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FTR #1131 Bio-Psy-Op Apocalypse Now, Part 7: Moderna Uber Alles

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FTR #1131 This pro­gram was record­ed in one, 60-minute seg­ment

Intro­duc­tion: This pro­gram con­tin­ues dis­cus­sion of Mod­er­na from FTR #1130. The fir­m’s mRNA (mes­sen­ger RNA) vac­cine that was high­light­ed in that pro­gram is a major top­ic of dis­cus­sion in this one as well.

Do note that DARPA sup­port for Mod­er­na and their work on “gene dri­ving” tech­nol­o­gy in the con­text of that vac­cine.

Intro­duc­ing the top­ic of Mod­er­na’s SARS Cov‑2 vac­cine as a mon­ey mak­er for both Mod­er­na and as a dri­ver for the mar­ket as a whole, we note last Mon­day’s announce­ment which gen­er­at­ed a major boost in the val­ue of Mod­er­na’s stock and a strong, gen­er­al ral­ly. The lat­ter appar­ent­ly stems from opti­mism that a suc­cess­ful vac­cine will alle­vi­ate the eco­nom­ic dam­age from Covid-19.

A Mar­ket­Watch piece about the rapid fluc­tu­a­tion of Mod­er­na’s stock under­scores the sig­nif­i­cance of the tim­ing of an announce­ment cast­ing Mod­er­na’s vac­cine tri­al in over­ly opti­mistic light:

  1. Mod­er­na’s CEO (Stephen Ban­cel) and CFO (Lorence Kim) both sold stock on Fri­day, in accor­dance with pre­arranged trans­ac­tions. Bear in mind, that (as dis­cussed in FTR #1130), Mod­er­na’s stock was trad­ing at $23.46 at the begin­ning of the year, and the company–which has nev­er mar­ket­ed a vaccine–was the ben­e­fi­cia­ry of $483 mil­lion dol­lars in fed­er­al fund­ing ear­li­er in the year.) ” . . . . On Fri­day, Ban­cel sold 11,046 shares at a weight­ed aver­age price of $65.56 for about $724,200, as part of a pre­de­ter­mined trad­ing plan adopt­ed Dec. 28, 2018, accord­ing to a Form 4 fil­ing with the Secu­ri­ties and Exchange Com­mis­sion. He also dis­posed of 1,577 shares as part of a ‘bona fide’ gift. . . . Also, on Fri­day, Kim sold 20,000 shares at a weight­ed aver­age price of $65.53 for about $1.31 mil­lion, as part of a pre­de­ter­mined trad­ing plan. . . .”
  2. Kim also simul­ta­ne­ous­ly bought and sold shares of his firm for a net prof­it of $16.79 mil­lion on Mon­day, the day of an over­ly opti­mistic announce­ment by Mod­er­na. The for­tu­itous­ly timed Mod­er­na announce­ment made the fir­m’s CFO rough­ly $4 mil­lion: ” . . . . On Mon­day, he [Kim] exer­cised options to buy 241,000 shares at a weight­ed aver­age price of $12.45 for about $3 mil­lion, also as part of a pre­de­ter­mined plan. At the same time, Kim exe­cut­ed sales of 241,000 shares, at a weight­ed aver­age price of $82.12 for about $19.79 mil­lion. That means Kim net­ted about $16.79 mil­lion on the simul­ta­ne­ous buy and sale of shares. . . . with Monday’s stock price surge fol­low­ing the announce­ment of ear­ly data on its vac­cine can­di­date poten­tial­ly adding $4 mil­lion to Kim’s cof­fers. . . .”
  3. The above-ref­er­enced announce­ment by Mod­er­na led to a dra­mat­ic increase in Mod­er­na’s stock and boost­ed the mar­ket as a whole. Mod­er­na announced that evening that it would sell $1.34 bil­lion in stock to help its vac­cine oper­a­tion: ” . . . . Shares of Mod­er­na closed at a record high of $80.00 on Mon­day after the com­pa­ny released a slice of pos­i­tive inter­im clin­i­cal data from the first phase of its COVID-19 vac­cine tri­al. That night it announced it would sell $1.34 bil­lion in stock to help fund man­u­fac­tur­ing costs asso­ci­at­ed with the exper­i­men­tal COVID-19 vac­cine. . . .”
  4. Mod­er­na’s stock nose­dived at the end of the trad­ing day on Tues­day, due to a crit­i­cal arti­cle from Stat News” . . . . The stock took a nose dive on Tues­day, clos­ing at $71.67, like­ly due in some degree to a Stat News sto­ry that ques­tioned a lack of clin­i­cal clar­i­ty in the data it pro­vid­ed to investors. . . .”
  5. Mod­er­na’s announce­ment was crit­i­cal­ly assessed by Stat News, which point­ed out that the results were incom­plete at best: ” . . . . In a clin­i­cal-tri­al data dis­clo­sure on Mon­day, Mod­er­na shared that eight out of 45 par­tic­i­pants in its COVID-19 vac­cine study devel­oped neu­tral­iz­ing anti­bod­ies, a deci­sion that Stat’s Helen Bran­swell described as a ‘rea­son for cau­tion.’ It didn’t share infor­ma­tion about the immune response to the exper­i­men­tal vac­cine in the remain­ing 37 par­tic­i­pants. . . .”
  6. Nonethe­less, Mod­er­na’s stock–bolstered by gov­ern­ment investment–has been on a dra­mat­ic upward swing: ” . . . . The company’s stock was up 3.8% in trad­ing on Wednes­day. Year-to-date, it has soared 270.2%, even though the com­pa­ny has no approved prod­ucts. . . .”

There are seri­ous ques­tions about the sub­stance of Mod­er­na’s state­ment:

  1. Moderna’s much tout­ed report on its vaccine—which trig­gered an upsurge in the mar­kets on Monday—appears to have been incom­plete, at best, and pur­pose­ful­ly decep­tive, at worst. “ . . . . While Mod­er­na blitzed the media, it revealed very lit­tle infor­ma­tion — and most of what it did dis­close were words, not data.. . . . If you ask sci­en­tists to read a jour­nal arti­cle, they will scour data tables, not cor­po­rate state­ments. With sci­ence, num­bers speak much loud­er than words. Even the fig­ures the com­pa­ny did release don’t mean much on their own, because crit­i­cal infor­ma­tion — effec­tive­ly the key to inter­pret­ing them — was with­held. . . .
  2. Part of the rea­son for alarm and skep­ti­cism con­cerns the behav­ior of the NIAID—whose direc­tor is Antho­ny Fau­ci: “ . . . . The Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases has part­nered with Mod­er­na on this vac­cine. Sci­en­tists at NIAID made the vaccine’s con­struct, or pro­to­type, and the agency is run­ning the Phase 1 tri­al. This week’s Mod­er­na read­out came from the ear­li­est of data from the NIAID-led Phase 1. NIAID doesn’t hide its light under a bushel. The insti­tute gen­er­al­ly trum­pets its find­ings, often offer­ing direc­tor Antho­ny Fau­ci . . . or oth­er senior per­son­nel for inter­views. But NIAID did not put out a press release Mon­day and declined to pro­vide com­ment on Moderna’s announce­ment. . . .”
  3. To begin with, Moderna’s announce­ment was only sta­tis­ti­cal­ly sub­stan­tive for 8 of the 45 vol­un­teer sub­jects: “ . . . . The company’s state­ment led with the fact that all 45 sub­jects (in this analy­sis) who received dos­es of 25 micro­grams (two dos­es each), 100 micro­grams (two dos­es each), or a 250 micro­grams (one dose) devel­oped bind­ing anti­bod­ies. Lat­er, the state­ment indi­cat­ed that eight vol­un­teers — four each from the 25-micro­gram and 100-micro­gram arms — devel­oped neu­tral­iz­ing anti­bod­ies. Of the two types, these are the ones you’d real­ly want to see. We don’t know results from the oth­er 37 tri­al par­tic­i­pants. . . .”
  4. It is pos­si­ble that neu­tral­iz­ing anti­bod­ies may have been devel­oped in the 37 test sub­jects whose data was not released because the test­ing process is exact­ing. Still the state­ment war­rants cau­tion, at the least. “ . . . . This doesn’t mean that they didn’t devel­op neu­tral­iz­ing anti­bod­ies.Test­ing for neu­tral­iz­ing anti­bod­ies is more time-con­sum­ing than oth­er anti­body tests and must be done in a biose­cu­ri­ty lev­el 3 lab­o­ra­to­ry. Mod­er­na dis­closed the find­ings from eight sub­jects because that’s all it had at that point. Still, it’s a rea­son for cau­tion . . . .”
  5. In addi­tion, the age of the sub­jects was not released and that is rel­e­vant. “ . . . . Sep­a­rate­ly, while the Phase 1 tri­al includ­ed healthy vol­un­teers ages 18 to 55 years, the exact ages of these eight peo­ple are unknown. If, by chance, they most­ly clus­tered around the younger end of the age spec­trum, you might expect a bet­ter response to the vac­cine than if they were most­ly from the senior end of it. And giv­en who is at high­est risk from the SARS-CoV­‑2 coro­n­avirus, pro­tect­ing old­er adults is what Covid-19 vac­cines need to do. . . .”
  6. In addi­tion, there was no data released as to the dura­bil­i­ty of the neu­tral­iz­ing anti­bod­ies. If, for the sake of argu­ment, they are not long-last­ing, the util­i­ty of the vac­cine is neg­li­gi­ble. “ . . . . The report of neu­tral­iz­ing anti­bod­ies in sub­jects who were vac­ci­nat­ed comes from blood drawn two weeks after they received their sec­ond dose of vac­cine. Two weeks. ‘That’s very ear­ly. We don’t know if those anti­bod­ies are durable,’ said Anna Durbin, a vac­cine researcher at Johns Hop­kins Uni­ver­si­ty. . . .”
  7. Still anoth­er point of contention/alarm con­cerns the vari­abil­i­ty in neu­tral­iz­ing anti­bod­ies among recov­ered patients: “ . . . . But stud­ies have shown anti­body lev­els among peo­ple who have recov­ered from the ill­ness vary enor­mous­ly; the range that may be influ­enced by the sever­i­ty of a person’s dis­ease. John ‘Jack’ Rose, a vac­cine researcher from Yale Uni­ver­si­ty, point­ed STAT to a study from Chi­na that showed that, among 175 recov­ered Covid-19 patients stud­ied, 10 had no detectable neu­tral­iz­ing anti­bod­ies. Recov­ered patients at the oth­er end of the spec­trum had real­ly high anti­body lev­els. So though the com­pa­ny said the anti­body lev­els induced by vac­cine were as good as those gen­er­at­ed by infec­tion, there’s no real way to know what that com­par­i­son means. . . .”
  8. It is less than encour­ag­ing that Mod­er­na dis­closed that more rel­e­vant data will be dis­closed in a report to be released in con­junc­tion with NIAID: “ . . . . STAT asked Mod­er­na for infor­ma­tion on the anti­body lev­els it used as a com­para­tor. The response: That will be dis­closed in an even­tu­al jour­nal arti­cle from NIAID, which is part of the Nation­al Insti­tutes of Health. . . .”
  9. Ann Durbin was struck by the word­ing of Moderna’s release: “ . . . . Durbin was struck by the word­ing of the company’s state­ment, point­ing to this sen­tence: ‘The lev­els of neu­tral­iz­ing anti­bod­ies at day 43 were at or above lev­els gen­er­al­ly seen in con­va­les­cent sera.’ ‘I thought: Gen­er­al­ly? What does that mean?’ Durbin said. Her ques­tion, for the time being, can’t be answered. . . .”
  10. Jack Rose com­ment­ed on the opaque nature of Moderna’s release: “. . . . Rose said the com­pa­ny should dis­close the infor­ma­tion. ‘When a com­pa­ny like Mod­er­na with such incred­i­bly vast resources says they have gen­er­at­ed SARS‑2 neu­tral­iz­ing anti­bod­ies in a human tri­al, I would real­ly like to see num­bers from what­ev­er assay they are using,’ he said. . . .”
  11. To date, Mod­er­na issues press releas­es, not papers that can be vet­ted by the sci­en­tif­ic com­mu­ni­ty: “ . . . . It doesn’t pub­lish on its work in sci­en­tif­ic jour­nals. What is known has been dis­closed through press releas­es. That’s not enough to gen­er­ate con­fi­dence with­in the sci­en­tif­ic com­mu­ni­ty. ‘My guess is that their num­bers are mar­gin­al or they would say more,’ Rose said about the company’s SARS‑2 vac­cine, echo­ing a sus­pi­cion that oth­ers have about some of the company’s oth­er work. ‘I do think it’s a bit of a con­cern that they haven’t pub­lished the results of any of their ongo­ing tri­als that they men­tion in their press release. They have not pub­lished any of that,’ Durbin not­ed. . . .”

After sum­ma­riz­ing a high­ly tech­ni­cal arti­cle warn­ing that of the pos­si­ble con­se­quences of intro­duc­ing a SARS Cov‑2 vac­cine that gen­er­ates inad­e­quate­ly high lev­els of anti­bod­ies, we detail a 2016 STAT News arti­cle about Mod­er­na high­lights a num­ber of areas of con­cern, giv­en the speed and rel­a­tive­ly opaque nature of the poten­tial intro­duc­tion of its Covid-19 vac­cine.

The financ­ing of the com­pa­ny by DARPA, and Mon­cef Slaoui’s join­ing with Four Star Gen­er­al Per­na (ele­vat­ed by the Chair­man of the Joint Chiefs of Staff, Gen­er­al Mark A. Mil­ley) are of addi­tion­al con­cern.

