­ed. For rather odd rea­sons.

    First, they note the two key fea­tures of SARS-CoV­‑2 that make it so infec­tious in humans: the virus appears to be “opti­mized” for bind­ing to human ACE2 recep­tors. And the inser­tion of a furin cleav­age site. A cleav­age site that also has the pre­dict­ed addi­tion of O‑linked gly­cans flank­ing it that help the virus elude the immune sys­tem. How those two key fea­tures emerged in this seem­ing­ly new virus remains the big mys­tery:

    ...
    Our com­par­i­son of alpha- and beta­coro­n­avirus­es iden­ti­fies two notable genom­ic fea­tures of SARS-CoV­‑2: (i) on the basis of struc­tur­al stud­ies7,8,9 and bio­chem­i­cal exper­i­ments1,9,10, SARS-CoV­‑2 appears to be opti­mized for bind­ing to the human recep­tor ACE2; and (ii) the spike pro­tein of SARS-CoV­‑2 has a func­tion­al poly­ba­sic (furin) cleav­age site at the S1–S2 bound­ary through the inser­tion of 12 nucleotides8, which addi­tion­al­ly led to the pre­dict­ed acqui­si­tion of three O‑linked gly­cans around the site.
    ...

    First, regard­ing the seem­ing­ly opti­mized recep­tor bind­ing domain that allows the virus to bind to the human ACE2 recep­tor, the authors note that the SARS-CoV­‑2 RBD would NOT have been pre­dict­ed based on mod­els. That alone is why the authors assume it could­n’t have been built in a lab. It’s a con­clu­sion that also assumes the virus could only have been built in a lab by inten­tion­al design, as opposed to using ani­mal pas­sage ‘gain-of-fuc­tion’ exper­i­ments:

    ...
    1. Muta­tions in the recep­tor-bind­ing domain of SARS-CoV­‑2

    The recep­tor-bind­ing domain (RBD) in the spike pro­tein is the most vari­able part of the coro­n­avirus genome1,2. Six RBD amino acids have been shown to be crit­i­cal for bind­ing to ACE2 recep­tors and for deter­min­ing the host range of SARS-CoV-like virus­es7. With coor­di­nates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which cor­re­spond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-27. Five of these six residues dif­fer between SARS-CoV­‑2 and SARS-CoV (Fig. 1a). On the basis of struc­tur­al stud­ies7,8,9 and bio­chem­i­cal exper­i­ments1,9,10, SARS-CoV­‑2 seems to have an RBD that binds with high affin­i­ty to ACE2 from humans, fer­rets, cats and oth­er species with high recep­tor homology77

    While the analy­ses above sug­gest that SARS-CoV­‑2 may bind human ACE2 with high affin­i­ty, com­pu­ta­tion­al analy­ses pre­dict that the inter­ac­tion is not ide­al7 and that the RBD sequence is dif­fer­ent from those shown in SARS-CoV to be opti­mal for recep­tor bind­ing7,11. Thus, the high-affin­i­ty bind­ing of the SARS-CoV­‑2 spike pro­tein to human ACE2 is most like­ly the result of nat­ur­al selec­tion on a human or human-like ACE2 that per­mits anoth­er opti­mal bind­ing solu­tion to arise. This is strong evi­dence that SARS-CoV­‑2 is not the prod­uct of pur­pose­ful manip­u­la­tion.
    ...

    Then the authors look to the furin cleav­age site. They note that no oth­er known beta­coro­n­avirus­es in the b lin­eage have this fea­ture, but since it’s a known fea­ture in oth­er coro­n­avirus­es they sug­gest that it’s like­ly we’ll find virus­es with par­tial or full furin (poly­ba­sic) cleav­age sites in oth­er species. That’s it. Remark­ably, they actu­al­ly note that sim­i­lar cleav­age sites were acquired dur­ing ani­mal pas­sage exper­i­ments using avian flu:

    ...
    2. Poly­ba­sic furin cleav­age site and O‑linked gly­cans

    The sec­ond notable fea­ture of SARS-CoV­‑2 is a poly­ba­sic cleav­age site (RRAR) at the junc­tion of S1 and S2, the two sub­units of the spike8 (Fig. 1b). This allows effec­tive cleav­age by furin and oth­er pro­teas­es and has a role in deter­min­ing viral infec­tiv­i­ty and host range12. In addi­tion, a lead­ing pro­line is also insert­ed at this site in SARS-CoV­‑2; thus, the insert­ed sequence is PRRA (Fig. 1b). The turn cre­at­ed by the pro­line is pre­dict­ed to result in the addi­tion of O‑linked gly­cans to S673, T678 and S686, which flank the cleav­age site and are unique to SARS-CoV­‑2 (Fig. 1b). Poly­ba­sic cleav­age sites have not been observed in relat­ed ‘lin­eage B’ beta­coro­n­avirus­es, although oth­er human beta­coro­n­avirus­es, includ­ing HKU1 (lin­eage A), have those sites and pre­dict­ed O‑linked gly­cans13. Giv­en the lev­el of genet­ic vari­a­tion in the spike, it is like­ly that SARS-CoV-2-like virus­es with par­tial or full poly­ba­sic cleav­age sites will be dis­cov­ered in oth­er species.

    The func­tion­al con­se­quence of the poly­ba­sic cleav­age site in SARS-CoV­‑2 is unknown, and it will be impor­tant to deter­mine its impact on trans­mis­si­bil­i­ty and patho­gen­e­sis in ani­mal mod­els. Exper­i­ments with SARS-CoV have shown that inser­tion of a furin cleav­age site at the S1–S2 junc­tion enhances cell–cell fusion with­out affect­ing viral entry14. In addi­tion, effi­cient cleav­age of the MERS-CoV spike enables MERS-like coro­n­avirus­es from bats to infect human cells15. In avian influen­za virus­es, rapid repli­ca­tion and trans­mis­sion in high­ly dense chick­en pop­u­la­tions selects for the acqui­si­tion of poly­ba­sic cleav­age sites in the hemag­glu­tinin (HA) pro­tein16, which serves a func­tion sim­i­lar to that of the coro­n­avirus spike pro­tein. Acqui­si­tion of poly­ba­sic cleav­age sites in HA, by inser­tion or recom­bi­na­tion, con­verts low-path­o­genic­i­ty avian influen­za virus­es into high­ly path­o­gen­ic forms1616. The acqui­si­tion of poly­ba­sic cleav­age sites by HA has also been observed after repeat­ed pas­sage in cell cul­ture or through ani­mals17.
    ...

    The authors note that the O‑linked gly­cans flank­ing the cleav­age site might be used for evad­ing the immune sys­tem but that unclear. They lat­er dis­cuss the pos­si­bil­i­ty that the virus could have emerged from ani­mal pas­sage exper­i­ments, not­ing that such exper­i­ments have been tak­ing place on coro­n­avirus­es in labs around the world for years. And while they acknowl­edge the pos­si­bil­i­ty that the virus’s opti­mized nov­el RBD for the ACE2 recep­tor emerged from such exper­i­ments, they find the idea that it evolved nat­u­ral­ly far more par­si­mo­nious. Why is it more par­si­mo­nious? Who knows. There’s no expla­na­tion for that:

    ...
    The func­tion of the pre­dict­ed O‑linked gly­cans is unclear, but they could cre­ate a ‘mucin-like domain’ that shields epi­topes or key residues on the SARS-CoV­‑2 spike pro­tein18. Sev­er­al virus­es uti­lize mucin-like domains as gly­can shields involved immu­no­eva­sion18. Although pre­dic­tion of O‑linked gly­co­sy­la­tion is robust, exper­i­men­tal stud­ies are need­ed to deter­mine if these sites are used in SARS-CoV­‑2.

    ...

    3. Selec­tion dur­ing pas­sage

    Basic research involv­ing pas­sage of bat SARS-CoV-like coro­n­avirus­es in cell cul­ture and/or ani­mal mod­els has been ongo­ing for many years in biosafe­ty lev­el 2 lab­o­ra­to­ries across the world27, and there are doc­u­ment­ed instances of lab­o­ra­to­ry escapes of SARS-CoV28. We must there­fore exam­ine the pos­si­bil­i­ty of an inad­ver­tent lab­o­ra­to­ry release of SARS-CoV­‑2.

    In the­o­ry, it is pos­si­ble that SARS-CoV­‑2 acquired RBD muta­tions (Fig. 1a) dur­ing adap­ta­tion to pas­sage in cell cul­ture, as has been observed in stud­ies of SARS-CoV11. The find­ing of SARS-CoV-like coro­n­avirus­es from pan­golins with near­ly iden­ti­cal RBDs, how­ev­er, pro­vides a much stronger and more par­si­mo­nious expla­na­tion of how SARS-CoV­‑2 acquired these via recom­bi­na­tion or muta­tion19.
    ...

    Then they note that the acqui­si­tion of furin cleav­age sites an O‑linked gly­cans has been observed in ani­mal pas­sage exper­i­ments with avian flu, and point out that this is an argu­ment against the virus being devel­oped in a cell cul­ture. Well, yeah, but what about ani­mal pas­sage exper­i­ments? Well, they sug­gests that, yes, it’s pos­si­ble. But such exper­i­ments would have required a viral prog­en­i­tor that is close enough to the SARS-CoV­‑2 sequence to be a viable start­ing point and such virus­es haven’t been described. It’s an expla­na­tion that com­plete­ly ignore the obvi­ous­ly pos­si­bil­i­ty of a man-made start­ing point. They they point out that the ani­mal pas­sage exper­i­ments would have had to take place in ani­mals with ACE2 recep­tors sim­i­lar enough to humans (like fer­rets!!) and note that no such research has been described. So they are lit­er­al­ly dis­miss­ing the ani­mal pas­sage exper­i­ment pos­si­bil­i­ty because the peo­ple who hypo­thet­i­cal­ly car­ried it out did­n’t pub­licly report it:

    ...
    The acqui­si­tion of both the poly­ba­sic cleav­age site and pre­dict­ed O‑linked gly­cans also argues against cul­ture-based sce­nar­ios. New poly­ba­sic cleav­age sites have been observed only after pro­longed pas­sage of low-path­o­genic­i­ty avian influen­za virus in vit­ro or in vivo17. Fur­ther­more, a hypo­thet­i­cal gen­er­a­tion of SARS-CoV­‑2 by cell cul­ture or ani­mal pas­sage would have required pri­or iso­la­tion of a prog­en­i­tor virus with very high genet­ic sim­i­lar­i­ty, which has not been described. Sub­se­quent gen­er­a­tion of a poly­ba­sic cleav­age site would have then required repeat­ed pas­sage in cell cul­ture or ani­mals with ACE2 recep­tors sim­i­lar to those of humans, but such work has also not pre­vi­ous­ly been described. Final­ly, the gen­er­a­tion of the pre­dict­ed O‑linked gly­cans is also unlike­ly to have occurred due to cell-cul­ture pas­sage, as such fea­tures sug­gest the involve­ment of an immune sys­tem18.
    ...

    So that was the recent Nature Med­i­cine let­ter that appar­ent­ly ‘proved’ the virus could­n’t emerge in a lab. A let­ter that, if read close­ly, based its firm con­clu­sions on the notion that if it was devel­oped in a lab it would have been report­ed by the peo­ple who did it. The opti­mized RBD for ACE2, the furin cleav­age site, and the O‑linked gly­cans all appear to be fea­tures that could be very plau­si­bly explained by ani­mal pas­sage exper­i­ments. But because spe­cif­ic ani­mal pas­sage exper­i­ments demon­strat­ing the acqui­si­tion of these fea­tures by a close­ly relat­ed prog­en­i­tor virus haven’t been pub­licly report­ed that means would should assume they did­n’t hap­pen and there­fore we can rule out ani­mal pas­sage exper­i­ments as a plau­si­ble source. An implau­si­bly bad argu­ment about plau­si­bil­i­ty. That’s the cut­ting edge of analy­sis on this virus. Yikes.

    Posted by Pterrafractyl | April 4, 2020, 4:19 pm
  7. @Pterrafractyl–

    This arti­cle is worthless–ANY virus can be made in a lab­o­ra­to­ry, as the “MIT Tech­nol­o­gy Review” arti­cle from 2/15/2020 reminds us.

    Claims that trum­pet “the virus was­n’t made in a lab­o­ra­to­ry” are more than a lit­tle suspect–they not only ignore the state of the art of virol­o­gy but ignore the desta­bi­liza­tion effort against Chi­na and the DARPA research into Chi­nese bat-borne coro­n­avirus­es.

    I will be address­ing this in a pro­gram to be record­ed short­ly.

    https://www.technologyreview.com/s/615231/biologists-rush-to-re-create-the-china-coronavirus-from-its-dna-code/

    Note also, the first arti­cle from this May, 2001 broad­cast:

    https://spitfirelist.com/for-the-record/ftr-282-a-shot-in-the-dark-designer-genes-the-aids-vaccine/

    “No Longer Sci­ence Fic­tion! Racial­ly-Tar­get­ed Weapons May Become Real­i­ty Soon;” Reuters; 1/21/1999.

    Best,

    Dave

    Posted by Dave Emory | April 6, 2020, 4:58 pm
  8. Intel­li­gence report warned of coro­n­avirus cri­sis as ear­ly as Novem­ber: Sources
    “Ana­lysts con­clud­ed it could be a cat­a­clysmic event,” a source says.

    By
    Josh Mar­golin
    and
    James Gor­don Meek
    April 8, 2020, 1:01 AM
    10 min read

    As far back as late Novem­ber, U.S. intel­li­gence offi­cials were warn­ing that a con­ta­gion was sweep­ing through China’s Wuhan region, chang­ing the pat­terns of life and busi­ness and pos­ing a threat to the pop­u­la­tion, accord­ing to four sources briefed on the secret report­ing.

    Con­cerns about what is now known to be the nov­el coro­n­avirus pan­dem­ic were detailed in a Novem­ber intel­li­gence report by the mil­i­tary’s Nation­al Cen­ter for Med­ical Intel­li­gence (NCMI), accord­ing to two offi­cials famil­iar with the document’s con­tents.

    The report was the result of analy­sis of wire and com­put­er inter­cepts, cou­pled with satel­lite images. It raised alarms because an out-of-con­trol dis­ease would pose a seri­ous threat to U.S. forces in Asia — forces that depend on the NCMI’s work. And it paints a pic­ture of an Amer­i­can gov­ern­ment that could have ramped up mit­i­ga­tion and con­tain­ment efforts far ear­li­er to pre­pare for a cri­sis poised to come home.

    “Ana­lysts con­clud­ed it could be a cat­a­clysmic event,” one of the sources said of the NCMI’s report. “It was then briefed mul­ti­ple times to” the Defense Intel­li­gence Agency, the Pentagon’s Joint Staff and the White House.

    “The time­line of the intel side of this may be fur­ther back than we’re dis­cussing,” the source said of pre­lim­i­nary reports from Wuhan. “But this was def­i­nite­ly being briefed begin­ning at the end of Novem­ber as some­thing the mil­i­tary need­ed to take a pos­ture on.”

    https://abcnews.go.com/Politics/intelligence-report-warned-coronavirus-crisis-early-november-sources/story?id=70031273

    [ed. note: This may serve as fur­ther cir­cum­stan­tial evi­dence to sup­port the the­sis devel­oped in this set of pro­grams regard­ing the ori­gins of this virus. It seems worth not­ing that the first report­ed cas­es did not reach the pub­lic atten­tion until 31 Decem­ber, while this arti­cle from the Busi­ness Insid­er web­site men­tions ‘Late Novem­ber’ as a pos­si­ble time in which this virus first began to spread. The pre­science of the US mil­i­tary-intel­li­gence estab­lish­ment seems notable, if not “remark­able.”]

    It seems rea­son­able to sug­gest that this intel report was sup­pressed in order for the US intel­li­gence appa­ra­tus to main­tain a cov­er of ‘plau­si­ble deni­a­bil­i­ty.’

    If the US intel appa­rat was aware of and pro­vid­ing intel­li­gence assess­ments on a virus that not even the Chi­nese gov­ern­ment real­ized was a new and dead­ly strain of an old neme­sis, it would sug­gest at the very least, pri­or knowl­edge of the actu­al lethality/severity of this “nov­el” virus. It would also lend cre­dence to the claims advanced in the TV Ahashi seg­ment regard­ing the North Amer­i­can prove­nance of the 5 pre­vi­ous strains which appar­ent­ly were com­bined to pro­duce this mon­ster. It may well be that the tim­ing of this release (ie, 1 o’clock in the morn­ing) was delib­er­ate­ly cho­sen to serve as a means of bury­ing the sto­ry in the same way that pub­li­ca­tion on a Fri­day evening would. Just my two Kopek’s worth- Ovid19]

    Posted by Ovid 19 | April 8, 2020, 7:06 am
  9. There was a poten­tial­ly sig­nif­i­cant study out of Chi­na about COVID-19 that could have big impli­ca­tions for the future impact of the virus and how long the cur­rent glob­al lock­down peri­od might last. The study is just a pre­lim­i­nary study on a rel­a­tive­ly small sam­ple of 175 patients Shang­hai Pub­lic Health Clin­i­cal Cen­tre who had pre­vi­ous­ly suf­fered from rel­a­tive­ly mild cas­es of COVID-19 and recov­ered.

    Alarm­ing­ly, they found that almost a third of the patients had sur­pris­ing­ly low lev­els of COVID-19 anti­bod­ies, with 10 of the patients hav­ing such low lev­els that they could­n’t be detect­ed. Intrigu­ing­ly, these patients with lit­tle to no anti­bod­ies skewed towards the younger patients. So the demo­graph­ic that appears to be least impact­ed by the virus also has a propen­si­ty to have a fleet­ing anti­body response if at all. It’s sug­gest­ed by the researchers that indi­vid­u­als with no detectable anti­bod­ies may have suc­cess­ful­ly fought off the dis­ease using a dif­fer­ent more gen­er­al immune response that did­n’t require the use of anti­bod­ies at all.

    If this study pans out and there real­ly is a sub­stan­tial num­ber of pri­mar­i­ly younger peo­ple who are fight­ing it off the dis­ease with­out an mean­ing­ful buildup of anti­bod­ies, it points to a poten­tial­ly seri­ous com­pli­ca­tion with the hopes of using a vac­cine to even­tu­al­ly con­trol this pan­dem­ic and pre­vent future pan­demics. Because if a third of the pop­u­lace does­n’t respond to the virus by build­ing up anti­bod­ies it’s pos­si­ble a vac­cine won’t actu­al­ly work for them either:

    South Chi­na Morn­ing Post

    Coro­n­avirus: low anti­body lev­els raise ques­tions about rein­fec­tion risk

    * Sci­en­tists in Shang­hai say some recov­ered patients show no signs of the neu­tral­is­ing pro­teins
    * Ear­ly-stage find­ings could have impli­ca­tions for vac­cine devel­op­ment and herd immu­ni­ty, they say

    Stephen Chen in Bei­jing
    Pub­lished: 10:00pm, 7 Apr, 2020

    Researchers in Shang­hai hope to deter­mine whether some recov­ered coro­n­avirus patients
    have a high­er risk of rein­fec­tion after find­ing sur­pris­ing­ly low lev­els of Covid-19 anti­bod­ies in a num­ber of peo­ple dis­charged from hos­pi­tal.

    A team from Fudan Uni­ver­si­ty analysed blood sam­ples from 175 patients dis­charged from the Shang­hai Pub­lic Health Clin­i­cal Cen­tre and found that near­ly a third had unex­pect­ed­ly low lev­els of anti­bod­ies.

    In some cas­es, anti­bod­ies could not be detect­ed at all.

    “Whether these patients were at high risk of rebound or rein­fec­tion should be explored in fur­ther stud­ies,” the team wrote in pre­lim­i­nary research released on Mon­day on Medrxiv.org, an online plat­form for preprint papers.

    Although the study was pre­lim­i­nary and not peer-reviewed, it was the world’s first sys­tem­at­ic exam­i­na­tion of anti­body lev­els in patients who had recov­ered from Covid-19, the dis­ease caused by the coro­n­avirus, the researchers said.

    All of the patients had recent­ly recov­ered from mild symp­toms of the dis­ease and most of those with low anti­body lev­els were young. The researchers exclud­ed patients who had been admit­ted to inten­sive care units because many of them already had anti­bod­ies from donat­ed blood plas­ma.

    Anti­bod­ies are gen­er­at­ed by the immune sys­tem and have unique chem­i­cal struc­tures to inhib­it spe­cif­ic pathogens. The coro­n­avirus anti­body inter­cepts the spike pro­tein on the viral enve­lope to pre­vent it from bind­ing with human cells.

    The researchers said they were sur­prised to find that the anti­body “titer” val­ue in about a third of the patients was less than 500, a lev­el that might be too low to pro­vide pro­tec­tion.

    “About 30 per cent of patients failed to devel­op high titers of neu­tral­is­ing anti­bod­ies after Covid-19 infec­tion. How­ev­er, the dis­ease dura­tion of these patients com­pared to oth­ers was sim­i­lar,” they said.

    The team also found that anti­body lev­els rose with age, with peo­ple in the 60–85 age group dis­play­ing more than three times the amount of anti­bod­ies as peo­ple in the 15–39 age group.

    The low amounts of anti­bod­ies could affect herd immu­ni­ty, resis­tance to the dis­ease among the gen­er­al pop­u­la­tion to stop its spread.

    “This is a clin­i­cal obser­va­tion we made at the front line. What this will mean to herd immu­ni­ty will require more data from oth­er parts of the world,” Pro­fes­sor Huang Jinghe, the leader of the team, said on Tues­day.

    Huang said 10 of the patients in the study had an anti­body pres­ence so low it could not even be detect­ed in the lab­o­ra­to­ry.

    These patients expe­ri­enced typ­i­cal Covid-19 symp­toms includ­ing fever, chill and a cough, but might have beat­en back the virus with oth­er parts of the immune sys­tem such as T‑cells or cytokines.

    How they did this was still unclear.

    “Vac­cine devel­op­ers may need to pay par­tic­u­lar atten­tion to these patients,” Huang said. If the real virus could not induce anti­body response, the weak­ened ver­sion in the vac­cine might not work in these patients either.

    The researchers also found that the Covid-19 anti­body could bind with a dis­tant­ly relat­ed strain that caused an out­break of severe acute res­pi­ra­to­ry syn­drome (Sars) in 2003.

    But the bind­ing could not sup­press Sars virus repli­ca­tion in cells, dash­ing hopes of devel­op­ing a vac­cine for two or even more coro­n­avirus strains at once.

    ...

    Pro­fes­sor Wang Chen, a senior sci­en­tif­ic advis­er to the cen­tral gov­ern­ment, told state media on Mon­day that it was way too ear­ly to declare vic­to­ry against the dis­ease even in Chi­na, where the sit­u­a­tion was under con­trol for now.

    “Who knows whether this will become some­thing like a sea­son­al flu, or chron­ic dis­ease like hepati­tis B, or just van­ish like Sars?” he was quot­ed in the offi­cial Sci­ence and Tech­nol­o­gy Dai­ly.

    “Up till now we still lack imag­i­na­tion [to tell].”

    ———–

    ” Coro­n­avirus: low anti­body lev­els raise ques­tions about rein­fec­tion risk” by Stephen Chen; South Chi­na Morn­ing Post; 04/07/2020

    “All of the patients had recent­ly recov­ered from mild symp­toms of the dis­ease and most of those with low anti­body lev­els were young. The researchers exclud­ed patients who had been admit­ted to inten­sive care units because many of them already had anti­bod­ies from donat­ed blood plas­ma.”

    A third of recov­ered patients have unex­pect­ed­ly low lev­els of anti­bod­ies and most of those peo­ple were the young, the one group that appears to be the least impact­ed by it. This is turn­ing out to be quite a virus.

    Does this mean that around 30 per­cent of peo­ple will be prone to rein­fec­tion after recov­ery? Maybe, but since that 30 per­cent is most­ly young it will at least thank­ful­ly be the group least like­ly to be killed by the virus who keep get­ting rein­fect­ed. But that risk of rein­fec­tion could still pose quite a risk to the over­all strat­e­gy of ‘flat­ten­ing the curve’ with social dis­tanc­ing and lock­ing the glob­al econ­o­my down with the hope of slow­ly build­ing up “herd immu­ni­ty” while we wait for a vac­cine to be devel­oped:

    ...
    The researchers said they were sur­prised to find that the anti­body “titer” val­ue in about a third of the patients was less than 500, a lev­el that might be too low to pro­vide pro­tec­tion.

    “About 30 per cent of patients failed to devel­op high titers of neu­tral­is­ing anti­bod­ies after Covid-19 infec­tion. How­ev­er, the dis­ease dura­tion of these patients com­pared to oth­ers was sim­i­lar,” they said.

    The team also found that anti­body lev­els rose with age, with peo­ple in the 60–85 age group dis­play­ing more than three times the amount of anti­bod­ies as peo­ple in the 15–39 age group.

    The low amounts of anti­bod­ies could affect herd immu­ni­ty, resis­tance to the dis­ease among the gen­er­al pop­u­la­tion to stop its spread.

    ...

    Huang said 10 of the patients in the study had an anti­body pres­ence so low it could not even be detect­ed in the lab­o­ra­to­ry.

    These patients expe­ri­enced typ­i­cal Covid-19 symp­toms includ­ing fever, chill and a cough, but might have beat­en back the virus with oth­er parts of the immune sys­tem such as T‑cells or cytokines.

    How they did this was still unclear.

    “Vac­cine devel­op­ers may need to pay par­tic­u­lar atten­tion to these patients,” Huang said. If the real virus could not induce anti­body response, the weak­ened ver­sion in the vac­cine might not work in these patients either.
    ...

    Also keep in mind that there have indeed been a hand­ful of report­ed cas­es of peo­ple catch­ing COVID-19, recov­er­ing, and then catch­ing it again. A women in Japan report­ed­ly caught it a sec­ond time over a few weeks after ini­tial­ly recov­er­ing, although it’s unclear if that’s what real­ly hap­pened and some experts point towards oth­er expla­na­tions. And late last month, there were con­cerns about the accu­ra­cy of COVID-19 tests in Wuhan after a num­ber of peo­ple who recov­ered and had test­ed neg­a­tive sud­den­ly test­ed pos­i­tive again. Was this a prob­lem with test kits? Or peo­ple actu­al­ly catch­ing the dis­ease a sec­ond time?

    The above study also rais­es the ques­tion about the employ­ment sta­tus of peo­ple who can’t devel­op anti­bod­ies and how to restart economies if a sub­stan­tial per­cent of the pop­u­lace can’t devel­op this immu­ni­ty. While most of the peo­ple in that 30 per­cent group were rel­a­tive­ly young, what about the elder­ly in that group? Will vac­cines work on them? Are they just going to be forced into some sort of per­ma­nent quar­an­tine or con­tin­u­al­ly risk expo­sure to a virus they can’t devel­op immu­ni­ty for? And are the young peo­ple who cur­rent­ly aren’t devel­op­ing anti­bod­ies going to even­tu­al­ly devel­op anti­bod­ies to future ver­sions of this virus as they get old­er? We’ll find out. More stud­ies are clear­ly nec­es­sary. But if the find­ing in the study — that 30 per­cent of peo­ple weren’t pro­duc­ing anti­bod­ies at lev­els high enough to pro­tect against future infec­tions — is accu­rate the whole world is going to find that out soon­er or lat­er. Pre­sum­ably via waves of rein­fec­tions.

    Posted by Pterrafractyl | April 8, 2020, 3:09 pm
  10. ASIA
    South Korea’s New Coro­n­avirus Twist: Recov­ered Patients Test Pos­i­tive Again
    Doc­tors believe that the dis­ease may have gone dor­mant and then come back, pos­ing more chal­lenges for test­ing

    By Dasl Yoon and Tim­o­thy W. Mar­tin
    April 17, 2020 1:40 pm ET
    SHARE
    TEXT
    SEOUL—More than 160 South Kore­ans have test­ed pos­i­tive a sec­ond time for the coro­n­avirus, a devel­op­ment that sug­gests the dis­ease may have a longer shelf life than expect­ed.

    https://www.wsj.com/articles/south-koreas-new-coronavirus-twist-recovered-patients-test-positive-again-11587145248

    Posted by Roberto Maldonado | April 18, 2020, 9:24 pm
  11. Here’s a set of sto­ries about the ongo­ing clin­i­cal tri­als of Gilead­’s remde­sivir drug as a COVID-19 treat­ment. It sound like the high hopes of remde­sivir just got dashed but as we’ll see, even if those hopes pan out there’s still almost no way enough remde­sivir could be man­u­fac­tured to meet glob­al demand any­way. It’s a sto­ry that also poten­tial­ly ties into the larg­er issue of the use of the COVID-19 pan­dem­ic to manip­u­late the stock mar­ket for mas­sive prof­its:

    There’s been a num­ber of reports over the past cou­ple of weeks giv­ing hints of how remde­sivir has per­formed in the var­i­ous clin­i­cal tri­als cur­rent­ly under­way. Last week we learned from STAT news that a study at the Uni­ver­si­ty of Chica­go on 115 COVID-19 patients — 113 with a severe case — appeared to be pret­ty pos­i­tive. Severe fevers were reced­ing and near­ly all patients were being dis­charged from the hos­pi­tal in less than a week. It was the kind of report that did­n’t just trig­ger a surge in Gilead­’s stock price but appeared to lit­er­al­ly trig­ger an broad­er stock mar­ket ral­ly on hopes that the drug could alle­vi­ate the eco­nom­ic shut­downs.

    But that Uni­ver­si­ty of Chica­go study was­n’t a ran­dom­ized con­trolled clin­i­cal tri­al, the gold stan­dard for deter­min­ing the effi­ca­cy of a drug. Well, STAT news just issued a report on the leaked ini­tial find­ings of a ran­dom­ized con­trolled tri­al in Chi­na and the results are a lot less pos­i­tive than than U of Chica­go study. The study was also of severe­ly ill patients and found no sta­tis­ti­cal sig­nif­i­cance between the group giv­en the drug and the con­trol group. So that’s a pret­ty mas­sive blow the hopes of remde­sivir.

    As the arti­cle notes, this isn’t the final word on the top­ic because there are more stud­ies under­way. In addi­tion, the results are being some­what dis­missed by opti­mists because the study was end­ed ear­ly due to peo­ple drop­ping out. Still, the gen­er­al lack of opti­mism over the results appears to be shared by the broad­er mar­kets, with a glob­al stock slump on Fri­day being attrib­uted in part to these neg­a­tive tri­al results. So we’re see­ing how poten­tial­ly pow­er­ful the news of these tri­al results are in mov­ing finan­cial mar­kets.

    Inter­est­ing­ly, the lat­est neg­a­tive report is just a ini­tial draft of the report that was appar­ent­ly acci­den­tal­ly pub­licly released by the World Health Orga­ni­za­tion (WHO) on their web­site and sub­se­quent­ly removed. So some­one could have made some good mon­ey short­ing Gilead­’s stock if that leak was­n’t an acci­dent.

    Anoth­er inter­est­ing angle that relates to finan­cial mar­kets is that the results turn out to be the oppo­site of what biotech ana­lyst at Ever­core ISI biotech ana­lyst Umer Raf­fat had pre­vi­ous­ly been telling investors to expect. The study found that patients on reme­di­sivir actu­al­ly recov­ered slight­ly more slow­ly than the con­trol group. Raf­fat had told investors to expect the oppo­site. Keep in mind this leaked report on the WHO web­site was just a rough draft so it’s pos­si­ble we’ll see that flipped in the final report. But as the fol­low­ing arti­cle notes, whether or not remde­sivir speeds up or slows down recov­ery is beside the point because the dif­fer­ences between the two groups were sta­tis­ti­cal­ly insignif­i­cant. So, to some extent, it does­n’t real­ly mat­ter from an invest­ment stand­point whether or not remde­sivir slight­ly sped up or slight­ly slowed down the recov­ery time. But mar­kets are still dri­ven by psy­chol­o­gy and hear­ing that remde­sivir actu­al­ly slight­ly harmed patients will have a very dif­fer­ent impact on Gilead­’s stock than a report that it slight­ly helped patients.

    So fol­low­ing the report of very pos­i­tive remde­sivir pre­lim­i­nary results last week (and sub­se­quent stock ral­ly) we get a WHO leak that shows remde­sivir does noth­ing to help and might actu­al­ly hurt patients. It’s been quite a week for Gilead investors...and any­one hop­ing for an actu­al drug to treat this pan­dem­ic:

    STAT

    New data on Gilead’s remde­sivir, released by acci­dent, show no ben­e­fit for coro­n­avirus patients. Com­pa­ny still sees rea­son for hope

    By Ed Sil­ver­man @Pharmalot, Adam Feuer­stein @adamfeuerstein, and Matthew Her­p­er @matthewherper

    April 23, 2020

    The antivi­ral med­i­cine remde­sivir from Gilead Sci­ences failed to speed the improve­ment of patients with Covid-19 or pre­vent them from dying, accord­ing to results from a long-await­ed clin­i­cal tri­al con­duct­ed in Chi­na. Gilead, how­ev­er, said the data sug­gest a “poten­tial ben­e­fit.”