  1. As of 2016, Mod­er­na had the largest val­u­a­tion of any pri­vate biotech firm and for­mer employ­ees felt that Mod­er­na prized mon­ey over sci­ence. Note that, as will be reviewed lat­er in the pro­gram, its stock has risen expo­nen­tial­ly as a result of the injec­tion of hun­dreds of mil­lions of dol­lars. Bear in mind that Mod­er­na has also been under­writ­ten by DARPA. “ . . . . Mod­er­na is worth more than any oth­er pri­vate biotech in the US, and for­mer employ­ees said they felt that Ban­cel prized the company’s ever-increas­ing val­u­a­tion, now approach­ing $5 bil­lion, over its sci­ence. . . .”
  2. Mod­er­na has main­tained a cul­ture of secre­cy, which in 2016, applied to the first two prod­ucts under­go­ing phase 1 tri­als: “ . . . . Mod­er­na just moved its first two poten­tial treat­ments — both vac­cines — into human tri­als. In keep­ing with the cul­ture of secre­cy, though, exec­u­tives won’t say which dis­eases the vac­cines tar­get, and they have not list­ed the stud­ies on the pub­lic fed­er­al reg­istry, ClinicalTrials.gov. List­ing is option­al for Phase 1 tri­als, which are meant to deter­mine if a drug is safe, but most com­pa­nies vol­un­tar­i­ly dis­close their work. . . .”
  3. Pro­tein ther­a­py has been a dri­ving eco­nom­ic and ther­a­peu­tic fac­tor in the phar­ma­ceu­ti­cal busi­ness: “ . . . . For decades, com­pa­nies have endeav­ored to craft bet­ter and bet­ter pro­tein ther­a­pies, lead­ing to new treat­ments for can­cer, autoim­mune dis­or­ders, and rare dis­eases. Such ther­a­pies are cost­ly to pro­duce and have many lim­i­ta­tions, but they’ve giv­en rise to a multi­bil­lion-dol­lar indus­try. The anti-inflam­ma­to­ry Humi­ra, the world’s top drug at $14 bil­lion in sales a year, is a shin­ing exam­ple of pro­tein ther­a­py. . . .”
  4. Mod­er­na aims at doing an end run around that tech­nol­o­gy with the injec­tion of mRNA (mes­sen­ger RNA) or DNA. This is a risky tech­nol­o­gy: “ . . . . Moderna’s tech­nol­o­gy promised to sub­vert the whole field, cre­at­ing ther­a­peu­tic pro­teins inside the body instead of in man­u­fac­tur­ing plants. The key: har­ness­ing mes­sen­ger RNA, or mRNA. . . . . It’s high­ly risky. Big phar­ma com­pa­nies had tried sim­i­lar work and aban­doned it because it’s exceed­ing­ly hard to get RNA into cells with­out trig­ger­ing nasty side effects. . . . .”
  5. CEO Ban­cel has main­tained the company’s opaque pro­fes­sion­al cul­ture, mixed with high-pro­file media pro­mo­tion: “ . . . . Under Ban­cel, Mod­er­na has been loath to pub­lish its work in Sci­ence or Nature, but enthu­si­as­tic to her­ald its poten­tial on CNBC and CNN, tak­ing part in seg­ments on the world’s most dis­rup­tive com­pa­niesand the poten­tial ‘cure for can­cer.’ . . .”
  6. Mod­er­na had dra­con­ian atti­tude toward employ­ees from its incep­tion: “ . . . . From the begin­ning, Ban­cel made clear that Moderna’s sci­ence sim­ply had to work. And that any­one who couldn’t make it work didn’t belong. The ear­ly Mod­er­na was a chaot­ic, unpre­dictable work­place, accord­ing to for­mer employ­ees. One recalls find­ing him­self out of a job when a quick-turn­around exper­i­ment failed to pan out. Anoth­er helped train a group of new hires only to real­ize they were his replace­ments. . . .”
  7. Joe Bolen exem­pli­fied the treat­ment Mod­er­na met­ed out: “ . . . . Most stun­ning to employ­ees was the abrupt depar­ture of Joseph Bolen, who came aboard in 2013 to lead Moderna’s R&D efforts. Bolen was a big-name hire in biotech cir­cles, an expe­ri­enced chief sci­en­tif­ic offi­cer who had guid­ed Mil­len­ni­um Phar­ma­ceu­ti­cals to FDA approval for a block­buster can­cer drug. . . ‘No sci­en­tist in his right mind would leave that job unless there was some­thing wrong with the sci­ence or the per­son­nel,’ said a per­son close to the com­pa­ny at the time.’ . . .”
  8. Bolen had com­pa­ny: “ . . . . Bolen wasn’t alone. Chief Infor­ma­tion Offi­cer John Reyn­ders joined in 2013 to make Mod­er­na what he called the world’s ‘first ful­ly dig­i­tal biotech,‘only to step down a year lat­er. Michael Morin, brought in to lead Moderna’s sci­en­tif­ic efforts in can­cer in 2014, last­ed less than 18 months. As did Greg Licholai, hired in 2015 to direct the company’s projects in rare dis­eases. The lat­ter two key lead­er­ship posi­tions remain unfilled. . . .”
  9. The expla­na­tion of CFO Lorence Kim is less than reas­sur­ing from the stand­point of prod­uct safe­ty and reli­a­bil­i­ty: “ . . . . ‘We force every­one to grow with the com­pa­ny at unprece­dent­ed speed,’ Mod­er­na Chief Finan­cial Offi­cer Lorence Kim said. ‘Some peo­ple grow with the com­pa­ny; oth­ers don’t.’ . . .”
  10. Begin­ning in 2013, Mod­er­na part­nered with a series of phar­ma­ceu­ti­cal giants, includ­ing AstraZeneca, which has been select­ed to devel­op a Covid-19 vac­cine: “ . . . . That’s when Mod­er­na — which had just 25 employ­ees — signed a stag­ger­ing $240 mil­lion part­ner­ship with UK phar­ma­ceu­ti­cal giant AstraZeneca. It was the most mon­ey phar­ma had ever spent on drugs that had not yet been test­ed in humans. . . .”
  11. The firm has been lav­ish­ly cap­i­tal­ized: “ . . . . In ear­ly 2015, Mod­er­na dis­closed a $450 mil­lion financ­ing round, the largest ever for a pri­vate biotech com­pa­ny. This month, the com­pa­ny broke its own record, rais­ing anoth­er $474 mil­lion. . . . Though it has yet to reveal data from a sin­gle clin­i­cal tri­al, Mod­er­na is now val­ued at $4.7 bil­lion, accord­ing to Pitch­book. . . .”
  12. Ini­tial­ly, Mod­er­na aimed at devel­op­ing prod­ucts that would be admin­is­tered for a peri­od of years: “ . . . . From the start, Mod­er­na her­ald­ed its abil­i­ty to pro­duce pro­teins with­in cells, which could open up a world of ther­a­peu­tic tar­gets unreach­able by con­ven­tion­al drugs. The most rev­o­lu­tion­ary treat­ments, which could chal­lenge the multi­bil­lion-dol­lar mar­ket for pro­tein ther­a­py, would involve repeat­ed dos­es of mRNA over many years, so a patient’s body con­tin­ued to pro­duce pro­teins to keep dis­ease at bay. . . .”
  13. Instead of pro­duc­ing treat­ments that would be admin­is­tered over a peri­od of years, the com­pa­ny focused on vac­cines: “ . . . . But Moderna’s first human tri­als aren’t so ambi­tious, focus­ing instead on the crowd­ed field of vac­cines, where the com­pa­ny has only been work­ing since 2014. . . . The choice to pri­or­i­tize vac­cines came as a dis­ap­point­ment to many in the com­pa­ny, accord­ing to a for­mer man­ag­er. The plan had been to rad­i­cal­ly dis­rupt the biotech indus­try, the man­ag­er said, so ‘why would you start with a clin­i­cal pro­gram that has very lim­it­ed upside and lots of com­pe­ti­tion?’” . . . .”
  14. The answer to Moderna’s focus on vac­cines may be due to issues of prod­uct safe­ty: “ . . . Deliv­ery — actu­al­ly get­ting RNA into cells — has long bedev­iled the whole field. On their own, RNA mol­e­cules have a hard time reach­ing their tar­gets. They work bet­ter if they’re wrapped up in a deliv­ery mech­a­nism, such as nanopar­ti­cles made of lipids. But those nanopar­ti­cles can lead to dan­ger­ous side effects, espe­cial­ly if a patient has to take repeat­ed dos­es over months or years. . . .”
  15. Vac­cines will only admin­is­ter mRNA at the time of vac­ci­na­tion, rather than over a long peri­od of time: “ . . . . ‘I would say that mRNA is bet­ter suit­ed for dis­eases where treat­ment for short dura­tion is suf­fi­cient­ly cura­tive, so the tox­i­c­i­ties caused by deliv­ery mate­ri­als are less like­ly to occur,’ said Katal­in Karikó, a pio­neer in the field who serves as a vice pres­i­dent at BioN­Tech. . . That makes vac­cines the low­est hang­ing fruit in mRNA, said Franz-Wern­er Haas, CureVac’s chief cor­po­rate offi­cer. ‘From our point of view, it’s obvi­ous why [Mod­er­na] start­ed there,’ he said.’ . . .”
  16. Moderna’s expla­na­tion for its focus on vac­cines is not reassuring—the speed with which it can pro­ceed to human tri­als. The firm’s secre­cy has gen­er­at­ed alarm: “ . . . . Mod­er­na said it pri­or­i­tized vac­cines because they pre­sent­ed the fastest path to human tri­als, not because of set­backs with oth­er projects. ‘The notion that [Mod­er­na] ran into dif­fi­cul­ties isn’t borne in real­i­ty,’ said [Chair­man of the board Noubar] Afeyan. But this is where Moderna’s secre­cy comes into play: Until there’s pub­lished data, only the com­pa­ny and its part­ners know what the data show. Every­one out­side is left guess­ing — and, in some cas­es, wor­ry­ing that Mod­er­na won’t live up to its hype. . . .”
  17. Mod­er­na applies soft­ware and a busi­ness mod­el derived from Tes­la, Ama­zon and Uber: “ . . . . Mod­er­na has pio­neered an auto­mat­ed sys­tem mod­eled on the soft­ware Tes­la uses to man­age orders, Ban­cel said: Sci­en­tists sim­ply enter the pro­tein they want a cell to express, and testable mRNA arrives with­in weeks. . . . That has always been part of the plan, for­mer employ­ees said, point­ing to Bancel’s fas­ci­na­tion with the tech indus­try. Uber and Ama­zon were not the first to come up with their respec­tive busi­ness ideas, but they were the ones that built enough scale to ward off com­pe­ti­tion. And Mod­er­na is posi­tion­ing itself to do the same in mRNA. . . .”

Mon­cef Slaoui

Mon­cef Slaoui’s  opti­mistic state­ment on the Fri­day before the Mon­day announce­ment, presents impor­tant con­text for Moderna’s Mon­day announce­ment. That announce­ment moved mar­kets based on inad­e­quate data. “Oper­a­tion Warp Speed” (head­ed by Slaoui) sug­gests that can­di­date Trump  is very inter­est­ed in those pre­lim­i­nary results as well. 

Eliz­a­beth War­ren scored Slaoui’s con­flict of interest–a con­sid­er­a­tion that will be dis­cussed at length: ” . . . . Fol­low­ing Mon­cef Slaoui’s Fri­day appoint­ment as a co-leader of the Warp Speed pro­gram, he’s set to sell about 155,000 shares in Mod­er­na, accord­ing to press reports. They were worth an esti­mat­ed $10 mil­lion Fri­day, but after Monday’s stock run-up on pos­i­tive ear­ly data, they’re now val­ued at about $12.4 mil­lion. . . . Fol­low­ing Slaoui’s selec­tion, Sen. Eliz­a­beth War­ren tweet­ed that it’s a ‘huge con­flict of inter­est’ for him to keep the Mod­er­na stock as he assumes the new role. She said he should ‘divest imme­di­ate­ly.’ In a now-delet­ed tweet, Slaoui respond­ed that there ‘is no con­flict of inter­est, and there nev­er has been,’ Busi­ness Insid­er reports. . . .”

Even after agree­ing to sell his Mod­er­na stock, Slaoui’s invest­ments raise alarm­ing ques­tions–note that he is a “ven­ture cap­i­tal­ist” and a long­time for­mer exec­u­tive at Glaxo-Smithk­line:

  1. The cir­cum­stances of his appoint­ment will per­mit him to avoid scruti­ny: ” . . . . In agree­ing to accept the posi­tion, Dr. Slaoui did not come on board as a gov­ern­ment employ­ee. Instead, he is on a con­tract, receiv­ing $1 for his ser­vice. That leaves him exempt from fed­er­al dis­clo­sure rules that would require him to list his out­side posi­tions, stock hold­ings and oth­er poten­tial con­flicts. And the con­tract posi­tion is not sub­ject to the same con­flict-of-inter­est laws and reg­u­la­tions that exec­u­tive branch employ­ees must fol­low. . . .”
  2. He will retain a great deal of Glaxo-Smithk­line stock: ” . . . . He did not say how much his GSK shares were worth. When he left the com­pa­ny in 2017, he held about [500,000 in West­ern Print Edi­tion] 240,000 shares and share equiv­a­lents, accord­ing to the drug company’s annu­al report and an analy­sis by the exec­u­tive com­pen­sa­tion firm Equi­lar. . . .”
  3. Fur­ther analy­sis of Slaoui’s posi­tion deep­ens con­cern about the integri­ty of the process: ” . . . . ‘This is basi­cal­ly absurd,’ said Vir­ginia Can­ter, who is chief ethics coun­sel for Cit­i­zens for Respon­si­bil­i­ty and Ethics in Wash­ing­ton. ‘It allows for no pub­lic scruti­ny of his con­flicts of inter­est.’ Ms. Can­ter also said fed­er­al law barred gov­ern­ment con­trac­tors from super­vis­ing gov­ern­ment employ­ees. . . . Ms. Can­ter, a for­mer ethics lawyer in the Oba­ma and Clin­ton admin­is­tra­tions, the Secu­ri­ties and Exchange Com­mis­sion and oth­er agen­cies, point­ed out that GSK’s vac­cine can­di­date with Sanofi could wind up com­pet­ing with oth­er man­u­fac­tur­ers vying for gov­ern­ment approval and sup­port. ‘If he retains stock in com­pa­nies that are invest­ing in the devel­op­ment of a vac­cine, and he’s involved in over­see­ing this process to select the safest vac­cine to com­bat Covid-19, regard­less of how won­der­ful a per­son he is, we can’t be con­fi­dent of the integri­ty of any process in which he is involved,’ Ms. Can­ter said. In addi­tion, his affil­i­a­tion with Medicxi could com­pli­cate mat­ters: Two of its investors are GSK and a divi­sion of John­son & John­son, which is also devel­op­ing a poten­tial vac­cine. . . .”

Mod­er­na stands to make bil­lions of dol­lars if their vac­cine goes to mar­ket:

  1. ” . . . . What investors are bet­ting on, for Mod­er­na and oth­ers devel­op­ing vac­cines against the SARS-CoV­‑2 virus, is that a third of the devel­oped world’s pop­u­la­tion will get vac­ci­nat­ed every year. That could amount to a $10 bil­lion annu­al busi­ness, at an esti­mat­ed price of $30 per vac­ci­na­tion. . . .”
  2. ” . . . . Mor­gan Stan­ley ana­lysts this past week­end sug­gest­ed that pric­ing might start at $5 to $10 a dose dur­ing this first pan­dem­ic cri­sis, then rise to a range of $13 to $30 for pre­ven­tive dos­es in future years. But at BMO Cap­i­tal Mar­kets, ana­lyst George Farmer spec­u­lat­ed that Mod­er­na could start charg­ing $125 per treat­ment in the U.S. mar­ket and raise that price over time to $200. . . . ”

We close the pro­gram with a reminder of the extent to which fed­er­al fund­ing dri­ves the val­ue of Mod­er­na: ” . . . . ‘Instead of wait­ing for the data and then scal­ing up with man­u­fac­tur­ing process … we can make as many dos­es as we can. We are doing both in par­al­lel,’ he said. The com­pa­ny plans to hire up to 150 peo­ple to sup­port the effort. Ban­cel said the com­pa­ny ‘couldn’t have done this’ with­out the fund­ing com­mit­ment from the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, which is part of the Depart­ment of Health and Human Ser­vices. . . .”

1a. We begin by Intro­duc­ing the top­ic of Mod­er­na’s SARS Cov‑2 vac­cine as a mon­ey mak­er for both Mod­er­na and as a dri­ver for the mar­ket as a whole, we note last Mon­day’s announce­ment which gen­er­at­ed a major boost in the val­ue of Mod­er­na’s stock and a strong, gen­er­al ral­ly. The lat­ter appar­ent­ly stems from opti­mism that a sucess­ful vac­cine will alle­vi­ate the eco­nom­ic dam­age from Covid-19:

“Vaccine’s Ear­ly Test Result Ele­vates Hopes and Stocks” by Denise Grady; The New York Times; 5/19/2020; pp. A1-A9 [West­ern Edi­tion].

. . . . The promis­ing ear­ly news sent Moderna’s stock soar­ing by more than 25 per­cent on Mon­day after­noon and helped dri­ve Wall Street to its best day in six weeks. . . . Trad­ing on Mon­day had all of the char­ac­ter­is­tics of a ral­ly focused on prospects for a return to nor­mal: The S&P 500 rose more than 3 per­cent; stock bench­marks in Europe were 4 per­cent to 6 per­cent high­er; and oil prices also jumped. Among the best per­form­ers in the S&P 500 were trav­el-relat­ed com­pa­nies, like Unit­ed Air­lines, Expe­dia Group and Mar­riott Inter­na­tion­al. . . .

1b. A Mar­ket­Watch piece about the rapid fluc­tu­a­tion of Mod­er­na’s stock under­scores the sig­nif­i­cance of the tim­ing of an announce­ment cast­ing Mod­er­na’s vac­cine tri­al in over­ly opti­mistic light:

  1. Mod­er­na’s CEO (Stephen Ban­cel) and CFO (Lorence Kim) both sold stock on Fri­day, in accor­dance with pre­arranged trans­ac­tions. Bear in mind, that (as dis­cussed in FTR #1130), Mod­er­na’s stock was trad­ing at $23.46 at the begin­ning of the year, and the company–which has nev­er mar­ket­ed a vaccine–was the ben­e­fi­cia­ry of $483 mil­lion dol­lars in fed­er­al fund­ing ear­li­er in the year.) ” . . . . On Fri­day, Ban­cel sold 11,046 shares at a weight­ed aver­age price of $65.56 for about $724,200, as part of a pre­de­ter­mined trad­ing plan adopt­ed Dec. 28, 2018, accord­ing to a Form 4 fil­ing with the Secu­ri­ties and Exchange Com­mis­sion. He also dis­posed of 1,577 shares as part of a ‘bona fide’ gift. . . . Also, on Fri­day, Kim sold 20,000 shares at a weight­ed aver­age price of $65.53 for about $1.31 mil­lion, as part of a pre­de­ter­mined trad­ing plan. . . .”
  2. Kim also simul­ta­ne­ous­ly bought and sold shares of his firm for a net prof­it of $16.79 mil­lion on Mon­day, the day of an over­ly opti­mistic announce­ment by Mod­er­na. The for­tu­itous­ly timed Mod­er­na announce­ment made the fir­m’s CFO rough­ly $4 mil­lion: ” . . . . On Mon­day, he [Kim] exer­cised options to buy 241,000 shares at a weight­ed aver­age price of $12.45 for about $3 mil­lion, also as part of a pre­de­ter­mined plan. At the same time, Kim exe­cut­ed sales of 241,000 shares, at a weight­ed aver­age price of $82.12 for about $19.79 mil­lion. That means Kim net­ted about $16.79 mil­lion on the simul­ta­ne­ous buy and sale of shares. . . . with Monday’s stock price surge fol­low­ing the announce­ment of ear­ly data on its vac­cine can­di­date poten­tial­ly adding $4 mil­lion to Kim’s cof­fers. . . .”
  3. The above-ref­er­enced announce­ment by Mod­er­na led to a dra­mat­ic increase in Mod­er­na’s stock and boost­ed the mar­ket as a whole. Mod­er­na announced that evening that it would sell $1.34 bil­lion in stock to help its vac­cine oper­a­tion: ” . . . . Shares of Mod­er­na closed at a record high of $80.00 on Mon­day after the com­pa­ny released a slice of pos­i­tive inter­im clin­i­cal data from the first phase of its COVID-19 vac­cine tri­al. That night it announced it would sell $1.34 bil­lion in stock to help fund man­u­fac­tur­ing costs asso­ci­at­ed with the exper­i­men­tal COVID-19 vac­cine. . . .”
  4. Mod­er­na’s stock nose­dived at the end of the trad­ing day on Tues­day, due to a crit­i­cal arti­cle from Stat News” . . . . The stock took a nose dive on Tues­day, clos­ing at $71.67, like­ly due in some degree to a Stat News sto­ry that ques­tioned a lack of clin­i­cal clar­i­ty in the data it pro­vid­ed to investors. . . .”
  5. Mod­er­na’s announce­ment was crit­i­cal­ly assessed by Stat News, which point­ed out that the results were incom­plete at best: ” . . . . In a clin­i­cal-tri­al data dis­clo­sure on Mon­day, Mod­er­na shared that eight out of 45 par­tic­i­pants in its COVID-19 vac­cine study devel­oped neu­tral­iz­ing anti­bod­ies, a deci­sion that Stat’s Helen Bran­swell described as a ‘rea­son for cau­tion.’ It didn’t share infor­ma­tion about the immune response to the exper­i­men­tal vac­cine in the remain­ing 37 par­tic­i­pants. . . .”
  6. Nonethe­less, Mod­er­na’s stock–bolstered by gov­ern­ment investment–has been on a dra­mat­ic upward swing: ” . . . . The company’s stock was up 3.8% in trad­ing on Wednes­day. Year-to-date, it has soared 270.2%, even though the com­pa­ny has no approved prod­ucts. . . .”

“Moderna’s stock soars, then dips, after ques­tions arise around the lim­it­ed data shared about its COVID-19 vac­cine” by Tomi Kil­go­re and Jaimy Lee; Mar­ket­Watch; 05/20/2020

Wall Street ana­lysts large­ly view the clin­i­cal-tri­al data released by Mod­er­na, how­ev­er lim­it­ed, as a pos­i­tive

Investors in Mod­er­na Inc., the pre­clin­i­cal biotech­nol­o­gy com­pa­ny devel­op­ing one of the front-run­ning COVID-19 vac­cine can­di­dates in the U.S., may be fac­ing a volatile ride through the clin­i­cal tri­al process.