    A sum­ma­ry of the study results was inad­ver­tent­ly post­ed to the web­site of the World Health Orga­ni­za­tion and seen by STAT on Thurs­day, but then removed.

    “A draft man­u­script was pro­vid­ed by the authors to WHO and inad­ver­tent­ly post­ed on the web­site and tak­en down as soon as the mis­take was noticed. The man­u­script is now under­go­ing peer review and we are wait­ing for a final ver­sion before WHO com­ments on it,” said WHO spokesper­son Daniela Bagozzi.

    Gilead spokesper­son Amy Flood said the com­pa­ny believes “the post includ­ed inap­pro­pri­ate char­ac­ter­i­za­tion of the study.” Because the study was stopped ear­ly because it had too few patients, she said, it can­not “enable sta­tis­ti­cal­ly mean­ing­ful con­clu­sions.” How­ev­er, she said, “trends in the data sug­gest a poten­tial ben­e­fit for remde­sivir, par­tic­u­lar­ly among patients treat­ed ear­ly in dis­ease.”

    The data (for details, see screen­shot below) will be close­ly scru­ti­nized but are also like­ly imper­fect. The study was ter­mi­nat­ed pre­ma­ture­ly, which could have affect­ed the results. The con­text that would be pro­vid­ed by a full man­u­script is miss­ing, and the data have not been reviewed as nor­mal­ly occurs before pub­li­ca­tion.

    Many stud­ies are being run to test remde­sivir, and this one will not be the final word. Results are expect­ed soon from a Gilead-run study in severe Covid-19 patients, although that study may be dif­fi­cult to inter­pret because the drug is not com­pared to patients receiv­ing only stan­dard treat­ment. Encour­ag­ing data from patients in that study at the Uni­ver­si­ty of Chica­go were described by researchers at a vir­tu­al town hall and obtained by STAT last week. How­ev­er, unlike those data, these new results are from a ran­dom­ized con­trolled tri­al, the med­ical gold stan­dard.

    Gilead is also run­ning a study with a con­trol group in more mod­er­ate Covid-19 patients, and the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases is run­ning a study that com­pares remde­sivir to place­bo. There are even more stud­ies of the drug ongo­ing.

    Accord­ing to the sum­ma­ry of the Chi­na study, remde­sivir was “not asso­ci­at­ed with a dif­fer­ence in time to clin­i­cal improve­ment” com­pared to a stan­dard of care con­trol. After one month, it appeared 13.9% of the remde­sivir patients had died com­pared to 12.8% of patients in the con­trol arm. The dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant.

    “In this study of hos­pi­tal­ized adult patients with severe COVID-19 that was ter­mi­nat­ed pre­ma­ture­ly, remde­sivir was not asso­ci­at­ed with clin­i­cal or viro­log­i­cal ben­e­fits,” the sum­ma­ry states. The study was ter­mi­nat­ed pre­ma­ture­ly because it was dif­fi­cult to enroll patients in Chi­na, where the num­ber of Covid-19 cas­es was decreas­ing.

    An out­side researcher said that the results mean that any ben­e­fit from remde­sivir is like­ly to be small.

    “If there is no ben­e­fit to remde­sivir in a study this size, this sug­gests that the over­all ben­e­fit of remde­sivir in this pop­u­la­tion with advanced infec­tion is like­ly to be small in the larg­er Gilead tri­al,” said Andrew Hill, senior vis­it­ing research fel­low at Liv­er­pool Uni­ver­si­ty.

    He added that the results of the study should be pooled with larg­er stud­ies being con­duct­ed by Gilead using a tech­nique called meta-analy­sis to allow for “a bal­anced view of the effi­ca­cy of remde­sivir from all ran­dom­ized tri­als.”

    ...

    As orig­i­nal­ly designed, the Chi­na study was meant to enroll 453 patients. The patients were allowed to enter the study up to 12 days from the onset of Covid-19 symp­toms. Once enrolled, the patients were ran­dom­ized in a dou­ble-blind fash­ion and were treat­ed with dai­ly infu­sions of remde­sivir or a place­bo for 10 days.

    The pri­ma­ry goal is to show that the drug is bet­ter than place­bo at improv­ing symp­toms with­in 28 days. That improve­ment is mea­sured with a six-point scor­ing sys­tem rang­ing from hos­pi­tal dis­charge (a score of 1) to death (a score of 6). In order to count as some­one who respond­ed to the drug, a patient must improve by at least two points. Patients can remain hos­pi­tal­ized at the end of the 28-day peri­od of the clin­i­cal tri­al but still improve enough clin­i­cal­ly — no longer need­ing intu­ba­tion or sup­ple­men­tal oxy­gen, for exam­ple — to count as a respon­der.

    Accord­ing to the abstract, 158 patients received remde­sivir and 79 patients were in the con­trol arm; one patient in the con­trol arm with­drew before receiv­ing treat­ment. The abstract said that for time to clin­i­cal improve­ment, the haz­ard ratio was 1.23, which would nor­mal­ly mean the patients on remde­sivir improved more slow­ly than those in the con­trol group.

    How­ev­er, in a pre­vi­ous note to investors prepar­ing them for the data, Umer Raf­fat, a biotech ana­lyst at Ever­core ISI, had said to expect the oppo­site arrange­ment: that a haz­ard ratio of 1.2 would show patients were doing bet­ter. It is not cer­tain how the haz­ard ratio is being described in the abstract.

    Whether or not the drug ben­e­fit is trend­ing in a pos­i­tive or neg­a­tive direc­tion, the dif­fer­ence described in the abstract is not sta­tis­ti­cal­ly sig­nif­i­cant, mean­ing that the study failed.

    There are dif­fer­ences in the enroll­ment cri­te­ria of Covid-19 patients and the way remde­sivir is being used that make extrap­o­lat­ing results from this Chi­na study to the ongo­ing stud­ies dif­fi­cult.

    ...

    ————

    “New data on Gilead’s remde­sivir, released by acci­dent, show no ben­e­fit for coro­n­avirus patients. Com­pa­ny still sees rea­son for hope” by Ed Sil­ver­man, Adam Feuer­stein, and Matthew Her­p­er; STAT; 04/23/2020

    Many stud­ies are being run to test remde­sivir, and this one will not be the final word. Results are expect­ed soon from a Gilead-run study in severe Covid-19 patients, although that study may be dif­fi­cult to inter­pret because the drug is not com­pared to patients receiv­ing only stan­dard treat­ment. Encour­ag­ing data from patients in that study at the Uni­ver­si­ty of Chica­go were described by researchers at a vir­tu­al town hall and obtained by STAT last week. How­ev­er, unlike those data, these new results are from a ran­dom­ized con­trolled tri­al, the med­ical gold stan­dard.

    How do we weigh these con­flict­ing results between last week and this week? By weight­ing the ran­dom­ized con­trolled tri­al more heav­i­ly, that’s how. Which is why this leak was so dev­as­tat­ing to those putting their hopes on remde­sivir:

    ...
    Accord­ing to the sum­ma­ry of the Chi­na study, remde­sivir was “not asso­ci­at­ed with a dif­fer­ence in time to clin­i­cal improve­ment” com­pared to a stan­dard of care con­trol. After one month, it appeared 13.9% of the remde­sivir patients had died com­pared to 12.8% of patients in the con­trol arm. The dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant.

    ...

    An out­side researcher said that the results mean that any ben­e­fit from remde­sivir is like­ly to be small.

    “If there is no ben­e­fit to remde­sivir in a study this size, this sug­gests that the over­all ben­e­fit of remde­sivir in this pop­u­la­tion with advanced infec­tion is like­ly to be small in the larg­er Gilead tri­al,” said Andrew Hill, senior vis­it­ing research fel­low at Liv­er­pool Uni­ver­si­ty.

    ...

    And it was­n’t just that there was no sta­tis­ti­cal­ly sig­nif­i­cant improve­ment. The remde­sivir actu­al­ly appear to slight­ly slow down patient recov­ery. Although, again, giv­en the lack of sta­tis­ti­cal sig­nif­i­cance we can real­ly just con­clude that there’s no dif­fer­ence. And yet Ever­core ISI invest­ment advi­sor had pre­vi­ous­ly been telling clients to expect the oppo­site of a slight decrease in recov­ery time for the remde­sivir group. So there might be some­thing some­thing weird going on here that has yet to be resolved:

    ...
    Accord­ing to the abstract, 158 patients received remde­sivir and 79 patients were in the con­trol arm; one patient in the con­trol arm with­drew before receiv­ing treat­ment. The abstract said that for time to clin­i­cal improve­ment, the haz­ard ratio was 1.23, which would nor­mal­ly mean the patients on remde­sivir improved more slow­ly than those in the con­trol group.

    How­ev­er, in a pre­vi­ous note to investors prepar­ing them for the data, Umer Raf­fat, a biotech ana­lyst at Ever­core ISI, had said to expect the oppo­site arrange­ment: that a haz­ard ratio of 1.2 would show patients were doing bet­ter. It is not cer­tain how the haz­ard ratio is being described in the abstract.

    Whether or not the drug ben­e­fit is trend­ing in a pos­i­tive or neg­a­tive direc­tion, the dif­fer­ence described in the abstract is not sta­tis­ti­cal­ly sig­nif­i­cant, mean­ing that the study failed.

    There are dif­fer­ences in the enroll­ment cri­te­ria of Covid-19 patients and the way remde­sivir is being used that make extrap­o­lat­ing results from this Chi­na study to the ongo­ing stud­ies dif­fi­cult.
    ...

    Ok, now here’s a Mot­ley Fool arti­cle that was pub­lished a day before that WHO leak, so the neg­a­tive results had­n’t been report­ed yet. Instead, the arti­cle is based on the opti­mism of the U of Chica­go sto­ry from last week and tries to answer the ques­tion of whether or not it’s at all fea­si­ble for Gilead to increase drug pro­duc­tion at suf­fi­cient lev­els if the drug is even­tu­al­ly proven to be effec­tive. And as the arti­cle describes it, there’s just no real­is­tic way Gilead can increase the pro­duc­tion of the drug to meet the imme­di­ate need. Of course, if remde­sivir does end up being approved for COVID-19 treat­ment a lack of ade­quate sup­ply does­n’t mean that Gilead would­n’t prof­it wild­ly it. If any­thing, the com­pa­ny could charge even more for the drug, lim­it­ing it large­ly to wealthy indi­vid­u­als and coun­tries. And that’s why opti­mism over remde­sivir should pri­mar­i­ly be opti­mism held by Gilead­’s share­hold­ers and the wealthy:

    The Mot­ley Fool

    Gilead Sci­ences Races to Man­u­fac­ture Remde­sivir, but Chem­istry Has Speed Lim­its
    The biotech is rac­ing to pro­duce remde­sivir for as many COVID-19 patients as pos­si­ble. Will it be enough?

    Maxx Chatsko
    Apr 22, 2020 at 11:15AM

    The world is eager­ly await­ing results from hun­dreds of clin­i­cal tri­als search­ing for treat­ments for COVID-19, the res­pi­ra­to­ry dis­ease caused by the SARS-CoV­‑2 virus. Much like stay-at-home orders were issued to buy time for health sys­tems and med­ical sup­ply chains to pre­pare for pos­si­ble surges in hos­pi­tal admis­sions, effec­tive treat­ments would buy time for the world to devel­op and man­u­fac­ture effec­tive vac­cines.

    One of most close­ly watched drug can­di­dates is remde­sivir from Gilead Sci­ences (NASDAQ:GILD). When promis­ing data leaked from an ongo­ing clin­i­cal tri­al, the phar­ma stock soared. It’s cer­tain­ly a promis­ing devel­op­ment at a time when the world could use some good news.

    But prov­ing remde­sivir is a safe and effec­tive COVID-19 treat­ment (which has­n’t hap­pened yet) is only the first step. Gilead Sci­ences must secure sup­ply chains, ramp-up man­u­fac­tur­ing capac­i­ty, and dis­trib­ute the drug through­out the world. That might prove more dif­fi­cult than investors real­ize.

    Could remde­sivir become an effec­tive COVID-19 treat­ment?

    Per­haps. The dig­i­tal pub­li­ca­tion STAT, which pro­vides health­care news and com­men­tary, obtained a video from the Uni­ver­si­ty of Chica­go Med­i­cine dis­cussing inter­im results from an ongo­ing clin­i­cal tri­al. The cen­ter is one of many par­tic­i­pat­ing in a larg­er clin­i­cal tri­al eval­u­at­ing remde­sivir as a treat­ment for COVID-19.

    The site enrolled 125 patients indi­vid­u­als with COVID-19, includ­ing 113 in severe con­di­tion, to receive dai­ly infu­sions of remde­sivir. Many of the patients had been safe­ly dis­charged from the hos­pi­tal, and only two had died at the time the com­ments were made. Severe fevers dis­si­pat­ed quick­ly, while oth­er patients have been removed from ven­ti­la­tors short­ly after start­ing ther­a­py.

    Most impor­tant­ly, many patients were dis­charged from the hos­pi­tal in six days. Gilead Sci­ences has been study­ing 10-day cours­es of remde­sivir to treat COVID-19. Treat­ing patients for a short­er dura­tion could allow the com­pa­ny to stretch a very lim­it­ed sup­ply of the drug, which is like­ly to be the biggest bot­tle­neck.

    What obsta­cles is Gilead Sci­ences star­ing down?

    As of Jan­u­ary 2020, Gilead Sci­ences was­n’t active­ly man­u­fac­tur­ing remde­sivir because the drug can­di­date had nev­er been com­mer­cial­ized. The com­pa­ny had enough fin­ished prod­uct for 5,000 patients assum­ing a 10-day course of treat­ment.

    After watch­ing a coro­n­avirus out­break put Chi­na on lock­down, Gilead Sci­ences raced to secure the rare mate­ri­als and pro­duc­tion capac­i­ty required to man­u­fac­ture the antivi­ral at scale. The biotech reduced the man­u­fac­tur­ing ramp-up time­line from a range of nine to 12 months to an esti­mat­ed six to eight months, and it’s work­ing to opti­mize the com­plex chem­istry required to man­u­fac­ture the drug can­di­date.

    But there are speed lim­its:

    Com­plex chem­istry: Antivi­rals — com­mon­ly iden­ti­fied by the suf­fix “-vir” — are gen­er­al­ly very dif­fi­cult to man­u­fac­ture at scale. Pro­duc­tion process­es are hin­dered by many com­plex organ­ic chem­istry steps that must be com­plet­ed sequen­tial­ly, are accom­pa­nied by low yields, and require ultra-rare chem­i­cal inputs with very lim­it­ed glob­al sup­ply. The lat­ter might be the most impor­tant lim­it­ing fac­tor for remde­sivir pro­duc­tion.

    Strict steril­i­ty require­ments: Drugs that are admin­is­tered intra­venous­ly (IV), such as remde­sivir, must be man­u­fac­tured in spe­cial­ty drug com­pound­ing facil­i­ties under strict steril­i­ty con­di­tions. The world has lim­it­ed pro­duc­tion capac­i­ty.

    Vol­ume: Man­u­fac­tur­ing antivi­ral drugs under nor­mal con­di­tions is dif­fi­cult enough, but the time crunch of a glob­al pan­dem­ic adds a new twist. Gilead Sci­ence will face pres­sure to man­u­fac­ture enough remde­sivir to treat tens of mil­lions of indi­vid­u­als, which might be an impos­si­ble task.

    How many cours­es of treat­ment could be man­u­fac­tured?

    Gilead Sci­ences has sig­nif­i­cant­ly increased the amount of remde­sivir on hand and made strides to bring future pro­duc­tion capac­i­ty online in North Amer­i­ca, Europe, and Asia. It still might not be enough to make the antivi­ral the world’s only COVID-19 treat­ment. Con­sid­er the com­pa­ny’s cur­rent fore­cast for pro­duc­tion based on treat­ments span­ning 10 days (the ini­tial expec­ta­tion) and five days (an end­point in new­er clin­i­cal tri­als).

    This lim­it­ed sup­ply will be saved for hos­pi­tal­ized patients. Based on cur­rent­ly avail­able data, it appears that rough­ly 15% to 20% of con­firmed coro­n­avirus cas­es require hos­pi­tal­iza­tion. The real num­ber is like­ly much low­er once asymp­to­matic cas­es are fac­tored into the cal­cu­la­tion, but sci­en­tists have no way to gauge the num­ber of asymp­to­matic cas­es at this time.

    For the sake of sim­ple math, the cur­rent 15% hos­pi­tal­iza­tion rate implies sev­er­al mil­lion dos­es of remde­sivir would be suf­fi­cient for every 20 mil­lion con­firmed coro­n­avirus cas­es. As of April 22, there are 2.6 mil­lion con­firmed coro­n­avirus cas­es glob­al­ly, although that low num­ber rep­re­sents lim­it­ed test­ing capac­i­ty and the pos­i­tive effects of stay-at-home orders.

    ...

    Can any­thing reduce sup­ply pres­sures on remde­sivir?

    Doc­tors are still learn­ing about COVID-19, but some of the mys­tery is begin­ning to fade. For exam­ple, emer­gency room doc­tor and intu­ba­tion instruc­tor Dr. Richard Lev­i­tan recent­ly wrote in The New York Times that mon­i­tor­ing oxy­gen lev­els, even in patients with­out breath­ing issues, can sig­nif­i­cant­ly reduce the need for inten­sive care and mechan­i­cal ven­ti­la­tion. That small change could help a lim­it­ed sup­ply of even­tu­al treat­ments go fur­ther.

    Mean­while, hos­pi­tals around the world are begin­ning to test whether plas­ma from recov­ered COVID-19 patients can lim­it the sever­i­ty of dis­ease in cur­rent patients. It will become eas­i­er to har­vest plas­ma as more patients recov­er. If plas­ma ther­a­py proves effec­tive, then it will be anoth­er arrow in human­i­ty’s quiver aimed at reduc­ing the impact of the coro­n­avirus pan­dem­ic.

    Gilead Sci­ences could also make a Hail Mary invest­ment to sig­nif­i­cant­ly increase the pro­duc­tion of remde­sivir: enzymes. These are the com­plex pro­teins that pow­er all liv­ing things. Enzymes are used to speed up, clean up, and increase yields of chem­i­cal reac­tions with­in the set­tings of bio­log­i­cal cells all the way up to indus­tri­al chem­i­cal pro­duc­tion. They’ve gar­nered tremen­dous inter­est from phar­ma­ceu­ti­cal com­pa­nies man­u­fac­tur­ing antivi­rals.

    For exam­ple, Mer­ck and Codex­is recent­ly pro­posed a nov­el man­u­fac­tur­ing process for the exper­i­men­tal HIV drug isla­travir, which belongs to the same class of drugs as remde­sivir. The pair engi­neered five enzymes to sim­pli­fy the com­plex organ­ic chem­istry required to pro­duce isla­travir. In the end, time-con­sum­ing purifi­ca­tion steps were elim­i­nat­ed, ultra-rare raw mate­ri­als were recy­cled, yields of the final drug prod­uct were sig­nif­i­cant­ly increased, and the num­ber of total pro­duc­tion process steps was reduced by more than half.

    On paper, enzymes could be used to sig­nif­i­cant­ly increase the yield of remde­sivir while reduc­ing over­all inputs and, impor­tant­ly, reduc­ing the impor­tance of ultra-rare chem­i­cal inputs with lim­it­ed glob­al sup­ply. In real­i­ty, it would be very chal­leng­ing for Gilead Sci­ences to engi­neer enzymes spe­cif­ic to remde­sivir syn­the­sis, incor­po­rate them into new pro­duc­tion process­es, and scale those pro­duc­tion process­es in the com­pressed time­lines it faces.

    But if there was ever a time for syn­thet­ic biol­o­gy to live up to its lofty poten­tial through a glob­al col­lab­o­ra­tive effort, now might be it.

    ...

    ———–

    “Gilead Sci­ences Races to Man­u­fac­ture Remde­sivir, but Chem­istry Has Speed Lim­its” by Maxx Chatsko; The Mot­ley Fool; 04/22/2020

    “But prov­ing remde­sivir is a safe and effec­tive COVID-19 treat­ment (which has­n’t hap­pened yet) is only the first step. Gilead Sci­ences must secure sup­ply chains, ramp-up man­u­fac­tur­ing capac­i­ty, and dis­trib­ute the drug through­out the world. That might prove more dif­fi­cult than investors real­ize.”

    Yep, prov­ing effec­tive­ness is only the first step. Then you have to actu­al­ly man­u­fac­ture the stuff en mass and that’s much eas­i­er said than done:

    ...
    Com­plex chem­istry: Antivi­rals — com­mon­ly iden­ti­fied by the suf­fix “-vir” — are gen­er­al­ly very dif­fi­cult to man­u­fac­ture at scale. Pro­duc­tion process­es are hin­dered by many com­plex organ­ic chem­istry steps that must be com­plet­ed sequen­tial­ly, are accom­pa­nied by low yields, and require ultra-rare chem­i­cal inputs with very lim­it­ed glob­al sup­ply. The lat­ter might be the most impor­tant lim­it­ing fac­tor for remde­sivir pro­duc­tion.

    Strict steril­i­ty require­ments: Drugs that are admin­is­tered intra­venous­ly (IV), such as remde­sivir, must be man­u­fac­tured in spe­cial­ty drug com­pound­ing facil­i­ties under strict steril­i­ty con­di­tions. The world has lim­it­ed pro­duc­tion capac­i­ty.

    Vol­ume: Man­u­fac­tur­ing antivi­ral drugs under nor­mal con­di­tions is dif­fi­cult enough, but the time crunch of a glob­al pan­dem­ic adds a new twist. Gilead Sci­ence will face pres­sure to man­u­fac­ture enough remde­sivir to treat tens of mil­lions of indi­vid­u­als, which might be an impos­si­ble task.

    ...

    For the sake of sim­ple math, the cur­rent 15% hos­pi­tal­iza­tion rate implies sev­er­al mil­lion dos­es of remde­sivir would be suf­fi­cient for every 20 mil­lion con­firmed coro­n­avirus cas­es. As of April 22, there are 2.6 mil­lion con­firmed coro­n­avirus cas­es glob­al­ly, although that low num­ber rep­re­sents lim­it­ed test­ing capac­i­ty and the pos­i­tive effects of stay-at-home orders.
    ...

    And now here’s an arti­cle in Chem­i­cal & Engi­neer­ing News that gives a few more details on the logis­tics of man­u­fac­tur­ing com­plex phar­ma­ceu­ti­cals. It sounds like Gilead ini­tial­ly took 9–12 months to man­u­fac­ture a new batch of the drug. That’s right, up to a year to cre­ate a batch from scratch. But in light of the cur­rent pan­dem­ic the com­pa­ny said in Jan­u­ary that it reduced the time­line to 6–8 months. And keep in mind that Gilead isn’t going to mass pro­duce this stuff unless it’s already been approved for COVID-19 treat­ment. So based on Gilead­’s own guid­ance it would be 6 months at best before the drug could be pro­duced in large vol­umes if the world sud­den­ly decides that remde­sivir is the go-to- COVID-19 drug. But as we just saw, there’s no real­is­tic way the nec­es­sary vol­ume of the drug could be cre­at­ed in time due to the glob­al logis­tics and lim­it­ed sup­plies of rare pre­cur­sor chem­i­cal inputs. And as the fol­low­ing arti­cle describes, there’s anoth­er fac­tor that could lim­it Gilead­’s abil­i­ty to pro­duce remde­sivir in large vol­umes: COVID-19. Yes, the virus itself could com­pli­cate this process sig­nif­i­cant­ly. Why? Because the man­u­fac­ture of phar­ma­ceu­ti­cals is now based on glob­al sup­ply chains, where the sequen­tial steps in the syn­the­sis of the drug is done by dif­fer­ent sub­con­trac­tors around the globe (e.g. hire com­pa­ny A to con­vert the start­ing com­pound to an inter­me­di­ate com­pound. then hire com­pa­ny B to con­vert the inter­me­di­ate com­pound to a dif­fer­ent inter­me­di­ate com­pound, etc). And putting togeth­er a glob­al sup­ply chain is a lot hard­er now that the glob­al econ­o­my is shut down:

    Chem­i­cal & Engi­neer­ing News

    Scal­ing up remde­sivir amid the coro­n­avirus cri­sis
    Man­u­fac­tur­ing experts weigh in on Gilead’s chal­lenge in mak­ing its poten­tial COVID-19 treat­ment

    by Lisa M. Jarvis
    April 20, 2020

    With soci­ety clam­or­ing for something—anything—that can stem the rapid­ly ris­ing death toll of the COVID-19 pan­dem­ic, Gilead Sci­ences’ antivi­ral remde­sivir has emerged as a close­ly-watched treat­ment option. Lab­o­ra­to­ry stud­ies of oth­er coro­n­avirus­es sug­gest­ed it might be able to take down this one, and as the out­break took hold in Chi­na in Jan­u­ary, it was among the first treat­ments that doc­tors tried.

    Now, with cas­es world­wide at near­ly 2.5 mil­lion, scruti­ny of data com­ing out of clin­i­cal tri­als of the drug has reached fever pitch. When the health-focused news site Stat post­ed a sto­ry based on leaked video of a Uni­ver­si­ty of Chica­go clin­i­cian talk­ing opti­misti­cal­ly about remdesivir’s pos­si­ble effec­tive­ness, it didn’t just prop up Gilead’s stock price; it lift­ed the entire stock mar­ket.

    With each new anec­dote, whether about an indi­vid­ual patient or a hunch from a doc­tor run­ning a tri­al, the pres­sure on Gilead mounts. If any of the five late-stage clin­i­cal stud­ies under­way show that remde­sivir works, Gilead will need to make a lot of it, and fast.

    Gilead declined inter­view requests, but C&EN talked with man­u­fac­tur­ing experts with expe­ri­ence in scal­ing up drugs amid crises to under­stand the chal­lenge Gilead faces and how fast the firm—or any com­pa­ny devel­op­ing a drug that might be effec­tive against COVID-19—could rea­son­ably meet demand. Past sit­u­a­tions pro­vide some guid­ance, though all con­cede that none of them match­es the lev­el of urgency being felt now.

    Drug man­u­fac­tur­ing today is like a buck­et brigade, explains Prince­ton Uni­ver­si­ty chemist Paul Rei­der, who pre­vi­ous­ly held chem­istry lead­er­ship posi­tions at Amgen and Mer­ck & Co. One sup­pli­er sends raw mate­ri­als to anoth­er, which uses those basic chem­i­cals to do the first step in the syn­the­sis of a molecule—say, cre­at­ing a sim­ple side chain. The result gets passed on to anoth­er com­pa­ny in the brigade, which per­forms the next step, and so on. Two or more of those buck­et lines might con­verge to put togeth­er the now-com­plex pieces into the final mol­e­cule.

    The effi­cien­cy of the brigade varies from drug to drug. One vari­able is the com­plex­i­ty of the mol­e­cule. The anti­malar­i­al hydrochloro­quine, also being test­ed in COVID-19, is at the easy end of the spec­trum. Mak­ing it in large quan­ti­ties, if the need aris­es, will require lit­tle more than high-qual­i­ty man­u­fac­tur­ing capac­i­ty. Remde­sivir, with its six chi­ral cen­ters, is “a medi­um com­plex­i­ty project,” says Ian Davies, direc­tor of inter­nal and exter­nal sci­en­tif­ic rela­tion­ships for the Prince­ton Catal­y­sis Ini­tia­tive.

    But beyond the mol­e­cule itself, ease of scale-up has much to do with a company’s man­u­fac­tur­ing design phi­los­o­phy, Davies notes. While all firms design a safe route, “most com­pa­nies approach this on suf­fi­cien­cy,” rather than effi­cien­cy, says Davies, who pre­vi­ous­ly led Mer­ck & Co.’s process chem­istry group. They esti­mate a drug’s mar­ket size and like­ly price tag, and weigh that against how much man­u­fac­tur­ing the active ingre­di­ent will cost. If the mar­gins look good enough, many com­pa­nies won’t invest much in mak­ing a process more effi­cient, he says.

    And when it comes to remde­sivir, experts say Gilead might not have been inclined, or even had the time, to make the process as effi­cient as it could be. Gilead devel­oped the com­pound dur­ing the 2014 Ebo­la virus out­break in West Africa and sped it along with the goal of test­ing it before the out­break waned. The process like­ly reflects the antic­i­pat­ed demand for an Ebo­la treat­ment: the 2014 Ebo­la out­break saw 29,000 cas­es over 2.5 years; the cur­rent coro­n­avirus pan­dem­ic is approach­ing 2.5 mil­lion cas­es in under 5 months.

    As the scope of the pan­dem­ic widens, Gilead has been open about the chal­lenges of man­u­fac­tur­ing the drug. The firm says it typ­i­cal­ly takes 9 to 12 months to make an antivi­ral like remde­sivir, but that since Jan­u­ary it has shrunk the time­line to 6 to 8 months. “We con­tin­ue to work on opti­miz­ing the chem­i­cal syn­the­sis process­es,” the com­pa­ny states.

    In a pub­lic com­mu­ni­ca­tion in ear­ly April, CEO Daniel O’Day out­lined a series of mea­sures Gilead was tak­ing to increase access to remde­sivir. At the time, the com­pa­ny said it had on hand enough active ingre­di­ent to cre­ate about 1.5 mil­lion dos­es, enough for rough­ly 140,000 treat­ment cours­es, based on a 10-day reg­i­men. The com­pa­ny has been work­ing to increase both inter­nal capac­i­ty and exter­nal part­ner­ships to gen­er­ate an addi­tion­al 500,000 cours­es by Octo­ber, 1 mil­lion cours­es by the end of the year, and, if need­ed, sev­er­al mil­lion cours­es in 2021.

    The ramp up is sig­nif­i­cant. But glob­al demand, which could include both treat­ment for the ongo­ing pan­dem­ic and gov­ern­ment stock­pil­ing, could dwarf those fig­ures if the drug proves to be ben­e­fi­cial in treat­ing COVID-19.

    Man­u­fac­tur­ing experts point to the astro­nom­i­cal demand for gov­ern­ment stock­piles of the influen­za treat­ment Tam­i­flu amid the H1N1 out­break, which began in 2004. The sit­u­a­tions have impor­tant differences—Tamiflu is oral, while remde­sivir is intra­venous, mean­ing its util­i­ty, if proven, would be more limited—but the thought exer­cise for how to tack­le the prob­lem is prob­a­bly sim­i­lar.

    Indeed, David LaPre, who led the team at Roche that scaled up Tam­i­flu pro­duc­tion, says the first ques­tion for com­pa­nies with promis­ing COVID-19 treat­ments is how many dos­es they will need. “There were a lot of debates as to what’s the right num­ber, and I’m sure that’s the prob­lem peo­ple are fac­ing today as they think about antivi­rals as a weapon in our arse­nal against COVID-19,” says LeP­re, who is now a phar­ma­ceu­ti­cal con­sul­tant. “I sense that now, like then, there’s not going to be a pre­cise number—you basi­cal­ly have to pick one that makes sense between your own think­ing and the think­ing of health author­i­ties. That becomes the tar­get.”

    In 2005, Roche based its Tam­i­flu tar­get on sev­er­al case stud­ies that pegged demand at more than 1 bil­lion dos­es, LaPre says.

    Anoth­er lay­er of com­plex­i­ty is the vast net­work of partners—the buck­et brigade—involved in tak­ing a drug from raw mate­ri­als to a fin­ished prod­uct deliv­ered to a hos­pi­tal or phar­ma­cy. Decades ago, big phar­ma firms per­formed many of those steps in-house across a hand­ful of man­u­fac­tur­ing sites. Dur­ing the late 1990s, when Mer­ck was prepar­ing for a surge in demand for the HIV treat­ment Crix­i­van, “we picked up every avail­able piece of equip­ment we need­ed” from sites in sev­er­al states, Rei­der, who worked on Crix­i­van, recalls.

    Roche, which licensed Tam­i­flu from Gilead in 1996, also was able to expand its inter­nal capac­i­ty while at the same time build­ing an exter­nal sup­ply chain. Between 2005 and 2007, Roche end­ed up pro­vid­ing rough­ly 200 mil­lion cours­es of Tam­i­flu for gov­ern­ment stock­piles around the globe.

    But over the past 15 years, drug com­pa­nies have scaled back their inter­nal capac­i­ty. “Peo­ple don’t rec­og­nize how many pieces are touched” by a vast net­work of con­tract man­u­fac­tur­ing part­ners around the globe, says James Bruno, pres­i­dent of the con­sult­ing firm Chem­i­cal and Phar­ma­ceu­ti­cal Solu­tions. And “if one of those pieces fails,” it cre­ates a bot­tle­neck that is felt down the entire buck­et brigade.

    Gilead typ­i­cal­ly out­sources the syn­the­sis of its drugs through late-stage inter­me­di­ates, per­form­ing the last crit­i­cal steps in-house. And while it says it is try­ing to increase its own capac­i­ty, its first step was like­ly “to quick­ly scan the globe as to who has the right capa­bil­i­ty that can be brought to bear,” LaPre says.

    The social-dis­tanc­ing guide­lines and trav­el restric­tions need­ed to com­bat the coro­n­avirus pan­dem­ic impose unprece­dent­ed chal­lenges for man­agers try­ing to exe­cute a man­u­fac­tur­ing plan, experts say.

    “What I would do, which is what we did, is take a small team and lock them in a con­fer­ence room and say, ‘We’re not leav­ing until this is done,’” LaPre says. But that can’t be done today, he acknowl­edges, and “it gets dif­fi­cult to do after you’ve been on Zoom for a few hours.”

    Tech­nol­o­gy trans­fer, or the process of teach­ing a part­ner how to do a dif­fi­cult chem­i­cal step at scale, is par­tic­u­lar­ly hard under cur­rent con­di­tions. “You don’t just dump the tech­nol­o­gy over the fence,” Princeton’s Rei­der says. Typ­i­cal­ly, an inter­nal expert “will go live some­place out of a suit­case for weeks at a time” while mak­ing sure a con­tract man­u­fac­tur­er is per­form­ing a syn­thet­ic step prop­er­ly.

    “Gilead is real­ly good at doing this,” says Rei­der, who has con­sult­ed for Gilead on projects that pre­date remde­sivir. In fact, some of Gilead’s cur­rent process devel­op­ment and man­u­fac­tur­ing team helped out while Roche scaled up Tam­i­flu, he notes.

    Oth­ers agree that the com­pa­ny is well pre­pared to tack­le the cri­sis. “They’ve lived through a cou­ple of these spikes before with their antivi­rals,” Bruno notes.

    ...

    ———–

    “Scal­ing up remde­sivir amid the coro­n­avirus cri­sis” by Lisa M. Jarvis; Chem­i­cal & Engi­neer­ing News; 04/20/2020

    “As the scope of the pan­dem­ic widens, Gilead has been open about the chal­lenges of man­u­fac­tur­ing the drug. The firm says it typ­i­cal­ly takes 9 to 12 months to make an antivi­ral like remde­sivir, but that since Jan­u­ary it has shrunk the time­line to 6 to 8 months. “We con­tin­ue to work on opti­miz­ing the chem­i­cal syn­the­sis process­es,” the com­pa­ny states.”

    6–8 months at best. That’s the opti­mists’ time­frame for cre­at­ing new batch­es of the drug. And even Gilead­’s own esti­mates of how much it could increase its man­u­fac­tur­ing vol­ume bey the end of the year could be dwarfed by the glob­al need:

    ...
    In a pub­lic com­mu­ni­ca­tion in ear­ly April, CEO Daniel O’Day out­lined a series of mea­sures Gilead was tak­ing to increase access to remde­sivir. At the time, the com­pa­ny said it had on hand enough active ingre­di­ent to cre­ate about 1.5 mil­lion dos­es, enough for rough­ly 140,000 treat­ment cours­es, based on a 10-day reg­i­men. The com­pa­ny has been work­ing to increase both inter­nal capac­i­ty and exter­nal part­ner­ships to gen­er­ate an addi­tion­al 500,000 cours­es by Octo­ber, 1 mil­lion cours­es by the end of the year, and, if need­ed, sev­er­al mil­lion cours­es in 2021.

    The ramp up is sig­nif­i­cant. But glob­al demand, which could include both treat­ment for the ongo­ing pan­dem­ic and gov­ern­ment stock­pil­ing, could dwarf those fig­ures if the drug proves to be ben­e­fi­cial in treat­ing COVID-19.
    ...

    And that opti­mistic project by Gilead assumes COVID-19 itself does­n’t dis­rupt the set­ting up of that sup­ply chain, which is a pret­ty huge assump­tion:

    ...
    But over the past 15 years, drug com­pa­nies have scaled back their inter­nal capac­i­ty. “Peo­ple don’t rec­og­nize how many pieces are touched” by a vast net­work of con­tract man­u­fac­tur­ing part­ners around the globe, says James Bruno, pres­i­dent of the con­sult­ing firm Chem­i­cal and Phar­ma­ceu­ti­cal Solu­tions. And “if one of those pieces fails,” it cre­ates a bot­tle­neck that is felt down the entire buck­et brigade.

    Gilead typ­i­cal­ly out­sources the syn­the­sis of its drugs through late-stage inter­me­di­ates, per­form­ing the last crit­i­cal steps in-house. And while it says it is try­ing to increase its own capac­i­ty, its first step was like­ly “to quick­ly scan the globe as to who has the right capa­bil­i­ty that can be brought to bear,” LaPre says.

    The social-dis­tanc­ing guide­lines and trav­el restric­tions need­ed to com­bat the coro­n­avirus pan­dem­ic impose unprece­dent­ed chal­lenges for man­agers try­ing to exe­cute a man­u­fac­tur­ing plan, experts say.
    ...

    So as we can see, the one drug that author­i­ties have been most active­ly push­ing as the like­li­est mir­a­cle treat­ment that could allow the world to reopen (not count­ing Pres­i­dent Trumps bizarre push­ing of hydrox­y­chloro­quine) is a drug that effec­tive­ly can’t be used to treat the world in time. Even if it’s an effec­tive treat­ment it can’t pos­si­bly be an effec­tive solu­tion. At best, remde­sivir could be used to treat a lucky sub­set of patients who hap­pen to get access to the lim­it­ed sup­plies.

    Also note that we’ve heard vir­tu­al­ly no updates about the oth­er promis­ing treat­ments that have been report­ed on like the “Thai cock­tail” or Oya­Gen’s Oya1 com­pound. Who know why there con­tin­ues to be zero inter­est in these seem­ing­ly promis­ing treat­ments but that lack of inter­est is still the case. In the mean time, there’s always bleach.

    Posted by Pterrafractyl | April 24, 2020, 1:04 pm
  12. ‘Tis the sea­son of Gilead news: there was a pair of updates about two dif­fer­ent COVID-19 tri­als of Gilead­’s remde­sivir drug on Wednes­day. These were the third and fourth pre­lim­i­nary updates from a Gilead tri­al in the last week or so. The new reports were broad­ly trum­pet­ed as pos­i­tive news. So pos­i­tive the finan­cial mar­kets ral­lied in response. As we’re going to see in the fol­low­ing arti­cles, it’s real­ly more ‘good-ish to bad-ish’ news. Good-ish to bad-ish news that nonethe­less man­aged to trig­gered a ral­ly in the finan­cial mar­kets:

    The pre­lim­i­nary reports released Wednes­day involved two large ongo­ing clin­i­cal tri­als of remde­sivir. One of the tri­als is being con­duct­ed by the US Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases (NIAID). The oth­er is run by Gilead itself.

    When com­plet­ed, the Gilead study will involved 6,000 COVID-19 patients under­go­ing treat­ments from 152 clin­i­cal tri­als from around the world. The pre­lim­i­nary results we heard about last week from the Uni­ver­si­ty of Chica­go involv­ing 115 patients that indi­cat­ed that the drug was help­ing patients recov­er more rapid­ly was one of the sites from this larg­er 6,000 per­son study. The new pre­lim­i­nary update from Wednes­day is based on 400 peo­ple.

    As we’ll see, it turns out the Gilead study is designed with­out any con­trol group so the ques­tion of how much remde­sivir actu­al­ly helps sick patients (or does­n’t help) sys­tem­at­i­cal­ly can’t be answered by that study. Yep. Due to a lack of a con­trol group, the study instead focus­es on just answer­ing the ques­tion of whether or not the recov­ery times for patients dif­fers between groups receiv­ing a 10-day course of the drug vs a 5‑day course. The patients were severe­ly ill but not on ven­ti­la­tors when enrolled in the study (so the patients that need the drug most weren’t test­ed). The pre­lim­i­nary results released Wednes­day sug­gest there is no dif­fer­ence between the recov­ery times for the two groups. Now, the pos­i­tive way to inter­pret those results is that it indi­cates patients will receive the ben­e­fits for remde­sivir with just half the dosage in half the time. It would dou­ble the num­ber of patients who could receive the drug. But there’s a far worse pos­si­ble inter­pre­ta­tion of the results: there’s no dif­fer­ence in recov­ery times because the drug was­n’t actu­al­ly help­ing patients recov­er. Because there’s no con­trol group we can’t know which of those sce­nar­ios we’re look­ing at.

    The NIAID study was for­tu­nate­ly a ran­dom­ized con­trolled tri­al that used place­bos so basic ques­tions about whether or not the drug actu­al­ly helps patients. Based on the results from 800 severe­ly ill patients, yes, there appears to be a mod­est ben­e­fit in the form of more rapid recov­ery times vs the con­trol group. The study found patients on remde­sivir recov­ered in 11 days vs 15 days for the group get­ting the place­bo, a 31% decrease. So based on those results it does appear that remde­sivir is help­ful, just not near­ly as help­ful as peo­ple were hop­ing. Cru­cial­ly, the mor­tal­i­ty rates between the case and con­trol groups were sta­tis­ti­cal­ly insignif­i­cant. So while this pre­lim­i­nary result does seem to indi­cate that remde­sivir speeds up recov­ery time, there’s no evi­dence yet it actu­al­ly helps pre­vent patients from dying. We are also warned that, because these results are pre­lim­i­nary, it’s pos­si­ble the observed decreased recov­ery time won’t pan out in the final analy­sis.

    It’s also impor­tant to recall that the NIAID pre­lim­i­nary results con­tra­dict the find­ings of the clin­i­cal tri­al con­duct­ed in Chi­na that found no sta­tis­ti­cal dif­fer­ence in the recov­ery times of patients on remde­sivir. As the fol­low­ing arti­cle notes, that study was also was pub­lished in Lancet on Wednes­day. So there real­ly was a flood of news about remde­sivir on Wednes­day. A flood of very mixed news. And that’s why the two pre­lim­i­nary reports can real­ly only be described as good-ish/bad-ish. The reports cer­tain­ly weren’t what peo­ple were hop­ing for but they could have been worse because they were large­ly incon­clu­sive:

    STAT News

    Crit­i­cal study of Gilead’s Covid-19 drug shows patients are respond­ing to treat­ment, NIH says

    By Matthew Her­p­er and Adam Feuer­stein
    April 29, 2020

    A gov­ern­ment-run study of Gilead’s remde­sivir, per­haps the most close­ly watched exper­i­men­tal drug to treat the nov­el coro­n­avirus, showed that the med­i­cine is effec­tive against Covid-19, the dis­ease caused by the virus.

    In a state­ment on Wednes­day, the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases, which is con­duct­ing the study, said pre­lim­i­nary data show patients who received remde­sivir recov­ered faster than sim­i­lar patients who received place­bo.

    The find­ing — although dif­fi­cult to ful­ly char­ac­ter­ize with­out full, detailed data for the study — would rep­re­sent the first treat­ment shown to improve out­comes in patients infect­ed with the virus that put the glob­al econ­o­my in a stand­still and killed at least 218,000 peo­ple world­wide.

    Dur­ing an appear­ance along­side Pres­i­dent Trump in the Oval Office, Antho­ny Fau­ci, the direc­tor of NIAID, part of the Nation­al Insti­tutes of Health, said the data are a “very impor­tant proof of con­cept” and that there was rea­son for opti­mism. He cau­tioned the data were not a “knock­out.” At the same time, the study achieved its pri­ma­ry goal, which was to improve the time to recov­ery, which was reduced by four days for patients on remde­sivir.

    The pre­lim­i­nary data showed that the time to recov­ery was 11 days on remde­sivir com­pared to 15 days for place­bo, a 31% decrease. The mor­tal­i­ty rate for the remde­sivir group was 8%, com­pared to 11.6% for the place­bo group; that mor­tal­i­ty dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant.

    That is “the first con­vinc­ing evi­dence that an antivi­ral drug can real­ly ben­e­fit Covid-19 patients, specif­i­cal­ly hos­pi­tal­ized Covid-19 patients,” said Fred­er­ick Hay­den, a pro­fes­sor emer­i­tus of clin­i­cal virol­o­gy and med­i­cine at the Uni­ver­si­ty of Vir­ginia School of Med­i­cine. “This will change the stan­dard of care in the Unit­ed States and oth­er coun­tries for the patients who have been shown to be ben­e­fit­ed,” he said, adding that deter­min­ing the exact group that should receive the drug will require fur­ther exam­i­na­tion of the data.

    Over the past few weeks, there have been con­flict­ing reports about the poten­tial ben­e­fit of remde­sivir, a drug that was pre­vi­ous­ly tried in Ebo­la. As pre­vi­ous­ly report­ed by STAT, an ear­ly peek at Gilead’s study in severe Covid-19 patients, based on data from a tri­al at a Chica­go hos­pi­tal, sug­gest­ed patients were doing bet­ter than expect­ed on remde­sivir. Days lat­er, a sum­ma­ry of results from a study in Chi­na showed that patients on the drug did not improve more than those in a con­trol group.

    ...

    But the NIAID study, which was not expect­ed to be released so soon, was by far the most impor­tant and rig­or­ous­ly designed test of remde­sivir in Covid-19. The study com­pared remde­sivir to place­bo in 800 patients, with nei­ther patients nor physi­cians know­ing who got the drug instead of a place­bo, mean­ing that uncon­scious bias­es will not affect the con­clu­sions.

    The main goal of the study is the time until patients improve, with dif­fer­ent mea­sures of improve­ment depend­ing on how sick they were to begin with. While the result means that the drug helps patients improve faster, it is not pos­si­ble to say how dra­mat­ic those improve­ments are.

    Scott Got­tlieb, the for­mer com­mis­sion­er of the Food and Drug Admin­is­tra­tion, said he expect­ed there was enough evi­dence for the agency to issue an “emer­gency use autho­riza­tion” for remde­sivir.

    Remde­sivir isn’t a home run but looks active and can be part of a tool­box of drugs and diag­nos­tics that sub­stan­tial­ly low­er our risk head­ing into the fall,” he said.

    Aneesh Mehta, a physi­cian at Emory Uni­ver­si­ty and an inves­ti­ga­tor in the NIAID study, said the results were “robust enough” to report pre­lim­i­nary find­ings, but a full analy­sis of all the data will be required to ful­ly under­stand the drug’s effect. The time to recov­ery seen in the final analy­sis “could be short­er, it could be longer. We don’t know yet.” Mehta also expects the final results to do some analy­ses on which patients might ben­e­fit most from remde­sivir.

    The FDA pre­vi­ous­ly issued an emer­gency autho­riza­tion for the malar­ia drug hydrox­y­chloro­quine to treat Covid-19, even though at least some stud­ies sug­gest­ed the med­i­cine was not effec­tive. “If hydrox­y­chloro­quine met [the emer­gency] stan­dard, then remde­sivir would have seemed to cross that line a while ago, espe­cial­ly in the set­ting of treat­ing crit­i­cal­ly ill patients,” Got­tlieb said.

    Remde­sivir, which must be giv­en intra­venous­ly, is like­ly to remain a treat­ment for patients who are hos­pi­tal­ized. But it is also like­ly that it will be most effec­tive in patients who have been infect­ed more recent­ly, said Nahid Bhadelia, med­ical direc­tor of the spe­cial pathogens unit at Boston Med­ical Cen­ter.

    “We know that with most antivi­ral med­ica­tions the ear­li­er you give it the bet­ter it is.” said Bhadelia, who had expe­ri­ence giv­ing remde­sivir as an exper­i­men­tal treat­ment for Ebo­la in Africa, where results are less encour­ag­ing. That means that bet­ter diag­nos­tic test­ing will be essen­tial to iden­ti­fy­ing patients who could ben­e­fit. “What will be impor­tant is that we find peo­ple on the out­pa­tient side,” Bhadelia said. “Again, test­ing becomes impor­tant, we want to have them come to the hos­pi­tal as soon as pos­si­ble.”

    Although the data have not yet been released, it’s stan­dard pro­ce­dure for phar­ma­ceu­ti­cal and biotech­nol­o­gy com­pa­nies to release mar­ket-mov­ing infor­ma­tion as soon as they have it, due to reg­u­la­to­ry require­ments.

    Gilead on Wednes­day did release data from its own study of remde­sivir in patients with severe Covid-19. This study showed sim­i­lar rates of clin­i­cal improve­ment in patients treat­ed with a five-day and 10-day course of remde­sivir, the com­pa­ny said.

    “Unlike tra­di­tion­al drug devel­op­ment, we are attempt­ing to eval­u­ate an inves­ti­ga­tion­al agent along­side an evolv­ing glob­al pan­dem­ic. Mul­ti­ple con­cur­rent stud­ies are help­ing inform whether remde­sivir is a safe and effec­tive treat­ment for COVID-19 and how to best uti­lize the drug,” said Mer­dad Parsey, Gilead’s chief med­ical offi­cer, in a state­ment.

    Gilead said that its own study in severe patients showed that it may be pos­si­ble to treat patients with a five-day treat­ment of remde­sivir, not the 10-day course that was used in the NIAID tri­al.

    The company’s study is enrolling approx­i­mate­ly 6,000 par­tic­i­pants from 152 dif­fer­ent clin­i­cal tri­al sites all over the world. The data dis­closed Wednes­day are from 397 patients, with a sta­tis­ti­cal com­par­i­son of patient improve­ment between the two remde­sivir treat­ment arms — the five-day and 10-day treat­ment cours­es. Improve­ment was mea­sured using a sev­en-point numer­i­cal scale that encom­pass­es death (at worst) and dis­charge from hos­pi­tal (best out­come), with var­i­ous degrees of sup­ple­men­tal oxy­gen and intu­ba­tion in between.

    The study design means that by itself it doesn’t reveal much about how well remde­sivir is work­ing, because there is no group of patients who were untreat­ed. The con­clu­sion is that the two dura­tions of treat­ment are basi­cal­ly the same.

    Peter Bach, the direc­tor of the Cen­ter for Health Pol­i­cy and Out­comes at Memo­r­i­al Sloan Ket­ter­ing Med­ical Cen­ter, said he is eager to see the data from the NIAID study but renewed his crit­i­cism of Gilead’s severe study for lack­ing a con­trol group of untreat­ed patients. That would have allowed researchers to make impor­tant con­clu­sions about how the drug works that are just not pos­si­ble now, he said.

    “They’ve squan­dered an unbe­liev­able oppor­tu­ni­ty,” Bach said. “It’s not going to tell us what to do with 80-year-olds with mul­ti­ple comor­bidi­ties com­pared to 30-year-olds who are oth­er­wise healthy. We’re still going to be founder­ing around in the dark, or at least in a dim room, when we could have learned more.”

    In the study, the medi­an time to clin­i­cal improve­ment was 10 days in the five-day treat­ment group and 11 days in the 10-day treat­ment group. More than half of the patients in both groups were dis­charged from the hos­pi­tal by day 14. At day 14, 64.5% of the patients in the five-day group and 53.8% of the patients in the 10-day group achieved clin­i­cal recov­ery.

    Patients in the tri­al gen­er­al­ly lived, though this may be because their ill­ness was not that severe to begin with. For most of the study, patients already on ven­ti­la­tors were not enrolled.

    Eight per­cent of the patients treat­ed with five days of remde­sivir died, com­pared to 11% of the patients treat­ed for 10 days. Out­side of Italy, where 77 patients were treat­ed, the over­all mor­tal­i­ty rate across the entire study was 7%, Gilead said. Those mor­tal­i­ty rates are low­er than those seen in oth­er stud­ies, which have been in the teens and twen­ties.

    Only 5% of patients in the five-day group and 10% in the 10-day group had side effects that led to a dis­con­tin­u­a­tion. The most com­mon bad effects — and it’s impos­si­ble to tell which were from the drug — were nau­sea and acute res­pi­ra­to­ry fail­ure. High liv­er enzymes occurred in 7.3% of patients, with 3% of patients dis­con­tin­u­ing the drug due to ele­vat­ed liv­er tests.

    ...

    In the Chi­na study, also pub­lished Wednes­day in the Lancet, inves­ti­ga­tors found that remde­sivir “did not sig­nif­i­cant­ly improve the time to clin­i­cal improve­ment, mor­tal­i­ty, or time to clear­ance of virus in patients with seri­ous COVID-19 com­pared with place­bo.”

    There was a 23% improve­ment in time to clin­i­cal improve­ment for remde­sivir com­pared to place­bo, but the dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant. At the medi­an, remde­sivir-treat­ed patients improved in 20 days com­pared to 23 days for place­bo patients. At one month, 14% of the remde­sivir patients had died com­pared to 13% of the place­bo-treat­ed patients.

    The Chi­na study enrolled patients with more severe Covid-19 than the study con­duct­ed by NIAID. The Chi­na study was also stopped ear­ly because of dif­fi­cul­ties enrolling patients as the pan­dem­ic waned in Chi­na.

    Hay­den, the Uni­ver­si­ty of Vir­ginia virol­o­gist, was one of the inves­ti­ga­tors in the Chi­na study and point­ed to the sim­i­lar­i­ty of the results. He said that while the NIAID inves­ti­ga­tors had been able to enroll enough patients, the decrease in cas­es in Wuhan due to the lock­down had made that impos­si­ble. “I was struck by the con­sis­ten­cy,” he said.

    ————

    “Crit­i­cal study of Gilead’s Covid-19 drug shows patients are respond­ing to treat­ment, NIH says” by Matthew Her­p­er and Adam Feuer­stein; STAT News; 04/29/2020

    “Dur­ing an appear­ance along­side Pres­i­dent Trump in the Oval Office, Antho­ny Fau­ci, the direc­tor of NIAID, part of the Nation­al Insti­tutes of Health, said the data are a “very impor­tant proof of con­cept” and that there was rea­son for opti­mism. He cau­tioned the data were not a “knock­out.” At the same time, the study achieved its pri­ma­ry goal, which was to improve the time to recov­ery, which was reduced by four days for patients on remde­sivir.”

    It’s not a knock­out but there’s rea­son for opti­mism. That’s the pos­i­tive way of spin­ning these results. Results that showed now sta­tis­ti­cal­ly sig­nif­i­cant dif­fer­ence in the mor­tal­i­ty rates of these patients:

    ...
    The pre­lim­i­nary data showed that the time to recov­ery was 11 days on remde­sivir com­pared to 15 days for place­bo, a 31% decrease. The mor­tal­i­ty rate for the remde­sivir group was 8%, com­pared to 11.6% for the place­bo group; that mor­tal­i­ty dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant.

    ...

    The main goal of the study is the time until patients improve, with dif­fer­ent mea­sures of improve­ment depend­ing on how sick they were to begin with. While the result means that the drug helps patients improve faster, it is not pos­si­ble to say how dra­mat­ic those improve­ments are.

    ...

    Aneesh Mehta, a physi­cian at Emory Uni­ver­si­ty and an inves­ti­ga­tor in the NIAID study, said the results were “robust enough” to report pre­lim­i­nary find­ings, but a full analy­sis of all the data will be required to ful­ly under­stand the drug’s effect. The time to recov­ery seen in the final analy­sis “could be short­er, it could be longer. We don’t know yet.” Mehta also expects the final results to do some analy­ses on which patients might ben­e­fit most from remde­sivir.
    ...

    And note one of the pos­si­ble end results of these tri­als: we might dis­cov­er that remde­sivir is most help­ful when tak­en ear­ly on before the cas­es get severe. And because the drug is deliv­ered intra­venous­ly, patients need to be in the hos­pi­tal to receive the drug. So if remde­sivir ends up being the only drug found to be help­ful against COVID-19 but it’s only help­ful if you start it ear­ly on in the ill­ness that’s a recipe for stick­ing almost all mod­er­ate­ly ill patients on the drug as a kind of pre­ven­tive mea­sure. And this, again, is a drug that can’t pos­si­bly be made in ade­quate sup­plies in short order to meet glob­al demand so the price of the drug dur­ing this kind of sce­nario could just sky­rock­et:

    ...
    Remde­sivir, which must be giv­en intra­venous­ly, is like­ly to remain a treat­ment for patients who are hos­pi­tal­ized. But it is also like­ly that it will be most effec­tive in patients who have been infect­ed more recent­ly, said Nahid Bhadelia, med­ical direc­tor of the spe­cial pathogens unit at Boston Med­ical Cen­ter.

    “We know that with most antivi­ral med­ica­tions the ear­li­er you give it the bet­ter it is.” said Bhadelia, who had expe­ri­ence giv­ing remde­sivir as an exper­i­men­tal treat­ment for Ebo­la in Africa, where results are less encour­ag­ing. That means that bet­ter diag­nos­tic test­ing will be essen­tial to iden­ti­fy­ing patients who could ben­e­fit. “What will be impor­tant is that we find peo­ple on the out­pa­tient side,” Bhadelia said. “Again, test­ing becomes impor­tant, we want to have them come to the hos­pi­tal as soon as pos­si­ble.”
    ...

    And then there was the release of the pre­lim­i­nary Gilead study results. No dif­fer­ences in recov­ery times were found between 5 and 10-day treat­ments, but whether that’s due to the drug not actu­al­ly improv­ing patient out­comes can’t be deter­mined because there’s no con­trol group. Gilead cre­at­ed a clin­i­cal tri­al that can’t answer the ques­tion of whether or not its drug actu­al­ly helps:

    ...
    Gilead on Wednes­day did release data from its own study of remde­sivir in patients with severe Covid-19. This study showed sim­i­lar rates of clin­i­cal improve­ment in patients treat­ed with a five-day and 10-day course of remde­sivir, the com­pa­ny said.

    ...

    The study design means that by itself it doesn’t reveal much about how well remde­sivir is work­ing, because there is no group of patients who were untreat­ed. The con­clu­sion is that the two dura­tions of treat­ment are basi­cal­ly the same.

    Peter Bach, the direc­tor of the Cen­ter for Health Pol­i­cy and Out­comes at Memo­r­i­al Sloan Ket­ter­ing Med­ical Cen­ter, said he is eager to see the data from the NIAID study but renewed his crit­i­cism of Gilead’s severe study for lack­ing a con­trol group of untreat­ed patients. That would have allowed researchers to make impor­tant con­clu­sions about how the drug works that are just not pos­si­ble now, he said.

    “They’ve squan­dered an unbe­liev­able oppor­tu­ni­ty,” Bach said. “It’s not going to tell us what to do with 80-year-olds with mul­ti­ple comor­bidi­ties com­pared to 30-year-olds who are oth­er­wise healthy. We’re still going to be founder­ing around in the dark, or at least in a dim room, when we could have learned more.”

    In the study, the medi­an time to clin­i­cal improve­ment was 10 days in the five-day treat­ment group and 11 days in the 10-day treat­ment group. More than half of the patients in both groups were dis­charged from the hos­pi­tal by day 14. At day 14, 64.5% of the patients in the five-day group and 53.8% of the patients in the 10-day group achieved clin­i­cal recov­ery.
    ...

    Final­ly, there’s the pub­li­ca­tion of the study out of Chi­na that appeared to con­tra­dict the NIAID find­ings: there was no sig­nif­i­cant dif­fer­ence in the time to clin­i­cal improve­ment, mor­tal­i­ty, or viral clear­ance times:

    ...
    In the Chi­na study, also pub­lished Wednes­day in the Lancet, inves­ti­ga­tors found that remde­sivir “did not sig­nif­i­cant­ly improve the time to clin­i­cal improve­ment, mor­tal­i­ty, or time to clear­ance of virus in patients with seri­ous COVID-19 com­pared with place­bo.”

    There was a 23% improve­ment in time to clin­i­cal improve­ment for remde­sivir com­pared to place­bo, but the dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant. At the medi­an, remde­sivir-treat­ed patients improved in 20 days com­pared to 23 days for place­bo patients. At one month, 14% of the remde­sivir patients had died com­pared to 13% of the place­bo-treat­ed patients.
    ...

    Ok, now here’s a STAT News excerpt that goes into more of the con­cerns about the Gilead study design. Con­cerns that include wor­ries that the study will ulti­mate­ly just mud­dy the waters about our under­stand­ing of drug’s effi­ca­cy. The arti­cle also gives Gilead­’s expla­na­tion for why they left out a con­trol group: due to the lim­it­ed sup­plies of the drug the com­pa­ny decid­ed to pri­or­i­tize on pro­duc­ing more of the drug itself rather than a place­bo con­trol. It’s an expla­na­tion that only makes sense of pro­duc­ng place­bo dos­es was some­how a sig­nif­i­cant tech­ni­cal chal­lenge. They also gave the expla­na­tion that, due to the dead­li­ness of the dis­ease for severe cas­es, many fam­i­lies would­n’t agree to enrolling their rel­a­tives in a tri­al that includ­ed the pos­si­bil­i­ty of a place­bo. Which, again, is a some­what odd expla­na­tion since that dilem­ma of dis­trib­ut­ing place­bos to patients that could ben­e­fit from the drug would pre­sum­ably apply to ran­dom­ized con­trolled tri­als for any poten­tial­ly dead­ly con­di­tion. Plus, if the choice is between enrolling your fam­i­ly mem­ber in a tri­al that involves place­bos vs not enrolling your fam­i­ly mem­ber in any tri­al it seems like enrolling in the tri­al is still going to be a tempt­ing option. And that’s part of the bad-ish news com­ing out of these tri­als: Gilead designed a study that could­n’t pos­si­bly answer the ques­tion of whether or not their drug improved clin­i­cal out­comes and then gave very ques­tion­able answers for why that hap­pened:

    STAT News

    The world wants answers on Gilead’s Covid-19 drug. Experts wor­ry next stud­ies may increase uncer­tain­ty

    By Matthew Her­p­er and Adam Feuer­stein
    April 27, 2020

    For weeks, the world has been eager­ly await­ing clin­i­cal tri­al results for one exper­i­men­tal drug, remde­sivir, to treat Covid-19. On some days, the entire stock mar­ket has moved up and down based on lim­it­ed amounts of data about the ther­a­py from Gilead Sci­ences.

    The sig­nals, so far, have been con­tra­dic­to­ry. An ear­ly peek at one study, based on data from patients treat­ed at a Chica­go hos­pi­tal, sug­gest­ed patients were doing bet­ter than expect­ed on remde­sivir. Days lat­er, a sum­ma­ry of results from a study in Chi­na showed that patients on the drug did not improve more than those in a con­trol group.

    A fuller pic­ture on remde­sivir is expect­ed any day now. Gilead has said that it will release data from one of its U.S. tri­als — the one from which the Chica­go results were dis­closed — by the end of this week. Even more data, from oth­er tri­als includ­ing the Chi­na study, could fol­low short­ly there­after.

    But out­side experts in clin­i­cal tri­al design wor­ry that the results, instead of lead­ing to a clear pic­ture of whether the med­i­cine is effec­tive, will instead mud­dy the waters fur­ther.

    The main con­cern, they say, stems from the fact that the Gilead tri­al expect­ed to read out this week, which was con­duct­ed among patients with severe dis­ease, lacks a con­trol group — that is, patients who are ran­dom­ly assigned to receive the best treat­ment avail­able, but not remde­sivir. As designed, the only ran­dom­iza­tion is the dura­tion of treat­ment: either five days or 10 days of drug. With­out a true con­trol group of patients, many experts say, it will be dif­fi­cult to deter­mine whether remde­sivir is effec­tive.

    “The over­all study itself has lit­tle or no sci­en­tif­ic val­ue since all patients are receiv­ing the drug,” said Steven Nis­sen, the chief aca­d­e­m­ic offi­cer at the Cleve­land Clin­ic and lead inves­ti­ga­tor of many tri­als for heart drugs that have been approved by the Food and Drug Admin­is­tra­tion.

    “The study, as designed, is essen­tial­ly use­less and can­not be used by the FDA for con­sid­er­a­tion of remde­sivir for approval to treat coro­n­avirus,” Nis­sen said.

    Peter Bach, direc­tor of the Cen­ter for Health Pol­i­cy and Out­comes at Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter, called the sit­u­a­tion “frus­trat­ing.”

    “For them to run the tri­al in severe but not include a con­trol group, it’s just such a waste,” Bach said.