Shares of Mod­er­na closed at a record high of $80.00 on Mon­day after the com­pa­ny released a slice of pos­i­tive inter­im clin­i­cal data from the first phase of its COVID-19 vac­cine tri­al. That night it announced it would sell $1.34 bil­lion in stock to help fund man­u­fac­tur­ing costs asso­ci­at­ed with the exper­i­men­tal COVID-19 vac­cine. The stock took a nose dive on Tues­day, clos­ing at $71.67, like­ly due in some degree to a Stat News sto­ry that ques­tioned a lack of clin­i­cal clar­i­ty in the data it pro­vid­ed to investors.

The company’s stock was up 3.8% in trad­ing on Wednes­day. Year-to-date, it has soared 270.2%, even though the com­pa­ny has no approved prod­ucts. In 2019, it had $60 mil­lion in rev­enue that came from col­lab­o­ra­tions and grants.

In a clin­i­cal-tri­al data dis­clo­sure on Mon­day, Mod­er­na shared that eight out of 45 par­tic­i­pants in its COVID-19 vac­cine study devel­oped neu­tral­iz­ing anti­bod­ies, a deci­sion that Stat’s Helen Bran­swell described as a “rea­son for cau­tion.” It didn’t share infor­ma­tion about the immune response to the exper­i­men­tal vac­cine in the remain­ing 37 par­tic­i­pants.

Mod­er­na, how­ev­er, said that the full data from the tri­al will be pub­lished by the Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases (NIAID), its spon­sor for the study.

The com­pa­ny had also already dis­closed that the Food and Drug Admin­is­tra­tion (FDA) has giv­en the go-ahead for the com­pa­ny to pro­ceed with the sec­ond phase of the clin­i­cal tri­al for its mRNA vac­cine can­di­date, set to begin before the end of June.

Despite the crit­ics cit­ed in the Stat News arti­cle, Wall Street ana­lysts large­ly view the clin­i­cal-tri­al data released by Mod­er­na, how­ev­er lim­it­ed, as a pos­i­tive.

“While sam­ples are not yet avail­able for remain­ing par­tic­i­pants, and we lack specifics on the exact lev­els of bind­ing anti­bod­ies, we view this data as demon­stra­tive of ear­ly signs of effi­ca­cy,” Gold­man Sachs ana­lysts wrote in an investor note on Mon­day.

Med­ical experts and ana­lysts have also raised ques­tions about the lack of com­plete data from Gilead Sci­ences Inc.’s late-stage study for remde­sivir, which was also con­duct­ed with the NIAID.) So far, only the topline results from that tri­al have been shared pub­licly, though that was enough to inform the emer­gency use autho­riza­tion grant­ed by the FDA ear­li­er this month, at least accord­ing to the FDA’s let­ter announc­ing the EUA.

“We need to see all that data, the pub­li­ca­tion,” Dr. Eric Topol, a car­di­ol­o­gist and direc­tor of the Scripps Research Trans­la­tion­al Insti­tute, said by email on May 1. “But I do believe the drug has effi­ca­cy based on what we now know, it’s just not that potent.”

Beyond lin­ger­ing ques­tions about access to the com­plete Phase 1 clin­i­cal tri­al data set for the inves­ti­ga­tion­al vac­cine, Moderna’s splashy offer­ing on Mon­day night aim­ing to sell about $1.3 bil­lion in stock may also have con­tributed to the dive on Tues­day.

The com­pa­ny dis­closed late Tues­day that Chief Exec­u­tive Stéphane Ban­cel and Chief Finan­cial Offi­cer Lorence Kim sold stock recent­ly, with Monday’s stock price surge fol­low­ing the announce­ment of ear­ly data on its vac­cine can­di­date poten­tial­ly adding $4 mil­lion to Kim’s cof­fers.

On Fri­day, Ban­cel sold 11,046 shares at a weight­ed aver­age price of $65.56 for about $724,200, as part of a pre­de­ter­mined trad­ing plan adopt­ed Dec. 28, 2018, accord­ing to a Form 4 fil­ing with the Secu­ri­ties and Exchange Com­mis­sion. He also dis­posed of 1,577 shares as part of a “bona fide” gift.

Also, on Fri­day, Kim sold 20,000 shares at a weight­ed aver­age price of $65.53 for about $1.31 mil­lion, as part of a pre­de­ter­mined trad­ing planOn Mon­day, he exer­cised options to buy 241,000 shares at a weight­ed aver­age price of $12.45 for about $3 mil­lion, also as part of a pre­de­ter­mined plan. At the same time, Kim exe­cut­ed sales of 241,000 shares, at a weight­ed aver­age price of $82.12 for about $19.79 mil­lion. That means Kim net­ted about $16.79 mil­lion on the simul­ta­ne­ous buy and sale of shares.

If Kim had exe­cut­ed Monday’s trades on Fri­day, before the coro­n­avirus vac­cine-relat­ed stock ral­ly, he might have net­ted $12.79 mil­lion, or about $4 mil­lion less.

Mor­gan Stan­ley ana­lysts on Wednes­day set a price tar­get of $90.00 for Mod­er­na, not­ing that they expect the com­pa­ny will sell an esti­mat­ed 1.5 bil­lion dos­es dur­ing the pan­dem­ic and about 150 mil­lion dos­es each year after that. “We are pos­i­tive on the ear­ly data,” they wrote.

Moderna’s mar­ket cap­i­tal­iza­tion is rough­ly $27.4 bil­lion, up from about $6.4 bil­lion on Jan. 2.

The S&P 500 is down 9.3% year-to-date.

2a. There are seri­ous ques­tions about the sub­stance of Mod­er­na’s state­ment:

  1. Moderna’s much tout­ed report on its vaccine—which trig­gered an upsurge in the mar­kets on Monday—appears to have been incom­plete, at best, and pur­pose­ful­ly decep­tive, at worst. “ . . . . While Mod­er­na blitzed the media, it revealed very lit­tle infor­ma­tion — and most of what it did dis­close were words, not data.. . . . If you ask sci­en­tists to read a jour­nal arti­cle, they will scour data tables, not cor­po­rate state­ments. With sci­ence, num­bers speak much loud­er than words. Even the fig­ures the com­pa­ny did release don’t mean much on their own, because crit­i­cal infor­ma­tion — effec­tive­ly the key to inter­pret­ing them — was with­held. . . .
  2. Part of the rea­son for alarm and skep­ti­cism con­cerns the behav­ior of the NIAID—whose direc­tor is Antho­ny Fau­ci: “ . . . . The Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases has part­nered with Mod­er­na on this vac­cine. Sci­en­tists at NIAID made the vaccine’s con­struct, or pro­to­type, and the agency is run­ning the Phase 1 tri­al. This week’s Mod­er­na read­out came from the ear­li­est of data from the NIAID-led Phase 1. NIAID doesn’t hide its light under a bushel. The insti­tute gen­er­al­ly trum­pets its find­ings, often offer­ing direc­tor Antho­ny Fau­ci . . . or oth­er senior per­son­nel for inter­views. But NIAID did not put out a press release Mon­day and declined to pro­vide com­ment on Moderna’s announce­ment. . . .”
  3. To begin with, Moderna’s announce­ment was only sta­tis­ti­cal­ly sub­stan­tive for 8 of the 45 vol­un­teer sub­jects: “ . . . . The company’s state­ment led with the fact that all 45 sub­jects (in this analy­sis) who received dos­es of 25 micro­grams (two dos­es each), 100 micro­grams (two dos­es each), or a 250 micro­grams (one dose) devel­oped bind­ing anti­bod­ies. Lat­er, the state­ment indi­cat­ed that eight vol­un­teers — four each from the 25-micro­gram and 100-micro­gram arms — devel­oped neu­tral­iz­ing anti­bod­ies. Of the two types, these are the ones you’d real­ly want to see. We don’t know results from the oth­er 37 tri­al par­tic­i­pants. . . .”
  4. It is pos­si­ble that neu­tral­iz­ing anti­bod­ies may have been devel­oped in the 37 test sub­jects whose data was not released because the test­ing process is exact­ing. Still the state­ment war­rants cau­tion, at the least. “ . . . . This doesn’t mean that they didn’t devel­op neu­tral­iz­ing anti­bod­ies.Test­ing for neu­tral­iz­ing anti­bod­ies is more time-con­sum­ing than oth­er anti­body tests and must be done in a biose­cu­ri­ty lev­el 3 lab­o­ra­to­ry. Mod­er­na dis­closed the find­ings from eight sub­jects because that’s all it had at that point. Still, it’s a rea­son for cau­tion . . . .”
  5. In addi­tion, the age of the sub­jects was not released and that is rel­e­vant. “ . . . . Sep­a­rate­ly, while the Phase 1 tri­al includ­ed healthy vol­un­teers ages 18 to 55 years, the exact ages of these eight peo­ple are unknown. If, by chance, they most­ly clus­tered around the younger end of the age spec­trum, you might expect a bet­ter response to the vac­cine than if they were most­ly from the senior end of it. And giv­en who is at high­est risk from the SARS-CoV­‑2 coro­n­avirus, pro­tect­ing old­er adults is what Covid-19 vac­cines need to do. . . .”
  6. In addi­tion, there was no data released as to the dura­bil­i­ty of the neu­tral­iz­ing anti­bod­ies. If, for the sake of argu­ment, they are not long-last­ing, the util­i­ty of the vac­cine is neg­li­gi­ble. “ . . . . The report of neu­tral­iz­ing anti­bod­ies in sub­jects who were vac­ci­nat­ed comes from blood drawn two weeks after they received their sec­ond dose of vac­cine. Two weeks. ‘That’s very ear­ly. We don’t know if those anti­bod­ies are durable,’ said Anna Durbin, a vac­cine researcher at Johns Hop­kins Uni­ver­si­ty. . . .”
  7. Still anoth­er point of contention/alarm con­cerns the vari­abil­i­ty in neu­tral­iz­ing anti­bod­ies among recov­ered patients: “ . . . . But stud­ies have shown anti­body lev­els among peo­ple who have recov­ered from the ill­ness vary enor­mous­ly; the range that may be influ­enced by the sever­i­ty of a person’s dis­ease. John ‘Jack’ Rose, a vac­cine researcher from Yale Uni­ver­si­ty, point­ed STAT to a study from Chi­na that showed that, among 175 recov­ered Covid-19 patients stud­ied, 10 had no detectable neu­tral­iz­ing anti­bod­ies. Recov­ered patients at the oth­er end of the spec­trum had real­ly high anti­body lev­els. So though the com­pa­ny said the anti­body lev­els induced by vac­cine were as good as those gen­er­at­ed by infec­tion, there’s no real way to know what that com­par­i­son means. . . .”
  8. It is less than encour­ag­ing that Mod­er­na dis­closed that more rel­e­vant data will be dis­closed in a report to be released in con­junc­tion with NIAID: “ . . . . STAT asked Mod­er­na for infor­ma­tion on the anti­body lev­els it used as a com­para­tor. The response: That will be dis­closed in an even­tu­al jour­nal arti­cle from NIAID, which is part of the Nation­al Insti­tutes of Health. . . .”
  9. Ann Durbin was struck by the word­ing of Moderna’s release: “ . . . . Durbin was struck by the word­ing of the company’s state­ment, point­ing to this sen­tence: ‘The lev­els of neu­tral­iz­ing anti­bod­ies at day 43 were at or above lev­els gen­er­al­ly seen in con­va­les­cent sera.’ ‘I thought: Gen­er­al­ly? What does that mean?’ Durbin said. Her ques­tion, for the time being, can’t be answered. . . .”
  10. Jack Rose com­ment­ed on the opaque nature of Moderna’s release: “. . . . Rose said the com­pa­ny should dis­close the infor­ma­tion. ‘When a com­pa­ny like Mod­er­na with such incred­i­bly vast resources says they have gen­er­at­ed SARS‑2 neu­tral­iz­ing anti­bod­ies in a human tri­al, I would real­ly like to see num­bers from what­ev­er assay they are using,’ he said. . . .”
  11. To date, Mod­er­na issues press releas­es, not papers that can be vet­ted by the sci­en­tif­ic com­mu­ni­ty: “ . . . . It doesn’t pub­lish on its work in sci­en­tif­ic jour­nals. What is known has been dis­closed through press releas­es. That’s not enough to gen­er­ate con­fi­dence with­in the sci­en­tif­ic com­mu­ni­ty. ‘My guess is that their num­bers are mar­gin­al or they would say more,’ Rose said about the company’s SARS‑2 vac­cine, echo­ing a sus­pi­cion that oth­ers have about some of the company’s oth­er work. ‘I do think it’s a bit of a con­cern that they haven’t pub­lished the results of any of their ongo­ing tri­als that they men­tion in their press release. They have not pub­lished any of that,’ Durbin not­ed. . . .”

“Vac­cine experts say Mod­er­na didn’t pro­duce data crit­i­cal to assess­ing Covid-19 vac­cine” by Helen Bran­swell; Stat News; 05/19/2020

Heavy hearts soared Mon­day with news that Moderna’s Covid-19 vac­cine can­di­date — the fron­trun­ner in the Amer­i­can mar­ket — seemed to be gen­er­at­ing an immune response in Phase 1 tri­al sub­jects. The company’s stock val­u­a­tion also surged, hit­ting $29 bil­lion, an aston­ish­ing feat for a com­pa­ny that cur­rent­ly sells zero prod­ucts.

But was there good rea­son for so much enthu­si­asm? Sev­er­al vac­cine experts asked by STAT con­clud­ed that, based on the infor­ma­tion made avail­able by the Cam­bridge, Mass.-based com­pa­ny, there’s real­ly no way to know how impres­sive — or not — the vac­cine may be.

While Mod­er­na blitzed the media, it revealed very lit­tle infor­ma­tion — and most of what it did dis­close were words, not data. That’s impor­tant: If you ask sci­en­tists to read a jour­nal arti­cle, they will scour data tables, not cor­po­rate state­ments. With sci­ence, num­bers speak much loud­er than words.

Even the fig­ures the com­pa­ny did release don’t mean much on their own, because crit­i­cal infor­ma­tion — effec­tive­ly the key to inter­pret­ing them — was with­held.

The silence of the NIAID

The Nation­al Insti­tute for Aller­gy and Infec­tious Dis­eases has part­nered with Mod­er­na on this vac­cine. Sci­en­tists at NIAID made the vaccine’s con­struct, or pro­to­type, and the agency is run­ning the Phase 1 tri­al. This week’s Mod­er­na read­out came from the ear­li­est of data from the NIAID-led Phase 1.

NIAID doesn’t hide its light under a bushel. The insti­tute gen­er­al­ly trum­pets its find­ings, often offer­ing direc­tor Antho­ny Fau­ci — who, fair enough, is pret­ty busy these days — or oth­er senior per­son­nel for inter­views.

But NIAID did not put out a press release Mon­day and declined to pro­vide com­ment on Moderna’s announce­ment.

The n = 8 thing

The company’s state­ment led with the fact that all 45 sub­jects (in this analy­sis) who received dos­es of 25 micro­grams (two dos­es each), 100 micro­grams (two dos­es each), or a 250 micro­grams (one dose) devel­oped bind­ing anti­bod­ies.

Lat­er, the state­ment indi­cat­ed that eight vol­un­teers — four each from the 25-micro­gram and 100-micro­gram arms — devel­oped neu­tral­iz­ing anti­bod­ies. Of the two types, these are the ones you’d real­ly want to see.

We don’t know results from the oth­er 37 tri­al par­tic­i­pants. This doesn’t mean that they didn’t devel­op neu­tral­iz­ing anti­bod­ies. Test­ing for neu­tral­iz­ing anti­bod­ies is more time-con­sum­ing than oth­er anti­body tests and must be done in a biose­cu­ri­ty lev­el 3 lab­o­ra­to­ry. Mod­er­na dis­closed the find­ings from eight sub­jects because that’s all it had at that point. Still, it’s a rea­son for cau­tion.

Sep­a­rate­ly, while the Phase 1 tri­al includ­ed healthy vol­un­teers ages 18 to 55 years, the exact ages of these eight peo­ple are unknown. If, by chance, they most­ly clus­tered around the younger end of the age spec­trum, you might expect a bet­ter response to the vac­cine than if they were most­ly from the senior end of it. And giv­en who is at high­est risk from the SARS-CoV­‑2 coro­n­avirus, pro­tect­ing old­er adults is what Covid-19 vac­cines need to do.

There’s no way to know how durable the response will be

The report of neu­tral­iz­ing anti­bod­ies in sub­jects who were vac­ci­nat­ed comes from blood drawn two weeks after they received their sec­ond dose of vac­cine.

Two weeks.

“That’s very ear­ly. We don’t know if those anti­bod­ies are durable,” said Anna Durbin, a vac­cine researcher at Johns Hop­kins Uni­ver­si­ty.

There’s no real way to con­tex­tu­al­ize the find­ings

Mod­er­na stat­ed that the anti­body lev­els seen were on a par with — or greater than, in the case of the 100-micro­gram dose — those seen in peo­ple who have recov­ered from Covid-19 infec­tion.

But stud­ies have shown anti­body lev­els among peo­ple who have recov­ered from the ill­ness vary enor­mous­ly; the range that may be influ­enced by the sever­i­ty of a person’s dis­ease. John “Jack” Rose, a vac­cine researcher from Yale Uni­ver­si­ty, point­ed STAT to a study from Chi­na that showed that, among 175 recov­ered Covid-19 patients stud­ied, 10 had no detectable neu­tral­iz­ing anti­bod­ies. Recov­ered patients at the oth­er end of the spec­trum had real­ly high anti­body lev­els.

So though the com­pa­ny said the anti­body lev­els induced by vac­cine were as good as those gen­er­at­ed by infec­tion, there’s no real way to know what that com­par­i­son means.

STAT asked Mod­er­na for infor­ma­tion on the anti­body lev­els it used as a com­para­tor. The response: That will be dis­closed in an even­tu­al jour­nal arti­cle from NIAID, which is part of the Nation­al Insti­tutes of Health.