    The predica­ment is symp­to­matic of one of the biggest prob­lems in med­i­cine: Col­lect­ing data quick­ly can actu­al­ly slow things down if stud­ies are not designed in a way that gives clear, defin­i­tive answers.

    Not every­one is as grim about prospects for use­ful data. Scott Got­tlieb, the for­mer com­mis­sion­er of the FDA and a fel­low at the Amer­i­can Enter­prise Insti­tute, defend­ed the Gilead study. He not­ed that while the tri­al expect­ed to read out first is “open label”— mean­ing that both doc­tors and patients know who is get­ting the drug and who is not — more tri­als are still being con­duct­ed.

    “There’s a rig­or­ous, place­bo-con­trolled tri­al that’s now ful­ly enrolled and will read out soon, but there’s also a place for open label stud­ies to broad­en the safe­ty data­base and answer dis­crete ques­tions,” Got­tlieb said, refer­ring to a study spon­sored by the Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases.

    Gilead says it had ‘only lim­it­ed sup­ply’

    Gilead said that its study was nev­er meant to be the first word on remdesivir’s effi­ca­cy. Instead, it was meant to fol­low two stud­ies from Chi­na and the U.S. gov­ern­ment study, run by NIAID.

    “In the ear­ly stages of the pan­dem­ic, we not only had a lim­it­ed sup­ply of remde­sivir but also a lim­it­ed sup­ply of the matched place­bo required for place­bo-con­trolled stud­ies,” said Amy Flood, a Gilead spokesper­son. “We chose to pri­or­i­tize man­u­fac­tur­ing active drug over place­bo, and we pro­vid­ed our sup­ply of place­bo to Chi­na and NIAID for their stud­ies of remde­sivir.”

    Giv­en that three ran­dom­ized, place­bo-con­trolled tri­als were either under­way or about to start, Flood said, Gilead designed its own stud­ies to be open label. But this makes any con­clu­sion from a study far weak­er, because uncon­scious bias­es can affect the results.

    Crit­ics point to Gilead’s deci­sion to com­pare two groups giv­en remde­sivir for either five days or 10 days. The prob­lem with this strat­e­gy, they say, is that an inef­fec­tive drug that did noth­ing and a very effec­tive drug that con­sis­tent­ly helped patients over­come the virus would look the same in such a study. Only if the 10-day course were more effec­tive, or if it was worse because of side effects, would the study have any clear result.

    Got­tlieb defend­ed Gilead, argu­ing that increas­ing the size of the study from 400 patients to 6,000 expand­ed access to the drug at a time when it was need­ed to help with the pub­lic health emer­gency, but also allows the com­pa­ny to col­lect more rig­or­ous data. “I think it’s far bet­ter to pro­vide access in an open label set­ting than to mere­ly give drug away in an expand­ed access pro­to­col where you’re col­lect­ing min­i­mal or no data,” he said.

    Yet anoth­er tri­al in less sick patients, also run by Gilead, does have a con­trol group and may give a clear­er answer. Nis­sen sees “a rea­son­able study design.” But Bach was more crit­i­cal, say­ing that even though that study has a con­trol group, the lack of a place­bo means the study might not be trust­wor­thy. That’s because its main goal, time to improve­ment of symp­toms, could be affect­ed by the per­cep­tions of clin­i­cians and the patients them­selves.

    Bach said the hos­pi­tals con­duct­ing the study “are eas­i­ly capa­ble of wrap­ping syringes in brown paper and blind­ing the whole thing. I don’t under­stand why you would run a tri­al like this.”

    The prob­lem of place­bo

    When case num­bers in the U.S. start­ed to spike in mid-March, North­well Health, New York’s largest health care provider, imme­di­ate­ly staffed a 200-per­son unit to run Covid-19 clin­i­cal tri­als. Kevin Tracey, Northwell’s exec­u­tive vice pres­i­dent of research, said that the group’s goal was to con­duct rig­or­ous clin­i­cal tri­als that includ­ed con­trol groups. Why not have a place­bo arm in the Gilead-run study of severe patients?

    “Obvi­ous­ly, that’s my first choice,” Tracey said. One rea­son it didn’t hap­pen was that every­one need­ed to move very fast.

    “In a qui­et time when you have a few years to fig­ure out the best way to low­er cho­les­terol or the best way to treat arthri­tis, there’s a dia­logue between the inves­ti­ga­tors and the com­pa­ny and the FDA and you nego­ti­ate the tri­al design,” Tracey said. “We didn’t do that with Gilead, in this case, because our hos­pi­tals were fill­ing up with peo­ple who were dying.”

    But Tracey points to anoth­er prob­lem, too. He said that more severe­ly affect­ed patients and their fam­i­lies, hav­ing read opti­mistic news reports about a med­i­cine, may not agree to be ran­dom­ly assigned to place­bo.

    “That’s a real­i­ty,” he said. “You know that your moth­er, your wife, or your father, your broth­er is in the bed dying and you’re sup­posed to sign the papers that say you might get a place­bo? No thank you, a lot of peo­ple say.”

    At the same time, it can be hard to answer ques­tions with­out ran­dom­ized data, and even then results can be con­fus­ing.

    What to expect from Gilead’s study

    Gilead’s severe Covid-19 study is enrolling approx­i­mate­ly 6,000 par­tic­i­pants from 152 dif­fer­ent clin­i­cal tri­al sites all over the world. The pri­ma­ry analy­sis to be dis­closed this week is expect­ed to encom­pass data from at least 400 patients, with a sta­tis­ti­cal com­par­i­son of patient improve­ment between the two remde­sivir treat­ment arms — the five-day and 10-day treat­ment course. Improve­ment will be mea­sured using a sev­en-point numer­i­cal scale that encom­pass­es death (at worst) and dis­charge from hos­pi­tal (best out­come), with var­i­ous degrees of sup­ple­men­tal oxy­gen and intu­ba­tion in between.

    Video footage of a town hall at the Uni­ver­si­ty of Chica­go, seen by STAT, pro­vides some clues about what the results might bring. The researcher speak­ing in the video, Kath­leen Mul­lane from the Uni­ver­si­ty of Chica­go, said, “Most of our patients are severe and most of them are leav­ing at six days, so that tells us dura­tion of ther­a­py doesn’t have to be 10 days. We have very few that went out 10 days, maybe three.”

    If Chicago’s expe­ri­ence holds true at the oth­er hos­pi­tals par­tic­i­pat­ing in Gilead’s study, there will be lit­tle or no dif­fer­ence in patient improve­ment between the two remde­sivir arms, mak­ing the com­par­i­son unin­ter­pretable.

    That, though, will not be the end of the con­ver­sa­tion or the debate.

    Gilead could also pro­vide addi­tion­al analy­ses on the time to clin­i­cal improve­ment for dif­fer­ent sub­sets of remde­sivir patients, based on dis­ease sever­i­ty, onset of symp­toms, or how quick­ly treat­ment was start­ed. With­out a con­trol arm, these data will be hard to inter­pret on their own.

    One approach: com­pare to oth­er tri­als, like the 199-patient study of the HIV drug lopinavir that was pub­lished in the New Eng­land Jour­nal of Med­i­cine in March. In the study con­duct­ed in Chi­na, lopinavir was 31% bet­ter than stan­dard of care in time to clin­i­cal improve­ment, but the result was not sta­tis­ti­cal­ly sig­nif­i­cant. Mor­tal­i­ty was sim­i­lar, with 19% of lopinavir-treat­ed patients ver­sus 25% of stan­dard of care patients dead after one month.

    Baird ana­lyst Bri­an Sko­r­ney, for instance, points out that 79% of the lopinavir-treat­ed patients were cured at one month, yet there was still no sig­nif­i­cant dif­fer­ence from the 70% cure rate in the con­trol arm. This sug­gests that high rates of patient recov­ery should be expect­ed, and that remde­sivir — a mod­est­ly effec­tive antivi­ral at best — will not make a big dif­fer­ence.

    But RBC Cap­i­tal biotech ana­lyst Bri­an Abra­hams sug­gests using the con­trol arm from the lopinavir tri­als as an admit­ted­ly rough com­para­tor when the Gilead data are released.

    At sev­en days, 2% of the patients treat­ed with stan­dard of care showed a clin­i­cal improve­ment, increas­ing to 30% at day 14 and 70% at day 28. If remde­sivir improves upon those results, per­haps dou­bling the time to clin­i­cal improve­ment at day 14, that might be seen as sug­gest­ing a ben­e­fit, Abra­hams believes.

    Umer Raf­fat, an ana­lyst at Ever­core ISI, push­es back against the con­clu­sion that lopinavir failed in the Chi­na study — which might bode well for remde­sivir. Raf­fat points to an analy­sis in the NEJM study that showed in a small group of less sick patients treat­ed before their symp­toms wors­ened sig­nif­i­cant­ly, the lopinavir mor­tal­i­ty rate was 45% low­er.

    Antivi­ral med­i­cines should be more effec­tive when giv­en ear­li­er. This is what Gilead is try­ing to do with remde­sivir in its severe Covid-19 study. The com­pa­ny is expect­ed to report mor­tal­i­ty rates when it announces results lat­er this week. If remde­sivir low­ers mor­tal­i­ty to 10–15% from the mid-20% range report­ed in oth­er stud­ies, that might also sug­gest a ben­e­fit.

    Com­par­isons across dif­fer­ent clin­i­cal tri­als may help paint a clear­er pic­ture of remdesivir’s effi­ca­cy, but they’re not like­ly to per­suade FDA to approve the drug. That will only come from pos­i­tive data in sub­se­quent clin­i­cal tri­als.

    What to expect: the Chi­na-run severe study

    The tri­al in severe patients con­duct­ed in Chi­na — the one acci­den­tal­ly post­ed on the WHO’s web­site last week — failed to show that remde­sivir sped the time it took for patients to improve. After one month, it appeared 13.9% of the remde­sivir patients had died com­pared to 12.8% of patients in the con­trol arm. The dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant.

    But the WHO did not post full data; rather, it was an abstract of the study and pub­lished with­out the full man­u­script. It’s pos­si­ble that the pub­lished ver­sion will be dif­fer­ent.

    It’s even pos­si­ble this study will be sup­port­ive of some effect for remde­sivir. The key is a sta­tis­tic, known as a haz­ard ratio, show­ing that the time to clin­i­cal improve­ment for patients in one group was 23% more than the oth­er. The key ques­tion is whether patients did bet­ter on remde­sivir or place­bo.

    Raf­fat, the Ever­core ISI ana­lyst, obtained a copy of the study pro­to­col, a plan for how it was going to be run, and wrote in a note to the bank’s clients that this fig­ure was planned to be 1.4 if remde­sivir were to have a sta­tis­ti­cal­ly sig­nif­i­cant ben­e­fit. If that holds true, the 1.23 fig­ure means that the study just missed show­ing the drug was effec­tive, leav­ing hope that future stud­ies could show the drug would be effec­tive.

    “It’s not a sil­ver bul­let, but I do believe remde­sivir is active,” Raf­fat said on a pod­cast for investors Fri­day.

    ...

    ————

    “The world wants answers on Gilead’s Covid-19 drug. Experts wor­ry next stud­ies may increase uncer­tain­ty” by Matthew Her­p­er and Adam Feuer­stein; STAT News; 04/27/2020

    “But out­side experts in clin­i­cal tri­al design wor­ry that the results, instead of lead­ing to a clear pic­ture of whether the med­i­cine is effec­tive, will instead mud­dy the waters fur­ther.”

    Would­n’t that be love­ly: a 6000 per­son study that only ends up mud­dy­ing the waters fur­ther. That could lit­er­al­ly be what hap­pens as a result of this study design. And as the arti­cle notes, there is anoth­er Gilead study that does include a con­trol group but only for less sick patients, and even in that case there’s no place­bo. Now, the lack of a place­bo is cer­tain­ly prob­lem­at­ic, but at least this oth­er study on less sick patients both­ered to include “con­trols” in the form of peo­ple not receiv­ing the drug but oth­er­wise get­ting stan­dard treat­ment. And that rais­es the obvi­ous ques­tion of why Gilead did­n’t do the same thing with this study of severe­ly ill patients?! Yes, lack­ing a place­bo for the con­trols would­n’t have been ide­al but it cer­tain­ly would be bet­ter than no con­trols at all. It’s not as if there’s a short­age of severe­ly ill patients who could serve as con­trols:

    ...
    The main con­cern, they say, stems from the fact that the Gilead tri­al expect­ed to read out this week, which was con­duct­ed among patients with severe dis­ease, lacks a con­trol group — that is, patients who are ran­dom­ly assigned to receive the best treat­ment avail­able, but not remde­sivir. As designed, the only ran­dom­iza­tion is the dura­tion of treat­ment: either five days or 10 days of drug. With­out a true con­trol group of patients, many experts say, it will be dif­fi­cult to deter­mine whether remde­sivir is effec­tive.

    “The over­all study itself has lit­tle or no sci­en­tif­ic val­ue since all patients are receiv­ing the drug,” said Steven Nis­sen, the chief aca­d­e­m­ic offi­cer at the Cleve­land Clin­ic and lead inves­ti­ga­tor of many tri­als for heart drugs that have been approved by the Food and Drug Admin­is­tra­tion.

    “The study, as designed, is essen­tial­ly use­less and can­not be used by the FDA for con­sid­er­a­tion of remde­sivir for approval to treat coro­n­avirus,” Nis­sen said.

    Peter Bach, direc­tor of the Cen­ter for Health Pol­i­cy and Out­comes at Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter, called the sit­u­a­tion “frus­trat­ing.”

    “For them to run the tri­al in severe but not include a con­trol group, it’s just such a waste,” Bach said.

    ...

    Crit­ics point to Gilead’s deci­sion to com­pare two groups giv­en remde­sivir for either five days or 10 days. The prob­lem with this strat­e­gy, they say, is that an inef­fec­tive drug that did noth­ing and a very effec­tive drug that con­sis­tent­ly helped patients over­come the virus would look the same in such a study. Only if the 10-day course were more effec­tive, or if it was worse because of side effects, would the study have any clear result.

    ...

    Yet anoth­er tri­al in less sick patients, also run by Gilead, does have a con­trol group and may give a clear­er answer. Nis­sen sees “a rea­son­able study design.” But Bach was more crit­i­cal, say­ing that even though that study has a con­trol group, the lack of a place­bo means the study might not be trust­wor­thy. That’s because its main goal, time to improve­ment of symp­toms, could be affect­ed by the per­cep­tions of clin­i­cians and the patients them­selves.

    Bach said the hos­pi­tals con­duct­ing the study “are eas­i­ly capa­ble of wrap­ping syringes in brown paper and blind­ing the whole thing. I don’t under­stand why you would run a tri­al like this.”
    ...

    And those ques­tions about why Gilead did­n’t sim­ply include non-place­bo con­trols aren’t exact­ly addressed by Gilead­’s expla­na­tion, oth­er than to sug­gest that peo­ple might not want to be enrolled in a tri­al where they might be in a group that does­n’t receive the drug. That was so doubt a com­pli­ca­tion, espe­cial­ly for severe­ly ill patients who could have their life saved from the drug. But, again, it’s not like this conun­drum is new. This how ran­dom­ized con­trolled clin­i­cal tri­als work: one group gets the drug and one does­n’t:

    ...
    Gilead says it had ‘only lim­it­ed sup­ply’

    Gilead said that its study was nev­er meant to be the first word on remdesivir’s effi­ca­cy. Instead, it was meant to fol­low two stud­ies from Chi­na and the U.S. gov­ern­ment study, run by NIAID.

    “In the ear­ly stages of the pan­dem­ic, we not only had a lim­it­ed sup­ply of remde­sivir but also a lim­it­ed sup­ply of the matched place­bo required for place­bo-con­trolled stud­ies,” said Amy Flood, a Gilead spokesper­son. We chose to pri­or­i­tize man­u­fac­tur­ing active drug over place­bo, and we pro­vid­ed our sup­ply of place­bo to Chi­na and NIAID for their stud­ies of remde­sivir.”

    Giv­en that three ran­dom­ized, place­bo-con­trolled tri­als were either under­way or about to start, Flood said, Gilead designed its own stud­ies to be open label. But this makes any con­clu­sion from a study far weak­er, because uncon­scious bias­es can affect the results.

    ...

    The prob­lem of place­bo

    When case num­bers in the U.S. start­ed to spike in mid-March, North­well Health, New York’s largest health care provider, imme­di­ate­ly staffed a 200-per­son unit to run Covid-19 clin­i­cal tri­als. Kevin Tracey, Northwell’s exec­u­tive vice pres­i­dent of research, said that the group’s goal was to con­duct rig­or­ous clin­i­cal tri­als that includ­ed con­trol groups. Why not have a place­bo arm in the Gilead-run study of severe patients?

    “Obvi­ous­ly, that’s my first choice,” Tracey said. One rea­son it didn’t hap­pen was that every­one need­ed to move very fast.

    “In a qui­et time when you have a few years to fig­ure out the best way to low­er cho­les­terol or the best way to treat arthri­tis, there’s a dia­logue between the inves­ti­ga­tors and the com­pa­ny and the FDA and you nego­ti­ate the tri­al design,” Tracey said. “We didn’t do that with Gilead, in this case, because our hos­pi­tals were fill­ing up with peo­ple who were dying.”

    But Tracey points to anoth­er prob­lem, too. He said that more severe­ly affect­ed patients and their fam­i­lies, hav­ing read opti­mistic news reports about a med­i­cine, may not agree to be ran­dom­ly assigned to place­bo.

    “That’s a real­i­ty,” he said. “You know that your moth­er, your wife, or your father, your broth­er is in the bed dying and you’re sup­posed to sign the papers that say you might get a place­bo? No thank you, a lot of peo­ple say.”

    At the same time, it can be hard to answer ques­tions with­out ran­dom­ized data, and even then results can be con­fus­ing.
    ...

    Next, regard­ing the pos­si­bil­i­ty that remde­sivir could end up being a drug rec­om­mend­ed for less sick patients, note how finan­cial ana­lyst Umer Raf­fat sug­gest­ed that Gilead­’s study of the 6000 patients is estab­lish­ing exact­ly that: that remde­sivir should be giv­en to less sick patients ear­li­er before they get sev­er­ly sick, point­ing out a sim­i­lar find­ing that dis­cov­ered with the HIV drug lopinavir that found the drug worked best when giv­en ear­li­er to less sick patients:

    ...
    One approach: com­pare to oth­er tri­als, like the 199-patient study of the HIV drug lopinavir that was pub­lished in the New Eng­land Jour­nal of Med­i­cine in March. In the study con­duct­ed in Chi­na, lopinavir was 31% bet­ter than stan­dard of care in time to clin­i­cal improve­ment, but the result was not sta­tis­ti­cal­ly sig­nif­i­cant. Mor­tal­i­ty was sim­i­lar, with 19% of lopinavir-treat­ed patients ver­sus 25% of stan­dard of care patients dead after one month.

    Baird ana­lyst Bri­an Sko­r­ney, for instance, points out that 79% of the lopinavir-treat­ed patients were cured at one month, yet there was still no sig­nif­i­cant dif­fer­ence from the 70% cure rate in the con­trol arm. This sug­gests that high rates of patient recov­ery should be expect­ed, and that remde­sivir — a mod­est­ly effec­tive antivi­ral at best — will not make a big dif­fer­ence.

    But RBC Cap­i­tal biotech ana­lyst Bri­an Abra­hams sug­gests using the con­trol arm from the lopinavir tri­als as an admit­ted­ly rough com­para­tor when the Gilead data are released.

    At sev­en days, 2% of the patients treat­ed with stan­dard of care showed a clin­i­cal improve­ment, increas­ing to 30% at day 14 and 70% at day 28. If remde­sivir improves upon those results, per­haps dou­bling the time to clin­i­cal improve­ment at day 14, that might be seen as sug­gest­ing a ben­e­fit, Abra­hams believes.

    Umer Raf­fat, an ana­lyst at Ever­core ISI, push­es back against the con­clu­sion that lopinavir failed in the Chi­na study — which might bode well for remde­sivir. Raf­fat points to an analy­sis in the NEJM study that showed in a small group of less sick patients treat­ed before their symp­toms wors­ened sig­nif­i­cant­ly, the lopinavir mor­tal­i­ty rate was 45% low­er.

    Antivi­ral med­i­cines should be more effec­tive when giv­en ear­li­er. This is what Gilead is try­ing to do with remde­sivir in its severe Covid-19 study. The com­pa­ny is expect­ed to report mor­tal­i­ty rates when it announces results lat­er this week. If remde­sivir low­ers mor­tal­i­ty to 10–15% from the mid-20% range report­ed in oth­er stud­ies, that might also sug­gest a ben­e­fit.
    ...

    And as we’ll see in the fol­low­ing piece, that’s the same response Umer Raf­fat had fol­low­ing the dis­ap­point­ing pre­lim­i­nary find­ings of the Chi­na tri­al last week: Because those dis­ap­point­ing results were on a tri­al of severe­ly ill patients we still don’t know how effec­tive the drug is on mod­er­ate­ly ill patients and that was the pop­u­la­tion Raf­fat is most inter­est­ed in. And from a finan­cial ana­lyst’s stand­point you can under­stand why: there’s going to be WAY more mod­er­ate­ly ill patients than severe­ly ill patients so if remde­sivir is found to be only effec­tive for the mod­er­ate­ly ill to ward off severe ill­ness the inher­ent demand for the drug will sky­rock­et:

    Fierce Biotech

    Did Gilead­’s remde­sivir flop a Chi­nese tri­al? Ana­lysts beg to dif­fer

    by Ami­rah Al Idrus | Apr 23, 2020 3:55pm

    Anoth­er day, anoth­er leak—or so it seems for Gilead Sci­ences’ COVID-19 hope­ful remde­sivir. This time, the World Health Orga­ni­za­tion (WHO) acci­den­tal­ly revealed data from a study in Chi­na show­ing that the treat­ment nei­ther improved patients’ con­di­tion nor tamped down on the amount of virus in their blood, the Finan­cial Times report­ed, call­ing the tri­al a “flop.”

    But was it real­ly a flop? Ana­lysts are say­ing no.

    The study test­ed remde­sivir in 158 patients, com­par­ing their response to 79 patients in a con­trol group. The treat­ment “was not asso­ci­at­ed with a dif­fer­ence in time to clin­i­cal improve­ment,” accord­ing to draft doc­u­ments inad­ver­tent­ly pub­lished by the WHO that were seen by the FT and Stat and have since been removed. Patients in both study arms expe­ri­enced side effects at rough­ly the same rate (about 65%), but more patients on remde­sivir stopped treat­ment ear­ly because of side effects com­pared with place­bo (12% ver­sus 5.1%).

    As Ever­core ISI ana­lyst Umer Raf­fat point­ed out in a note to clients, though, the study allowed patients to start the Gilead can­di­date up to 12 days after symp­toms first appeared. “That is a VERY long win­dow,” he wrote, not­ing that with antivi­rals for acute infec­tion, “the ear­li­er you start, the bet­ter the effi­ca­cy.”

    “For me, the real detail is NOT out yet: effi­ca­cy in patients that start ear­ly,” he said.

    ....

    ———–

    “Did Gilead­’s remde­sivir flop a Chi­nese tri­al? Ana­lysts beg to dif­fer” by Ami­rah Al Idrus; Fierce Biotech; 04/23/2020

    ““For me, the real detail is NOT out yet: effi­ca­cy in patients that start ear­ly,” he said.”

    It real­ly is quite an impor­tant detail for any­one invest­ed in Gilead: does it work on the much, much larg­er pop­u­la­tion of mod­er­ate­ly ill patients? If so, and if the drug does­n’t actu­al­ly work very well on the severe­ly ill, the rec­om­mend­ed use for remde­sivir could be dra­mat­i­cal­ly dif­fer­ent, and more lucra­tive, than what was orig­i­nal­ly hoped for: instead of a drug to help save the severe­ly ill, Gilead might have a drug that can at best stop the mod­er­ate­ly ill from get­ting severe­ly ill.

    Of course, as we’ve seen, there’s no pos­si­ble way for Gilead to ramp up the pro­duc­tion of the drug enough to meet the glob­al demand for the severe­ly ill, let alone the much larg­er pop­u­la­tion of mod­er­ate­ly ill patients. So the sup­ply and demand bal­ance could end up swing­ing even more in favor of Gilead­’s investors, at least as long as an alter­na­tive drug for the severe­ly ill patients isn’t dis­cov­ered and run through clin­i­cal tri­als.

    If remde­sivir ends up being used on the mod­er­ate­ly ill that’s also going to make the issue of side-effects much more impor­tant. It’s eas­i­er to jus­ti­fy side-effects for the severe­ly ill. So it’s also going to be inter­est­ing to see what infor­ma­tion about side-effects gets released by these tri­als. Oth­er than the side-effect of mas­sive prof­its for Gilead investors.

    So as we can see, the pri­ma­ry good news cur­rent­ly avail­able to us regard­ing the clin­i­cal effi­ca­cy of remde­sivir is that there’s still some ongo­ing tri­als that might actu­al­ly yield con­clu­sion results in the future.

    Posted by Pterrafractyl | April 30, 2020, 2:38 pm
  13. Now that remde­sivir is offi­cial­ly human­i­ty’s best hope for a drug to treat COVID cas­es accord­ing to the US gov­ern­ment — despite the very mixed results from mul­ti­ple clin­i­cal tri­als at this point — the ques­tion of just how much Gilead is going to charge for the drug is becom­ing much more urgent. And based on the fol­low­ing arti­cle, that’s a ques­tion with­out an obvi­ous answer. Because while we’re hear­ing from the non-prof­it group Pub­lic Cit­i­zen is call­ing for Gilead to price remde­sivir at $1, not­ing stud­ies that say the drug can be made for only $0.93 per day, Wall Street ana­lysts unsur­pris­ing­ly have a very dif­fer­ent set of price rec­om­men­da­tion. The Insti­tute for Clin­i­cal and Eco­nom­ic Review — a non-prof­it heav­i­ly fund­ed by the drug mak­ers, health insur­ance com­pa­nies, and con­ser­v­a­tive mega-donorssug­gest­ed the drug should cost about $4,500. At least that’s what they sug­gest­ed assum­ing fur­ther clin­i­cal data does­n’t show that it pre­vents or reduce deaths, which case the group says it should cost $390. Bern­stein Research ana­lyst Ron­ny Gal esti­mat­ed that Gilead could price the treat­ment at about $5,000 and Sun­Trust ana­lyst Robyn Kar­nauskas said Gilead could charge $10,000! That’s pre­sum­ably $10,000 for a 10 day dose.

    So will we see prices for a 10-day treat­ment clos­er to $10 or $10,000? That is yet to be deter­mined, but it sure sounds like it’s going to be legal­ly pos­si­ble for Gilead to $10,000 for a round of treat­ment:

    Politi­co

    Remde­sivir helps coro­n­avirus patients — but at what cost?

    Drug­mak­er Gilead is known for cre­at­ing break­through drugs and sell­ing them at a pre­mi­um.

    By ZACHARY BRENNAN
    05/06/2020 01:44 PM EDT
    Updat­ed: 05/06/2020 01:51 PM EDT

    Gilead has rock­et­ed into the pub­lic con­scious­ness with one of the most promis­ing coro­n­avirus treat­ments, but the company’s his­to­ry of sky high drug pric­ing is draw­ing increas­ing scruti­ny from Con­gress about how much it will charge for remde­sivir and who will get access.

    But Gilead, which suf­fered through a spate of bad pub­lic­i­ty in 2015 for charg­ing $84,000 for a hepati­tis C drug, isn’t just under fire over the poten­tial price of its coro­n­avirus treat­ment. It’s under pres­sure from Wall Street investors to recoup the $1 bil­lion invest­ment in remde­sivir, which has been proven to accel­er­ate recov­ery from the coro­n­avirus. How Gilead nav­i­gates finan­cial pres­sures from investors and polit­i­cal pres­sures from Wash­ing­ton may very well deter­mine the mass pro­duc­tion and avail­abil­i­ty of one of the most promis­ing coro­n­avirus drugs on the mar­ket.

    “An unaf­ford­able drug is com­plete­ly inef­fec­tive,” Demo­c­ra­t­ic Reps. Lloyd Doggett (Texas) and Rosa DeLau­ro (Conn.) wrote to Health and Human Ser­vices Sec­re­tary Alex Azar last week, rais­ing ques­tions about remde­sivir.

    It’s not clear exact­ly how much the drug will cost. For con­text, one non-prof­it that eval­u­ates drug costs says it costs about $9.32 to man­u­fac­ture a 10-day course of remde­sivir treat­ment for one patient. Cal­cu­lat­ing the cost of devel­op­ment and tri­als, the Insti­tute for Clin­i­cal and Eco­nom­ic Review says Gilead could charge as lit­tle as $390 for the drug. But Wall Street ana­lysts are on an entire­ly dif­fer­ent page, sug­gest­ing a price between $5,000 to $10,000, lead­ing to bil­lions in prof­its.

    Gilead man­age­ment “remains vague on their plans to recoup the pro­duc­tion, dis­tri­b­u­tion, and tri­al costs — cit­ing a bal­ance between access and sus­tain­abil­i­ty,” said Bri­an Abra­hams, an ana­lyst at RBC Cap­i­tal Mar­kets, in a recent investor note. This ret­i­cence, “along­side the unpre­dictabil­i­ty of the future pandemic/stockpiling con­tin­ues to make mod­el­ing its poten­tial impact chal­leng­ing,” he said.

    ...

    Remde­sivir isn’t a knock­out punch for Covid-19. But a clin­i­cal tri­al by the Nation­al Insti­tute of Aller­gies and Infec­tious Dis­ease, the agency head­ed by Antho­ny Fau­ci, showed it did lop sev­er­al days off recov­ery time for seri­ous­ly ill patients — get­ting them out of the hos­pi­tal faster and per­haps reduc­ing the num­ber of deaths. Sci­en­tists are still study­ing the drug and the search for bet­ter ther­a­pies con­tin­ues. In the mean­time, the Food and Drug Admin­is­tra­tion swift­ly grant­ed an emer­gency use autho­riza­tion for remde­sivir so doc­tors can use it now.

    Con­gres­sion­al Democ­rats are now rais­ing ques­tions about the drug’s cost — in part because Gilead received about $70 mil­lion in tax­pay­er dol­lars and assis­tance from the Nation­al Insti­tutes of Health to run clin­i­cal tri­als. Euro­pean offi­cials are plot­ting con­tin­gency steps, fear­ing the Trump admin­is­tra­tion may take an “Amer­i­ca First” approach and block every­one else from get­ting the med­i­cine. A Bangladesh-based gener­ic drug­mak­er is already plan­ning its own ver­sion of the antivi­ral drug under an inter­na­tion­al pro­gram that lets very poor coun­tries make copy­cats of expen­sive patent­ed drugs.

    Right now, Gilead is giv­ing away about 1.5 mil­lion dos­es, and FEMA and HHS are in charge of dis­trib­ut­ing them. That’s prob­a­bly enough for about 140,000 patients — but Wall Street ana­lysts expect the sup­ply to run out by late June, if not ear­li­er. Gilead did not respond to a request for com­ment, but its CEO Daniel O’Day reit­er­at­ed to share­hold­ers Wednes­day that the com­pa­ny “donat­ed our exist­ing sup­plies for glob­al use.”

    O’Day said that Gilead was just begin­ning to digest the results from the NIAID tri­al and would announce a price for remde­sivir at a lat­er date. “We’ll eval­u­ate that data dur­ing the dona­tion peri­od and will con­sid­er the path of the pan­dem­ic and what role remde­sivir can play,” he told share­hold­ers.

    The first coro­n­avirus stim­u­lus law, the CARES Act, says drugs must have “fair and rea­son­able” prices, although there’s no enforce­ment mech­a­nism and stronger pro­posed lan­guage enabling HHS to help set a treatment’s price was dropped from the bill. Gilead spent $2.45 mil­lion lob­by­ing the Sen­ate in the first quar­ter of 2020, more than it ever had before, accord­ing to Open Secrets.

    House Speak­er Nan­cy Pelosi spokesper­son Hen­ry Con­nel­ly said that “fair and rea­son­able” lan­guage would like­ly apply to remde­sivir because of the NIH involve­ment and because the fed­er­al gov­ern­ment will like­ly have to pur­chase and dis­trib­ute large quan­ti­ties of it and oth­er coro­n­avirus med­i­cines. Sev­er­al Repub­li­cans in the Sen­ate declined to com­ment or did not respond to a request for com­ment.