“The con­va­les­cent sera lev­els are not being detailed in our data read­out, but would be expect­ed in a down­stream full data expo­si­tion with NIH and its aca­d­e­m­ic col­lab­o­ra­tors,” Colleen Hussey, the company’s senior man­ag­er for cor­po­rate com­mu­ni­ca­tions, said in an email.

Durbin was struck by the word­ing of the company’s state­ment, point­ing to this sen­tence: “The lev­els of neu­tral­iz­ing anti­bod­ies at day 43 were at or above lev­els gen­er­al­ly seen in con­va­les­cent sera.”

“I thought: Gen­er­al­ly? What does that mean?” Durbin said. Her ques­tion, for the time being, can’t be answered.

Rose said the com­pa­ny should dis­close the infor­ma­tion. “When a com­pa­ny like Mod­er­na with such incred­i­bly vast resources says they have gen­er­at­ed SARS‑2 neu­tral­iz­ing anti­bod­ies in a human tri­al, I would real­ly like to see num­bers from what­ev­er assay they are using,” he said.

Moderna’s approach to dis­clo­sure

The com­pa­ny has not yet brought a vac­cine to mar­ket, but it has a vari­ety of vac­cines for infec­tious dis­eases in its pipeline. It doesn’t pub­lish on its work in sci­en­tif­ic jour­nals. What is known has been dis­closed through press releas­es. That’s not enough to gen­er­ate con­fi­dence with­in the sci­en­tif­ic com­mu­ni­ty.

“My guess is that their num­bers are mar­gin­al or they would say more,” Rose said about the company’s SARS‑2 vac­cine, echo­ing a sus­pi­cion that oth­ers have about some of the company’s oth­er work.

“I do think it’s a bit of a con­cern that they haven’t pub­lished the results of any of their ongo­ing tri­als that they men­tion in their press release. They have not pub­lished any of that,” Durbin not­ed.

Still, she char­ac­ter­ized her­self as “cau­tious­ly opti­mistic” based on what the com­pa­ny has said so far.

“I would like to see the data to make my own inter­pre­ta­tion of the data. But I think it is at least encour­ag­ing that we’ve seen immune respons­es with this RNA vac­cine that we haven’t seen with pre­vi­ous RNA vac­cines for oth­er pathogens. Whether it’s going to be enough, we don’t know,” Durbin said.

Mod­er­na has been more forth­com­ing with data on at least one of its oth­er vac­cine can­di­dates. In a state­ment issued in Jan­u­ary about a Phase 1 tri­al for its cytomegalovirus (CMV) vac­cine, it quan­ti­fied how far over base­line mea­sures anti­body lev­els rose in vac­cines.

2a. The fol­low­ing arti­cle from Nature Reviews Immunol­o­gy warns us of a poten­tial safe­ty issue with the SARS-CoV­‑2 vac­cine: In the orig­i­nal SARS out­break, we learned that if some­one devel­ops antibodies–but not at a high enough lev­el to neu­tral­ize the infec­tion–that can actu­al­ly make that infec­tion more severe. This process is known as anti­body-depen­dent enhance­ment (ADE). This only hap­pens when the neu­tral­iz­ing anti­body lev­els are below some thresh­old.

If a vac­cine induced an immune response that isn’t high enough it could actu­al­ly make the even­tu­al infec­tions even worse. This has been demon­strat­ed in Mice with SARS vac­cines. As the authors also note, there’s some evi­dence aged ani­mals might have a hard­er time gen­er­at­ing the required lev­els of anti­bod­ies after vac­ci­na­tion. So it’s pos­si­ble to have a vac­cine that pro­tects the young and actu­al­ly makes the elder­ly more vul­ner­a­ble:

“The poten­tial dan­ger of sub­op­ti­mal anti­body respons­es in COVID-19” by Akiko Iwasa­ki & Yex­in Yang; Nature Reviews Immunol­o­gy; 04/21/2020

There is a des­per­ate need for effec­tive ther­a­pies and vac­cines for SARS-CoV­‑2 to mit­i­gate the grow­ing eco­nom­ic cri­sis that has ensued from soci­etal lock­down. Vac­cines are being devel­oped at an unprece­dent­ed speed and are already in clin­i­cal tri­als, with­out pre­clin­i­cal test­ing for safe­ty and effi­ca­cy. Yet, safe­ty eval­u­a­tion of can­di­date vac­cines must not be over­looked.

The qual­i­ty and quan­ti­ty of the anti­body response dic­tates func­tion­al out­comes. High-affin­i­ty anti­bod­ies can elic­it neu­tral­iza­tion by rec­og­niz­ing spe­cif­ic viral epi­topes (Fig.1a). Neu­tral­iz­ing anti­bod­ies are defined in vit­ro by their abil­i­ty to block viral entry, fusion or egress. In vivo, neu­tral­iz­ing anti­bod­ies can func­tion with­out addi­tion­al medi­a­tors, although the Fc region is required for neu­tral­iza­tion of influen­za virus2. In the case of SARS-CoV, viral dock­ing on ACE2 on host cells is blocked when neu­tral­iz­ing anti­bod­ies, for exam­ple, rec­og­nize the recep­tor-bind­ing domain (RBD) on the spike (S) pro­tein3. S pro­tein-medi­at­ed viral fusion can be blocked by neu­tral­iz­ing anti­bod­ies tar­get­ing the hep­tad repeat 2 (HR2) domain3. In addi­tion, neu­tral­iz­ing anti­bod­ies can inter­act with oth­er immune com­po­nents, includ­ing com­ple­ment, phago­cytes and nat­ur­al killer cells. These effec­tor respons­es can aid in pathogen clear­ance, with engage­ment of phago­cytes shown to enhance anti­body-medi­at­ed clear­ance of SARS-CoV4How­ev­er, in rare cas­es, pathogen-spe­cif­ic anti­bod­ies can pro­mote pathol­o­gy, result­ing in a phe­nom­e­non known as anti­body-depen­dent enhance­ment (ADE).

Fig. 1: Poten­tial out­comes of anti­body response to coro­n­avirus.

Anti­body-depen­dent enhance­ment

Although anti­bod­ies are gen­er­al­ly pro­tec­tive and ben­e­fi­cial, the ADE phe­nom­e­non is doc­u­ment­ed for dengue virus and oth­er virus­es. In SARS-CoV infec­tion, ADE is medi­at­ed by the engage­ment of Fc recep­tors (FcRs) expressed on dif­fer­ent immune cells, includ­ing mono­cytes, macrophages and B cells5,6Pre-exist­ing SARS-CoV-spe­cif­ic anti­bod­ies may thus pro­mote viral entry into FcR-express­ing cells (Fig. 1b). This process is inde­pen­dent of ACE2 expres­sion and endo­so­mal pH and pro­teas­es, sug­gest­ing dis­tinct cel­lu­lar path­ways of ACE2-medi­at­ed and FcR-medi­at­ed viral entry6There is no evi­dence that ADE facil­i­tates the spread of SARS-CoV in infect­ed hosts. In fact, infec­tion of macrophages through ADE does not result in pro­duc­tive viral repli­ca­tion and shed­ding7Instead, inter­nal­iza­tion of virus–antibody immune com­plex­es can pro­mote inflam­ma­tion and tis­sue injury by acti­vat­ing myeloid cells via FcRs5. Virus intro­duced into the endo­some through this path­way will like­ly engage the RNA-sens­ing Toll-like recep­tors (TLRs) TLR3, TLR7 and TLR8 (Fig. 1c). Uptake of SARS-CoV through ADE in macrophages led to ele­vat­ed pro­duc­tion of TNF and IL‑6 (ref.5). In mice infect­ed with SARS-CoV, ADE was asso­ci­at­ed with decreased lev­els of the anti-inflam­ma­to­ry cytokines IL-10 and TGFß and increased lev­els of the pro-inflam­ma­to­ry chemokines CCL2 and CCL3 (ref.8). Fur­ther­more, immu­niza­tion of non-human pri­mates with a mod­i­fied vac­cinia Ankara (MVA) virus encod­ing the full-length S pro­tein of SARS-CoV pro­mot­ed acti­va­tion of alve­o­lar macrophages, lead­ing to acute lung injury9.

Pro­tec­tive ver­sus path­o­gen­ic anti­bod­ies

Mul­ti­ple fac­tors deter­mine whether an anti­body neu­tral­izes a virus and pro­tects the host or caus­es ADE and acute inflam­ma­tion. These include the speci­fici­ty, con­cen­tra­tion, affin­i­ty and iso­type of the anti­body. Viral vec­tor vac­cines encod­ing SARS-CoV S pro­tein and nucle­o­cap­sid (N) pro­tein pro­voke anti‑S and anti‑N IgG in immu­nized mice, respec­tive­ly, to a sim­i­lar extent. How­ev­er, upon re-chal­lenge, N pro­tein-immu­nized mice show sig­nif­i­cant upreg­u­la­tion of pro-inflam­ma­to­ry cytokine secre­tion, increased neu­trophil and eosinophil lung infil­tra­tion, and more severe lung pathol­o­gy8Sim­i­lar­ly, anti­bod­ies tar­get­ing dif­fer­ent epi­topes on the S pro­tein may vary in their poten­tial to induce neu­tral­iza­tion or ADE. For exam­ple, anti­bod­ies reac­tive to the RBD domain or the HR2 domain of the S pro­tein induce bet­ter pro­tec­tive anti­body respons­es in non-human pri­mates, where­as anti­bod­ies spe­cif­ic for oth­er S pro­tein epi­topes can induce ADE10In vit­ro data sug­gest that for cells express­ing FcRs, ADE occurs when anti­body is present at a low con­cen­tra­tion but damp­ens at the high-con­cen­tra­tion range. Mean­while, increas­ing anti­body con­cen­tra­tions pro­motes SARS-CoV neu­tral­iza­tion by block­ing viral entry into host cells6. For oth­er virus­es, high-affin­i­ty anti­bod­ies capa­ble of block­ing recep­tor bind­ing tend to not induce ADE.

In the ‘mul­ti­ple hit’ mod­el of neu­tral­iza­tion, the virus-block­ing effect cor­re­lates with the num­ber of anti­bod­ies coat­ing the viri­on, which is col­lec­tive­ly affect­ed by anti­body con­cen­tra­tion and affin­i­ty11. Mon­o­clon­al anti­bod­ies with high­er affin­i­ty for the enve­lope (E) pro­tein of West Nile Virus (WNV) induced bet­ter pro­tec­tion in mice receiv­ing a lethal dose of WNV11. For a giv­en con­cen­tra­tion of anti­body and a spe­cif­ic tar­get­ing domain, the sto­i­chiom­e­try of anti­body engage­ment on a viri­on is depen­dent on the strength of inter­ac­tion between anti­body and anti­gen. ADE is induced when the sto­i­chiom­e­try is below the thresh­old for neu­tral­iza­tion. There­fore, high­er affin­i­ty anti­bod­ies can reach that thresh­old at a low­er con­cen­tra­tion and medi­ate bet­ter pro­tec­tion11.

Anti­body iso­types con­trol their effec­tor func­tions. IgM is con­sid­ered more pro-inflam­ma­to­ry as it acti­vates com­ple­ment effi­cient­ly. IgG sub­class­es mod­u­late immune respons­es via the engage­ment of dif­fer­ent FcRs. Most FcγRs sig­nal through ITA­Ms, but FcγRI­Ib con­tains an ITIM on its cyto­plas­mic tail that medi­ates an anti-inflam­ma­to­ry response. Ectopic expres­sion of FcγRI­Ia and FcγRI­Ib, but not of FcγRI or FcγRI­I­Ia, induced ADE of SARS-CoV infec­tion6. Allel­ic poly­mor­phisms in FcγRI­Ia are asso­ci­at­ed with SARS pathol­o­gy, and indi­vid­u­als with an FcγRI­Ia iso­form that binds to both IgG1 and IgG2 were found to devel­op more severe dis­ease than indi­vid­u­als with Fcγthat only binds to IgG2 (ref.12).

Vac­cine approach­es

It is cru­cial to deter­mine which vac­cines and adju­vants can elic­it pro­tec­tive anti­body respons­es to SARS-CoV­‑2. Pre­vi­ous stud­ies have shown that the immu­niza­tion of mice with inac­ti­vat­ed whole SARS-CoV13, the immu­niza­tion of rhe­sus macaques9 with MVA-encod­ed S pro­tein and the immu­niza­tion of mice with DNA vac­cine encod­ing full-length S pro­tein14 could induce ADE or eosinophil-medi­at­ed immunopathol­o­gy to some extent, pos­si­bly owing to low qual­i­ty and quan­ti­ty of anti­body pro­duc­tion. Addi­tion­al­ly, we need to con­sid­er whether a vac­cine is safe and effec­tive in aged hosts. For instance, dou­ble-inac­ti­vat­ed SARS-CoV vac­cine failed to induce neu­tral­iz­ing anti­body respons­es in aged mice13. Fur­ther­more, although an alum-adju­vant­ed dou­ble-inac­ti­vat­ed SARS-CoV vac­cine elicit­ed high­er anti­body titres in aged mice, it skewed the IgG sub­class toward IgG1 instead of IgG2, which was asso­ci­at­ed with a T helper 2 (TH2)-type immune response, enhanced eosinophil­ia and lung pathol­o­gy13. By con­trast, stud­ies in mice showed that sub­unit or pep­tide vac­cines that focus the anti­body response against spe­cif­ic epi­topes with­in the RBD of the S pro­tein con­ferred pro­tec­tive anti­body respons­es3. In addi­tion, live atten­u­at­ed SARS-CoV vac­cine induced pro­tec­tive immune respons­es in aged mice15. Routes of vac­cine admin­is­tra­tion can fur­ther affect vac­cine effi­ca­cy. Com­pared with the intra­mus­cu­lar route, intranasal admin­is­tra­tion of a recom­bi­nant ade­no-asso­ci­at­ed virus vac­cine encod­ing SARS-CoV RBD induced sig­nif­i­cant­ly high­er titres of mucos­al IgA in the lung and reduced lung pathol­o­gy upon chal­lenge with SARS-CoV3.

Con­clud­ing remarks

There are now mul­ti­ple vac­cine can­di­dates (includ­ing nucle­ic acid vac­cines, viral vec­tor vac­cines and sub­unit vac­cines) in the pre­clin­i­cal and clin­i­cal tri­al stages as researchers and insti­tutes from all over the world come togeth­er to accel­er­ate the devel­op­ment of a SARS-CoV­‑2 vac­cine. Recent stud­ies of anti­body respons­es in patients with COVID-19 have asso­ci­at­ed high­er titres of anti‑N IgM and IgG at all time points fol­low­ing the onset of symp­toms with a worse dis­ease out­come16. More­over, high­er titres of anti‑S and anti‑N IgG and IgM cor­re­late with worse clin­i­cal read­outs and old­er age17, sug­gest­ing poten­tial­ly detri­men­tal effects of anti­bod­ies in some patients. How­ev­er, 70% of patients who recov­ered from mild COVID-19 had mea­sur­able neu­tral­iz­ing anti­bod­ies that per­sist­ed upon revis­it to the hospital18. Thus, insights gained from study­ing the anti­body fea­tures that cor­re­late with recov­ery as opposed to wors­en­ing of dis­ease will inform the type of anti­bod­ies to assess in vac­cine stud­ies. We argue that ADE should be giv­en full con­sid­er­a­tion in the safe­ty eval­u­a­tion of emerg­ing can­di­date vac­cines for SARS-CoV­‑2. In addi­tion to vac­cine approach­es, mon­o­clon­al anti­bod­ies could be used to tack­le this virus. Unlike vac­cine-induced anti­bod­ies, mon­o­clon­al anti­bod­ies can be engi­neered with mol­e­c­u­lar pre­ci­sion. Safe and effec­tive neu­tral­iz­ing anti­bod­ies could be pro­duced on a mass-scale for deliv­ery to pop­u­la­tions across the world in the com­ing months. . . .

3. A 2016 STAT News arti­cle about Mod­er­na high­lights a num­ber of areas of con­cern, giv­en the speed and rel­a­tive­ly opaque nature of the poten­tial intro­duc­tion of its Covid-19 vac­cine. The financ­ing of the com­pa­ny by DARPA, and Mon­cef Slaoui’s join­ing with Four Star Gen­er­al Per­na (ele­vat­ed by the Chair­man of the Joint Chiefs of Staff, Gen­er­al Mark A. Mil­ley) are of addi­tion­al con­cern.

  1. As of 2016, Mod­er­na had the largest val­u­a­tion of any pri­vate biotech firm and for­mer employ­ees felt that Mod­er­na prized mon­ey over sci­ence. Note that, as will be reviewed lat­er in the pro­gram, its stock has risen expo­nen­tial­ly as a result of the injec­tion of hun­dreds of mil­lions of dol­lars. Bear in mind that Mod­er­na has also been under­writ­ten by DARPA. “ . . . . Mod­er­na is worth more than any oth­er pri­vate biotech in the US, and for­mer employ­ees said they felt that Ban­cel prized the company’s ever-increas­ing val­u­a­tion, now approach­ing $5 bil­lion, over its sci­ence. . . .”
  2. Mod­er­na has main­tained a cul­ture of secre­cy, which in 2016, applied to the first two prod­ucts under­go­ing phase 1 tri­als: “ . . . . Mod­er­na just moved its first two poten­tial treat­ments — both vac­cines — into human tri­als. In keep­ing with the cul­ture of secre­cy, though, exec­u­tives won’t say which dis­eases the vac­cines tar­get, and they have not list­ed the stud­ies on the pub­lic fed­er­al reg­istry, ClinicalTrials.gov. List­ing is option­al for Phase 1 tri­als, which are meant to deter­mine if a drug is safe, but most com­pa­nies vol­un­tar­i­ly dis­close their work. . . .”
  3. Pro­tein ther­a­py has been a dri­ving eco­nom­ic and ther­a­peu­tic fac­tor in the phar­ma­ceu­ti­cal busi­ness: “ . . . . For decades, com­pa­nies have endeav­ored to craft bet­ter and bet­ter pro­tein ther­a­pies, lead­ing to new treat­ments for can­cer, autoim­mune dis­or­ders, and rare dis­eases. Such ther­a­pies are cost­ly to pro­duce and have many lim­i­ta­tions, but they’ve giv­en rise to a multi­bil­lion-dol­lar indus­try. The anti-inflam­ma­to­ry Humi­ra, the world’s top drug at $14 bil­lion in sales a year, is a shin­ing exam­ple of pro­tein ther­a­py. . . .”
  4. Mod­er­na aims at doing an end run around that tech­nol­o­gy with the injec­tion of mRNA (mes­sen­ger RNA) or DNA. This is a risky tech­nol­o­gy: “ . . . . Moderna’s tech­nol­o­gy promised to sub­vert the whole field, cre­at­ing ther­a­peu­tic pro­teins inside the body instead of in man­u­fac­tur­ing plants. The key: har­ness­ing mes­sen­ger RNA, or mRNA. . . . . It’s high­ly risky. Big phar­ma com­pa­nies had tried sim­i­lar work and aban­doned it because it’s exceed­ing­ly hard to get RNA into cells with­out trig­ger­ing nasty side effects. . . . .”
  5. CEO Ban­cel has main­tained the company’s opaque pro­fes­sion­al cul­ture, mixed with high-pro­file media pro­mo­tion: “ . . . . Under Ban­cel, Mod­er­na has been loath to pub­lish its work in Sci­ence or Nature, but enthu­si­as­tic to her­ald its poten­tial on CNBC and CNN, tak­ing part in seg­ments on the world’s most dis­rup­tive com­pa­niesand the poten­tial ‘cure for can­cer.’. . .”
  6. Mod­er­na had dra­con­ian atti­tude toward employ­ees from its incep­tion: “ . . . . From the begin­ning, Ban­cel made clear that Moderna’s sci­ence sim­ply had to work. And that any­one who couldn’t make it work didn’t belong. The ear­ly Mod­er­na was a chaot­ic, unpre­dictable work­place, accord­ing to for­mer employ­ees. One recalls find­ing him­self out of a job when a quick-turn­around exper­i­ment failed to pan out. Anoth­er helped train a group of new hires only to real­ize they were his replace­ments. . . .”
  7. Joe Bolen exem­pli­fied the treat­ment Mod­er­na met­ed out: “ . . . . Most stun­ning to employ­ees was the abrupt depar­ture of Joseph Bolen, who came aboard in 2013 to lead Moderna’s R&D efforts. Bolen was a big-name hire in biotech cir­cles, an expe­ri­enced chief sci­en­tif­ic offi­cer who had guid­ed Mil­len­ni­um Phar­ma­ceu­ti­cals to FDA approval for a block­buster can­cer drug. . . ‘No sci­en­tist in his right mind would leave that job unless there was some­thing wrong with the sci­ence or the per­son­nel,’ said a per­son close to the com­pa­ny at the time.’ . . .”
  8. Bolen had com­pa­ny: “ . . . . Bolen wasn’t alone. Chief Infor­ma­tion Offi­cer John Reyn­ders joined in 2013 to make Mod­er­na what he called the world’s ‘first ful­ly dig­i­tal biotech,‘only to step down a year lat­er. Michael Morin, brought in to lead Moderna’s sci­en­tif­ic efforts in can­cer in 2014, last­ed less than 18 months. As did Greg Licholai, hired in 2015 to direct the company’s projects in rare dis­eases. The lat­ter two key lead­er­ship posi­tions remain unfilled. . . .”
  9. The expla­na­tion of CFO Lorence Kim is less than reas­sur­ing from the stand­point of prod­uct safe­ty and reli­a­bil­i­ty: “ . . . . ‘We force every­one to grow with the com­pa­ny at unprece­dent­ed speed,’ Mod­er­na Chief Finan­cial Offi­cer Lorence Kim said. ‘Some peo­ple grow with the com­pa­ny; oth­ers don’t.’ . . .”
  10. Begin­ning in 2013, Mod­er­na part­nered with a series of phar­ma­ceu­ti­cal giants, includ­ing AstraZeneca, which has been select­ed to devel­op a Covid-19 vac­cine: “ . . . . That’s when Mod­er­na — which had just 25 employ­ees — signed a stag­ger­ing $240 mil­lion part­ner­ship with UK phar­ma­ceu­ti­cal giant AstraZeneca. It was the most mon­ey phar­ma had ever spent on drugs that had not yet been test­ed in humans. . . .”
  11. The firm has been lav­ish­ly cap­i­tal­ized: “ . . . . In ear­ly 2015, Mod­er­na dis­closed a $450 mil­lion financ­ing round, the largest ever for a pri­vate biotech com­pa­ny. This month, the com­pa­ny broke its own record, rais­ing anoth­er $474 mil­lion. . . . Though it has yet to reveal data from a sin­gle clin­i­cal tri­al, Mod­er­na is now val­ued at $4.7 bil­lion, accord­ing to Pitch­book. . . .”
  12. Ini­tial­ly, Mod­er­na aimed at devel­op­ing prod­ucts that would be admin­is­tered for a peri­od of years: “ . . . . From the start, Mod­er­na her­ald­ed its abil­i­ty to pro­duce pro­teins with­in cells, which could open up a world of ther­a­peu­tic tar­gets unreach­able by con­ven­tion­al drugs. The most rev­o­lu­tion­ary treat­ments, which could chal­lenge the multi­bil­lion-dol­lar mar­ket for pro­tein ther­a­py, would involve repeat­ed dos­es of mRNA over many years, so a patient’s body con­tin­ued to pro­duce pro­teins to keep dis­ease at bay. . . .”
  13. Instead of pro­duc­ing treat­ments that would be admin­is­tered over a peri­od of years, the com­pa­ny focused on vac­cines: “ . . . . But Moderna’s first human tri­als aren’t so ambi­tious, focus­ing instead on the crowd­ed field of vac­cines, where the com­pa­ny has only been work­ing since 2014. . . . The choice to pri­or­i­tize vac­cines came as a dis­ap­point­ment to many in the com­pa­ny, accord­ing to a for­mer man­ag­er. The plan had been to rad­i­cal­ly dis­rupt the biotech indus­try, the man­ag­er said, so ‘why would you start with a clin­i­cal pro­gram that has very lim­it­ed upside and lots of com­pe­ti­tion?’” . . . .”
  14. The answer to Moderna’s focus on vac­cines may be due to issues of prod­uct safe­ty: “ . . . Deliv­ery — actu­al­ly get­ting RNA into cells — has long bedev­iled the whole field. On their own, RNA mol­e­cules have a hard time reach­ing their tar­gets. They work bet­ter if they’re wrapped up in a deliv­ery mech­a­nism, such as nanopar­ti­cles made of lipids. But those nanopar­ti­cles can lead to dan­ger­ous side effects, espe­cial­ly if a patient has to take repeat­ed dos­es over months or years. . . .”
  15. Vac­cines will only admin­is­ter mRNA at the time of vac­ci­na­tion, rather than over a long peri­od of time: “ . . . . ‘I would say that mRNA is bet­ter suit­ed for dis­eases where treat­ment for short dura­tion is suf­fi­cient­ly cura­tive, so the tox­i­c­i­ties caused by deliv­ery mate­ri­als are less like­ly to occur,’ said Katal­in Karikó, a pio­neer in the field who serves as a vice pres­i­dent at BioN­Tech. . . That makes vac­cines the low­est hang­ing fruit in mRNA, said Franz-Wern­er Haas, CureVac’s chief cor­po­rate offi­cer. ‘From our point of view, it’s obvi­ous why [Mod­er­na] start­ed there,’ he said.’ . . .”
  16. Moderna’s expla­na­tion for its focus on vac­cines is not reassuring—the speed with which it can pro­ceed to human tri­als. The firm’s secre­cy has gen­er­at­ed alarm: “ . . . . Mod­er­na said it pri­or­i­tized vac­cines because they pre­sent­ed the fastest path to human tri­als, not because of set­backs with oth­er projects. ‘The notion that [Mod­er­na] ran into dif­fi­cul­ties isn’t borne in real­i­ty,’ said [chair­man of the board Noubar] Afeyan. But this is where Moderna’s secre­cy comes into play: Until there’s pub­lished data, only the com­pa­ny and its part­ners know what the data show. Every­one out­side is left guess­ing — and, in some cas­es, wor­ry­ing that Mod­er­na won’t live up to its hype. . . .”
  17. Mod­er­na applies soft­ware and a busi­ness mod­el derived from Tes­la, Ama­zon and Uber: “ . . . . Mod­er­na has pio­neered an auto­mat­ed sys­tem mod­eled on the soft­ware Tes­la uses to man­age orders, Ban­cel said: Sci­en­tists sim­ply enter the pro­tein they want a cell to express, and testable mRNA arrives with­in weeks. . . . That has always been part of the plan, for­mer employ­ees said, point­ing to Bancel’s fas­ci­na­tion with the tech indus­try. Uber and Ama­zon were not the first to come up with their respec­tive busi­ness ideas, but they were the ones that built enough scale to ward off com­pe­ti­tion. And Mod­er­na is posi­tion­ing itself to do the same in mRNA. . . .”

“Ego, ambi­tion, and tur­moil: Inside one of biotech’s most secre­tive star­tups” by Dami­an Garde; STAT News; 09/13/2016

At first glance, Mod­er­na Ther­a­peu­tics looks like the most envi­able biotech start­up in the world. It has smashed fundrais­ing records and teamed up with phar­ma­ceu­ti­cal giants as it pur­sues a rad­i­cal plan to rev­o­lu­tion­ize med­i­cine by trans­form­ing human cells into drug fac­to­ries.

But the real­i­ty is more com­pli­cat­ed.

A STAT inves­ti­ga­tion found that the company’s caus­tic work envi­ron­ment has for years dri­ven away top tal­ent and that behind its obses­sion with secre­cy, there are signs Mod­er­na has run into road­blocks with its most ambi­tious projects.

At the cen­ter of it all is Stéphane Ban­cel, a first-time biotech CEO with an unwa­ver­ing belief that Moderna’s sci­ence will work — and that employ­ees who don’t “live the mis­sion” have no place in the com­pa­ny. Con­fi­dent and intense, Ban­cel told STAT that Moderna’s sci­ence is on track and, when it is final­ly made pub­lic, that it will meet the brash goal he him­self has set: The new drugs will change the world.

But inter­views with more than 20 cur­rent and for­mer employ­ees and asso­ciates sug­gest Ban­cel has ham­pered progress at Mod­er­na because of his ego, his need to assert con­trol and his impa­tience with the set­backs that are an inevitable part of sci­enceMod­er­na is worth more than any oth­er pri­vate biotech in the US, and for­mer employ­ees said they felt that Ban­cel prized the company’s ever-increas­ing val­u­a­tion, now approach­ing $5 bil­lion, over its sci­ence.

As he pur­sued a com­plex and risky strat­e­gy for drug devel­op­ment, Ban­cel built a cul­ture of recrim­i­na­tion at Mod­er­na, for­mer employ­ees said. Failed exper­i­ments have been met with rep­ri­mands and even on-the-spot fir­ings. They recalled abu­sive emails, dress­ings down at com­pa­ny meet­ings, exceed­ing­ly long hours, and unex­plained ter­mi­na­tions.

At least a dozen high­ly placed exec­u­tives have quit in the past four years, includ­ing heads of finance, tech­nol­o­gy, man­u­fac­tur­ing, and sci­ence. In just the past 12 months, respect­ed lead­ers of Moderna’s can­cer and rare dis­ease pro­grams both resigned, even though the company’s remark­able fundrais­ing had put ample resources at their dis­pos­al. Each had been at the com­pa­ny less than 18 months, and the posi­tions have yet to be filled.

Low­er-rank­ing employ­ees, mean­while, said they’ve been dis­ap­point­ed and con­fused by Moderna’s piv­ot to less ambi­tious — and less trans­for­ma­tive — treat­ments. Mod­er­na has pushed off projects meant to upend the drug indus­try to focus first on the less daunt­ing (and most like­ly, far less lucra­tive) field of vac­cines — though it is years behind com­peti­tors in that are­na.

The com­pa­ny has pub­lished no data sup­port­ing its vaunt­ed tech­nol­o­gy, and it’s so secre­tive that some job can­di­dates have to sign nondis­clo­sure agree­ments before they come in to inter­view. Out­side ven­ture cap­i­tal­ists said Mod­er­na has so many investors clam­or­ing to get in that it can afford to turn away any who ask too many ques­tions. Some small play­ers have been giv­en only a peek at Moderna’s data before com­mit­ting mil­lions to the com­pa­ny, accord­ing to peo­ple famil­iar with the mat­ter.

“It’s a case of the emperor’s new clothes,” said a for­mer Mod­er­na sci­en­tist. “They’re run­ning an invest­ment firm, and then hope­ful­ly it also devel­ops a drug that’s suc­cess­ful.”

Like many employ­ees and for­mer employ­ees, the sci­en­tist request­ed anonymi­ty because of a nondis­clo­sure agree­ment. Oth­ers would not per­mit their names to be pub­lished out of fear that speak­ing can­did­ly about big play­ers in the indus­try would hurt their job prospects down the road.

Mod­er­na just moved its first two poten­tial treat­ments — both vac­cines — into human tri­als. In keep­ing with the cul­ture of secre­cy, though, exec­u­tives won’t say which dis­eases the vac­cines tar­get, and they have not list­ed the stud­ies on the pub­lic fed­er­al reg­istry, ClinicalTrials.gov. List­ing is option­al for Phase 1 tri­als, which are meant to deter­mine if a drug is safe, but most com­pa­nies vol­un­tar­i­ly dis­close their work.

An ambi­tious CEO dreams big

Ban­cel, 44, had no expe­ri­ence run­ning a drug devel­op­ment oper­a­tion when one of biotech’s most suc­cess­ful ven­ture cap­i­tal­ists tapped him to lead Mod­er­na. He’d spent most of his career in sales and oper­a­tions, not sci­ence.

But he had made no secret of his ambi­tion.

A native of France, Ban­cel earned a master’s in chem­i­cal engi­neer­ing from the Uni­ver­si­ty of Min­neso­ta and an MBA from Har­vard in 2000. As Har­vard Busi­ness School class­mates rushed to cash in on the dot-com boom, Ban­cel laid out a plan to play “chess, not check­ers.”

“I was always think­ing, one day, some­body will have to make a deci­sion about me get­ting a CEO job,” he told an audi­ence at his alma mater in April. “… How do I make sure I’m not the brides­maid? How do I make sure that I’m not always the per­son who’s almost select­ed but doesn’t get the role?”

He went into sales and rose through the oper­a­tional ranks at phar­ma­ceu­ti­cal giant Eli Lil­ly, even­tu­al­ly lead­ing the company’s Bel­gian oper­a­tion. And in 2007, at just 34, he achieved his goal, step­ping in as CEO of the French diag­nos­tics firm bio­Mérieux, which employs rough­ly 6,000 peo­ple.

The com­pa­ny improved its mar­gins under Bancel’s tenure, and he devel­oped a rep­u­ta­tion as a stern man­ag­er who got results, accord­ing to an equi­ties ana­lyst who cov­ered bio­Mérieux at the time.

“He doesn’t suf­fer fools light­ly,” the ana­lyst said, speak­ing on con­di­tion of anonymi­ty to com­ply with com­pa­ny pol­i­cy. “I think if you’re under­per­form­ing, you’ll prob­a­bly find your­self look­ing for anoth­er job.”

Bancel’s rise caught the eye of the biotech invest­ment firm Flag­ship Ven­tures, based here in Cam­bridge. Flag­ship CEO Noubar Afeyan repeat­ed­ly tried to entice him to take over one of the firm’s many star­tups, Ban­cel said. But he reject­ed one prospect after anoth­er because the star­tups seemed too nar­row in scope.

Mod­er­na was dif­fer­ent.

The company’s core idea was seduc­tive­ly sim­ple: cut out the mid­dle­man in biotech.

For decades, com­pa­nies have endeav­ored to craft bet­ter and bet­ter pro­tein ther­a­pies, lead­ing to new treat­ments for can­cer, autoim­mune dis­or­ders, and rare dis­eases. Such ther­a­pies are cost­ly to pro­duce and have many lim­i­ta­tions, but they’ve giv­en rise to a multi­bil­lion-dol­lar indus­try. The anti-inflam­ma­to­ry Humi­ra, the world’s top drug at $14 bil­lion in sales a year, is a shin­ing exam­ple of pro­tein ther­a­py.

Moderna’s tech­nol­o­gy promised to sub­vert the whole field, cre­at­ing ther­a­peu­tic pro­teins inside the body instead of in man­u­fac­tur­ing plants. The key: har­ness­ing mes­sen­ger RNA, or mRNA.

In nature, mRNA mol­e­cules func­tion like recipe books, direct­ing cel­lu­lar machin­ery to make spe­cif­ic pro­teins. Mod­er­na believes it can play that sys­tem to its advan­tage by using syn­thet­ic mRNA to com­pel cells to pro­duce whichev­er pro­teins it choos­es. In effect, the mRNA would turn cells into tiny drug fac­to­ries.

It’s high­ly risky. Big phar­ma com­pa­nies had tried sim­i­lar work and aban­doned it because it’s exceed­ing­ly hard to get RNA into cells with­out trig­ger­ing nasty side effects. But if Mod­er­na can get it to work, the process could be used to treat scores of dis­eases, includ­ing can­cers and rare dis­eases that can be death sen­tences for chil­dren.

Under Ban­cel, Mod­er­na has been loath to pub­lish its work in Sci­ence or Nature, but enthu­si­as­tic to her­ald its poten­tial on CNBC and CNN, tak­ing part in seg­ments on the world’s most dis­rup­tive com­pa­nies and the poten­tial “cure for can­cer.”

Res­ig­na­tions, dis­missals, and churn

From the begin­ning, Ban­cel made clear that Moderna’s sci­ence sim­ply had to work. And that any­one who couldn’t make it work didn’t belong.

The ear­ly Mod­er­na was a chaot­ic, unpre­dictable work­place, accord­ing to for­mer employ­ees. One recalls find­ing him­self out of a job when a quick-turn­around exper­i­ment failed to pan out. Anoth­er helped train a group of new hires only to real­ize they were his replace­ments.