    HHS didn’t respond to ques­tions about its pos­si­ble role in set­ting or nego­ti­at­ing remdesivir’s price. “HHS and FEMA are work­ing togeth­er to final­ize the process for equi­table dis­tri­b­u­tion of the lim­it­ed dos­es of remde­sivir donat­ed by Gilead to reach patients in hotspots,” the depart­ment said in a state­ment. “We are encour­aged to have so many pri­vate sec­tor col­lab­o­ra­tors step­ping up to assist in the whole-of-Amer­i­ca pan­dem­ic response.”

    Pres­i­dent Don­ald Trump has gen­er­al­ly left a lot of pan­dem­ic pro­cure­ment and price nego­ti­a­tion to the states. While many coun­tries nego­ti­ate drug prices, the U.S. does not. Trump has pro­posed some prece­dent-set­ting bench­marks for cer­tain high-cost med­i­cines, based on what oth­er coun­tries pay, but nei­ther the White House nor Con­gress has put that plan into action.

    There is prece­dent for the gov­ern­ment to inter­vene in drug pric­ing, how­ev­er: After the anthrax attacks in 2001, the George W. Bush admin­is­tra­tion pur­chased large amounts of the antibi­ot­ic Cipro and pres­sured the drug’s mak­er to cut its price.

    Now, with­out any actu­al tools to con­trol how much Gilead charges for remde­sivir, a group of 10 con­gres­sion­al Democ­rats is writ­ing let­ters to the drug­mak­er and HHS.

    “This is a moment unlike any we’ve ever seen,” one of those law­mak­ers, Rep. Jan Schakowsky (D‑Ill), told POLITICO. If drug com­pa­nies are allowed to hold the pub­lic “hostage” through high prices and the gov­ern­ment doesn’t respond, “that’s an abdi­ca­tion of our respon­si­bil­i­ty as gov­ern­ment,” she said.

    Gilead — which has been embroiled for years in con­tro­ver­sy about the cost of its hepati­tis treat­ments, and is in court with HHS over its land­mark HIV/AIDS pre­ven­tion drug devel­oped with Cen­ters for Dis­ease Con­trol and Pre­ven­tion assis­tance — has already weath­ered one remde­sivir con­tro­ver­sy.

    The com­pa­ny ear­li­er this year ini­tial­ly sought an “orphan” drug des­ig­na­tion from the FDA for remde­sivir. That gives a drug­mak­er sev­er­al finan­cial incen­tives, includ­ing extra pro­tec­tion against com­pe­ti­tion. But orphan drug sta­tus is intend­ed to incen­tivize the devel­op­ment of treat­ments for rare dis­eases that affect few­er than 200,000 U.S. patients — and the U.S has more than 1 mil­lion con­firmed coro­n­avirus cas­es. Amid out­cry, Gilead rescind­ed its request for orphan sta­tus in March.

    Wall Street ana­lysts have float­ed var­i­ous num­bers about what Gilead may charge for remde­sivir, and health groups have put forth data about what they say it should charge. The company’s total rev­enue from the drug could eas­i­ly top $10 or $11 bil­lion, sev­er­al ana­lysts say.

    The Insti­tute for Clin­i­cal and Eco­nom­ic Review sug­gest­ed the coro­n­avirus drug should cost about $4,500, unless fur­ther clin­i­cal data show it does not pre­vent or reduce deaths — in which case the group says it should be priced at $390. The first data released from the NIAID tri­al shows the drug helps some patients recu­per­ate faster but may not affect over­all mor­tal­i­ty.

    The non-prof­it group Pub­lic Cit­i­zen, a fre­quent crit­ic of drug­mak­ers, is urg­ing Gilead to price remde­sivir at $1, not­ing stud­ies that say the drug can be made for only $0.93 per day.

    Peter Neu­mann, an expert at the Insti­tute for Clin­i­cal Research and Health Pol­i­cy Stud­ies at Tufts Med­ical Cen­ter, said the U.S. will always pay more than less-devel­oped coun­tries for med­i­cines. But with Gilead under pres­sure on remde­sivir, he pre­dict­ed the com­pa­ny will hun­ker down with its pub­lic rela­tions team to con­sid­er com­pet­ing fac­tors like pub­lic opin­ion, val­ue and share­hold­er demands.

    Invest­ment ana­lysts, mean­while, have sug­gest­ed the price could be even high­er than the ICER tar­get. Sun­Trust ana­lyst Robyn Kar­nauskas said Gilead could charge $10,000 for the drug and make more than $5 bil­lion over three years. Sim­i­lar­ly, Bern­stein Research ana­lyst Ron­ny Gal esti­mat­ed that Gilead could price the treat­ment at about $5,000, which is on par with oth­er antivi­rals, and still make $11 bil­lion.

    ———–

    “Remde­sivir helps coro­n­avirus patients — but at what cost?” by ZACHARY BRENNAN; Politi­co; 05/06/2020

    “It’s not clear exact­ly how much the drug will cost. For con­text, one non-prof­it that eval­u­ates drug costs says it costs about $9.32 to man­u­fac­ture a 10-day course of remde­sivir treat­ment for one patient. Cal­cu­lat­ing the cost of devel­op­ment and tri­als, the Insti­tute for Clin­i­cal and Eco­nom­ic Review says Gilead could charge as lit­tle as $390 for the drug. But Wall Street ana­lysts are on an entire­ly dif­fer­ent page, sug­gest­ing a price between $5,000 to $10,000, lead­ing to bil­lions in prof­its.

    Non-prof­its that care about pub­lic health want the drug as cheap as pos­si­ble and Wall Street wants it as expen­sive as pos­si­ble. It’s one of those fre­quent moments that should trig­ger ques­tions about why on earth the man­date of prof­it-max­i­miza­tion is built into the fab­ric of how soci­ety func­tions but that’s where we are in the US. And that just might mean remde­sivir is unaf­ford­able to large num­bers of peo­ple:

    ...
    The Insti­tute for Clin­i­cal and Eco­nom­ic Review sug­gest­ed the coro­n­avirus drug should cost about $4,500, unless fur­ther clin­i­cal data show it does not pre­vent or reduce deaths — in which case the group says it should be priced at $390. The first data released from the NIAID tri­al shows the drug helps some patients recu­per­ate faster but may not affect over­all mor­tal­i­ty.

    The non-prof­it group Pub­lic Cit­i­zen, a fre­quent crit­ic of drug­mak­ers, is urg­ing Gilead to price remde­sivir at $1, not­ing stud­ies that say the drug can be made for only $0.93 per day.

    ...

    Invest­ment ana­lysts, mean­while, have sug­gest­ed the price could be even high­er than the ICER tar­get. Sun­Trust ana­lyst Robyn Kar­nauskas said Gilead could charge $10,000 for the drug and make more than $5 bil­lion over three years. Sim­i­lar­ly, Bern­stein Research ana­lyst Ron­ny Gal esti­mat­ed that Gilead could price the treat­ment at about $5,000, which is on par with oth­er antivi­rals, and still make $11 bil­lion.
    ...

    Also keep in mind that with all of the dif­fi­cul­ties Gilead is going to run into when try­ing to scale up its pro­duc­tion of remde­sivir to deal with glob­al demand, that means we should expect there to be a sup­ply short­age whether or not the drug is $10 or $10,000 for a treat­ment. So there real­ly could be a supply/demand sit­u­a­tion ear­ly on that helps to increase the cost of drug. It could be effec­tive­ly lim­it­ed to the wealthy in 2020 until Gilead gets its sup­ply chain up and run­ning.

    But would Gilead be that crass in the mid­dle of glob­al pan­dem­ic? Well, based on the vague­ness of their pub­lic plans so far the answer appears to be a sold ‘maybe, they are think­ing about it’. The com­pa­ny donat­ed the ini­tial sup­ply of 1.5 mil­lion dos­es but that sup­ply is expect­ed to run out by late June if note ear­li­er. That means Gilead could be direct­ly mak­ing mon­ey for the sale of the drug in about a month. In addi­tion, the com­pa­ny noto­ri­ous­ly request­ed “orphan” sta­tus for remde­sivir as the pan­dem­ic was break­ing out...a move the com­pa­ny would only have done if it was plan­ning on charg­ing extra high prices for an extra long peri­od of time. All of that, com­bined with Gilead­’s record spend­ing on lob­by­ing this year, points in the direc­tion of the com­pa­ny try­ing to fig­ure out how it can charge as much as pos­si­ble with­out pro­vok­ing too much pub­lic back­lash:

    ...
    Gilead man­age­ment “remains vague on their plans to recoup the pro­duc­tion, dis­tri­b­u­tion, and tri­al costs — cit­ing a bal­ance between access and sus­tain­abil­i­ty,” said Bri­an Abra­hams, an ana­lyst at RBC Cap­i­tal Mar­kets, in a recent investor note. This ret­i­cence, “along­side the unpre­dictabil­i­ty of the future pandemic/stockpiling con­tin­ues to make mod­el­ing its poten­tial impact chal­leng­ing,” he said.

    ...

    Right now, Gilead is giv­ing away about 1.5 mil­lion dos­es, and FEMA and HHS are in charge of dis­trib­ut­ing them. That’s prob­a­bly enough for about 140,000 patients — but Wall Street ana­lysts expect the sup­ply to run out by late June, if not ear­li­er. Gilead did not respond to a request for com­ment, but its CEO Daniel O’Day reit­er­at­ed to share­hold­ers Wednes­day that the com­pa­ny “donat­ed our exist­ing sup­plies for glob­al use.”

    ...

    The first coro­n­avirus stim­u­lus law, the CARES Act, says drugs must have “fair and rea­son­able” prices, although there’s no enforce­ment mech­a­nism and stronger pro­posed lan­guage enabling HHS to help set a treatment’s price was dropped from the bill. Gilead spent $2.45 mil­lion lob­by­ing the Sen­ate in the first quar­ter of 2020, more than it ever had before, accord­ing to Open Secrets.

    ...

    The com­pa­ny ear­li­er this year ini­tial­ly sought an “orphan” drug des­ig­na­tion from the FDA for remde­sivir. That gives a drug­mak­er sev­er­al finan­cial incen­tives, includ­ing extra pro­tec­tion against com­pe­ti­tion. But orphan drug sta­tus is intend­ed to incen­tivize the devel­op­ment of treat­ments for rare dis­eases that affect few­er than 200,000 U.S. patients — and the U.S has more than 1 mil­lion con­firmed coro­n­avirus cas­es. Amid out­cry, Gilead rescind­ed its request for orphan sta­tus in March.
    ...

    And don’t for­get that Gilead did­n’t sim­ply request “orphan” sta­tus for the drug. The FDA grant­ed that “orphan” sta­tus in late March. Gilead did­n’t rescind its orphan sta­tus request until after the pub­lic out­cry fol­low­ing that FDA approval:

    Nation­al Pub­lic Radio

    FDA Grants Exper­i­men­tal Coro­n­avirus Drug Ben­e­fits For Rare Dis­ease Treat­ments

    Syd­ney Lup­kin
    March 24, 2020 7:26 PM ET

    The Food and Drug Admin­is­tra­tion gave an exper­i­men­tal med­i­cine called remde­sivir to treat COVID-19 what’s called orphan drug sta­tus on Mon­day.

    To qual­i­fy for an orphan des­ig­na­tion, drug com­pa­nies must show that their prod­uct will treat a pop­u­la­tion of few­er than 200,000 patients or that it would be unprof­itable.

    With more than 52,000 con­firmed U.S. cas­es of COVID-19 report­ed as of Tues­day after­noon, the ill­ness is under the tech­ni­cal thresh­old for a rare dis­ease. But cas­es are ris­ing quick­ly and it seems inevitable that they will sur­pass 200,000.

    The agen­cy’s deci­sion would pro­vide lucra­tive incen­tives to the drug’s mak­er, Gilead Sci­ences, and could keep low­er-priced gener­ic ver­sions of the med­i­cine off the mar­ket for sev­er­al years if remde­sivir is approved for use, pub­lic health advo­cates say.

    Remde­sivir is an intra­venous, antivi­ral med­i­cine that is being stud­ied in clin­i­cal tri­als around the world as a pos­si­ble treat­ment for COVID-19.

    Clin­i­cal tri­als for remde­sivir as a COVID-19 treat­ment got start­ed in Chi­na in ear­ly Feb­ru­ary. Tests of the drug are now enrolling patients else­where, includ­ing the Unit­ed States.

    The FDA’s grant­i­ng of orphan sta­tus for remde­sivir as a treat­ment for COVID-19 came with finan­cial incen­tives for Gilead that include tax breaks, waiv­er of FDA fees and mar­ket exclu­siv­i­ty for sev­en years if the drug is approved. New drug mol­e­cules typ­i­cal­ly only get five years of this exclu­siv­i­ty.

    The agency deci­sion drew crit­i­cism from con­sumer advo­cates.

    “FDA should not pro­vide long-term finan­cial incen­tives for a treat­ment that would be very wide­ly used if it works,” said Diana Zuck­er­man, who heads the Nation­al Cen­ter for Health Research, a con­sumer advo­ca­cy and research orga­ni­za­tion. The goal of the orphan drug pro­gram is to “make it more lucra­tive for a com­pa­ny to devel­op a treat­ment that won’t have a lot of cus­tomers.”

    With more than 50,000 con­firmed cas­es of COVID-19 report­ed as of Tues­day after­noon, the dis­ease is under the tech­ni­cal thresh­old for a rare dis­ease. The law states that the num­ber of patients must be few­er than 200,000 “at the time of the sub­mis­sion of the request for orphan-drug des­ig­na­tion.”

    The FDA told NPR that this is why remde­sivir was giv­en orphan sta­tus this week, adding that it met the “stan­dard cri­te­ria for preva­lence for des­ig­na­tion.”

    In an emailed state­ment, a Gilead spokesper­son wrote that when it sought the orphan des­ig­na­tion, “only a small num­ber of Amer­i­cans were affect­ed by COVID-19.” A com­pa­ny spokesper­son declined to say when this was. The drug com­pa­ny said it “has been mak­ing sig­nif­i­cant at-risk invest­ments” to study remde­sivir and increase its sup­ply dur­ing the glob­al health emer­gency.

    If remde­sivir is approved, Gilead­’s state­ment said, “we are com­mit­ted to mak­ing the med­i­cine both acces­si­ble and afford­able to gov­ern­ments and patients around the world.”

    Advo­cates voiced con­cern that the FDA’s deci­sion paves the way for Gilead to charge a high price for remde­sivir. Many orphan drugs are among the most expen­sive med­ica­tions in the Unit­ed States, in part because gener­ic com­peti­tors are delayed.

    “Gilead­’s pur­suit of an orphan des­ig­na­tion is uncon­scionable and could be deeply harm­ful,” Peter May­bar­duk, who directs Pub­lic Cit­i­zen’s access to med­i­cines pro­gram, wrote in a state­ment. “Remde­sivir is one of rel­a­tive­ly few med­i­cines that may prove effec­tive in treat­ing COVID-19 this year. The gov­ern­ment should be urgent­ly con­cerned with its afford­abil­i­ty for cit­i­zens.”

    Ear­li­er this month, Pub­lic Cit­i­zen and 70 oth­er orga­ni­za­tions co-authored a let­ter to Pres­i­dent Trump, urg­ing his admin­is­tra­tion not to award monop­o­lies to phar­ma­ceu­ti­cal com­pa­nies work­ing on COVID-19 vac­cines and cures. The let­ter cit­ed Pub­lic Cit­i­zen’s report, which found that tax­pay­ers had already spent $700 mil­lion on phar­ma­ceu­ti­cal research and devel­op­ment for coro­n­avirus­es since 2002.

    Dur­ing a con­gres­sion­al hear­ing in late Feb­ru­ary, Depart­ment of Health and Human Ser­vices Sec­re­tary Alex Azar declined to promise that coro­n­avirus treat­ments would be afford­able.

    “We can’t con­trol that price because we need the pri­vate sec­tor to invest,” he said dur­ing the hear­ing with the House Com­mit­tee on Ener­gy and Com­merce.

    The deci­sion to award remde­sivir orphan des­ig­na­tion as a treat­ment for COVID-19 also puz­zled Ken Kaitin, who directs the Tufts Cen­ter for the Study of Drug Devel­op­ment. If the FDA’s goal was to speed devel­op­ment, he said it could do that in oth­er ways.

    “I could see that Gilead would like that,” Kaitin said of the orphan drug tax breaks and promise of sev­en years with­out gener­ic com­peti­tors. “But at the same time, it’s hard to imag­ine the FDA would say, OK, we’re going to call it an orphan drug even though it’s not [rare.]’ ”

    The Gov­ern­ment Account­abil­i­ty Office fin­ished a year­long inves­ti­ga­tion of the FDA’s orphan drug pro­gram in 2018. It found that the agency was­n’t always ensur­ing that the intent of the Orphan Drug Act was being met. Instead, FDA reviews that deter­mined orphan des­ig­na­tion were often incon­sis­tent and incom­plete.

    The GAO report fol­lowed a Kaiser Health News inves­ti­ga­tion into manip­u­la­tion of the orphan drug pro­gram that showed that many phar­ma­ceu­ti­cals that received rare dis­ease perks start­ed off as block­buster prod­ucts with mil­lions of cus­tomers.

    ...

    ———–

    “FDA Grants Exper­i­men­tal Coro­n­avirus Drug Ben­e­fits For Rare Dis­ease Treat­ments” by Syd­ney Lup­kin; Nation­al Pub­lic Radio; 03/24/2020

    “To qual­i­fy for an orphan des­ig­na­tion, drug com­pa­nies must show that their prod­uct will treat a pop­u­la­tion of few­er than 200,000 patients or that it would be unprof­itable.”

    The patient pop­u­la­tion has to be under 200,000. That’s one of the core rules for grant­i­ng a drug “orphan” sta­tus. It’s not a bad con­cept as a pro­gram that encour­ages com­pa­nies to devel­op drugs that have a rel­a­tive­ly small mar­ket. But that’s a very dif­fer­ent sit­u­a­tion than request­ing orphan sta­tus at the begin­ning of a glob­al pan­dem­ic when case num­bers are low but rapid­ly grow­ing. And yet that’s exact­ly what Gilead did in an ultra-cyn­i­cal move and the FDA reward­ed them:

    ...
    The FDA’s grant­i­ng of orphan sta­tus for remde­sivir as a treat­ment for COVID-19 came with finan­cial incen­tives for Gilead that include tax breaks, waiv­er of FDA fees and mar­ket exclu­siv­i­ty for sev­en years if the drug is approved. New drug mol­e­cules typ­i­cal­ly only get five years of this exclu­siv­i­ty.

    ...

    With more than 50,000 con­firmed cas­es of COVID-19 report­ed as of Tues­day after­noon, the dis­ease is under the tech­ni­cal thresh­old for a rare dis­ease. The law states that the num­ber of patients must be few­er than 200,000 “at the time of the sub­mis­sion of the request for orphan-drug des­ig­na­tion.”

    The FDA told NPR that this is why remde­sivir was giv­en orphan sta­tus this week, adding that it met the “stan­dard cri­te­ria for preva­lence for des­ig­na­tion.”

    ...

    Advo­cates voiced con­cern that the FDA’s deci­sion paves the way for Gilead to charge a high price for remde­sivir. Many orphan drugs are among the most expen­sive med­ica­tions in the Unit­ed States, in part because gener­ic com­peti­tors are delayed.
    ...

    And note how HHS sec­re­tary Alex Azar, him­self a for­mer phar­ma­ceu­ti­cal lob­by­ist, refused to pledge to ensure approved COVID treat­ments are afford­able dur­ing a con­gres­sion­al hear­ing in late Feb­ru­ary. So we’re see­ing a con­stel­la­tion of moves by the Trump admin­is­tra­tion indi­cat­ing that prof­itabil­i­ty, not afford­abil­i­ty, is going to be the pri­or­i­ty for the admin­is­tra­tion too:

    ...

    Dur­ing a con­gres­sion­al hear­ing in late Feb­ru­ary, Depart­ment of Health and Human Ser­vices Sec­re­tary Alex Azar declined to promise that coro­n­avirus treat­ments would be afford­able.

    “We can’t con­trol that price because we need the pri­vate sec­tor to invest,” he said dur­ing the hear­ing with the House Com­mit­tee on Ener­gy and Com­merce.
    ...

    And, again, it was only after the FDA made that egre­gious orphan sta­tus deci­sion and the pub­lic out­cry that fol­lowed that Gilead rescind­ed its orphan sta­tus request. It was too shame­ful even for Gilead (although not too shame­ful for the Trump admin­is­tra­tion, appar­ent­ly). Still, apart for rescind­ing that request, all oth­er signs are point­ing towards Gilead being intent on mak­ing as much as it feels it can get away with. Pub­lic out­rage is real­ly the only thing stop­ping them for charg­ing as much as pos­si­ble. For­tu­nate­ly the com­pa­ny’s schemes are inher­ent­ly out­ra­geous so there should hope­ful­ly be much more pub­lic out­rage if Gilead decides to set prices clos­er to the $10,000 end of the price spec­trum than $10. But that’s the line the com­pa­ny is going to be walk­ing: how much can it charge with­out spark­ing an lev­el of pub­lic out­rage the com­pa­ny finds unac­cept­able. Which seems like the kind of sit­u­a­tion that the pub­lic should find unac­cept­able and out­ra­geous.

    At the same time, we’re now hear­ing that Gilead is in talks with oth­er drug man­u­fac­tur­ers to pro­duce the drug for oth­er parts of the world. So that might help address the severe sup­ply crunch some­what but we’re still like­ly look­ing at a sit­u­a­tion where there’s a sev­er sup­ply crunch for the fore­see­able future. That’s WHY Gilead is engaged in these talks. And even Bex­im­co — an Banglade­sch drug mak­er in talks with Gilead — is sug­gest­ing the cost could still be between $295 to $781 per patient in Bangladesh, which is effec­tive­ly unaf­ford­able for that coun­try. It’s also the kind of arrange­ment that could shield Gilead from charges that it priced the devel­op­ing world out of access to the drug and make it eas­i­er for the com­pa­ny to charge much more in the US and price poor Amer­i­cans out of the drug:

    Reuters

    Who can make Gilead­’s coro­n­avirus drug, licence free?

    May 6, 2020 / 5:37 AM

    (Reuters) — Gilead Sci­ences Inc is in talks with chem­i­cal and drug mak­ers to pro­duce its exper­i­men­tal drug remde­sivir, a poten­tial coro­n­avirus treat­ment, for Europe, Asia and the devel­op­ing world, the firm has said.

    Its patent gives the U.S. com­pa­ny exclu­sive rights to make the antivi­ral. But inter­na­tion­al trade rules allow nations defined by the Unit­ed Nations as least-devel­oped coun­tries (LDCs) to ignore the patent and make drugs such as remde­sivir more afford­able in their mar­kets.

    Here is how pro­duc­tion and dis­tri­b­u­tion of remde­sivir would work in less devel­oped coun­tries, under World Trade Organ­i­sa­tion (WTO) rules.

    WHICH ARE THE LEAST DEVELOPED COUNTRIES?

    Of the 47 coun­tries in this U.N. cat­e­go­ry, 36 here belong to the WTO and tech­ni­cal­ly qual­i­fy for a waiv­er on drug patents under the Agree­ment on Trade-Relat­ed Aspects of Intel­lec­tu­al Prop­er­ty Rights (TRIPS).

    The coun­tries are: Afghanistan; Ango­la; Bangladesh; Benin; Burk­i­na Faso; Burun­di; Cam­bo­dia; Cen­tral African Repub­lic; Chad; Demo­c­ra­t­ic Repub­lic of the Con­go; Dji­bouti; Gam­bia; Guinea; Guinea Bis­sau; Haiti; Lao People’s Demo­c­ra­t­ic Repub­lic; Lesotho; Liberia; Mada­gas­car; Malawi; Mali; Mau­ri­ta­nia; Mozam­bique; Myan­mar; Nepal; Niger; Rwan­da; Sene­gal; Sier­ra Leone; Solomon Islands; Tan­za­nia; Togo; Ugan­da; Van­u­atu; Yemen and Zam­bia.

    HOW DO LDCs BENEFIT?

    The TRIPS pact here allows LDCs to grant a “com­pul­so­ry licence” for cer­tain uses of a patent­ed inven­tion with­out the con­sent of the patent hold­er.

    It orig­i­nal­ly restrict­ed drug pro­duc­tion to serve main­ly domes­tic mar­kets, but amend­ed rules let LDCs export med­i­cines to coun­tries in need because some nations may lack man­u­fac­tur­ing infra­struc­ture.

    The agree­ment will run until at least 2033.

    One of Bangladesh’s largest drug­mak­ers, Bex­im­co Phar­ma­ceu­ti­cals Ltd, told Reuters it planned to pro­duce the drug ini­tial­ly for domes­tic use and would seek gov­ern­ment approval for exports.

    WHAT ABOUT OTHER COUNTRIES?

    Oth­er WTO mem­bers typ­i­cal­ly have to seek licens­es for patent­ed drugs, but may have oth­er recourse.

    India, for instance, can issue a com­pul­so­ry local license to make and sell a drug in cir­cum­stances such as pub­lic need or if a patent­ed drug is not avail­able at an afford­able price. India issued here such a licence in 2012 to a domes­tic firm to make Ger­man drug­mak­er Bay­er’s can­cer med­i­cine Nex­avar.

    Indi­an drug­mak­ers, a key sup­pli­er of cheap med­i­cines to the world, have also struck licens­ing deals. Gilead issued vol­un­tary licens­es here to sev­er­al Indi­an firms in 2014 to make cheap­er ver­sions of its block­buster hepati­tis C drug sofos­bu­vir for India and oth­er coun­tries in need.

    Sim­i­lar deals are like­ly for remde­sivir, after Gilead said state­ment here it was nego­ti­at­ing with sev­er­al gener­ic drug­mak­ers in India and neigh­bour­ing Pak­istan to license and pro­duce the drug for devel­op­ing coun­tries. Gilead did not give details.

    ...

    HOW MANY DOSES WILL BE AVAILABLE?

    Gilead, which has cut by rough­ly a third the process time to make remde­sivir at scale, expects to have more than 1 mil­lion cours­es of treat­ment by Decem­ber and to be able to pro­duce sev­er­al mil­lion in 2021.

    It also said it would donate the first 1.5 mil­lion dos­es.

    While the glob­al drug indus­try races to devel­op a treat­ment or vac­cine for the fast-spread­ing virus, more than 3.68 mil­lion infec­tions have been report­ed world­wide, with over 256,000 deaths.

    HOW MUCH WILL IT COST?

    The Insti­tute for Clin­i­cal and Eco­nom­ic Review (ICER), which weighs drug effec­tive­ness to decide appro­pri­ate prices, put the pro­duc­tion cost of a 10-day course at $10, but sug­gest­ed the price could rise to $4,500 based on patient ben­e­fits shown in clin­i­cal tri­als.

    Bex­im­co said a course of remde­sivir treat­ment could cost between $295 and $781 per patient in Bangladesh.

    ———–

    “Who can make Gilead­’s coro­n­avirus drug, licence free?”; Reuters; 05/06/2020

    “Bex­im­co said a course of remde­sivir treat­ment could cost between $295 and $781 per patient in Bangladesh.”

    How many peo­ple in Bangladesh — A coun­try with a per capi­ta annu­al income of $602 in 2016 — are going to be able to afford $295 to $781 for a course of treat­ments? We just might find out. And that’s the rel­a­tive­ly cheap cost that will pre­sum­ably be much less than what Gilead will be charg­ing in coun­tries like the US. All in all, it’s a pret­ty awful sit­u­a­tion sur­round­ing what is seen as the best hope for med­ical­ly address this dis­ease in the short-run.

    Then again, giv­en that remde­sivir does­n’t actu­al­ly appear to be the won­der drug we were hop­ing for in treat­ing COVID it’s pos­si­ble this will all be moot because the drug is a total bust. Which would be a dif­fer­ent kind of awful sit­u­a­tion.

    Posted by Pterrafractyl | May 7, 2020, 2:26 pm
  14. Here’s a set of arti­cles relat­ed to the sto­ry of remde­sivir and how it became ‘The’ drug that was almost exclu­sive­ly pushed by the Trump admin­is­tra­tion as the top can­di­date for treat­ing severe COVID-19 cas­es despite all the ear­ly indi­ca­tions that should have tem­pered expec­ta­tions:

    First, here’s a State News arti­cle the clin­i­cal tri­al of remde­sivir run by the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases (NIAID) that goes into the inter­nal delib­er­a­tions made on the deci­sion to change the study after the study had already start­ed and then cut it short. Recall how it was the NIAID study that found that remde­sivir cut the days to recov­ery from 15 down to 11 days but did­n’t find a sta­tis­ti­cal­ly sig­nif­i­cant dif­fer­ence in the mor­tal­i­ty rates and based on those results the FDA an “emer­gency use autho­riza­tion” for remde­sivir.

    The arti­cle describes now, ini­tial­ly, the NIAID study was design to test whether or not remde­sivir could save lives (mor­tal­i­ty rates). Patients would received remde­sivir or a place­bo and after 15 days their sta­tus would be assessed on a 1 to 8 scale. But as the results from anoth­er remde­sivir clin­i­cal tri­al in Chi­na start­ed trick­ling in, the NIAID researchers became con­cerned that their study design of only look­ing at the patient sta­tus on day 15 would­n’t be able to show remde­sivir was effec­tive even if it real­ly was effec­tive (recall that the Chi­nese clin­i­cal tri­al found no sta­tis­ti­cal­ly sig­nif­i­cant ben­e­fit to remde­sivir in terms of mor­tal­i­ty). In light this pre­lim­i­nary infor­ma­tion, they made the deci­sion in late March — when only 77 peo­ple were enrolled in the NIAID study — to change the study design to instead mea­sure how long it took for patients to reach a thresh­old lev­el of improve­ment and com­pare the times to improve­ment between the remde­sivir and place­bo group. So they essen­tial­ly mod­i­fied the study to make it eas­i­er to find some sort of pos­i­tive result for remde­sivir based on the pre­lim­i­nary data they were see­ing from stud­ies in Chi­na.

    This deci­sion to change the study design also end­ed up chang­ing the num­ber of peo­ple required to find a sta­tis­ti­cal­ly sig­nif­i­cant result. OF the 1000+ patients ulti­mate­ly enrolled in the study, they only need­ed to wait for 400 of them to achieve that “improved” sta­tus to answer the ques­tion they were answer. So the redesigned study pro­ceed­ed along through April until the inde­pen­dent data and safe­ty mon­i­tor­ing board (DSMB) met and made the rec­om­men­da­tion that the sec­ond phase of the study — com­par­ing a group get­ting remde­sivir to a group get­ting remde­sivir + Eli Lilly’s arthri­tis drug Olu­mi­ant — did­n’t require a place­bo. That deci­sion prompt­ed the researchers to take the peo­ple who had been receiv­ing the place­bo in the first phase of the tri­al and instead put them on remde­sivir.

    It was this deci­sion to take the place­bo patients off of the place­bo in phase I of the tri­al that lim­it­ed the abil­i­ty for the researchers to ulti­mate­ly make a sta­tis­ti­cal­ly sig­nif­i­cant con­clu­sion on whether or not remde­sivir helps reduce mor­tal­i­ty. As the fol­low­ing arti­cle describes, it was a pret­ty con­tro­ver­sial deci­sion, with a num­ber of observers sug­gest­ing they real­ly should have stuck with the ongo­ing place­bo cohort in order to gath­er enough data to make a call on mor­tal­i­ty. As some point­ed out, there was indeed a near­ly sta­tis­ti­cal­ly sig­nif­i­cant result show­ing remde­sivir help with­in mor­tal­i­ty so if they had just stuck with the study a while longer that could have been achieved. The researchers car­ry­ing out the study counter that the results were basi­cal­ly close enough to demon­strate remde­sivir helps patients and so with­hold­ing access to the remde­sivir from the place­bo group just to get a small about a sta­tis­ti­cal boost was­n’t worth it in terms of the poten­tial costs to lives.

    As the arti­cle makes clear, there is no obvi­ous answer on whether or not they should have stuck with the place­bo tri­al to get a sta­tis­ti­cal­ly sig­nif­i­cant result and all of those inter­viewed agree it was dif­fi­cult deci­sion either way. But at the very end of the arti­cle, Ethan Weiss, a car­di­ol­o­gist at the Uni­ver­si­ty of Cal­i­for­nia, San Fran­cis­co, makes per­haps the most rel­e­vant point about this debate: the fact that there are A LOT more clin­i­cal tri­als going on right now to test all sorts of dif­fer­ent drugs is the real fail­ing here. It’s not real­ly con­tro­ver­sial that these dif­fi­cult deci­sions had to be made in this remde­sivir clin­i­cal tri­al giv­en twin needs to treat death­ly ill patients while find­ing answers to ques­tions about which treat­ments work. The prob­lem is the infra­struc­ture does­n’t exist to con­duct a lot more stud­ies like this dur­ing an emerg­ing pan­dem­ic. As Weiss puts it, “We’ve squan­dered an incred­i­ble oppor­tu­ni­ty to do good sci­ence. If we could ever go back and do some­thing all over, it would be the infra­struc­ture to actu­al­ly learn some­thing. Because we’re not learn­ing enough.”

    And that cri­tique again leads us to the ques­tion of why remde­sivir has been almost exclu­sive­ly focused in on in the quest for COVID drugs. Why has there been almost no mean­ing­ful inter­est in the ear­ly reports of remark­able results from “Thai cock­tail” or Oya­Gen’s Oya1 com­pound while almost all of the atten­tion has been on remde­sivir, a drug that’s dif­fi­cult to man­u­fac­ture and can only be admin­is­tered in a hos­pi­tal set­ting? Those are the kinds of ques­tions that need to be asked in the con­text of the broad­er chal­lenge of set­ting up a greater capac­i­ty for clin­i­cal tri­als.

    Now, as we’re going to see in the sec­ond and third arti­cle excerpts below, it turns out a group of bil­lion­aires and ven­ture cap­i­tal­ists have been basi­cal­ly design­ing the White House­’s approach to lead­ing the efforts to find­ing a covid drug ther­a­py and just so hap­pens that the groups has been pro­mot­ing remde­sivir. The group is call­ing itself “Sci­en­tists to Stop COVID-19,” and describes itself as an “ad hoc review board” for the tor­rent of coro­n­avirus research, “weed­ing out” flawed data before it reach­es pol­i­cy­mak­ers. The group has ties to Peter Thiel and oth­er Trump admin­is­tra­tion fig­ures and is also report­ed­ly act­ing as a go-between for phar­ma­ceu­ti­cal com­pa­nies seek­ing to build a com­mu­ni­ca­tion chan­nel with Trump admin­is­tra­tion offi­cials. Recall how Thiel’s Palan­tir has already been giv­en major fed­er­al con­tracts for han­dling the data aggre­ga­tion and analy­sis for track­ing the pan­dem­ic. So there’s an infor­mal group of bil­lion­aires with phar­ma­ceu­ti­cal com­pa­ny ties that appears to be shap­ing the Trump admin­is­tra­tion’s efforts to find a drug ther­a­py and this group has appar­ent­ly been push­ing remde­sivir quite a bit.

    As we’re going to see, the group set of rec­om­men­da­tions were almost sin­gu­lar­ly focused on remde­sivir. You can see it’s 17-page set of rec­om­men­da­tions here. Look at the “First Wave: Repur­posed drugs” part of the doc­u­ment. It’s almost ALL about remde­sivir. The group is so pro-remde­sivir that it even men­tion how the group is now rec­om­mend­ing remde­sivir be giv­en in an ear­ly stage of the infec­tion, the kind of move that makes the drug effec­tive­ly worth­less because almost EVERYONE will need to be put on remde­sivir for that ther­a­py approach to work. Giv­ing it ear­ly on in an infec­tion might be appro­pri­ate for peo­ple in very high risk groups (e.g. peo­ple with com­pro­mised immune sys­tems), but it would have to be lim­it­ed to those patients for the sup­ply to be remote­ly ade­quate. It’s basi­cal­ly look­ing for an excuse to use rem­di­sivir after the ini­tial high hopes for the drug fiz­zled.

    So over­all it sounds like one of the big ques­tions fac­ing the world in terms of how to deal with future nov­el viral out­breaks is the ques­tion of what needs to be done in advance of that out­break to ensure there’s the avail­able capac­i­ty for large num­bers of par­al­lel clin­i­cal tri­als. But that’s a ques­tion for future out­breaks. It’s too late to do that in this out­break. We’ve already wast­ed that pre­cious time in set­ting up the infra­struc­ture for car­ry­ing out more clin­i­cal tri­als. So for this out­break the more rel­e­vant ques­tion is whether or not the bil­lion­aire-backed “Sci­en­tists to Stop COVID-19” is using its influ­ence with the Trump admin­is­tra­tion to ensure only their favored drugs get the favored treat­ment when pri­or­i­tiz­ing which drug are tapped for those lim­it­ed tri­als.

    Ok, here’s that Stat News arti­cle on inter­nal delib­er­a­tions behind the deci­sions to mod­i­fy the NIAID study design and then cut it short before the ques­tion of remde­sivir’s impact on mor­tal­i­ty could actu­al­ly be answered:

    Stat News

    Inside the NIH’s con­tro­ver­sial deci­sion to stop its big remde­sivir study

    By Matthew Her­p­er @matthewherper
    May 11, 2020

    The drug mak­er Gilead Sci­ences released a bomb­shell two weeks ago: A study con­duct­ed by a U.S. gov­ern­ment agency had found that the company’s exper­i­men­tal drug, remde­sivir, was the first treat­ment shown to have even a small effect against Covid-19.

    Behind that ray of hope, though, was one of the tough­est quan­daries in med­i­cine: how to bal­ance the need to rig­or­ous­ly test a new med­i­cine for safe­ty and effec­tive­ness with the moral imper­a­tive to get patients a treat­ment that works as quick­ly as pos­si­ble. At the heart of the deci­sion about when to end the tri­al was a process that was — as is often in the case in clin­i­cal tri­als — by turns secre­tive and bureau­crat­ic.

    The Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases has described to STAT in new detail how it made its fate­ful deci­sion: to start giv­ing remde­sivir to patients who had been assigned to receive a place­bo in the study, essen­tial­ly lim­it­ing researchers’ abil­i­ty to col­lect more data about whether the drug saves lives — some­thing the study, called ACTT‑1, sug­gests but does not prove. In the tri­al, 8% of the par­tic­i­pants giv­en remde­sivir died, com­pared with 11.6% of the place­bo group, a dif­fer­ence that was not sta­tis­ti­cal­ly sig­nif­i­cant.

    A top NIAID offi­cial said he had no regrets about the deci­sion.

    “There cer­tain­ly was una­nim­i­ty with­in the insti­tute that this was the right thing to do,” said H. Clif­ford Lane, NIAID’s clin­i­cal direc­tor. “While I think there might’ve been some dis­cus­sion, [because] every­one always tries to play devil’s advo­cate in these dis­cus­sions, I think there was a pret­ty uni­form opin­ion that this was what we should do.”

    From the stand­point of the agency, he said, the study had answered the ques­tion it was designed to answer: The medi­an time that hos­pi­tal­ized Covid-19 patients on remde­sivir took to stop need­ing oxy­gen or exit the hos­pi­tal was, at 11 days, four days short­er than those who were on place­bo. “How many patients would we want to put at risk of dying,” he asked, for that last lit­tle bit of proof? Remde­sivir, he not­ed, was not a home run, but is prob­a­bly bet­ter than noth­ing.

    Steven Nis­sen, a vet­er­an tri­al­ist and car­di­ol­o­gist at the Cleve­land Clin­ic, dis­agreed that giv­ing place­bo patients remde­sivir was the right call. “I believe it is in society’s best inter­est to deter­mine whether remde­sivir can reduce mor­tal­i­ty, and with the release of this infor­ma­tion doing a place­bo-con­trolled tri­al to deter­mine if there is a mor­tal­i­ty ben­e­fit will be very dif­fi­cult,” he said. “The ques­tion is: Was there a route, or is there a route, to deter­mine if the drug can pre­vent death?” The deci­sion is “a lost oppor­tu­ni­ty,” he said.

    Peter Bach, the direc­tor of the Cen­ter for Health Pol­i­cy and Out­comes at Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter, agreed with Nis­sen. “The core under­stand­ing of clin­i­cal research par­tic­i­pa­tion and clin­i­cal research con­duct is we run the tri­al rig­or­ous­ly to pro­vide the most accu­rate infor­ma­tion about the right treat­ment,” he said. And that answer, he argued, should ide­al­ly have deter­mined whether remde­sivir saves lives.

    The rea­son we have shut our whole soci­ety down, Bach said, is not to pre­vent Covid-19 patients from spend­ing a few more days in the hos­pi­tal. It is to pre­vent patients from dying. “Mor­tal­i­ty is the right end­point,” he said.

    Most experts con­tact­ed by STAT expressed opin­ions that fell between Nis­sen and Lane, believ­ing that the deci­sion was a dif­fi­cult case, with sev­er­al defend­ing the NIAID.

    “I think it was a real­ly tough call,” said Janet Wittes, a promi­nent sta­tis­ti­cian and the pres­i­dent of Sta­tis­tics Col­lab­o­ra­tive.

    When the remde­sivir results were announced, the NIH said the data came from an “inter­im” analy­sis. This means that a study was stopped ear­ly because a drug’s ben­e­fit was so unde­ni­able that it would be uneth­i­cal to con­tin­ue the study. But Lane said this was incor­rect. The data come from a pre­lim­i­nary final analy­sis, a point at which the study would nor­mal­ly end.

    The ACTT study (short for Adap­tive Covid-19 Treat­ment Tri­al) began in late Feb­ru­ary. The first patient dosed in the study was an Amer­i­can repa­tri­at­ed from the Dia­mond Princess, a British cruise ship where there was an out­break of more than 800 Covid-19 cas­es. By the terms of the study, hos­pi­tal­ized patients were ran­dom­ly assigned to receive either intra­venous remde­sivir or a place­bo. On day 15, the study would score patients on a scale from 1 (dead) to 8 (not hos­pi­tal­ized, with no restric­tions on activ­i­ties).

    As results from oth­er Covid-19 stud­ies con­duct­ed in Chi­na start­ed to trick­le in, Lane and his team began to wor­ry that look­ing at the out­come on only the 15th day could lead the study to fail even if the drug was effec­tive. On March 22, with only 77 patients enrolled in the study, mem­bers of the NIAID team had a con­fer­ence call on which they decid­ed to change the mea­sure that would be used. Instead of mea­sur­ing patients on an eight-point scale on one day, the study would mea­sure the time until the patients scored one of the best three out­comes on the scale. This deci­sion was final­ized on April 2; it was post­ed to clinicaltrials.gov, a gov­ern­ment reg­istry of clin­i­cal tri­als, on April 16.

    Iron­i­cal­ly, Lane said, the study would still have been pos­i­tive if the change had not been made. But the change in the study’s main goal also changed the way the study would be ana­lyzed. Now, the NIAID decid­ed, the analy­sis would be cal­cu­lat­ed when 400 patients out of the 1,063 patients the study enrolled had recov­ered. If remde­sivir turned out to be much more effec­tive than expect­ed, “inter­im” analy­ses would be con­duct­ed at a third and two-thirds that num­ber.

    The job of review­ing these analy­ses would fall to a com­mit­tee of out­side experts on what is known as an inde­pen­dent data and safe­ty mon­i­tor­ing board, or DSMB. Though they gen­er­al­ly go unseen, DSMBs are among the most impor­tant and pow­er­ful forces in med­ical research. They are allowed to ana­lyze the data from a tri­al while it’s ongo­ing, even as drug com­pa­nies, doc­tors, and patients are kept from know­ing who is get­ting the med­i­cine and who is get­ting place­bo. These boards have two jobs: to make sure that patients aren’t being harmed by the exper­i­men­tal drug, and to ensure that it’s not already clear beyond a doubt that a med­i­cine is effec­tive.

    Those deci­sions bring moments of tri­umph, despair, and, occa­sion­al­ly, con­fu­sion.

    When Mer­ck decid­ed to with­draw the painkiller Vioxx in 2004, it was because a DSMB had rec­om­mend­ed stop­ping a study of the drug when it became clear the med­i­cine increased the risk of heart attacks and strokes. In 2014, when a study of the can­cer immunother­a­py Opdi­vo first proved that drug extend­ed sur­vival in melanoma, it was because a DSMB had found the result incon­tro­vert­ible and rec­om­mend­ed stop­ping the study.

    But the DSMB for the remde­sivir study did not ever meet for an inter­im effi­ca­cy analy­sis, Lane said. All patients had been enrolled by April 20. The data for a DSMB meet­ing was cut off on April 22. The DSMB met and, on April 27, it made a rec­om­men­da­tion to the NIAID.

    That rec­om­men­da­tion was not about whether the patients on place­bo should receive remde­sivir. Instead, the DSMB rec­om­mend­ed that in the next phase of the study, test­ing Eli Lilly’s arthri­tis drug Olu­mi­ant against remde­sivir, there was no need for a place­bo-only group.

    That deci­sion, Lane said, led the NIAID to con­clude that patients who had been giv­en place­bo should be offered remde­sivir, some­thing that start­ed hap­pen­ing after April 28.

    This is where Nis­sen and Bach dis­agree. There were 1,063 patients in the study, but only 480 had recov­ered at the time of the analy­sis. Researchers could have col­lect­ed more data, they argue, and per­haps have learned if remde­sivir saves lives. They were already close, both note. Results are con­sid­ered “sig­nif­i­cant” if a mea­sure called a p‑value is less than 0.05; the val­ue for mor­tal­i­ty in the pre­lim­i­nary analy­sis was 0.059. “How many patients would we want to put at risk of dying to get that 0.01 on the p‑value,” Lane retort­ed.

    Marc Pfef­fer, a car­di­ol­o­gist at the Brigham and Women’s Hos­pi­tal in Boston, said he believes NIAID made the right call. He said that he was “very sym­pa­thet­ic” to the fact that researchers were get­ting this study done dur­ing a pan­dem­ic. “If you make the deci­sion that remde­sivir should be part of everybody’s ther­a­py in the next phase, then those vol­un­teers tak­ing the risks in the cur­rent tri­al should be switched to the active ther­a­py now con­sid­ered effec­tive,” he said.

    ...

    Wittes, of Sta­tis­tics Col­lab­o­ra­tive, said she is glad she wasn’t on this DSMB, adding, “I don’t know where I would have come out.” And she said that when full results of the study are avail­able, she would be “shocked” if the NIAID had not done things prop­er­ly.

    “I think there are groups of peo­ple who you’d real­ly respect who would not have stopped a study like this with­out a mor­tal­i­ty ben­e­fit,” Wittes said. “And I think you can argue that both ways.”

    But she also wor­ried that the evi­dence might not be strong enough to make the deci­sion soci­ety is now mak­ing: that every new Covid-19 treat­ment must be giv­en with or com­pared to remde­sivir.

    “The dan­ger is now it’s the treat­ment for every­body,” she said. “Now this is the base drug and every­thing is going to be that plus some­thing or the con­trol. I think we don’t know if it’s strong enough for it to be the stan­dard of care. I don’t think we know who should be treat­ed.”

    Steven Joffe, an ethics expert at the Uni­ver­si­ty of Penn­syl­va­nia, said he believes the NIAID like­ly took the right steps in mak­ing its deci­sion to give remde­sivir to the place­bo patients. But he wor­ries about decid­ing to use time to improve­ment, not death, as the mea­sure of suc­cess, in the first place.

    “I don’t find this end­point very com­pelling, and to me the real issue is the deci­sion to design the tri­al around the end­point of time to recov­ery defined in the way they defined recov­ery,” Joffe said. “To me, the deci­sions that are this weighty ought to be based on clin­i­cal­ly impor­tant end­points.”

    All of this would nor­mal­ly wait until the full results were pub­lished, at which point the ros­ter of the DSMB may be revealed. (Lane would not share their names.) But what is unusu­al in this case is that, before the data are even ful­ly ana­lyzed, the FDA has autho­rized remdesivir’s use. A Chi­nese study, mean­while, failed to show remde­sivir had a ben­e­fit. Sev­er­al more stud­ies of the drug expect­ed to read out soon.

    Ethan Weiss, a car­di­ol­o­gist at the Uni­ver­si­ty of Cal­i­for­nia, San Fran­cis­co, who trav­eled to New York two weeks ago to treat Covid-19 patients, said that he does wor­ry that we have missed “a fleet­ing oppor­tu­ni­ty” to under­stand how well remde­sivir works. “It is sad to me that we’re not going to get a com­plete answer about it.” But he said he also thinks the issue is “inside base­ball.” Remde­sivir, as sev­er­al experts have point­ed out, is not a game chang­er.

    The real prob­lem, Weiss said, is not the han­dling of this par­tic­u­lar study but that there aren’t more like it. He said he wished the U.S. had built the infra­struc­ture need­ed to do more stud­ies like this when the pan­dem­ic in New York was at its height. He wished there were more stud­ies, with more DSMBs.

    “We’ve squan­dered an incred­i­ble oppor­tu­ni­ty to do good sci­ence,” Weiss said. “If we could ever go back and do some­thing all over, it would be the infra­struc­ture to actu­al­ly learn some­thing. Because we’re not learn­ing enough.”

    ———-

    “Inside the NIH’s con­tro­ver­sial deci­sion to stop its big remde­sivir study” by Matthew Her­p­er; Stat News; 05/11/2020

    The Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases has described to STAT in new detail how it made its fate­ful deci­sion: to start giv­ing remde­sivir to patients who had been assigned to receive a place­bo in the study, essen­tial­ly lim­it­ing researchers’ abil­i­ty to col­lect more data about whether the drug saves lives — some­thing the study, called ACTT‑1, sug­gests but does not prove. In the tri­al, 8% of the par­tic­i­pants giv­en remde­sivir died, com­pared with 11.6% of the place­bo group, a dif­fer­ence that was not sta­tis­ti­cal­ly sig­nif­i­cant. ”

    One thing we can say for sure about the deci­sion to end the place­bo part of the tri­al and give place­bo patients remde­sivir is that it could­n’t have been an easy deci­sion. It was a deci­sion of whether or not to let the peo­ple on place­bos get the drug after there was sta­tis­ti­cal­ly insignif­i­cant (but near­ly sig­nif­i­cant evi­dence) that the drug helps. Do they with­hold treat­ments in order to prove the treat­ment helps if they already strong­ly sus­pect it helps? That’s the ques­tion they faced and the NIAID decid­ed to grant the place­bo cohort the treat­ment and leave the ques­tion of whether or not remde­sivir helps with mor­tal­i­ty an open ques­tion:

    ...
    The ACTT study (short for Adap­tive Covid-19 Treat­ment Tri­al) began in late Feb­ru­ary. The first patient dosed in the study was an Amer­i­can repa­tri­at­ed from the Dia­mond Princess, a British cruise ship where there was an out­break of more than 800 Covid-19 cas­es. By the terms of the study, hos­pi­tal­ized patients were ran­dom­ly assigned to receive either intra­venous remde­sivir or a place­bo. On day 15, the study would score patients on a scale from 1 (dead) to 8 (not hos­pi­tal­ized, with no restric­tions on activ­i­ties).

    As results from oth­er Covid-19 stud­ies con­duct­ed in Chi­na start­ed to trick­le in, Lane and his team began to wor­ry that look­ing at the out­come on only the 15th day could lead the study to fail even if the drug was effec­tive. On March 22, with only 77 patients enrolled in the study, mem­bers of the NIAID team had a con­fer­ence call on which they decid­ed to change the mea­sure that would be used. Instead of mea­sur­ing patients on an eight-point scale on one day, the study would mea­sure the time until the patients scored one of the best three out­comes on the scale. This deci­sion was final­ized on April 2; it was post­ed to clinicaltrials.gov, a gov­ern­ment reg­istry of clin­i­cal tri­als, on April 16.

    Iron­i­cal­ly, Lane said, the study would still have been pos­i­tive if the change had not been made. But the change in the study’s main goal also changed the way the study would be ana­lyzed. Now, the NIAID decid­ed, the analy­sis would be cal­cu­lat­ed when 400 patients out of the 1,063 patients the study enrolled had recov­ered. If remde­sivir turned out to be much more effec­tive than expect­ed, “inter­im” analy­ses would be con­duct­ed at a third and two-thirds that num­ber.

    ...

    But the DSMB for the remde­sivir study did not ever meet for an inter­im effi­ca­cy analy­sis, Lane said. All patients had been enrolled by April 20. The data for a DSMB meet­ing was cut off on April 22. The DSMB met and, on April 27, it made a rec­om­men­da­tion to the NIAID.

    That rec­om­men­da­tion was not about whether the patients on place­bo should receive remde­sivir. Instead, the DSMB rec­om­mend­ed that in the next phase of the study, test­ing Eli Lilly’s arthri­tis drug Olu­mi­ant against remde­sivir, there was no need for a place­bo-only group.

    That deci­sion, Lane said, led the NIAID to con­clude that patients who had been giv­en place­bo should be offered remde­sivir, some­thing that start­ed hap­pen­ing after April 28.

    This is where Nis­sen and Bach dis­agree. There were 1,063 patients in the study, but only 480 had recov­ered at the time of the analy­sis. Researchers could have col­lect­ed more data, they argue, and per­haps have learned if remde­sivir saves lives. They were already close, both note. Results are con­sid­ered “sig­nif­i­cant” if a mea­sure called a p‑value is less than 0.05; the val­ue for mor­tal­i­ty in the pre­lim­i­nary analy­sis was 0.059. “How many patients would we want to put at risk of dying to get that 0.01 on the p‑value,” Lane retort­ed.

    ...

    Note that next phase of the tri­al, com­par­ing remde­sivir to remde­sivir + Olu­mi­ant, is just get­ting under­way now.

    But it’s Ethan Weiss who makes per­haps the most impor­tant point regard­ing the debates over these remde­sivir study designs: it’s insane that there aren’t more clin­i­cal tri­als going on right now for more drug ther­a­pies:

    ...
    Ethan Weiss, a car­di­ol­o­gist at the Uni­ver­si­ty of Cal­i­for­nia, San Fran­cis­co, who trav­eled to New York two weeks ago to treat Covid-19 patients, said that he does wor­ry that we have missed “a fleet­ing oppor­tu­ni­ty” to under­stand how well remde­sivir works. “It is sad to me that we’re not going to get a com­plete answer about it.” But he said he also thinks the issue is “inside base­ball.” Remde­sivir, as sev­er­al experts have point­ed out, is not a game chang­er.

    The real prob­lem, Weiss said, is not the han­dling of this par­tic­u­lar study but that there aren’t more like it. He said he wished the U.S. had built the infra­struc­ture need­ed to do more stud­ies like this when the pan­dem­ic in New York was at its height. He wished there were more stud­ies, with more DSMBs.

    “We’ve squan­dered an incred­i­ble oppor­tu­ni­ty to do good sci­ence,” Weiss said. “If we could ever go back and do some­thing all over, it would be the infra­struc­ture to actu­al­ly learn some­thing. Because we’re not learn­ing enough.”
    ...

    Civ­i­liza­tion basi­cal­ly put all of its drug ‘eggs’ in the remde­sivir ‘bas­ket’. That’s why the debates over these stud­ies are so important...because we haven’t real­ly been aggres­sive­ly look­ing into oth­er drugs simul­ta­ne­ous­ly like we should have. So why is that? Is it a lack of phys­i­cal infra­struc­ture or is it a lack of orga­ni­za­tion? Those are impor­tant ques­tions to answer going for­ward regard­ing future epi­demics. But for this one, a big­ger loom­ing ques­tion is what on earth is the agen­da of “Sci­en­tists to Stop COVID-19” because it sure sounds like this is the group that’s shap­ing the US’s fed­er­al pol­i­cy on seek­ing out drug ther­a­pies. And while the group claims to have no finan­cial inter­ests in mind for their efforts, that’s a lit­tle hard to believe when you look at who is behind:

    New York Post

    Sci­en­tists, bil­lion­aires team up to aid White House in coro­n­avirus bat­tle

    By Mark Moore

    April 28, 2020 | 3:55pm | Updat­ed

    A group of sci­en­tists and bil­lion­aires has joined forces to form a con­tem­po­rary “Man­hat­tan Project” designed to help the White House bat­tle the coro­n­avirus out­break, accord­ing to a report.

    Call­ing them­selves “Sci­en­tists to Stop COVID-19,” the col­lec­tion of top researchers, bil­lion­aires and indus­try cap­tains will act as an “ad hoc review board” for the tor­rent of coro­n­avirus research, “weed­ing out” flawed data before it reach­es pol­i­cy­mak­ers, the Wall Street Jour­nal report­ed on Mon­day.

    They are also act­ing as a go-between for phar­ma­ceu­ti­cal com­pa­nies seek­ing to build a com­mu­ni­ca­tion chan­nel with Trump admin­is­tra­tion offi­cials.

    The group — who have likened their effort to the World War II-era “Man­hat­tan Project,” which devel­oped the atom­ic bomb — has advised Nick Ayers, an aide to Vice Pres­i­dent Mike Pence, as well as oth­er agency heads, in the past month.

    Pence is head­ing up the White House coro­n­avirus task force.

    The brainy bunch is led by Thomas Cahill, a 33-year-old doc­tor who became a ven­ture cap­i­tal­ist, and includes 2017 Nobel Prize win­ner Michael Ros­bash, a neu­ro­sci­en­tist and pro­fes­sor of biol­o­gy at Bran­deis Uni­ver­si­ty, and Stu­art Schreiber, a Har­vard chem­istry and chem­i­cal biol­o­gy pro­fes­sor.

    Cahill’s clout comes from build­ing con­nec­tions through his invest­ment firm, New­path Part­ners, with Sil­i­con Valley’s Peter Thiel, the founder of Pay­Pal, and bil­lion­aire busi­ness­men Jim Palot­ta and Michael Milken.

    Mem­bers of the group say they aren’t in it for finan­cial gain, but are moti­vat­ed by pro­vid­ing assis­tance for a fight that has strained fed­er­al and state gov­ern­ments, dealt a cru­cial blow to the econ­o­my and ulti­mate­ly infect­ed more than 3 mil­lion world­wide.

    “We may fail,” Schreiber told the Jour­nal. “But if it suc­ceeds, it could change the world.”

    The group has com­piled a 17-page plan that offers “four action­able, non-par­ti­san pro­pos­als to pro­duce safe and effec­tive COVID-19 ther­a­peu­tics and vac­cines in the short­est pos­si­ble time­frame, and to reopen our soci­ety in a man­ner that reduces the risk of future COVID-19 out­breaks,” the Wall Street Jour­nal report­ed.

    Steve Pagli­u­ca, the co-own­er of the Boston Celtics, who helped copy edit some of the report, passed a copy to the CEO of Gold­man Sachs Group Inc., David Solomon, who got it to Trea­sury Sec­re­tary Steven Mnuchin.

    Among the pro­pos­als are repur­pos­ing estab­lished drugs on a “great­ly accel­er­at­ed time scale” and devel­op­ing anti­bod­ies that could be used to “pro­tect healthy crit­i­cal work­ers, as well as ‘high-risk’ indi­vid­u­als.”

    One of the promis­ing drugs is remde­sivir, which was devel­oped for use against Ebo­la.

    ...

    ———–

    “Sci­en­tists, bil­lion­aires team up to aid White House in coro­n­avirus bat­tle” by Mark Moore; New York Post; 04/28/2020

    “Call­ing them­selves “Sci­en­tists to Stop COVID-19,” the col­lec­tion of top researchers, bil­lion­aires and indus­try cap­tains will act as an “ad hoc review board” for the tor­rent of coro­n­avirus research, “weed­ing out” flawed data before it reach­es pol­i­cy­mak­ers, the Wall Street Jour­nal report­ed on Mon­day.”

    An “ad hoc review board” that will be “weed­ing out” flawed data before it reach­es pol­i­cy mak­ers. So this pri­vate group has basi­cal­ly assumed the role of data-gate­keep­er for the Trump White House. Now, if this was just a group of sci­en­tists that would be one thing, but this is a group led by a ven­ture cap­i­tal­ists with ties to fig­ures like Peter Thiel of bil­lion­aire and is act­ing as a go-between for phar­ma­ceu­ti­cal com­pa­nies. That’s the group that’s “weed­ing out” flawed data before it reach­es pol­i­cy­mak­ers:

    ...
    They are also act­ing as a go-between for phar­ma­ceu­ti­cal com­pa­nies seek­ing to build a com­mu­ni­ca­tion chan­nel with Trump admin­is­tra­tion offi­cials.

    The group — who have likened their effort to the World War II-era “Man­hat­tan Project,” which devel­oped the atom­ic bomb — has advised Nick Ayers, an aide to Vice Pres­i­dent Mike Pence, as well as oth­er agency heads, in the past month.

    Pence is head­ing up the White House coro­n­avirus task force.

    The brainy bunch is led by Thomas Cahill, a 33-year-old doc­tor who became a ven­ture cap­i­tal­ist, and includes 2017 Nobel Prize win­ner Michael Ros­bash, a neu­ro­sci­en­tist and pro­fes­sor of biol­o­gy at Bran­deis Uni­ver­si­ty, and Stu­art Schreiber, a Har­vard chem­istry and chem­i­cal biol­o­gy pro­fes­sor.

    Cahill’s clout comes from build­ing con­nec­tions through his invest­ment firm, New­path Part­ners, with Sil­i­con Valley’s Peter Thiel, the founder of Pay­Pal, and bil­lion­aire busi­ness­men Jim Palot­ta and Michael Milken.

    Mem­bers of the group say they aren’t in it for finan­cial gain, but are moti­vat­ed by pro­vid­ing assis­tance for a fight that has strained fed­er­al and state gov­ern­ments, dealt a cru­cial blow to the econ­o­my and ulti­mate­ly infect­ed more than 3 mil­lion world­wide.

    “We may fail,” Schreiber told the Jour­nal. “But if it suc­ceeds, it could change the world.”
    ...

    And note how the group com­piled a 17-page plan on devel­op­ing ther­a­pies that includes pro­mot­ing remde­sivir:

    ...
    The group has com­piled a 17-page plan that offers “four action­able, non-par­ti­san pro­pos­als to pro­duce safe and effec­tive COVID-19 ther­a­peu­tics and vac­cines in the short­est pos­si­ble time­frame, and to reopen our soci­ety in a man­ner that reduces the risk of future COVID-19 out­breaks,” the Wall Street Jour­nal report­ed.

    Steve Pagli­u­ca, the co-own­er of the Boston Celtics, who helped copy edit some of the report, passed a copy to the CEO of Gold­man Sachs Group Inc., David Solomon, who got it to Trea­sury Sec­re­tary Steven Mnuchin.

    Among the pro­pos­als are repur­pos­ing estab­lished drugs on a “great­ly accel­er­at­ed time scale” and devel­op­ing anti­bod­ies that could be used to “pro­tect healthy crit­i­cal work­ers, as well as ‘high-risk’ indi­vid­u­als.”

    One of the promis­ing drugs is remde­sivir, which was devel­oped for use against Ebo­la.
    ...

    So is Gilead one of the phar­ma­ceu­ti­cal com­pa­nies that’s been work­ing with this group?

    Now, it’s unclear from that report just how much empha­sis this group has been plac­ing on remde­sivir as opposed to oth­er drugs. But based on the fol­low­ing arti­cle, it sounds like the group rec­om­mend­ed the US fed­er­al gov­ern­ment work with Gilead to expe­dite clin­i­cal tri­als on remde­sivir and is now rec­om­mend­ing the drug be used at an ear­ly stage of the infec­tion. Again, don’t for­get that the rec­om­men­da­tions that remde­sivir be giv­en at an ear­ly stage of the infec­tion is basi­cal­ly fall­back posi­tion after the drug has failed to show a strong effect on severe­ly ill patients, but it’s a fall­back posi­tion that could cause demand for remde­sivir to spike and make Gilead a lot more mon­ey. So, again, we have to ask: has the fed­er­al gov­ern­ments extreme focus on remde­sivir been shaped, in part, by the influ­ence of “Sci­en­tists to Stop COVID-19”?:

    The Hill

    Elite group of sci­en­tists and bil­lion­aires are work­ing togeth­er to fight the coro­n­avirus pan­dem­ic

    A mod­ern Man­hat­tan Project, called Sci­en­tists to Stop COVID-19, has been formed to help the U.S. cre­ate a treat­ment plan to fight the COVID-19 out­break.

    By Alexan­dra Kel­ley
    Pub­lished on Apr 28, 2020

    A new Wall Street Jour­nal report chron­i­cles the for­ma­tion of a Jus­tice League-esque team of sci­en­tists, doc­tors, ven­ture cap­i­tal­ists and Nobel lau­re­ates ded­i­cat­ed to devel­op­ing a com­pre­hen­sive plan to fight the coro­n­avirus.

    The group, apt­ly named Sci­en­tists to Stop COVID-19, describe them­selves as “pas­sion­ate cit­i­zen-sci­en­tists” who have devel­oped “four action­able, non-par­ti­san pro­pos­als to pro­duce safe and effec­tive COVID-19 ther­a­peu­tics and vac­cines in the short­est pos­si­ble time­frame,” per a 17-page intro­duc­to­ry doc­u­ment obtained by reporter Rob Copeland.