“There was a kind of Jack Welch-ian, ‘We fire the bot­tom 10 per­cent’ from the very begin­ning,” said a for­mer Mod­er­na man­ag­er. “That’s prob­a­bly the biggest HR dif­fer­ence between Mod­er­na and vir­tu­al­ly any oth­er biotech, where they talk so much about devel­op­ing their peo­ple.”

Mod­er­na went through two heads of chem­istry in a sin­gle year, accord­ing to for­mer employ­ees, and its chief sci­en­tif­ic offi­cer and head of man­u­fac­tur­ing left short­ly there­after. Those who fell out of favor with Ban­cel would find them­selves exclud­ed from key meet­ings, pushed aside until they resigned or ulti­mate­ly got dis­missed, employ­ees said.

Most stun­ning to employ­ees was the abrupt depar­ture of Joseph Bolen, who came aboard in 2013 to lead Moderna’s R&D efforts.

Bolen was a big-name hire in biotech cir­cles, an expe­ri­enced chief sci­en­tif­ic offi­cer who had guid­ed Mil­len­ni­um Phar­ma­ceu­ti­cals to FDA approval for a block­buster can­cer drug. He’d been pro­filed in The Sci­en­tist, which dubbed him “the people’s CSO” for his abil­i­ty to keep morale high and research focused. Land­ing him was a coup.

But two years into his tenure at Mod­er­na, he abrupt­ly stepped down last Octo­ber, mak­ing no pub­lic state­ment save for chang­ing his LinkedIn sta­tus to “resigned.”

“No sci­en­tist in his right mind would leave that job unless there was some­thing wrong with the sci­ence or the per­son­nel,” said a per­son close to the com­pa­ny at the time.

Insid­ers said Ban­cel had effec­tive­ly pushed Bolen out, hir­ing par­al­lel exec­u­tives until Bolen was in charge of just “a postage stamp” worth of ter­ri­to­ry, as one for­mer Mod­er­na man­ag­er put it. Bolen declined to com­ment.

For his part, Ban­cel acknowl­edged the changes that lim­it­ed Bolen’s pow­er but insist­ed the part­ing was friend­ly. Ban­cel said he tried to con­vince Bolen to stay, but the sci­en­tist “vot­ed him­self off the island.”

Bolen wasn’t alone. Chief Infor­ma­tion Offi­cer John Reyn­ders joined in 2013 to make Mod­er­na what he called the world’s “first ful­ly dig­i­tal biotech,” only to step down a year lat­er. Michael Morin, brought in to lead Moderna’s sci­en­tif­ic efforts in can­cer in 2014, last­ed less than 18 months. As did Greg Licholai, hired in 2015 to direct the company’s projects in rare dis­eases. The lat­ter two key lead­er­ship posi­tions remain unfilled.

“You won­der,” influ­en­tial biotech blog­ger Derek Lowe wrote last year, “if Mod­er­na real­ly is a rock­et ship get­ting ready to launch and spray a for­ma­tion of new drugs across the sky, then why are these peo­ple leav­ing?”

The com­pa­ny has a sim­ple expla­na­tion: Mod­er­na lives in dog years com­pared with oth­er biotechs.

“We force every­one to grow with the com­pa­ny at unprece­dent­ed speed,” Mod­er­na Chief Finan­cial Offi­cer Lorence Kim said. “Some peo­ple grow with the com­pa­ny; oth­ers don’t.”

A gold rush for Mod­er­na

Hoge, who joined the com­pa­ny in 2012, describes the ear­ly days of Mod­er­na as “when we were liv­ing in the caves.” The com­pa­ny often had only enough cash to keep the lights on for six months at a time, he said. “The strat­e­gy was just to sur­vive.”

Mod­er­na 1.0, and life in the caves, came to a close in 2013, accord­ing to com­pa­ny lore.

That’s when Mod­er­na — which had just 25 employ­ees — signed a stag­ger­ing $240 mil­lion part­ner­ship with UK phar­ma­ceu­ti­cal giant AstraZeneca. It was the most mon­ey phar­ma had ever spent on drugs that had not yet been test­ed in humans.

The agree­ment is com­mem­o­rat­ed in one of Moderna’s offices by a framed clip­ping from the New York Times. Page B7 of the March 21, 2013 edi­tion: “AstraZeneca Makes a Bet On an Untest­ed Tech­nique.”

For AstraZeneca, the unprece­dent­ed deal came at a time of uncer­tain­ty. A series of clin­i­cal fail­ures had led the firm to fire its head of research and lay off 1,600 sci­en­tists. Pas­cal Sori­ot, just six months into his tenure as CEO, was under pres­sure from investors to chart a new course. And Mod­er­na, with its brash ambi­tion to bring 100 drugs to clin­i­cal tri­als with­in a decade, gave Sori­ot a way for­ward.

The rich deal start­ed a gold rush for Mod­er­na. Every­one, it seemed, want­ed in.

Before the end of 2013, Mod­er­na would turn heads again with a $110 mil­lion invest­ment round, fol­lowed by a high-dol­lar part­ner­ship with biotech giant Alex­ion.

In ear­ly 2015, Mod­er­na dis­closed a $450 mil­lion financ­ing round, the largest ever for a pri­vate biotech com­pa­ny. This month, the com­pa­ny broke its own record, rais­ing anoth­er $474 mil­lion.

The run-up was “biotech fer­vor to the extreme,” accord­ing to a ven­ture cap­i­tal­ist not involved with the com­pa­ny, request­ing anonymi­ty to speak can­did­ly. While big­ger investors got to see all the company’s data from ani­mal exper­i­ments, some of Moderna’s small­er investors put in funds based on just a peek, accord­ing to peo­ple famil­iar with the process. Moderna’s fundrais­ing suc­cess had cre­at­ed a seller’s mar­ket: Why deal with the ques­tions of one poten­tial investor when it had 10 more lined up?

Afeyan, Moderna’s chair­man and cofounder, insists the company’s investors have done their home­work. To say they bought in with­out due dili­gence “would be a bit of an insult to these peo­ple,” he said.

Though it has yet to reveal data from a sin­gle clin­i­cal tri­al, Mod­er­na is now val­ued at $4.7 bil­lion, accord­ing to Pitch­book.

That’s twice as much as Spark Ther­a­peu­tics, the com­pa­ny wide­ly expect­ed to mar­ket the Unit­ed States’s first gene ther­a­py, which has shown signs in clin­i­cal tri­als that it can reverse blind­ness caused by a rare genet­ic dis­or­der. Mod­er­na is also worth bil­lions more than Juno Ther­a­peu­tics and Kite Phar­ma, star­tups devel­op­ing nov­el treat­ments for can­cer that have demon­strat­ed promis­ing results in ear­ly human tri­als.

Mod­er­na has long shak­en off rumors that it is soon to mar­ket its shares on Wall Street, with Hoge liken­ing the com­pa­ny to a child star: “You don’t want to go through your ado­les­cence pub­licly,” he told STAT.

But that’s about to change. Moderna’s next planned step is an ini­tial pub­lic offer­ing, accord­ing to a per­son close to the com­pa­ny. Ban­cel declined to say just when Mod­er­na might go pub­lic, but the com­pa­ny has already pre­pared: In its lat­est fil­ings with the Secu­ri­ties and Exchange Com­mis­sion, Mod­er­na changed its busi­ness struc­ture from an LLC to a C cor­po­ra­tion, com­plet­ing a nec­es­sary step before mount­ing an IPO.

A strate­gic shift to less ambi­tious tar­gets

With a pub­lic list­ing come required dis­clo­sures, and many are eager to see what Moderna’s been keep­ing under wraps all these years.

Out­siders and com­peti­tors, look­ing only at Moderna’s pub­lic state­ments, have not­ed a shift in strat­e­gy that might sig­nal undis­closed set­backs.

From the start, Mod­er­na her­ald­ed its abil­i­ty to pro­duce pro­teins with­in cells, which could open up a world of ther­a­peu­tic tar­gets unreach­able by con­ven­tion­al drugs. The most rev­o­lu­tion­ary treat­ments, which could chal­lenge the multi­bil­lion-dol­lar mar­ket for pro­tein ther­a­py, would involve repeat­ed dos­es of mRNA over many years, so a patient’s body con­tin­ued to pro­duce pro­teins to keep dis­ease at bay.

But Moderna’s first human tri­als aren’t so ambi­tious, focus­ing instead on the crowd­ed field of vac­cines, where the com­pa­ny has only been work­ing since 2014.

First are the two vac­cine tri­als for undis­closed infec­tious dis­eases. Com­ing next is a one-time treat­ment for heart fail­ure, devel­oped in part­ner­ship with AstraZeneca, fol­lowed by anoth­er exper­i­men­tal vac­cine, for Zika virus, which sev­er­al oth­er phar­ma com­pa­nies are also work­ing to devel­op. And after that, Mod­er­na is plan­ning a human tri­al of a per­son­al­ized can­cer vac­cine using mRNA, some­thing it just came up with last year.

The choice to pri­or­i­tize vac­cines came as a dis­ap­point­ment to many in the com­pa­ny, accord­ing to a for­mer man­ag­er. The plan had been to rad­i­cal­ly dis­rupt the biotech indus­try, the man­ag­er said, so “why would you start with a clin­i­cal pro­gram that has very lim­it­ed upside and lots of com­pe­ti­tion?”

The answer could be the chal­lenge of ensur­ing drug safe­ty, out­siders said.

Deliv­ery — actu­al­ly get­ting RNA into cells — has long bedev­iled the whole field. On their own, RNA mol­e­cules have a hard time reach­ing their tar­gets. They work bet­ter if they’re wrapped up in a deliv­ery mech­a­nism, such as nanopar­ti­cles made of lipids. But those nanopar­ti­cles can lead to dan­ger­ous side effects, espe­cial­ly if a patient has to take repeat­ed dos­es over months or years.

Novar­tis aban­doned the relat­ed realm of RNA inter­fer­ence over con­cerns about tox­i­c­i­ty, as did Mer­ck and Roche.

Moderna’s most advanced com­peti­tors, Cure­Vac and BioN­Tech, have acknowl­edged the same chal­lenge with mRNA. Each is prin­ci­pal­ly focused on vac­cines for infec­tious dis­ease and can­cer, which the com­pa­nies believe can be attacked with just a few dos­es of mRNA. And each has already test­ed its tech­nol­o­gy on hun­dreds of patients.

“I would say that mRNA is bet­ter suit­ed for dis­eases where treat­ment for short dura­tion is suf­fi­cient­ly cura­tive, so the tox­i­c­i­ties caused by deliv­ery mate­ri­als are less like­ly to occur,” said Katal­in Karikó, a pio­neer in the field who serves as a vice pres­i­dent at BioN­Tech.

That makes vac­cines the low­est hang­ing fruit in mRNA, said Franz-Wern­er Haas, CureVac’s chief cor­po­rate offi­cer. “From our point of view, it’s obvi­ous why [Mod­er­na] start­ed there,” he said.

Mod­er­na said it pri­or­i­tized vac­cines because they pre­sent­ed the fastest path to human tri­als, not because of set­backs with oth­er projects. “The notion that [Mod­er­na] ran into dif­fi­cul­ties isn’t borne in real­i­ty,” said Afeyan.

But this is where Moderna’s secre­cy comes into play: Until there’s pub­lished data, only the com­pa­ny and its part­ners know what the data show. Every­one out­side is left guess­ing — and, in some cas­es, wor­ry­ing that Mod­er­na won’t live up to its hype.

“Frankly, I hope that there’s real sub­stance and I hope they solve those chal­lenges, because it’s not going to be good for the broad­er biotech indus­try in gen­er­al if this thing implodes,” said one investor not involved with Mod­er­na.

And it could still go either way, for­mer employ­ees said. If Moderna’s promis­es come to fruition, it could be a pil­lar of the biotech indus­try. If they don’t, it could find a place among a short list of com­pa­nies that have cast a shad­ow over the entire indus­try and left investors dis­il­lu­sioned.

“Either we’ll be talk­ing about it as the next Genen­tech,” a for­mer Mod­er­na man­ag­er said, “or we’ll think, ‘Well, back then, first there was Tur­ing, then there was Valeant, and then there was Mod­er­na.”

Enough cash to absorb some set­backs

Moderna’s man­age­ment and its investors are keep­ing the faith, point­ing to the company’s pipeline of 11 drug can­di­dates and more than 90 pre­clin­i­cal projects.

And with Moderna’s huge cash reserves — esti­mat­ed at $1.5 bil­lion — it can afford a few set­backs, pro­po­nents said. The com­pa­ny said it’s pour­ing mon­ey into its man­u­fac­tur­ing oper­a­tion, plan­ning to spend $100 mil­lion this year on a new plant. Mod­er­na has pio­neered an auto­mat­ed sys­tem mod­eled on the soft­ware Tes­la uses to man­age orders, Ban­cel said: Sci­en­tists sim­ply enter the pro­tein they want a cell to express, and testable mRNA arrives with­in weeks.

“If we have a bump in the road in the clin­ic, we will not have to wait years to go back to the draw­ing board,” Ban­cel said.

That has always been part of the plan, for­mer employ­ees said, point­ing to Bancel’s fas­ci­na­tion with the tech indus­try. Uber and Ama­zon were not the first to come up with their respec­tive busi­ness ideas, but they were the ones that built enough scale to ward off com­pe­ti­tion. And Mod­er­na is posi­tion­ing itself to do the same in mRNA.

“Now, as we’re going to human [tri­als], it’s pret­ty clear no one else is going to catch us,” said Dr. Ken­neth Chien, a pro­fes­sor at Karolin­s­ka Insti­tutet work­ing with Mod­er­na and AstraZeneca.

Dr. Tal Zaks, Moderna’s chief med­ical offi­cer, promis­es that the com­pa­ny will soon break its silence on the pub­lish­ing front. He said next year Mod­er­na will dis­close the ani­mal data that helped get its two vac­cines into the clin­ic. The com­pa­ny has also com­mit­ted to pub­lish­ing full results from all of its human tri­als, start­ing with the vac­cine stud­ies next year.

Moderna’s ret­i­cence to share data ear­li­er is “not because we decid­ed to be secret,” Zaks said. “This is the nat­ur­al evo­lu­tion of a plat­form. As we go into the clin­ic, we will be very trans­par­ent.”

4. Mon­cef Slaoui’s  opti­mistic state­ment on the Fri­day before the Mon­day announce­ment, presents impor­tant con­text for Moderna’s Mon­day announce­ment. That announce­ment moved mar­kets based on inad­e­quate data. “Oper­a­tion Warp Speed” (head­ed by Slaoui) sug­gests that can­di­date Trump  is very inter­est­ed in those pre­lim­i­nary results as well. 

” . . . . Fol­low­ing Mon­cef Slaoui’s Fri­day appoint­ment as a co-leader of the Warp Speed pro­gram, he’s set to sell about 155,000 shares in Mod­er­na, accord­ing to press reports. They were worth an esti­mat­ed $10 mil­lion Fri­day, but after Monday’s stock run-up on pos­i­tive ear­ly data, they’re now val­ued at about $12.4 mil­lion. . . . Fol­low­ing Slaoui’s selec­tion, Sen. Eliz­a­beth War­ren tweet­ed that it’s a ‘huge con­flict of inter­est’ for him to keep the Mod­er­na stock as he assumes the new role. She said he should ‘divest imme­di­ate­ly.’ In a now-delet­ed tweet, Slaoui respond­ed that there ‘is no con­flict of inter­est, and there nev­er has been,’ Busi­ness Insid­er reports. . . .”

“‘Warp Speed’ head Slaoui, chal­lenged for ‘huge con­flict of inter­est,’ sells off $12.4M in Mod­er­na stock” by Eric Sagonowsky; Fier­cePhar­ma; 05/19/2020

As the Oper­a­tion Warp Speed pro­gram races ahead with COVID-19 vac­cine can­di­dates, one of its new lead­ers kept mil­lions of dol­lars of stock in Mod­er­na, the biotech lead­ing the pack.

But now, after an influ­en­tial sen­a­tor chal­lenged that own­er­ship inter­est, he’s plan­ning to sell.

Fol­low­ing Mon­cef Slaoui’s Fri­day appoint­ment as a co-leader of the Warp Speed pro­gram, he’s set to sell about 155,000 shares in Mod­er­na, accord­ing to press reports. They were worth an esti­mat­ed $10 mil­lion Fri­day, but after Monday’s stock run-up on pos­i­tive ear­ly data, they’re now val­ued at about $12.4 mil­lion.

Slaoui is set to donate to can­cer research the excess pro­ceeds from the sale, or about $2.4 mil­lion, accord­ing to CNBC. Slaoui also resigned as a Mod­er­na board mem­ber with the appoint­ment.

Pres­i­dent Don­ald Trump unveiled the “Warp Speed” project at a Rose Gar­den event on Fri­day. Aside from Slaoui, a Glax­o­SmithK­line vet­er­an, the four-star gen­er­al Gus­tave Per­na will also lead the pro­gram.

Fol­low­ing Slaoui’s selec­tion, Sen. Eliz­a­beth War­ren tweet­ed that it’s a “huge con­flict of inter­est” for him to keep the Mod­er­na stock as he assumes the new role. She said he should “divest imme­di­ate­ly.”

In a now-delet­ed tweet, Slaoui respond­ed that there “is no con­flict of inter­est, and there nev­er has been,” Busi­ness Insid­er reports.

Slaoui spent near­ly three decades at Glax­o­SmithK­line and retired in 2017. Then, he joined the boards of Mod­er­na and oth­er life sci­ences com­pa­nies.

Oper­a­tion Warp Speed is aim­ing to deliv­er a COVID-19 vac­cine by the end of the year. At Friday’s event, Slaoui said he was “con­fi­dent” in that goal after view­ing ear­ly data from an undis­closed pro­gram. Mod­er­na announced its promis­ing data, from eight patients in a phase 1 study, ear­ly Mon­day morn­ing. . . .

5. Even after agree­ing to sell his Mod­er­na stock, Slaoui’s invest­ments raise alarm­ing ques­tions–note that he is a “ven­ture cap­i­tal­ist” and a long­time for­mer exec­u­tive at Glaxo-Smithk­line:

  1. The cir­cum­stances of his appoint­ment will per­mit him to avoid scruti­ny: ” . . . . In agree­ing to accept the posi­tion, Dr. Slaoui did not come on board as a gov­ern­ment employ­ee. Instead, he is on a con­tract, receiv­ing $1 for his ser­vice. That leaves him exempt from fed­er­al dis­clo­sure rules that would require him to list his out­side posi­tions, stock hold­ings and oth­er poten­tial con­flicts. And the con­tract posi­tion is not sub­ject to the same con­flict-of-inter­est laws and reg­u­la­tions that exec­u­tive branch employ­ees must fol­low. . . .”
  2. He will retain a great deal of Glaxo-Smithk­line stock: ” . . . . He did not say how much his GSK shares were worth. When he left the com­pa­ny in 2017, he held about [500,000 in West­ern Print Edi­tion] 240,000 shares and share equiv­a­lents, accord­ing to the drug company’s annu­al report and an analy­sis by the exec­u­tive com­pen­sa­tion firm Equi­lar. . . .”
  3. Fur­ther analy­sis of Slaoui’s posi­tion deep­ens con­cern about the integri­ty of the process: ” . . . . ‘This is basi­cal­ly absurd,’ said Vir­ginia Can­ter, who is chief ethics coun­sel for Cit­i­zens for Respon­si­bil­i­ty and Ethics in Wash­ing­ton. ‘It allows for no pub­lic scruti­ny of his con­flicts of inter­est.’ Ms. Can­ter also said fed­er­al law barred gov­ern­ment con­trac­tors from super­vis­ing gov­ern­ment employ­ees. . . . Ms. Can­ter, a for­mer ethics lawyer in the Oba­ma and Clin­ton admin­is­tra­tions, the Secu­ri­ties and Exchange Com­mis­sion and oth­er agen­cies, point­ed out that GSK’s vac­cine can­di­date with Sanofi could wind up com­pet­ing with oth­er man­u­fac­tur­ers vying for gov­ern­ment approval and sup­port. ‘If he retains stock in com­pa­nies that are invest­ing in the devel­op­ment of a vac­cine, and he’s involved in over­see­ing this process to select the safest vac­cine to com­bat Covid-19, regard­less of how won­der­ful a per­son he is, we can’t be con­fi­dent of the integri­ty of any process in which he is involved,’ Ms. Can­ter said.In addi­tion, his affil­i­a­tion with Medicxi could com­pli­cate mat­ters: Two of its investors are GSK and a divi­sion of John­son & John­son, which is also devel­op­ing a poten­tial vac­cine. . . .”

“Trump’s Vac­cine Chief Has Vast Ties to Drug Indus­try, Pos­ing Pos­si­ble Con­flicts” by Sheila Kaplan, Matthew Gold­stein and Alexan­dra Steven­son; The New York Times; 5/21/2020.

. . . . The sci­en­tist, Mocef Slaoui, is a ven­ture cap­i­tal­ist and a for­mer long­time exec­u­tive at Glaxo-Smithk­line . . .

. . . . In agree­ing to accept the posi­tion, Dr. Slaoui did not come on board as a gov­ern­ment employ­ee. Instead, he is on a con­tract, receiv­ing $1 for his ser­vice. That leaves him exempt from fed­er­al dis­clo­sure rules that would require him to list his out­side posi­tions, stock hold­ings and oth­er poten­tial con­flicts. And the con­tract posi­tion is not sub­ject to the same con­flict-of-inter­est laws and reg­u­la­tions that exec­u­tive branch employ­ees must fol­low. . . .

. . . . He did not say how much his GSK shares were worth. When he left the com­pa­ny in 2017, he held about [500,000 in West­ern Edi­tion] 240,000 shares and share equiv­a­lents, accord­ing to the drug company’s annu­al report and an analy­sis by the exec­u­tive com­pen­sa­tion firm Equi­lar.

He said he told admin­is­tra­tion offi­cials that he did not want to sell his com­pa­ny stock.

‘I have worked for 29 years for GSK,’ Dr. Slaoui said. ‘I have nev­er sold a sin­gle share of any com­pa­ny in my life. This is my retire­ment. What I said regard­ing the GSK shares, I said I can­not take the job if I have to sell them.’ . . .

. . . . With­out pub­lic dis­clo­sure, some ethics experts called his con­tract an end-run around the rules.

“This is basi­cal­ly absurd,” said Vir­ginia Can­ter, who is chief ethics coun­sel for Cit­i­zens for Respon­si­bil­i­ty and Ethics in Wash­ing­ton. “It allows for no pub­lic scruti­ny of his con­flicts of inter­est.”

Ms. Can­ter also said fed­er­al law barred gov­ern­ment con­trac­tors from super­vis­ing gov­ern­ment employ­ees. . . .

. . . . Ms. Can­ter, a for­mer ethics lawyer in the Oba­ma and Clin­ton admin­is­tra­tions, the Secu­ri­ties and Exchange Com­mis­sion and oth­er agen­cies, point­ed out that GSK’s vac­cine can­di­date with Sanofi could wind up com­pet­ing with oth­er man­u­fac­tur­ers vying for gov­ern­ment approval and sup­port.

“If he retains stock in com­pa­nies that are invest­ing in the devel­op­ment of a vac­cine, and he’s involved in over­see­ing this process to select the safest vac­cine to com­bat Covid-19, regard­less of how won­der­ful a per­son he is, we can’t be con­fi­dent of the integri­ty of any process in which he is involved,” Ms. Can­ter said.

In addi­tion, his affil­i­a­tion with Medicxi could com­pli­cate mat­ters: Two of its investors are GSK and a divi­sion of John­son & John­son, which is also devel­op­ing a poten­tial vac­cine. . . .

6. Mod­er­na stands to make bil­lions of dol­lars if their vac­cine goes to mar­ket:

  1. ” . . . . What investors are bet­ting on, for Mod­er­na and oth­ers devel­op­ing vac­cines against the SARS-CoV­‑2 virus, is that a third of the devel­oped world’s pop­u­la­tion will get vac­ci­nat­ed every year. That could amount to a $10 bil­lion annu­al busi­ness, at an esti­mat­ed price of $30 per vac­ci­na­tion. . . .”
  2. ” . . . . Mor­gan Stan­ley ana­lysts this past week­end sug­gest­ed that pric­ing might start at $5 to $10 a dose dur­ing this first pan­dem­ic cri­sis, then rise to a range of $13 to $30 for pre­ven­tive dos­es in future years. But at BMO Cap­i­tal Mar­kets, ana­lyst George Farmer spec­u­lat­ed that Mod­er­na could start charg­ing $125 per treat­ment in the U.S. mar­ket and raise that price over time to $200. . . . ”

“A Covid-19 Vac­cine Could Be Worth Bil­lions for Mod­er­na and Its Rivals” by Bill Alpert; Barron’s; 05/19/2020

Fresh on the heels of the first data from human tests of its Covid-19 vac­cine, Mod­er­na sold $1.3 bil­lion worth of stock on Mon­day at a price of $76 a share. That’s a four­fold rise from price where the biotech’s stock start­ed the year, and a mar­ket val­ue of $30 bil­lion for a com­pa­ny that has yet to sell its first prod­uct.

What investors are bet­ting on, for Mod­er­na and oth­ers devel­op­ing vac­cines against the SARS-CoV­‑2 virus, is that a third of the devel­oped world’s pop­u­la­tion will get vac­ci­nat­ed every year. That could amount to a $10 bil­lion annu­al busi­ness, at an esti­mat­ed price of $30 per vac­ci­na­tion. At high­er prices, Covid vac­cine rev­enue would be big­ger still.

In Tues­day morn­ing trad­ing, Mod­er­na stock was down 5% from Monday’s close, at $76.

On a Mon­day con­fer­ence call, Mod­er­na CEO Stéphane Ban­cel said the Cam­bridge, Mass., com­pa­ny had not yet decid­ed on a price , in the event that their mRNA-1273 vac­cine proves effec­tive in the Phase 2 and 3 tri­als it will run this year. He said that Mod­er­na was think­ing about what Covid-19 ill­ness costs the health-care sys­tem.

Covid’s cost obvi­ous­ly goes beyond the hos­pi­tal, and it’s already been gigan­tic . In the U.S. alone, near­ly 90,000 have died in a few months’ time. The scale of the coro­n­avirus’ impact explains why there’s such a range of esti­mates on Wall Street for what vac­cine mak­ers will charge. Mor­gan Stan­ley ana­lysts this past week­end sug­gest­ed that pric­ing might start at $5 to $10 a dose dur­ing this first pan­dem­ic cri­sis, then rise to a range of $13 to $30 for pre­ven­tive dos­es in future years.

But at BMO Cap­i­tal Mar­kets, ana­lyst George Farmer spec­u­lat­ed that Mod­er­na could start charg­ing $125 per treat­ment in the U.S. mar­ket and raise that price over time to $200. Most of the world’s health-care sys­tems are gov­ern­ment-run, so Farmer’s mod­el assumes that pric­ing abroad will be a frac­tion of America’s gen­er­ous pric­ing.

Vac­ci­na­tions will like­ly con­sist of a first shot and then a boost­er one month lat­er. After clin­i­cal tri­als answer the first cru­cial ques­tion of whether vac­cine can­di­dates like Moderna’s pre­vent Covid in humans, the next ques­tion will be how long immu­ni­ty lasts. Assum­ing some­what less muta­bil­i­ty than is the case with the flu virus, researchers are guess­ing that peo­ple might need a SARS-CoV­‑2 vac­ci­na­tion every few years. That’s how ana­lysts like BMO’s Farmer arrive at a count of rough­ly a third of the pop­u­la­tion need­ing a vac­ci­na­tion per year.

The U.S. pop­u­la­tion could rise from about 330 mil­lion today to more than 360 mil­lion by the decade’s end, depend­ing on a bunch of social and eco­nom­ic fac­tors, such as future immi­gra­tion lev­els. Dif­fer­ent age groups will get vac­ci­nat­ed at dif­fer­ing rates—hopefully unim­ped­ed by anti­vac­ci­na­tion sen­ti­mentsBMO esti­mates that will work out to about 30% of America’s head count get­ting vac­ci­nat­ed each year, or some 100 mil­lion treat­ments a year by the sec­ond half of this decade. Put a price from $30 to $130 on those num­bers, and you get $3 bil­lion to $13 bil­lion in U.S. sales.

Glob­al sales are hard­er to fore­cast, with prices and vac­ci­na­tion rates like­ly to vary wide­ly through­out the devel­oped and devel­op­ing coun­tries. BMO’s Farmer guessti­mates that sales in the devel­oped world will amount to half or two-thirds the dol­lar lev­els of the U.S. Poor­er nations will only be able to chip in around 5%. Still, he sees Covid vac­cines exceed­ing $30 bil­lion in sales by the end of the decade. That mar­ket size embold­ened him to raise his price tar­get on Mod­er­na stock to $112 from $83, after yesterday’s encour­ag­ing news on the first hand­ful of patients in Moderna’s Phase 1 tri­al.

Even if Moderna’s vac­cine becomes the first one available—perhaps this fall, for front-line workers—it won’t be the only one. Pfiz­er (PFE) and its part­ner BioN­Tech (BNTX) are also in the clin­ic with a vac­cine that uses tech­nol­o­gy sim­i­lar to Moderna’s. And oth­er vac­cine approach­es are being test­ed by the likes of John­son & John­son (JNJ) and the vac­cine mar­ket incum­bents Sanofi (SNY) and Glax­o­SmithK­line (GSK). . . .

7. We close the dis­cus­sion with a reminder of the extent to which fed­er­al fund­ing dri­ves the val­ue of Mod­er­na: ” . . . . ‘Instead of wait­ing for the data and then scal­ing up with man­u­fac­tur­ing process … we can make as many dos­es as we can. We are doing both in par­al­lel,’ he said. The com­pa­ny plans to hire up to 150 peo­ple to sup­port the effort. Ban­cel said the com­pa­ny ‘couldn’t have done this’ with­out the fund­ing com­mit­ment from the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, which is part of the Depart­ment of Health and Human Ser­vices. . . .”

“Mod­er­na soars after get­ting $483 mil­lion in fed­er­al fund­ing for coro­n­avirus vac­cine devel­op­ment” by Kevin Stankiewicz; CNBC; 04/17/2020

Moderna’s stock was surg­ing Fri­day after the biotech com­pa­ny announced it has received as much as $483 mil­lion in fed­er­al fund­ing to accel­er­ate devel­op­ment of a coro­n­avirus vac­cine.

Shares of the Cam­bridge, Mass­a­chu­setts-based firm closed 15.4% high­er to $46.85. Dur­ing Friday’s ses­sion, the stock hit an intra­day all-time high of $49.

Mod­er­na CEO Stephane Ban­cel said Fri­day on CNBC’s “Squawk Box” that the fund­ing is par­tic­u­lar­ly crit­i­cal in aid­ing man­u­fac­tur­ing efforts.

“Instead of wait­ing for the data and then scal­ing up with man­u­fac­tur­ing process … we can make as many dos­es as we can. We are doing both in par­al­lel,” he said. The com­pa­ny plans to hire up to 150 peo­ple to sup­port the effort.

Ban­cel said the com­pa­ny “couldn’t have done this” with­out the fund­ing com­mit­ment from the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, which is part of the Depart­ment of Health and Human Ser­vices.

Mod­er­na has part­nered with the Nation­al Insti­tutes of Health on devel­op­ment of its Covid-19 vac­cine. Phase 1 human tri­als of the poten­tial vac­cine began in the Seat­tle area in mid-March.

The tri­al was launched in “record speed,” White House health advi­sor Dr. Antho­ny Fau­ci said at the time.

Ban­cel on Fri­day reit­er­at­ed Moderna’s time­line for vac­cine devel­op­ment. He said he hopes to have safe­ty data from the phase 1 tri­al this spring, which could allow it to advance to the next stage in the sec­ond quar­ter of this year.

The phase 1 tri­al is being con­duct­ed with 45 peo­ple, while phase 2 would involve an expan­sion into “hun­dreds of healthy sub­jects,” Ban­cel said.

Devel­op­ment also needs to include a large effec­tive­ness study involv­ing thou­sands of peo­ple, Ban­cel said. Mod­er­na hopes to start that phase in the fall, depend­ing on results from all the pre­ced­ing stages. . . .

 

 

 

Discussion

2 comments for “FTR #1131 Bio-Psy-Op Apocalypse Now, Part 7: Moderna Uber Alles”

  1. There was some good news on the COVID vac­cine hunt revealed on Fri­day. Of course, as we’ll see, it’s the kind of good news that could pos­si­bly be used in a very bad way. So what’s the good news? Well, Mod­er­na just released pre­lim­i­nary data on Fri­day about some safe­ty stud­ies on its COVID-19 vac­cine. The results were pret­ty pos­i­tive but they’re pos­i­tive safe­ty results from stud­ies on mice, so it’s not real­ly clear the find­ings will trans­late to humans. And that’s where this good news could pos­si­bly be used for bad ends. Because as we’ll see, there are grow­ing con­cerns that, as the Novem­ber 2020 US elec­tion grows clos­er the tempt­ing for the Trump admin­is­tra­tion to declare the dis­cov­ery of a vac­cine is only going to grow too. So the temp­ta­tion to basi­cal­ly rush the safe­ty test­ing on a vac­cine will be enor­mous and its a temp­ta­tion that’s going to be felt by Mod­er­na and the rest of the phar­ma­ceu­ti­cal indus­try too.

    And what about the human clin­i­cal tri­als that should be the ulti­mate arbiter of the safe­ty of these vac­cines? Well, those tri­als are under­way too. And as we’ll see in the sec­ond arti­cle below, they’re still con­duct­ing the phase II clin­i­cal tri­als and phase III is going to be get­ting under­way in July. But that’s part of what’s kind of alarm­ing about the sit­u­a­tion: the human clin­i­cal tri­als are already under­way at the same time the ani­mal safe­ty tri­als have yet to be com­plet­ed. That’s how rushed every­thing is with this pan­dem­ic. And the phase II tri­al is going to be fol­low­ing peo­ple for the next year so it’s not real­ly pos­si­ble for the human clin­i­cal tri­als to real­ly run to com­ple­tion before Novem­ber. Side effects can take a while to man­i­fest. So it’s not real­ly pos­si­ble for a human safe­ty tri­als to be com­plete before Novem­ber but it is pos­si­ble for ani­mal safe­ty tri­als to be com­plet­ed. It points to kind of night­mare sit­u­a­tion where polit­i­cal pres­sure results in side-effects that take a while to man­i­fest get­ting missed as deci­sion-mak­ers decide to give undo weight to the ani­mal safe­ty results and just hope for the best.

    So what were the pos­i­tive results from the ani­mal tri­als in mice? Well, mice were giv­en the vac­cine in a range of dos­es, includ­ed dos­es expect­ed to elic­it sub-pro­tec­tive response. Recall how explor­ing the inter­ac­tion of COVID-19 with sub-pro­tec­tive immune respons­es (so low lev­els of anti­bod­ies that can’t pre­vent the dis­ease) is one of the key safe­ty issues to test giv­en the pos­si­bil­i­ty of Anti­body Depen­dent Enhance­ment (ADE), a phe­nom­e­na where low lev­els of inef­fec­tive anti­bod­ies latch onto the virus and exac­er­bate an over­ac­tive immune response that leads to the dead­liest symp­toms likes cytokine-storms. This dan­ger was seen with SARS and attempts to cre­ate a SARS vac­cine so it’s a rea­son­able fear with SARS-CoV­‑2. So find­ing that mice don’t appear to suf­fer from ADE is actu­al­ly great news giv­en on dan­ger­ous ADE could be, espe­cial­ly in the con­text of cre­at­ing a vac­cine. We could lit­er­al­ly cre­ate a vac­cine that pro­tects those who get a strong immune response while endan­ger­ing those with sub-pro­tec­tive respons­es. A kind of eugenic vac­cine. So this should be good news, assum­ing this good news isn’t used in place of mean­ing­ful safe­ty tri­als in humans:

    Reuters

    Mod­er­na COVID-19 vac­cine appears to clear safe­ty hur­dle in mouse study

    Julie Steen­huy­sen
    June 12, 2020 / 12:55 PM / Updat­ed

    CHICAGO (Reuters) — A series of stud­ies in mice of Mod­er­na Inc’s COVID-19 lent some assur­ance that it may not increase the risk of more severe dis­ease, and that one dose may pro­vide pro­tec­tion against the nov­el coro­n­avirus, accord­ing to pre­lim­i­nary data released on Fri­day.