    A ven­ture cap­i­tal­ist and physi­cian named Tom Cahill report­ed­ly orga­nized the group to help fast-track a viable treat­ment for the coro­n­avirus. His con­nec­tions in both the elite finan­cial and med­ical spheres helped him pitch the idea of a group ded­i­cat­ed to devel­op­ing research to fight the virus.

    Sci­en­tists to Stop COVID-19, who have effec­tive­ly become a van­guard for coro­n­avirus research, high­light the steps the U.S. must under­take in order to safe­ly recov­er from the virus. The group envi­sions the recov­ery in waves, the first char­ac­ter­ized by the use of exist­ing drugs to gain a sol­id foothold against the virus. The sec­ond wave will fea­ture treat­ments com­posed of new anti­body drugs to neu­tral­ize the virus.

    The third wave envi­sioned by the orga­ni­za­tion con­sists of long-term vac­ci­na­tions to com­bat the coro­n­avirus that will offer sea­son­al and mul­ti-year immu­ni­ty. Simul­ta­ne­ous­ly, busi­ness­es, schools and oth­er pub­lic insti­tu­tions should begin to reopen around May and June of 2020, guid­ed by symp­tom report­ing, test­ing and per­son­al pro­tec­tive gear to min­i­mize future out­breaks.

    Cur­rent­ly, the U.S. is in the first wave of the plan. Sci­en­tists to Stop COVID-19 rec­om­mends that in this phase, the U.S. Food and Drug Admin­is­tra­tion (FDA) should work to coor­di­nate with Gilead phar­ma­ceu­ti­cals to focus on expe­dit­ing the results of clin­i­cal tri­als of remde­sivir, a drug iden­ti­fied as a poten­tial treat­ment for COVID-19. The group also rec­om­mends admin­is­ter­ing dos­es of the drug to patients in an ear­ly stage of infec­tion, and notes remde­sivir will essen­tial­ly be a place­hold­er until a more effec­tive treat­ment is pro­duced.

    Gov­ern­ment enti­ties and agen­cies appear to adhere to the rec­om­men­da­tions out­lined by the group, with the Jour­nal report­ing that the FDA and the Depart­ment of Vet­er­ans Affairs (VA) have imple­ment­ed some of the sug­ges­tions, name­ly relax­ing drug man­u­fac­tur­er reg­u­la­tions and require­ments for poten­tial coro­n­avirus treat­ment drugs.

    Sci­en­tists to Stop COVID-19’s reach and influ­ence can be attrib­uted to the pres­tige of both its mem­ber­ship and its investor base. The pow­er­ful net­work­ing these con­tacts facil­i­tat­ed even­tu­al­ly helped get the group’s report to the White House Coro­n­avirus Task Force mem­bers like Trea­sury Sec­re­tary Steven Mnuchin.

    Sci­en­tists to Stop COVID-19 wrote that no one cur­rent­ly involved in the group has any direct or known indi­rect finan­cial inter­est that they stand to gain from when par­tic­i­pat­ing in research.

    ...

    ———–

    “Elite group of sci­en­tists and bil­lion­aires are work­ing togeth­er to fight the coro­n­avirus pan­dem­ic” by Alexan­dra Kel­ley; The Hill; 04/28/2020

    Gov­ern­ment enti­ties and agen­cies appear to adhere to the rec­om­men­da­tions out­lined by the group, with the Jour­nal report­ing that the FDA and the Depart­ment of Vet­er­ans Affairs (VA) have imple­ment­ed some of the sug­ges­tions, name­ly relax­ing drug man­u­fac­tur­er reg­u­la­tions and require­ments for poten­tial coro­n­avirus treat­ment drugs.”

    Gov­ern­ment enti­ties and agen­cies appear to adhere to the rec­om­men­da­tions out­lined by the group. That’s what we’re see­ing. So whether or not the group for­mal­ly has author­i­ty to make these deci­sions, it appears to have infor­mal author­i­ty. And it’s been using that infor­mal author­i­ty to rec­om­mend exact­ly what we’ve seen: the US fed­er­al gov­ern­ment work­ing with Gilead to expe­dite the clin­i­cal tri­als of remde­sivir. And now the group is also rec­om­mend­ing admin­is­ter­ing remde­sivir to patients ear­ly on, a rec­om­men­da­tion that’s tac­it admis­sion that the drug has mod­est ben­e­fits at best but they’re con­tin­u­ing to push it any­way:

    ...
    Cur­rent­ly, the U.S. is in the first wave of the plan. Sci­en­tists to Stop COVID-19 rec­om­mends that in this phase, the U.S. Food and Drug Admin­is­tra­tion (FDA) should work to coor­di­nate with Gilead phar­ma­ceu­ti­cals to focus on expe­dit­ing the results of clin­i­cal tri­als of remde­sivir, a drug iden­ti­fied as a poten­tial treat­ment for COVID-19. The group also rec­om­mends admin­is­ter­ing dos­es of the drug to patients in an ear­ly stage of infec­tion, and notes remde­sivir will essen­tial­ly be a place­hold­er until a more effec­tive treat­ment is pro­duced.
    ...

    And notice what we aren’t hear­ing in those rec­om­men­da­tions: that the US fed­er­al gov­ern­ment work with oth­er com­pa­nies to expe­dite the clin­i­cal tri­als of oth­er drugs. And it turns out if you look at that 17-page list of rec­om­men­da­tions, ALMOST THE ENTIRE SECTION ABOUT DEVELOPING DRUGS IS ABOUT REMDESIVIR. Yep. It briefly men­tions a few oth­er drugs and then has three pages talk­ing about remde­sivir. That doc­u­ment is avail­able for down­load here: Look at the “First Wave: RERPURPOSED DRUGS” sec­tion on Pages 5–7. Vir­tu­al­ly the entire sec­tion is ded­i­cat­ed to pro­mot­ing remde­sivir. So it sure sounds like this group of bil­lion­aires and ven­ture cap­i­tal­ists (with a few legit sci­en­tists thrown in) has been one of the groups pro­mot­ing this almost sin­gu­lar fed­er­al focus on remde­sivir.

    So when it comes to the ques­tion of how to ensure the US has ade­quate capac­i­ty for large-scale clin­i­cal test­ing of new drugs in the face of an emerg­ing pan­dem­ic, it’s going to be impor­tant to keep in mind that secre­tive groups of bil­lion­aires push­ing their pet agen­das is one of the issues that’s going to have to be addressed.

    And in oth­er covid clin­i­cal tri­al news...

    Posted by Pterrafractyl | May 13, 2020, 2:16 pm
  15. Fol­low­ing up on the Sci­en­tists to Stop Covid-19 group of bil­lion­aires and ven­ture cap­i­tal­ists (which some actu­al sci­en­tists thrown in for good mea­sure) who appear to be call­ing the shots on the Trump admin­is­tra­tion’s COVID drug devel­op­ment strat­e­gy, it’s worth not­ing a rather sig­nif­i­cant point about the fig­ure said to be behind the for­ma­tion of this group: Dr. Tom Cahill.

    As we saw, Dr. Cahill’s con­nec­tions in Sil­i­con Val­ley include Peter Thiel. And as we’ve also seen, Thiel’s Palan­tir has emerged as a cen­tral enti­ty in for­mu­lat­ing the track­ing the White House­’s coro­n­avirus response. Also recall how Trump turned to Thiel back in Decem­ber of 2016 dur­ing the tran­si­tion peri­od to help fill a num­ber of impor­tant posi­tions involved health and sci­ence, with Thiel report­ed­ly being focused on the FDA, NIH, Health and Human Ser­vices, and the Office of Sci­ence and Tech­nol­o­gy Pol­i­cy. So Trump has been turn­ing to Thiel for mat­ters involv­ing sci­ence and pub­lic health from the very begin­ning of his admin­is­tra­tion, which makes it a good bet that Trump once again turned to Thiel for advice on how to han­dle this pan­dem­ic.

    Here’s the very inter­est­ing part involv­ing Dr. Cahill and Thiel: it sounds like Dr. Cahill basi­cal­ly owes his career to Thiel. Or rather, the net­work of investors around Thiel. Because as we’ll see in the fol­low­ing arti­cle, the 33-year-old Cahill grad­u­at­ed from Duke Uni­ver­si­ty with his MD and PhD just two years ago. He got a job at the invest­ment firm Rap­tor Group and then went on to start his ven­ture cap­i­tal firm New­path Part­ners. It was just last year that New­path raised its ini­tial $125 mil­lion on fund­ing which came from a small group of investors includ­ing Thiel. That’s basi­cal­ly a descrip­tion of Thiel’s investor net­work set­ting up New­path Part­ners which strong­ly implies Cahill owes his cur­rent wealth and career as a ven­ture cap­i­tal­ist to Thiel.

    So the guy who is appar­ent­ly the dri­ving force behind this out­side group of advi­sors that has tak­en the lead on the White House­’s drug devel­op­ment response is basi­cal­ly a vas­sal of Thiel and the oth­er ear­ly investors in New­path.

    As the fol­low­ing arti­cle notes, anoth­er ini­tial investor in New­path was ven­ture cap­i­tal­ist Bri­an Sheth, who arranged for the group to con­tact the White House via his con­nec­tions to Repub­li­can Nation­al Com­mit­tee chair­man Tom­my Hicks, Jr. As we’ve seen, Hicks isn’t just the head of the RNC. He’s also hunt­ing bud­dies with Don­ald Trump, Jr. and a friend of J. Kyle Bass and brought Bass into the White House to for­mu­late the Trump admin­is­tra­tion’s poli­cies regard­ing Chi­na (a pol­i­cy that would be wild­ly prof­itable for Bass if it end­ed up tank­ing the Chi­nese econ­o­my).

    Yes, two key finan­cial back­ers of Cahill’s New­path, Thiel and Sheth, both had deep ties to the Trump admin­is­tra­tion. And, lo and behold, it’s Cahill who emerges at the offi­cial ring-leader for this ‘pri­vate’ group of COVID advi­sors that has appar­ent­ly been deter­min­ing the fed­er­al gov­ern­ments COVID response poli­cies. Don’t for­get what we’re told about the influ­ence of this group on the White House: it’s act­ing as an ad hoc advi­so­ry board that “weeds out” data before it reach­es pol­i­cy-mak­ers and gov­ern­ment agen­cies appear to have adhered to their rec­om­men­da­tions. In oth­er words, they might tech­ni­cal­ly just be giv­ing “advice” to the Trump admin­is­tra­tion but fed­er­al agen­cies appear to be treat­ed that advice as orders.

    So we have to ask: did the White House request that some­one set up this group? Was a osten­si­bly third-par­ty group giv­ing advice seen as a means of allow­ing the White House to get the ‘out­side advice’ it already desired? Per­haps as a means of deflect­ing blame if the advice ends up back­fir­ing? It’s an intrigu­ing pos­si­bil­i­ty because we know the White House has turned to Thiel’s Palan­tir and has like­ly been coor­di­nat­ing exten­sive­ly with the RNC via Hicks. And both Thiel and Hick­s’s friend Sheth basi­cal­ly helped cre­ate the career of Dr. Cahill just last year. Were they the actu­al fig­ures behind the for­ma­tion of Sci­en­tists to Stop Covid-19, set­ting up Cahill as the offi­cial face for the group?

    For­tune

    The ven­ture cap­i­tal­ist at the cen­ter of the coro­n­avirus fight

    BY LUCINDA SHEN
    April 28, 2020 8:38 AM CDT

    How do you get a mes­sage from lib­er­al-lean­ing sci­en­tists into a flam­ing-red White House in the mid­dle of the pan­dem­ic?

    A group of sci­en­tists and bil­lion­aires that came togeth­er to fight coro­n­avirus have man­aged to do so, per a fas­ci­nat­ing read at the Wall Street Jour­nal.

    Sci­en­tists to Stop Covid-19 culled togeth­er a 17-page report for offi­cials on how best to bat­tle the virus. Unlike with oth­er rec­om­men­da­tions that fade into obscu­ri­ty, gov­ern­ment agen­cies appear to be actu­al­ly read­ing and imple­ment­ing guid­ance to low­er man­u­fac­tur­ing reg­u­la­tions around spe­cif­ic coro­n­avirus drugs.

    At the helm of the effort: The 33-year-old and very-much-under-the-radar ven­ture cap­i­tal­ist Tom Cahill, who leads life sci­ences-focused New­path Part­ners. Cahill com­plet­ed his M.D. and PhD at Duke Uni­ver­si­ty a mere two years ago before land­ing at blue-chip invest­ment firm Rap­tor Group through a friend. He went on to found New­path with some $125 mil­lion after impress­ing well-con­nect­ed names like ven­ture cap­i­tal­ist Peter Thiel and Vista Equi­ty Part­ners co-founder Bri­an Sheth.

    As the pan­dem­ic spread, Cahill turned his atten­tion toward fight­ing Covid-19, his con­nec­tions now becom­ing his main asset in his efforts. It was through Sheth, for exam­ple, that Sci­en­tists to Stop Covid-19 con­nect­ed with the co-chair­man of the Repub­li­can Nation­al Com­mit­tee, Thomas Hicks Jr.

    Cahill and his group have also been in fre­quent con­tact with Nice Ayers, a long­time aide to Vice Pres­i­dent Mike Pence. It was only fol­low­ing a call to Ayers that the FDA gave Regeneron—which need­ed to shift man­u­fac­tur­ing abroad in order to pro­duce its promis­ing coro­n­avirus treat­ment in suf­fi­cient quantities—permission to take pro­duc­tion to Dublin, per the sto­ry.

    ...

    ————

    “The ven­ture cap­i­tal­ist at the cen­ter of the coro­n­avirus fight” BY LUCINDA SHEN; For­tune; 04/28/2020

    “At the helm of the effort: The 33-year-old and very-much-under-the-radar ven­ture cap­i­tal­ist Tom Cahill, who leads life sci­ences-focused New­path Part­ners. Cahill com­plet­ed his M.D. and PhD at Duke Uni­ver­si­ty a mere two years ago before land­ing at blue-chip invest­ment firm Rap­tor Group through a friend. He went on to found New­path with some $125 mil­lion after impress­ing well-con­nect­ed names like ven­ture cap­i­tal­ist Peter Thiel and Vista Equi­ty Part­ners co-founder Bri­an Sheth.

    From grad­u­ate stu­dent to ven­ture cap­i­tal­ist guid­ing the White House­’s pan­dem­ic response in just two years. Tom Cahill is quite the high-fly­er. Thanks large­ly to the ~$125 mil­lion in cap­i­tal used to cre­ate Cahill’s New­path Part­ners just last year. And the small group of investors in New­path just hap­pens to include Peter Thiel and Bri­an Sheth, a good friend of RNC chair­man Tom­my Hicks Jr.:

    ...
    As the pan­dem­ic spread, Cahill turned his atten­tion toward fight­ing Covid-19, his con­nec­tions now becom­ing his main asset in his efforts. It was through Sheth, for exam­ple, that Sci­en­tists to Stop Covid-19 con­nect­ed with the co-chair­man of the Repub­li­can Nation­al Com­mit­tee, Thomas Hicks Jr.
    ...

    So who real­ly assem­bled this ini­tia­tive? Well, accord­ing to the fol­low­ing Strait Times arti­cle describ­ing how the group orig­i­nal­ly formed, we’re told that Cahill was get­ting pep­pered with ques­tions from New­path’s investors in ear­ly March about the virus so he orga­nized a con­fer­ence call to shared some ideas with them. He appar­ent­ly expect­ed about 20 peo­ple on the call, but when it actu­al­ly hap­pened he dis­cov­ered there were hun­dreds of peo­ple on the call, includ­ing advi­sors to Vice Pres­i­dent Mike Pence. So Pence’s advi­sors were involved with this group before it was even a for­mal group:

    The Strait Times

    Sci­en­tists and bil­lion­aires dri­ve ‘Man­hat­tan Project’ seek­ing to com­bat Covid-19

    Pub­lished
    Apr 28, 2020, 5:31 pm SGT

    WASHINGTON — A group of top Amer­i­can sci­en­tists backed by bil­lion­aires and indus­try titans says it has the answer to the coro­n­avirus pan­dem­ic, and has deliv­ered a report to the White House through back­door chan­nels.

    The sci­en­tists com­piled a con­fi­den­tial 17-page report that sug­gests a num­ber of unortho­dox mea­sures to com­bat the coro­n­avirus, includ­ing the use of pow­er­ful drugs that were intend­ed to be used against Ebo­la in far hefti­er dos­es than tried in the past, report­ed The Wall Street Jour­nal.

    Spe­cif­ic rec­om­men­da­tions made by the group, such as slash­ing man­u­fac­tur­ing reg­u­la­tions and require­ments for spe­cif­ic coro­n­avirus drugs, have already been imple­ment­ed by the Food and Drug Admin­is­tra­tion (FDA) and the Depart­ment of Vet­er­an Affairs.

    Call­ing them­selves Sci­en­tists to Stop Covid-19, the group of a dozen sci­en­tists — includ­ing chem­i­cal biol­o­gists, an immuno­bi­ol­o­gist, a neu­ro­bi­ol­o­gist, a chrono­bi­ol­o­gist, an oncol­o­gist, a gas­troen­terol­o­gist, an epi­demi­ol­o­gist and a nuclear sci­en­tist — are mar­shalling brains and mon­ey to dis­til unortho­dox ideas from around the globe.

    They have described their work as a lock­down-era Man­hat­tan Project — a ref­er­ence to the World War II sci­en­tists who helped devel­op the atom­ic bomb — and are led by a 33-year-old physi­cian-turned-ven­ture cap­i­tal­ist, Dr Tom Cahill.

    Liv­ing in a one-bed­room rental apart­ment near Boston’s Fen­way Park, Dr Cahill owns just one suit, but has enough lofty con­nec­tions to influ­ence gov­ern­ment deci­sion-mak­ing in the war against the coro­n­avirus.

    Of the oth­er sci­en­tists at the cen­tre of the project, biol­o­gist Michael Ros­bash, a 2017 Nobel Prize win­ner, said, “There’s no ques­tion that I’m the least qual­i­fied.”

    The group has helped phar­ma­ceu­ti­cal com­pa­nies estab­lish a link to Trump admin­is­tra­tion deci­sion mak­ers. Its mem­bers also act­ed as an ad hoc review board for research on the coro­n­avirus, reject­ing flawed stud­ies before they reach pol­i­cy­mak­ers.

    The direc­tor of the Nation­al Insti­tutes of Health, Dr Fran­cis Collins, told peo­ple this month that he agreed with most of the report’s rec­om­men­da­tions, accord­ing to doc­u­ments reviewed by The Wall Street Jour­nal and peo­ple famil­iar with the mat­ter.

    The report was deliv­ered to Vice-Pres­i­dent Mike Pence, the head of the Trump admin­is­tra­tion’s coro­n­avirus task­force, and Cab­i­net mem­bers.

    Dr Cahill’s con­nec­tions come through his invest­ment firm and include bil­lion­aires such as Mr Peter Thiel, Mr Jim Palot­ta and Mr Michael Milken, who enabled him to reach offi­cials in the mid­dle of the cri­sis.

    Mr Nick Ayers, Mr Pence’s long-time aide, has been fre­quent­ly advised by the group of sci­en­tists, as have agency heads through phone calls over the past month.

    The sci­en­tists say they are moti­vat­ed by the chance to add their own con­nec­tions and sci­ence to the coro­n­avirus bat­tle, with none of them gain­ing finan­cial­ly.

    “We may fail,” said Pro­fes­sor Stu­art Schreiber, a Har­vard Uni­ver­si­ty chemist and a mem­ber of the group. “But if it suc­ceeds, it could change the world.”

    The co-own­er of the Boston Celtics and co-chair­man of Bain Cap­i­tal, Mr Steve Pagli­u­ca — who is also one of Dr Cahill’s investors — helped copy-edit drafts of the report and passed it on to Gold­man Sachs Group Inc Chief Exec­u­tive David Solomon, who in turn passed it on to Trea­sury Sec­re­tary Steven Mnuchin.

    The sci­en­tists says they are aware that their rec­om­men­da­tions may be ignored by the Trump admin­is­tra­tion.

    GROUP ORIGINS

    Just two years ago, Dr Cahill was study­ing for his MD and PhD at Duke Uni­ver­si­ty, con­duct­ing research on rare genet­ic dis­eases. But after grad­u­a­tion, a friend intro­duced him to a job at his father’s blue-chip invest­ment firm Rap­tor Group.

    After a stint at Rap­tor, Dr Cahill formed his own fund, New­path Part­ners, with US$125 mil­lion (S$177.14 mil­lion) from a small group of wealthy investors, includ­ing Sil­i­con Val­ley stal­wart Mr Thiel and pri­vate equi­ty founders like Mr Pagli­u­ca.

    In ear­ly March, as the coro­n­avirus death toll mount­ed, Dr Cahill’s investors pep­pered him with ques­tions about the virus and he organ­ised a con­fer­ence call to share some against-the-grain ideas on how to accel­er­ate drug devel­op­ment, among oth­er things.

    But while Dr Cahill expect­ed about 20 peo­ple, when he tried to dial into the meet­ing, he was reject­ed because the call was at capac­i­ty, with hun­dreds of peo­ple on the line, includ­ing Mr Milken.

    Dr Cahill then received a call from Nation­al Bas­ket­ball Asso­ci­a­tion Com­mis­sion­er Adam Sil­ver, who also want­ed to par­tic­i­pate in the meet­ing. Dr Cahill lat­er gave him a per­son­al brief­ing.

    When Dr Cahill final­ly got on the call, he said he had been work­ing with friends to whit­tle down poten­tial Covid-19 treat­ments to the most promis­ing ones, and that he had large­ly dropped his invest­ing work to focus on the hunt for a cure.

    After hang­ing up an hour lat­er, Dr Cahill found his e‑mail inbox full of ideas and offers to help, includ­ing from Mr Milken’s team.

    “For the 50 years I’ve been involved in med­ical research, I have nev­er seen col­lab­o­ra­tion as we have today,” Mr Milken said.

    In addi­tion, Dr Cahill received notes from advis­ers to the Vice-Pres­i­dent, who had also been on the call.

    TRACING CONTACTS

    One of the first peo­ple Dr Cahill called was Mr Schreiber, the founder of sev­er­al pri­vate com­pa­nies.

    Mr Screiber looped in a long-time friend, Mr Edward Scol­nick, the for­mer head of research and devel­op­ment at phar­ma­ceu­ti­cal giant Mer­ck & Co, who said that a vac­cine would take 18 months to hit the mar­ket “if you’re damn lucky”. Mr Screiber said, “What about six months?”

    The team of sci­en­tists drew up a list of rough­ly two dozen com­pa­nies that could ben­e­fit from their rec­om­men­da­tions and pledged to sell any stocks they held in them imme­di­ate­ly. One ear­ly mem­ber refused and was kicked out.

    Much of the ear­ly work involved pars­ing through hun­dreds of sci­en­tif­ic papers from around the world and sep­a­rat­ing promis­ing ideas from dubi­ous ones. Each mem­ber went through as many as 20 papers in a day and gath­ered to debate via video con­fer­ence, text mes­sages and phone calls.

    Dr Michael Lin, a Stan­ford Uni­ver­si­ty neu­ro­bi­ol­o­gist, began dis­abling the cam­era on his phone to pro­tect his van­i­ty.

    “A cou­ple of days, I’ve had sev­en or eight Zoom meet­ings, which will itself I’m sure cause some kind of dis­ease,” joked Dr David Liu, a Har­vard Uni­ver­si­ty chem­i­cal biol­o­gist.

    The debates weren’t always pure­ly sci­ence, with the group at one point con­sid­er­ing whether to rec­om­mend that the virus be renamed “Sars‑2” after the 2003 Chi­na ani­mal virus. The idea was dropped.

    The team also pledged to avoid pol­i­tics in an elec­tion year. Hydrox­y­chloro­quine, a malar­ia drug pro­mot­ed by the Pres­i­dent, received only a pass­ing men­tion in the final report.

    The group also dis­par­aged the idea of anti­body test­ing to allow peo­ple back to work. Dr Cra­vatt, a chemi­al biol­o­gist, called it the “worst idea I’ve ever heard”, point­ing out that pri­or expo­sure may not pre­vent peo­ple from giv­ing the virus to oth­ers. There were also con­cerns that peo­ple might inten­tion­al­ly infect them­selves to obtain a clean bill of health lat­er.

    The groups ini­tial rec­om­men­da­tions in the report cen­tre on the gov­ern­men­t’s response. One sug­ges­tion was to buy med­i­cines not yet proven effec­tive as a way to encour­age man­u­fac­tur­ers to ramp up pro­duc­tion . Anoth­er was to slash the time required for a clin­i­cal review of new drugs to a week from up to a year at present.

    AN INTRODUCTION

    In order to get the rec­om­men­da­tions to the right peo­ple in the Trump admin­is­tra­tion, Dr Cahill tapped Mr Bri­an Sheth, co-founder of pri­vate-equi­ty firm Vista Equi­ty Part­ners, and a Demo­c­rat.

    Mr Sheth was friend­ly with Mr Thomas Hicks Jr, the Dal­las busi­ness­man and co-chair­man of the Repub­li­can Nation­al Com­mit­tee. Mr Sheth intro­duced Mr Hicks to Dr Cahill’s group. That con­nec­tion clinched ties between the group of sci­en­tists from left-lean­ing insti­tu­tions and a Repub­li­can stal­wart who hunts birds with Mr Don­ald Trump Jr.

    In his first chat with the group, Mr Hicks said, “I’m not a sci­en­tist. Make it clear enough for me, and then tell me where the red tape is.”

    One major con­cern was the FDA, which required a month-long wait for approval of a pro­pos­al that iden­ti­fied mon­o­clon­al anti­body drugs as the most promis­ing treat­ment, which would involve drug­mak­er Regen­eron Phamaceu­ti­cals Inc shift­ing its exist­ing man­u­fac­tur­ing facil­i­ties to Ire­land in order to make the med­i­cine in suf­fi­cient quan­ti­ties.

    Mr Scol­nick attempt­ed to con­vince bureau­crats, bu the effort end­ed poor­ly, prompt­ing one sci­en­tist to remark of the FDA: “They’re the prob­lem here.”

    Dr Cahill then called the vice-pres­i­den­t’s aide, Mr Ayers. That same evening, Regen­eron received FDA approval to imme­di­ate­ly shift pro­duc­tion to Dublin.

    “That was proof pos­i­tive that what we were doing was start­ing to work,” Mr Ros­bash said.

    Inroads were also made with­in the Vet­er­an’s Asso­ci­a­tion, the largest health­care sys­tem in the US. The sci­en­tists con­vinced the VA’s chief med­ical offi­cer and secu­ri­ty on the need to allow vet­er­ans with Covid-19 to join exist­ing stud­ies in areas such as prostate can­cer, with a view to see if already-approved drugs might be efec­tive.

    The team is also look­ing to devel­op a plan for reopen­ing the Unit­ed States. Their ideas include devel­op­ment of a sali­va test and the sched­ul­ing of tests at the end of the work­day so that results would be avail­able by morn­ing.

    They also sug­gest­ed a nation­wide smart­phone app that requires res­i­dents to con­firm each day that they don’t have any symp­toms asso­ci­at­ed with the coro­n­avirus, The Wall Street Jour­nal report­ed.

    ...

    ———–

    “Sci­en­tists and bil­lion­aires dri­ve ‘Man­hat­tan Project’ seek­ing to com­bat Covid-19”; The Strait Times; 04/28/2020

    “In ear­ly March, as the coro­n­avirus death toll mount­ed, Dr Cahill’s investors pep­pered him with ques­tions about the virus and he organ­ised a con­fer­ence call to share some against-the-grain ideas on how to accel­er­ate drug devel­op­ment, among oth­er things.”

    It was sup­posed to just be an inno­cent con­fer­ence call to 20 or so New­path investors. Investors that would obvi­ous­ly include Thiel and Sheth. But then Cahill dis­cov­ers hun­dreds of peo­ple on the call, includ­ing advi­sors to the Vice Pres­i­dent:

    ...
    But while Dr Cahill expect­ed about 20 peo­ple, when he tried to dial into the meet­ing, he was reject­ed because the call was at capac­i­ty, with hun­dreds of peo­ple on the line, includ­ing Mr Milken.

    ...

    In addi­tion, Dr Cahill received notes from advis­ers to the Vice-Pres­i­dent, who had also been on the call.
    ...

    So the White House was clear­ly inter­est­ed in this group before it even formed. And yet the way this group is por­tray itself to the media, it’s just a bunch of con­cerned sci­en­tists who are giv­ing their unfil­tered advice. And note this strange anec­dote we keep see­ing in reports about this group: it was Mr Steve Pagli­u­ca, one of New­path’s investors, who passed the report to Trea­sury Sec­re­tary Steve Mnuchin:

    ...
    The co-own­er of the Boston Celtics and co-chair­man of Bain Cap­i­tal, Mr Steve Pagli­u­ca — who is also one of Dr Cahill’s investors — helped copy-edit drafts of the report and passed it on to Gold­man Sachs Group Inc Chief Exec­u­tive David Solomon, who in turn passed it on to Trea­sury Sec­re­tary Steven Mnuchin.
    ...

    An aide to the Vice Pres­i­dent was lit­er­al­ly on the call and yet some­how Steve Mnuchin is the one who receives the report?! It’s the kind of detail about this group that has the feel of being inten­tion­al­ly put out there to make it seem like the group real­ly was inde­pen­dent of the White House and had to jump through hoops to make the White House know about its rec­om­men­da­tions.

    So it’s look­ing more and more like this group that has emerged as a key deci­sion-mak­er in the Trump admin­is­tra­tion’s COVID response was set up either at the behest of the White House or at least with the close coop­er­a­tion of the White House and that extreme­ly close rela­tion­ship is some­thing they would pre­fer the pub­lic not rec­og­nize. Why is that? It’s an impor­tant ques­tion that’s going to be increas­ing­ly impor­tant the more the Trump admin­is­tra­tion’s COVID response con­tin­ues to flail, along with the relat­ed grim ques­tion of who might be prof­it­ing from all that flail­ing.

    Posted by Pterrafractyl | May 14, 2020, 3:12 pm
  16. Here’s a pair of arti­cles worth keep­ing in mind regard­ing remde­sivir, the focus that’s been put on that drug as human­i­ty’s best ther­a­peu­tic hope for a covid treat­ment despite all of the obvi­ous prob­lems with that strat­e­gy, and the appar­ent influ­ence of the “Sci­en­tists to Stop COVID-19” indus­try-backed group in push­ing remde­sivir:

    There was a notable depar­ture from the White House late last month. Notable in part because of who it was and also some­what notable for the tim­ing. Recall how we had that mix of good-ish/bad-ish news from two remde­sivir clin­i­cal tri­als on the same day and in response the FDA imme­di­ate­ly autho­rized remde­sivir for emer­gency use. Well, on that same day we had the announce­ment that long-time Gilead lob­by­ist Joe Gro­gan was leav­ing his posi­tion as the head of the White House Domes­tic Pol­i­cy Coun­cil. So at a min­i­mum it was inter­est­ing tim­ing, espe­cial­ly since he was part of the orig­i­nal coro­n­avirus task force the Trump admin­is­tra­tion formed in Jan­u­ary.

    Gro­gan’s depar­ture from the White House report­ed­ly expect­ed for some time so it’s unclear if Gro­gan’s deci­sion to choose that day to announce his depar­ture has has any­thing to do with the White House­’s treat­ment of remde­sivir but the fact that he announced his depar­ture on the same day the FDA grant­ed the drug emer­gency use sta­tus fol­low­ing some rather dis­ap­point­ing clin­i­cal tri­al results at least hints at some pos­si­ble sen­si­tiv­i­ty to the polit­i­cal optics of the sit­u­a­tion.

    And as we’ll see in the sec­ond arti­cle below, one of Gro­gan’s spe­cial­ties in the White House appears to be a greater polit­i­cal sen­si­tiv­i­ty to bad optics. Specif­i­cal­ly, greater sen­si­tiv­i­ty to bad optics than Health and Human Ser­vices (HHS) Sec­re­tary Alex Azar. That’s the pic­ture that emerges when we hear about a pol­i­cy bat­tle between Gro­gan and Azar that pits Gro­gans as the voice of rel­a­tive rea­son com­pared to Azar when it come to shilling for the phar­ma­ceu­ti­cal indus­try. The fight was over duel­ing plan to address high drug prices and Azar was push­ing a plan that was such a mas­sive give­away to the phar­ma­ceu­ti­cal indus­try Gro­gan had to step in. Azar’s plan was to pass a reg­u­la­tion that would ban the prac­tice of hav­ing drug man­u­fac­tur­ers pay rebates to insur­ers. Yes, the plan for con­trol­ling ris­ing drug prices was seri­ous­ly to ban dis­counts drug man­u­fac­tur­ers offered to insur­ers, a plan that like­ly would have led to a rise in pre­mi­ums. It turns out this was the ‘fix’ to drug prices the drug man­u­fac­tur­ers had been aggres­sive­ly lob­by­ing for and Alex Azar, the for­mer phar­ma­ceu­ti­cal lob­by­ist and exec­u­tive, was all in favor or it. Sur­prise!

    What was actu­al­ly some­what sur­pris­ing was that it was Gro­gan, anoth­er for­mer phar­ma­ceu­ti­cal lob­by­ist, who had to step in and block the plan. That’s how bad it would have looked to ‘fix’ high drug prices by block­ing drug dis­counts. Gro­gan instead advo­cat­ed for a drug con­trol plan that involved tying prices for US con­sumers to inter­na­tion­al prices which sur­prised many because that’s a solu­tion gen­er­al­ly not favored by Repub­li­cans. It was spun as one of those exam­ples when Trump and his team might be will­ing to be more ‘pop­ulist’ than past Repub­li­cans, so of course the plan was only talked about and was nev­er actu­al­ly imple­ment­ed.

    So Gro­gan’s big lega­cy at the White House was block­ing bill intend­ed to low­er drug prices that would have saved drug man­u­fac­tur­ers bil­lions and prob­a­bly raised drug prices. It’s not the great­est lega­cy but it could be worse. It could be Alex Azar’s lega­cy, which is still being built.

    Ok, here’s a piece about the announce­ment of Gro­gan’s depar­ture. The depar­ture was announced in the Wall Street Jour­nal on the morn­ing of Wednes­day, Feb­ru­ary 29, the same day we got our first pub­lic reports of the NIAID clin­i­cal tri­al of remde­sivir that was pos­i­tive enough to show it short­ened the time to recov­ery and the same day the FDA grant­ed remde­sivir emer­gency use sta­tus:

    The Hill

    Top Trump pol­i­cy advis­er Joe Gro­gan to leave post

    By Mor­gan Chal­fant — 04/29/20 08:43 PM EDT

    Joe Gro­gan, head of the White House Domes­tic Pol­i­cy Coun­cil, intends to leave his posi­tion at the end of May.

    A White House offi­cial con­firmed Grogan’s planned depar­ture, which was first report­ed by The Wall Street Jour­nal. Gro­gan told the Jour­nal that he was leav­ing the White House on good terms with Pres­i­dent Trump and that he planned to leave the posi­tion on May 24, hav­ing stayed in the role longer than he antic­i­pat­ed.

    Grogan’s depar­ture had been rumored as a pos­si­bil­i­ty for weeks, par­tic­u­lar­ly fol­low­ing the arrival of Mark Mead­ows, a for­mer North Car­oli­na con­gress­man, as Trump’s fourth chief of staff.

    “I had a great con­ver­sa­tion with the pres­i­dent and a great con­ver­sa­tion with Mead­ows,” Gro­gan told the Jour­nal in an inter­view pub­lished Wednes­day evening.

    Gro­gan has served as the direc­tor of the White House Domes­tic Pol­i­cy Coun­cil since Feb­ru­ary 2019, over­see­ing a broad array of pol­i­cy issues includ­ing health care and reg­u­la­tion.

    Before that, he worked as a top health care offi­cial in the Office of Man­age­ment and Bud­get begin­ning in 2017 and was a close ally of Mick Mul­vaney, Trump’s third chief of staff, whom Mead­ows replaced in March. Gro­gan worked as a lob­by­ist for drug com­pa­ny Gilead Sci­ences before join­ing the Trump admin­is­tra­tion.

    ...

    Gro­gan was one of the orig­i­nal mem­bers of the White House coro­n­avirus task force launched in late Jan­u­ary. It was not imme­di­ate­ly clear who would replace him as head of the Domes­tic Pol­i­cy Coun­cil.

    ———-

    “Top Trump pol­i­cy advis­er Joe Gro­gan to leave post” by Mor­gan Chal­fant; The Hill; 04/29/2020

    Gro­gan was one of the orig­i­nal mem­bers of the White House coro­n­avirus task force launched in late Jan­u­ary. It was not imme­di­ate­ly clear who would replace him as head of the Domes­tic Pol­i­cy Coun­cil.”

    The Gilead lob­by­ist who went on to assume a pow­er role shap­ing White House pol­i­cy also hap­pened to be one of the orig­i­nal coro­n­avirus task force mem­bers. Might that have had some­thing to do with the dis­pro­por­tion­ate focus placed on Gilead­’s remde­sivir from the begin­ning of the pan­dem­ic? And did the so-so reports of remde­sivir’s effec­tive­ness against COVID in the NIAID study have some­thing to do with Gro­gan’s deci­sion to leave on the same day? Who knows but the tim­ing was cer­tain­ly inter­est­ing. And sad­ly, as the fol­low­ing arti­cle describes, while hav­ing a for­mer Gilead lob­by­ist craft­ing pol­i­cy is obvi­ous­ly prob­lem­at­ic, Gro­gan’s lega­cy was defined by being not as big a shill as Alex Azar (who is still HHS Sec­re­tary and still shap­ing the fed­er­al coro­n­avirus response):

    STAT News

    How Joe Gro­gan, a for­mer phar­ma lob­by­ist, upend­ed Trump’s drug pric­ing agen­da

    By Lev Fach­er
    Octo­ber 22, 2019

    WASHINGTON — As the Marine Band warmed up and White House aides scur­ried to set up chairs in a sun-soaked Rose Gar­den for per­haps the most con­se­quen­tial health care address of the Trump pres­i­den­cy, a brazen mid-lev­el bud­get aide was bat­tling to jet­ti­son the entire event.

    Pres­i­dent Trump was set to take the stage in bare­ly an hour to unveil a “blue­print” to low­er pre­scrip­tion drug prices. But on that after­noon in May 2018, Joe Gro­gan refused to sign off on either the remarks or the pol­i­cy roll­out.

    Gro­gan, who found the doc­u­ment hasty and wrong­head­ed, launched a behind-the-scenes mutiny from Trump’s bud­get office, three for­mer admin­is­tra­tion health offi­cials told STAT. His actions infu­ri­at­ed health sec­re­tary Alex Azar, they said, and Gro­gan relent­ed only after Azar’s staff shout­ed him down by speak­er­phone. Trump deliv­ered his address, lay­ing out a sweep­ing agen­da to low­er drug costs.

    Still, the episode was the begin­ning of a larg­er effort from Gro­gan, unde­terred by his scold­ing, to roll back the core of the administration’s drug pric­ing agen­da.

    The Trump admin­is­tra­tion has only reward­ed Grogan’s unruli­ness: In a remark­able two-year span, he has vault­ed from lob­by­ist for the phar­ma­ceu­ti­cal giant Gilead Sci­ences to White House bud­get advis­er to direc­tor of the president’s Domes­tic Pol­i­cy Coun­cil. Grogan’s chaot­ic ascent to the White House’s high­est ranks, described to STAT in inter­views with eight cur­rent and for­mer Trump admin­is­tra­tion health offi­cials and an array of con­ser­v­a­tive lob­by­ists, is defined more by feud than by pol­i­cy tri­umph — and on drug pric­ing in par­tic­u­lar, his track record con­sists more of block­ing oth­ers’ poli­cies than advanc­ing new ones.

    The White House declined to make Gro­gan, who rarely speaks to reporters on the record, avail­able for an inter­view. His guer­ril­la pol­i­cy takeover, how­ev­er, has left in his wake a col­lec­tion of resent­ful West Wing aides and dis­en­chant­ed right-wing advo­ca­cy groups. Long­time GOP insid­ers have sought to down­play the fric­tion, insist­ing Gro­gan and Azar have band­ed togeth­er to push Con­gress toward an unlike­ly drug pric­ing accord and final­ize the administration’s more recent ini­tia­tives.

    ...

    Trump’s cam­paign-trail pledge to “drain the swamp” of D.C. cor­rup­tion includ­ed a bold pledge: His admin­is­tra­tion would refrain from hir­ing lob­by­ists. But the new White House bud­get direc­tor, for­mer con­gress­man Mick Mul­vaney, missed the memo.

    In one of his first per­son­nel moves, Mul­vaney plucked Gro­gan from his perch as Gilead’s head of fed­er­al affairs. Mul­vaney hadn’t just vio­lat­ed Trump’s no-lob­by­ist pledge (Trump, in the end, hired hun­dreds) — to orches­trate his health care efforts, he had hired a top offi­cial from a com­pa­ny vil­lainized for per­ceived price goug­ing, first for the hepati­tis C treat­ment, Soval­di, and lat­er for its HIV-pre­ven­tion drug, Tru­va­da.

    “What I thought orig­i­nal­ly was: Isn’t that inter­est­ing? He’s bring­ing in some­one who knows where the bod­ies are buried,” said Joel White, a Wash­ing­ton pol­i­cy expert who chairs a coali­tion of health indus­try groups and is reg­is­tered to lob­by for the trade group PhRMA.

    In 2017, long before Azar’s arrival and with for­mer health sec­re­tary Tom Price pre­oc­cu­pied by the GOP’s failed “repeal and replace” insur­ance reform attempts, Gro­gan even briefly orches­trat­ed the White House’s drug pric­ing efforts, lead­ing meet­ings of a “Drug Pric­ing and Inno­va­tion Work­ing Group.”

    At one gath­er­ing, he invit­ed Robert Shapiro, a mem­ber of a Gilead advi­so­ry board, to present to the assem­bled pol­i­cy staffers. Though the group nev­er issued for­mal rec­om­men­da­tions, Gro­gan was accused of giv­ing drug man­u­fac­tur­ers too large a plat­form. The meet­ings received lit­tle atten­tion from White House high­er-ups, and quick­ly fiz­zled.

    But Gro­gan, even­tu­al­ly, con­found­ed the expec­ta­tion that he would shill for indus­try.

    In fact, his high­est-pro­file White House work has not been kind to major drug man­u­fac­tur­ers. Aides have cred­it­ed Gro­gan for almost sin­gle-hand­ed­ly killing the Trump administration’s “rebate rule,” a coun­ter­in­tu­itive pol­i­cy, pushed large­ly by Azar, that the phar­ma­ceu­ti­cal lob­by aggres­sive­ly favored. Gro­gan feared the polit­i­cal fall­out from ban­ning rebates paid by drug com­pa­nies to insur­ers, which could have been per­ceived as a drug com­pa­ny give­away cost­ing tax­pay­ers near­ly $200 bil­lion in the next decade.

    Gro­gan has also become the advo­cate-in-chief for an inher­it­ed project: the Trump administration’s “inter­na­tion­al price index” mod­el, which would tie some U.S. drug pay­ments to for­eign prices. It is an unprece­dent­ed price-cap­ping scheme for any admin­is­tra­tion, much less a Repub­li­can one, and con­ser­v­a­tive groups have staunch­ly opposed the idea despite Trump’s sup­port. (Pro­gres­sive Democ­rats, how­ev­er, have embraced it whole­heart­ed­ly.)

    And recent­ly, Gro­gan has enthu­si­as­ti­cal­ly advo­cat­ed for Trump’s plan to import pre­scrip­tion drugs from Cana­da — a worst-case sce­nario for drug man­u­fac­tur­ers that many Repub­li­can pol­i­cy experts have long opposed.

    Nonethe­less, the odd optics of Grogan’s shift on phar­ma have peri­od­i­cal­ly haunt­ed him. His role devel­op­ing a new reim­burse­ment pol­i­cy for pricey, inno­v­a­tive can­cer drugs known as CAR‑T, in par­tic­u­lar — a ther­a­py Gilead began sell­ing soon after Gro­gan joined the admin­is­tra­tion — has made him the focus of ethics probes by Democ­rats on the House Over­sight Com­mit­tee and the left-lean­ing watch­dog group Democ­ra­cy For­ward.

    Grogan’s allies said his time at Gilead, in fact, pushed him clos­er to favor­ing aggres­sive price reforms out­side the Repub­li­can main­stream. Soval­di, in par­tic­u­lar, is one of the most-tread exam­ples of an inter­na­tion­al price dis­par­i­ty — Gilead has been crit­i­cized for charg­ing rough­ly $1,000 per pill in the U.S. while licens­ing gener­ic man­u­fac­tur­ers to sell it for rough­ly $4 per pill in India.

    “If you just think about the Soval­di issue, you had all of the rel­e­vant dis­cus­sions wrapped up in one,” White said. “Folks were say­ing this is going to bank­rupt Amer­i­ca and every Med­ic­aid pro­gram in the coun­try — but on the oth­er side, you had peo­ple say­ing these are exact­ly the types of cura­tive treat­ments we need.”

    Those who have cast a wary eye toward Grogan’s indus­try past are miss­ing the point, accord­ing to Dou­glas Holtz-Eakin, an influ­en­tial con­ser­v­a­tive econ­o­mist who has opposed sev­er­al Trump drug pric­ing poli­cies includ­ing the inter­na­tion­al price index and impor­ta­tion.

    “Peo­ple get the whole lob­by­ist thing wrong,” Holtz-Eakin said. “Lob­by­ists aren’t valu­able because of cash or influ­ence — they’re valu­able because they know things. They’re smart.”

    Grogan’s will­ing­ness to chal­lenge author­i­ty — the same trait that would lat­er ani­mate a West Wing shout­ing match, and his sub­se­quent face­offs with Azar — has been a through­line since his ear­ly days in Wash­ing­ton.

    Even in 1995, when he worked along­side his room­mate, Sean Spicer, as a junior researcher at the Nation­al Repub­li­can Sen­a­to­r­i­al Com­mit­tee, Gro­gan cared lit­tle about the chain of com­mand.

    Gro­gan, a recent SUNY-Albany grad­u­ate, spent a sin­gle elec­tion cycle work­ing at NRSC before begin­ning law school at the Col­lege of William and Mary. From base­ment-lev­el desks at NRSC’s Capi­tol Hill offices, they spent their days archiv­ing com­ments from the Con­gres­sion­al Record for use in future adver­tise­ments and fundrais­ing cam­paigns.

    By night, they’d retreat to their near­by row­house and pool their funds — they made rough­ly $4 per hour, Spicer recalled in an inter­view — for cas­es of beer. Yet when the hol­i­days rolled around, a staff admin­is­tra­tor informed employ­ees they’d be expect­ed to chip in $10 apiece to attend the committee’s Christ­mas par­ty.

    In a caus­tic reply-all that fore­shad­owed his Trump admin­is­tra­tion ascent, Gro­gan expressed mock delight. Who wouldn’t want to chip in two and a half hours’ pay, he asked, tongue in cheek, to spend the evening in a stuffy, smoke-filled room mak­ing small talk with his senior col­leagues?

    The mes­sage, Spicer recount­ed, land­ed Gro­gan a dress­ing-down from the NRSC’s then-exec­u­tive direc­tor John Heubusch. But it also caught the eye of the committee’s finance direc­tor, Phil Smith, who admired Grogan’s prose so much that he offered him a pro­mo­tion on the spot. Gro­gan, Smith said, went on to craft some of the most lucra­tive direct-mail fundrais­ing cam­paigns in NRSC his­to­ry.

    “I did meet with him, and I did chew him out,” recalled Heubusch, who now works as exec­u­tive direc­tor for Ronald Rea­gan Pres­i­den­tial Library. “It wasn’t real­ly the sub­ject. It was more him step­ping out into a role he didn’t belong in at the time.”

    Grogan’s brash­ness, how­ev­er, has not abat­ed since his ear­ly years in D.C., and at times he has test­ed the will­ing­ness of con­ser­v­a­tive orga­ni­za­tions typ­i­cal­ly in lock­step with Trump to back the White House on health pol­i­cy.

    Con­ser­v­a­tive groups have argued the price-index pro­pos­al Gro­gan has cham­pi­oned “imports for­eign price con­trols.” Even the right-wing Her­itage Foun­da­tion and its polit­i­cal advo­ca­cy arm, Her­itage Action, have spo­ken out pub­licly in a rare break from Trump.

    “Any plan that ties Amer­i­can drug prices to an inter­na­tion­al price index should be a non­starter for con­ser­v­a­tives, whether it’s com­ing from Con­gress or from the admin­is­tra­tion,” said Jes­si­ca Ander­son, Her­itage Action’s vice pres­i­dent, who worked along­side Gro­gan for over a year in Trump’s bud­get depart­ment.

    Adver­tise­ments from oth­er con­ser­v­a­tive groups have even likened Trump’s drug pol­i­cy to that of Sen. Bernie Sanders (I‑Vt.), Trump’s most pro­gres­sive chal­lenger in the 2020 elec­tion, cau­tion­ing the pres­i­dent: “Don’t be a Bernie Bro.”

    While Gro­gan is gen­er­al­ly described as gre­gar­i­ous, he has enthu­si­as­ti­cal­ly played the role of coun­ter­at­tack dog. At one meet­ing in July, he lashed out against an assem­bly of Repub­li­can-lean­ing lob­by­ists and health pol­i­cy advo­cates, warn­ing with his voice raised that “the pres­i­dent will not be out­flanked on the left on drug prices.”

    The remarks were con­sis­tent with Grogan’s long­time self-iden­ti­fi­ca­tion as a Repub­li­can out­side the main­stream, despite his years work­ing as an HIV/AIDS advis­er to Thomp­son and Pres­i­dent George W. Bush. Accord­ing to for­mer cowork­ers, Gro­gan instead has long sym­pa­thized more with a pop­ulist, non­con­formist brand of con­ser­vatism that Trump has come to per­son­i­fy.

    His defi­ance of estab­lish­ment GOP ortho­doxy began, in a sense, before Trump was elect­ed — in Octo­ber 2016, when Repub­li­can brass was scur­ry­ing to dis­tance itself from the party’s decid­ed­ly atyp­i­cal nom­i­nee.

    The rea­son: On Oct. 7, the Wash­ing­ton Post pub­lished years-old remarks that Trump char­ac­ter­ized as “lock­er-room talk,” in which he bragged to a tele­vi­sion host that he habit­u­al­ly grabbed women by their gen­i­tals.

    On Oct. 17, with Hillary Clinton’s elec­tion appear­ing all but cer­tain, Gro­gan made his only polit­i­cal con­tri­bu­tion of 2016: a $2,000 check to Trump.

    Three years lat­er, his invest­ment has paid off. Gro­gan is rou­tine­ly pho­tographed sit­ting next to Trump in high-pro­file meet­ings, and a rash of depar­tures in recent months has left Gro­gan the last man stand­ing from Trump’s orig­i­nal cast of health offi­cials. But since his pro­mo­tion, many con­ser­v­a­tives have only come to view the administration’s remain­ing efforts — the price index and Cana­di­an drug impor­ta­tion — as more dis­ap­point­ing.

    “The pres­i­dent promised to do some­thing about drug prices,” said Holtz-Eakin, the econ­o­mist. “The pres­i­dent has thus far done noth­ing about drug prices. This strikes me, increas­ing­ly, as almost des­per­ate.”

    A year after Grogan’s attempt to quash Azar’s drug pric­ing “blue­print” and to can­cel the president’s Rose Gar­den address, the tables had turned. Over Azar’s protes­ta­tions, Gro­gan, with Mulvaney’s back­ing, was argu­ing that Trump’s “rebate rule” — a cen­ter­piece of that very blue­print — should be with­drawn.

    This time, Gro­gan won.

    The rule, in his view, was a hand­out to drug com­pa­nies, a bur­den to tax­pay­ers, and risked leav­ing Medicare ben­e­fi­cia­ries on the hook for high­er pre­mi­ums. Trump sided with Gro­gan and offi­cial­ly killed his health secretary’s sig­na­ture drug pric­ing pro­pos­al.

    It was the third blow in two months to Azar’s blue­print — in essence, the out­come Gro­gan had agi­tat­ed for in May 2018.

    Days before, a fed­er­al court had thrown out anoth­er of the blueprint’s key ele­ments: Trump’s effort to force drug com­pa­nies to include list prices in tele­vi­sion adver­tise­ments, which had gar­nered Grogan’s skep­ti­cism on the grounds that it failed to pass First Amend­ment muster and would do lit­tle to low­er prices.

    And two months ear­li­er, Gro­gan struck his first blow, forc­ing Azar to with­draw his attempt to reform Medicare’s “pro­tect­ed class” require­ments, which would have allowed insur­ance plans to end cov­er­age of med­ica­tions for men­tal health con­di­tions and rare dis­eases if their prices increased faster than infla­tion. Gro­gan was par­tic­u­lar­ly fear­ful of the polit­i­cal fall­out asso­ci­at­ed with deny­ing cov­er­age for expen­sive anti­retro­vi­ral drugs — and the ensu­ing blow­back from HIV/AIDS groups.

    Gro­gan appeared to rel­ish his clash­es with Azar’s staff, accord­ing to for­mer White House aides. He also feud­ed with Domes­tic Pol­i­cy Coun­cil mem­bers before his pro­mo­tion to lead the pan­el in Feb­ru­ary 2019 — espe­cial­ly once Mul­vaney was pro­mot­ed to act­ing White House chief of staff in Decem­ber 2018.

    Gro­gan has also ben­e­fit­ed from Azar’s about-face on the pol­i­cy that ties U.S. drug prices to inter­na­tion­al ones. The May 2018 blue­print was stark­ly opposed to that pro­pos­al, declar­ing that cap­ping U.S. drug costs based on over­seas prices would fun­da­men­tal­ly threat­en access to cut­ting-edge treat­ments.

    Six months lat­er, how­ev­er, the admin­is­tra­tion unveiled a pol­i­cy that did exact­ly that: It would cap U.S. pay­ments for some Medicare drugs based on over­seas prices in Cana­da, Japan, and an array of devel­oped Euro­pean coun­tries.

    While aides said the idea was not Grogan’s, he has come to enthu­si­as­ti­cal­ly sup­port the pro­pos­al. He has even devel­oped a brief tirade, avail­able on demand, about phar­ma­ceu­ti­cal com­pa­nies that house intel­lec­tu­al prop­er­ty in Ire­land and man­u­fac­ture med­ica­tions in Cana­da only to sell them in the U.S. at — in his view — an egre­gious markup.

    With Grogan’s sup­port, the admin­is­tra­tion has also dra­mat­i­cal­ly shift­ed its stance on for­eign drug imports. It is anoth­er dra­mat­ic rever­sal for Azar, who as HHS gen­er­al coun­sel in 2005 sat on a com­mis­sion that declared Cana­di­an drug imports a threat to Amer­i­can patient safe­ty.

    A decade and a half lat­er, Azar — who, like Gro­gan, worked for a major phar­ma­ceu­ti­cal man­u­fac­tur­er in the inter­im — is enthu­si­as­ti­cal­ly sup­port­ing an impor­ta­tion plan that pol­i­cy experts large­ly view with skep­ti­cism. The plan, aimed at giv­ing Amer­i­cans access to the cheap­er drug prices offered beyond U.S. bor­ders, fits per­fect­ly into Trump’s “Amer­i­ca First” world­view.

    “This is the president’s posi­tion, and Alex is his sec­re­tary,” said Thomp­son, the for­mer health sec­re­tary who cre­at­ed the 2005 task force. While Thomp­son said there is “nobody more knowl­edge­able” on drug pric­ing than Gro­gan, he called Azar a “gen­uine con­vert” on much of the Trump administration’s pol­i­cy.

    “Alex has evolved,” Thomp­son said, “and right­ly so.”

    Yet with the 2020 elec­tion loom­ing, the Trump admin­is­tra­tion has lit­tle to show for its drug pric­ing efforts, thanks in large part to Grogan’s resis­tance. Instead, the White House’s mes­sag­ing has focused on drug impor­ta­tion and inter­na­tion­al price caps — two atyp­i­cal­ly Repub­li­can pol­i­cy ideas that may nev­er be imple­ment­ed.

    ...

    ———–

    “How Joe Gro­gan, a for­mer phar­ma lob­by­ist, upend­ed Trump’s drug pric­ing agen­da” by Lev Fach­er; STAT News; 10/22/2019

    “The Trump admin­is­tra­tion has only reward­ed Grogan’s unruli­ness: In a remark­able two-year span, he has vault­ed from lob­by­ist for the phar­ma­ceu­ti­cal giant Gilead Sci­ences to White House bud­get advis­er to direc­tor of the president’s Domes­tic Pol­i­cy Coun­cil. Grogan’s chaot­ic ascent to the White House’s high­est ranks, described to STAT in inter­views with eight cur­rent and for­mer Trump admin­is­tra­tion health offi­cials and an array of con­ser­v­a­tive lob­by­ists, is defined more by feud than by pol­i­cy tri­umph — and on drug pric­ing in par­tic­u­lar, his track record con­sists more of block­ing oth­ers’ poli­cies than advanc­ing new ones.”

    He may not have received much atten­tion, but Joe Gro­gan qui­et­ly became one of the most influ­en­tial fig­ures in the Trump admin­is­tra­tion. Despite Trump’s pledge to not hire a bunch of lob­by­ist:

    ...
    Trump’s cam­paign-trail pledge to “drain the swamp” of D.C. cor­rup­tion includ­ed a bold pledge: His admin­is­tra­tion would refrain from hir­ing lob­by­ists. But the new White House bud­get direc­tor, for­mer con­gress­man Mick Mul­vaney, missed the memo.

    In one of his first per­son­nel moves, Mul­vaney plucked Gro­gan from his perch as Gilead’s head of fed­er­al affairs. Mul­vaney hadn’t just vio­lat­ed Trump’s no-lob­by­ist pledge (Trump, in the end, hired hun­dreds) — to orches­trate his health care efforts, he had hired a top offi­cial from a com­pa­ny vil­lainized for per­ceived price goug­ing, first for the hepati­tis C treat­ment, Soval­di, and lat­er for its HIV-pre­ven­tion drug, Tru­va­da.

    ...

    In 2017, long before Azar’s arrival and with for­mer health sec­re­tary Tom Price pre­oc­cu­pied by the GOP’s failed “repeal and replace” insur­ance reform attempts, Gro­gan even briefly orches­trat­ed the White House’s drug pric­ing efforts, lead­ing meet­ings of a “Drug Pric­ing and Inno­va­tion Work­ing Group.”

    At one gath­er­ing, he invit­ed Robert Shapiro, a mem­ber of a Gilead advi­so­ry board, to present to the assem­bled pol­i­cy staffers. Though the group nev­er issued for­mal rec­om­men­da­tions, Gro­gan was accused of giv­ing drug man­u­fac­tur­ers too large a plat­form. The meet­ings received lit­tle atten­tion from White House high­er-ups, and quick­ly fiz­zled.
    ...

    And much of that time in the Trump White House was appar­ent­ly spent fight­ing with Alex Azar, anoth­er for­mer lob­by­ist, to block poli­cies that were so egre­gious­ly designed to ben­e­fit the drug indus­try that Gro­gan it would end up back­fir­ing. Poli­cies like low­er drug prices by block­ing drug dis­counts to insur­ers. Or allow­ing insur­ers to drop cov­er­age or drugs for men­tal health or rare dis­or­ders if the prices rose faster than infla­tion. Azar was all in favor of those poli­cies and Gro­gan had enough sense to real­ize that they would look hor­rif­ic if imple­ment­ed. That was the sta­tus of the drug pol­i­cy-mak­ing insid­er the Trump admin­is­tra­tion: the bat­tle of the shills between the sane shill and the insane shill:

    ...
    But Gro­gan, even­tu­al­ly, con­found­ed the expec­ta­tion that he would shill for indus­try.

    In fact, his high­est-pro­file White House work has not been kind to major drug man­u­fac­tur­ers. Aides have cred­it­ed Gro­gan for almost sin­gle-hand­ed­ly killing the Trump administration’s “rebate rule,” a coun­ter­in­tu­itive pol­i­cy, pushed large­ly by Azar, that the phar­ma­ceu­ti­cal lob­by aggres­sive­ly favored. Gro­gan feared the polit­i­cal fall­out from ban­ning rebates paid by drug com­pa­nies to insur­ers, which could have been per­ceived as a drug com­pa­ny give­away cost­ing tax­pay­ers near­ly $200 bil­lion in the next decade.

    Gro­gan has also become the advo­cate-in-chief for an inher­it­ed project: the Trump administration’s “inter­na­tion­al price index” mod­el, which would tie some U.S. drug pay­ments to for­eign prices. It is an unprece­dent­ed price-cap­ping scheme for any admin­is­tra­tion, much less a Repub­li­can one, and con­ser­v­a­tive groups have staunch­ly opposed the idea despite Trump’s sup­port. (Pro­gres­sive Democ­rats, how­ev­er, have embraced it whole­heart­ed­ly.)

    And recent­ly, Gro­gan has enthu­si­as­ti­cal­ly advo­cat­ed for Trump’s plan to import pre­scrip­tion drugs from Cana­da — a worst-case sce­nario for drug man­u­fac­tur­ers that many Repub­li­can pol­i­cy experts have long opposed.

    ...

    Con­ser­v­a­tive groups have argued the price-index pro­pos­al Gro­gan has cham­pi­oned “imports for­eign price con­trols.” Even the right-wing Her­itage Foun­da­tion and its polit­i­cal advo­ca­cy arm, Her­itage Action, have spo­ken out pub­licly in a rare break from Trump.

    “Any plan that ties Amer­i­can drug prices to an inter­na­tion­al price index should be a non­starter for con­ser­v­a­tives, whether it’s com­ing from Con­gress or from the admin­is­tra­tion,” said Jes­si­ca Ander­son, Her­itage Action’s vice pres­i­dent, who worked along­side Gro­gan for over a year in Trump’s bud­get depart­ment.

    ...

    A year after Grogan’s attempt to quash Azar’s drug pric­ing “blue­print” and to can­cel the president’s Rose Gar­den address, the tables had turned. Over Azar’s protes­ta­tions, Gro­gan, with Mulvaney’s back­ing, was argu­ing that Trump’s “rebate rule” — a cen­ter­piece of that very blue­print — should be with­drawn.

    This time, Gro­gan won.

    The rule, in his view, was a hand­out to drug com­pa­nies, a bur­den to tax­pay­ers, and risked leav­ing Medicare ben­e­fi­cia­ries on the hook for high­er pre­mi­ums. Trump sided with Gro­gan and offi­cial­ly killed his health secretary’s sig­na­ture drug pric­ing pro­pos­al.

    It was the third blow in two months to Azar’s blue­print — in essence, the out­come Gro­gan had agi­tat­ed for in May 2018.

    Days before, a fed­er­al court had thrown out anoth­er of the blueprint’s key ele­ments: Trump’s effort to force drug com­pa­nies to include list prices in tele­vi­sion adver­tise­ments, which had gar­nered Grogan’s skep­ti­cism on the grounds that it failed to pass First Amend­ment muster and would do lit­tle to low­er prices.

    And two months ear­li­er, Gro­gan struck his first blow, forc­ing Azar to with­draw his attempt to reform Medicare’s “pro­tect­ed class” require­ments, which would have allowed insur­ance plans to end cov­er­age of med­ica­tions for men­tal health con­di­tions and rare dis­eases if their prices increased faster than infla­tion. Gro­gan was par­tic­u­lar­ly fear­ful of the polit­i­cal fall­out asso­ci­at­ed with deny­ing cov­er­age for expen­sive anti­retro­vi­ral drugs — and the ensu­ing blow­back from HIV/AIDS groups.

    ...

    Yet with the 2020 elec­tion loom­ing, the Trump admin­is­tra­tion has lit­tle to show for its drug pric­ing efforts, thanks in large part to Grogan’s resis­tance. Instead, the White House’s mes­sag­ing has focused on drug impor­ta­tion and inter­na­tion­al price caps — two atyp­i­cal­ly Repub­li­can pol­i­cy ideas that may nev­er be imple­ment­ed.
    ...

    As we can see, Gro­gan won many these pol­i­cy bat­tles in in the end but he did­n’t win any fights for actu­al­ly bet­ter poli­cies. He just helped avoid much, much worse poli­cies that would look so bad they pro­voke a back­lash. And now he is leav­ing while his pol­i­cy foe, Azar, remains in place, at least for now.

    So as the world con­tin­ues to search for some sort of covid drug ther­a­py as soon as pos­si­ble, it’s worth not­ing that one of the top drug indus­try shill’s inside the Trump admin­is­tra­tion is leav­ing very soon leav­ing and his depar­ture is prob­a­bly going to allow the remain­ing drug indus­try shill, Alex Azar, to become an even big­ger shill. That’s how big the White House­’s indus­try-shill prob­lems are: A major pharm-shill leaves and some­how that made the White House­’s shill prob­lem even big­ger.

    Posted by Pterrafractyl | May 18, 2020, 3:31 pm

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