    Pri­or stud­ies on a vac­cine for SARS — a close cousin to the new virus that caus­es COVID-19 — sug­gests vac­cines against this type of virus might have the unin­tend­ed effect of caus­ing more severe dis­ease when the vac­ci­nat­ed per­son is lat­er exposed to the pathogen, espe­cial­ly in indi­vid­u­als who do not pro­duce an ade­quate­ly strong immune response.

    Sci­en­tists have seen this risk as a hur­dle to clear before vac­cines can be safe­ly test­ed in thou­sands of healthy peo­ple.

    While the data released by the U.S. Nation­al Insti­tutes of Aller­gy and Infec­tious Dis­ease (NIAID) and Mod­er­na offered some assur­ance, the stud­ies do not ful­ly answer the ques­tion.

    “This is the barest begin­ning of pre­lim­i­nary infor­ma­tion,” said Dr. Gre­go­ry Poland, an immu­nol­o­gist and vac­cine researcher at the Mayo Clin­ic who has seen the paper, which has yet to under­go peer-review.

    Poland said the paper was incom­plete, dis­or­ga­nized and the num­bers of ani­mals test­ed were small.

    The authors said they have sub­mit­ted the work to a top-tier jour­nal. Moderna’s vac­cine is in mid­stage test­ing in healthy vol­un­teers. Mod­er­na said on Thurs­day it plans to begin final-stage tri­als enrolling 30,000 peo­ple in July.

    In the ani­mal stud­ies, mice received one or two shots of a vari­ety of dos­es of Moderna’s vac­cine, includ­ing dos­es con­sid­ered not strong enough to elic­it a pro­tec­tive immune response. Researchers then exposed the mice to the virus.

    Sub­se­quent analy­ses sug­gest “sub-pro­tec­tive” immune respons­es do not cause what is known as vac­cine-asso­ci­at­ed enhanced res­pi­ra­to­ry dis­ease, a sus­cep­ti­bil­i­ty to more severe dis­ease in the lungs.

    “Sub­pro­tec­tive dos­es did not prime mice for enhanced immunopathol­o­gy fol­low­ing (expo­sure),” Dr. Bar­ney Gra­ham of the Vac­cine Research Cen­ter at NIAID and col­leagues wrote in the man­u­script, post­ed on the bioRx­iv web­site.

    Fur­ther test­ing sug­gest­ed the vac­cine induces anti­body respons­es to block the virus from infect­ing cells.

    The vac­cine also appeared to pro­tect against infec­tion by the coro­n­avirus in the lungs and noses with­out evi­dence of tox­ic effects, the team wrote.

    They not­ed the mice that received just one dose before expo­sure to the virus sev­en weeks lat­er were “com­plete­ly pro­tect­ed against lung viral repli­ca­tion,” sug­gest­ing a sin­gle vac­ci­na­tion pre­vent­ed the virus from repli­cat­ing in the lungs.

    “At first glance, it looks promis­ing in induc­ing neu­tral­iz­ing anti­body pro­tec­tion in mice,” Dr. Peter Hotez, a researcher at Bay­lor Col­lege of Med­i­cine said in an email. He had not reviewed the paper in detail.

    Poland, who was not involved with the research, said the paper leaves out “impor­tant para­me­ters” that could help sci­en­tists judge the work.

    ...

    ————–

    “Mod­er­na COVID-19 vac­cine appears to clear safe­ty hur­dle in mouse study” by Julie Steen­huy­sen; Reuters; 06/12/2020

    “Pri­or stud­ies on a vac­cine for SARS — a close cousin to the new virus that caus­es COVID-19 — sug­gests vac­cines against this type of virus might have the unin­tend­ed effect of caus­ing more severe dis­ease when the vac­ci­nat­ed per­son is lat­er exposed to the pathogen, espe­cial­ly in indi­vid­u­als who do not pro­duce an ade­quate­ly strong immune response.”

    Unin­tend­ed side effects that may future expo­sure worse. Yeah, that’s def­i­nite­ly some­thing we don’t want to do. But at least with mice that does­n’t seem to hap­pen:

    ...
    In the ani­mal stud­ies, mice received one or two shots of a vari­ety of dos­es of Moderna’s vac­cine, includ­ing dos­es con­sid­ered not strong enough to elic­it a pro­tec­tive immune response. Researchers then exposed the mice to the virus.

    Sub­se­quent analy­ses sug­gest “sub-pro­tec­tive” immune respons­es do not cause what is known as vac­cine-asso­ci­at­ed enhanced res­pi­ra­to­ry dis­ease, a sus­cep­ti­bil­i­ty to more severe dis­ease in the lungs.

    “Sub­pro­tec­tive dos­es did not prime mice for enhanced immunopathol­o­gy fol­low­ing (expo­sure),” Dr. Bar­ney Gra­ham of the Vac­cine Research Cen­ter at NIAID and col­leagues wrote in the man­u­script, post­ed on the bioRx­iv web­site.
    ...

    Then again, it’s pos­si­ble the study is incom­plete and dis­or­ga­nized, as one sci­en­tist appeared to see it. It’s a reminder that this good news is actu­al­ly pre­lim­i­nary ten­ta­tive good news:

    ...
    “This is the barest begin­ning of pre­lim­i­nary infor­ma­tion,” said Dr. Gre­go­ry Poland, an immu­nol­o­gist and vac­cine researcher at the Mayo Clin­ic who has seen the paper, which has yet to under­go peer-review.

    Poland said the paper was incom­plete, dis­or­ga­nized and the num­bers of ani­mals test­ed were small.

    ...

    Poland, who was not involved with the research, said the paper leaves out “impor­tant para­me­ters” that could help sci­en­tists judge the work.
    ...

    Ok, now here’s an update on Mod­er­na’s clin­i­cal tri­als on humans. It sounds like the Phase III tri­al is going to be start­ed in July. It’s going to involve 30,000 peo­ple. Alarm­ing­ly, those 30,000 peo­ple will all be receiv­ing the exact same dosage, 100 micro­grams, and that means the phase III tri­al won’t be test­ing sub-opti­mal dosages. It will implic­it­ly be test­ing sub-pro­tec­tive immune respons­es since some of those 30,000 peo­ple will have sub-pro­tec­tive respons­es. But it does­n’t sound like the explo­ration of sub-pro­tec­tive dosages will be thor­ough­ly explored using this large sam­ple size. So we’re already learn­ing that the big Phase III tri­al basi­cal­ly won’t be very inter­est­ed in test­ing ADE in humans.

    What about the Phase II tri­al? Well, that tri­al of 600 healthy peo­ple is ongo­ing. The vol­un­teers will be fol­lowed for a year after their injec­tions to exam­ine the safe­ty of the vac­cine. The Phase II tri­al will also include peo­ple from key pop­u­la­tions like health care work­ers and res­i­dents in long-term care facil­i­ties. So the Phase II tri­al is going to pro­vide cru­cial safe­ty infor­ma­tion on the most vul­ner­a­ble and impor­tant pop­u­la­tions to watch out for with this vac­cine but it won’t be com­plet­ed for a year. All in all, it’s the per­fect storm for hav­ing just enough safe­ty infor­ma­tion to make rushed vague edu­ca­tion guess­es and that’s about it:

    Time

    Mod­er­na Plans To Start Phase 3 Test­ing of its COVID-19 Vac­cine Can­di­date in July

    By Alice Park
    June 11, 2020 10:14 AM EDT

    On June 11, biotech com­pa­ny Mod­er­na announced it had final­ized plans for phase 3 test­ing of its COVID-19 vac­cine can­di­date. The late-stage tri­al will include 30,000 par­tic­i­pants and is expect­ed to begin in July.

    The tri­al will test just one dose lev­el of the vac­cine, 100 micro­grams, giv­en in two shots. In the ear­li­er phase 1 study involv­ing 45 healthy vol­un­teers, the com­pa­ny explored low­er and high­er dos­es, but pre­lim­i­nary results revealed by the com­pa­ny from this tri­al sug­gest­ed that 100 micro­grams pro­vid­ed the desired immune response safe­ly. Accord­ing to the com­pa­ny, the vac­cine pro­duced anti­bod­ies against the COVID-19 virus in those who were vac­ci­nat­ed, and in tests involv­ing a hand­ful of par­tic­i­pants, those anti­bod­ies were able to neu­tral­ize the virus in the lab. The full details of that study aren’t avail­able yet; that will soon be pub­lished by Moderna’s col­lab­o­ra­tors, a team of sci­en­tists at the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases.

    The phase 2 study is ongo­ing, and is enrolling 600 healthy peo­ple who will be fol­lowed for a year after their injec­tions. This stage will con­tin­ue to look at the vaccine’s safe­ty as well as col­lect fur­ther data on its effec­tive­ness. This study will include more peo­ple who might be a high risk of expo­sure to COVID-19, such as health care work­ers and res­i­dents in long-term care facil­i­ties.

    In June, Mod­er­na became one of five vac­cine devel­op­ers cho­sen to be part of Pres­i­dent Trump’s Oper­a­tion Warp Speed pro­gram to speed devel­op­ment of a COVID-19 vac­cine. The selec­tion qual­i­fies Mod­er­na to receive fed­er­al gov­ern­ment fund­ing to con­tin­ue devel­op­ment of vac­cine, con­duct tests, as well as scale up man­u­fac­tur­ing to meet the goal of begin­ning to inoc­u­late 300 mil­lion peo­ple begin­ning ear­ly next year. Mod­er­na said it plans to deliv­er 500 mil­lion to 1 bil­lion dos­es a year begin­ning in 2021.

    ————

    “Mod­er­na Plans To Start Phase 3 Test­ing of its COVID-19 Vac­cine Can­di­date in July” by Alice Park; Time; 06/11/2020

    The tri­al will test just one dose lev­el of the vac­cine, 100 micro­grams, giv­en in two shots. In the ear­li­er phase 1 study involv­ing 45 healthy vol­un­teers, the com­pa­ny explored low­er and high­er dos­es, but pre­lim­i­nary results revealed by the com­pa­ny from this tri­al sug­gest­ed that 100 micro­grams pro­vid­ed the desired immune response safe­ly. Accord­ing to the com­pa­ny, the vac­cine pro­duced anti­bod­ies against the COVID-19 virus in those who were vac­ci­nat­ed, and in tests involv­ing a hand­ful of par­tic­i­pants, those anti­bod­ies were able to neu­tral­ize the virus in the lab. The full details of that study aren’t avail­able yet; that will soon be pub­lished by Moderna’s col­lab­o­ra­tors, a team of sci­en­tists at the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases.”

    So based on the Phase I tri­al of 45 healthy vol­un­teers, 100 micro­grams was deter­mined to pro­vide the desired immune response safe­ly and that’s the dosage that’s going to be used on 30,000 vol­un­teers for the Phase III tri­al. Let’s hope that Phase I tri­al’s sam­ple size was ade­quate and rep­re­sen­ta­tive of the pop­u­la­tion. Espe­cial­ly the unhealthy part of the pop­u­la­tion that’s going to be most vul­ner­a­ble to side-effects.

    And this Phase III tri­al is going to tak­ing place at the same time Phase II is con­tin­u­ing. It sounds like it’s Phase II where key pop­u­la­tions, like health care work­ers and long-term care facil­i­ty res­i­dents are going to be exam­ined. Specif­i­cal­ly healthy vol­un­teers. So healthy long-term care res­i­dents are being used as the test sam­ple for the safe­ty of this vac­cine. And we’ll find out the results in a year. Hmmm...

    ...
    The phase 2 study is ongo­ing, and is enrolling 600 healthy peo­ple who will be fol­lowed for a year after their injec­tions. This stage will con­tin­ue to look at the vaccine’s safe­ty as well as col­lect fur­ther data on its effec­tive­ness. This study will include more peo­ple who might be a high risk of expo­sure to COVID-19, such as health care work­ers and res­i­dents in long-term care facil­i­ties.
    ...

    Ok, final­ly, here’s a New York Times opin­ion piece by by Drs Ezekiel J. Emanuel and Paul A. Offit where they spec­u­late bout the pos­si­bil­i­ty of some sort of near-future dystopi­an sci-fi night­mare sce­nario play­ing out in the com­ing months. A near-future dystopi­an sci-fi night­mare sce­nario that seems all too plau­si­ble giv­en the dystopi­an polit­i­cal night­mare real­i­ty of present-day Amer­i­ca and its dystopi­an fas­cist pres­i­dent who is des­per­ate for a big COVID ‘win’ ASAP:

    The New York Times

    Could Trump Turn a Vac­cine Into a Cam­paign Stunt?
    In a des­per­ate search for a boost, he could release a coro­n­avirus vac­cine that has not been shown to be safe and effec­tive as an Octo­ber sur­prise.

    By Ezekiel J. Emanuel and Paul A. Offit
    Dr. Emanuel and Dr. Offit are pro­fes­sors at the Uni­ver­si­ty of Penn­syl­va­nia.
    June 8, 2020

    Oct. 23, 2020, 9 a.m., with 10 days before the elec­tion, Fox New releas­es a poll show­ing Pres­i­dent Trump trail­ing Joe Biden by eight per­cent­age points.

    Oct. 23, 2020, 3 p.m., at a hasti­ly con­vened news con­fer­ence, Pres­i­dent Trump announces that the Food and Drug Admin­is­tra­tion has just issued an Emer­gency Use Autho­riza­tion for a coro­n­avirus vac­cine. Mr. Trump declares vic­to­ry over Covid-19, demands that all busi­ness­es reopen imme­di­ate­ly and pre­dicts a rapid eco­nom­ic recov­ery.

    Giv­en how this pres­i­dent has behaved, this incred­i­bly dan­ger­ous sce­nario is not far-fetched. In a des­per­ate search for a polit­i­cal boost, he could release a coro­n­avirus vac­cine before it had been thor­ough­ly test­ed and shown to be safe and effec­tive.

    There are 123 can­di­date Covid-19 vac­cines in devel­op­ment, and 10 are in human tri­als. Many have not even been test­ed, or only per­func­to­ri­ly test­ed, in ani­mals. In July, the Nation­al Insti­tutes of Health is plan­ning to begin ran­dom­ized phase III tri­als to test whether some of the 10 vac­cines pre­vent infec­tion with coro­n­avirus. Some phar­ma­ceu­ti­cal com­pa­nies are plan­ning to start their own tri­als at about the same time. Astra Zeneca has already men­tioned it plans to begin deliv­ery of its vac­cine in Octo­ber.

    Pfiz­er is plan­ning to give its vac­cine to approx­i­mate­ly 8,000 patients. The N.I.H. is plan­ning to enroll 30,000 par­tic­i­pants — 20,000 get­ting a can­di­date vac­cine and 10,000 research con­trols.

    By com­par­i­son, the Phase III effec­tive­ness tri­al for one rotavirus vac­cine, RotaTeq, to pre­vent diar­rhea involved about 70,000 infants from 2001 to 2004 and anoth­er rotavirus vac­cine tri­al, Rotar­ix, involved 63,000 infants, from 2003 to 2006.

    Researchers are expect­ing that it will be like­ly to take at least anoth­er eight to 12 months to deter­mine whether these coro­n­avirus vac­cines are effec­tive. Sci­en­tists have to wait until a suf­fi­cient num­ber of patients are exposed to coro­n­avirus to see if the vac­cine real­ly reduces the infec­tion rate, as well as how many peo­ple devel­op uncom­mon side effects. For com­par­i­son, the effec­tive­ness tri­al for the rotavirus vac­cines took about four years and the human papil­lo­mavirus vac­cine stud­ies to pre­vent cer­vi­cal can­cer took sev­en years.

    So could Mr. Trump real­ly pull an “Octo­ber Sur­prise” with a vac­cine less than five months from today?

    One high­ly unlike­ly pos­si­bil­i­ty is that recruit­ment of vol­un­teers in a coro­n­avirus “hot spot” would be so rapid that it would allow for an ade­quate assess­ment of the vaccine’s safe­ty and effec­tive­ness very quick­ly.

    There is anoth­er sce­nario that is far more omi­nous: Three months after the N.I.H. tri­als begin in July — so, mid Octo­ber — stud­ies reveal many patients are devel­op­ing high lev­els of anti­bod­ies to the coro­n­avirus with­out severe side effects. As the White House did with its relent­less pro­mo­tion of hydrox­y­chloro­quine as a cure, it would bad­ger the F.D.A. to per­mit use of the vac­cine. More pres­sure would come from drug com­pa­nies, some of whom may spend up to $1 bil­lion on research and are intense­ly com­pet­ing for pres­tige and glo­ry. They are plan­ning to begin man­u­fac­tur­ing their vac­cine can­di­dates at-risk — that is, before com­plet­ed stud­ies show­ing their vac­cine is actu­al­ly effec­tive.

    Cog­nizant of the fate of Rick Bright — the head of the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, who was sum­mar­i­ly demot­ed when he resist­ed the president’s wish­es to ramp up pur­chase of hydrox­y­chloro­quine — the F.D.A. could issue an Emer­gency Use Autho­riza­tion for one or more vac­cines. These autho­riza­tions only require that the F.D.A. finds it “rea­son­able to believe” that a vac­cine “may be effec­tive” in pre­vent­ing a life-threat­en­ing dis­ease for it to be put on the mar­ket, with­out being for­mal­ly licensed.

    An emer­gency autho­riza­tion would allow Mr. Trump to hold his news con­fer­ence and declare vic­to­ry. But like Pres­i­dent George W. Bush’s “Mis­sion Accom­plished” procla­ma­tion, it has the poten­tial to be a trav­es­ty. Mil­lions of vac­cines could be dis­trib­uted with­out proof that the vac­cine can pre­vent dis­ease or trans­mis­sion.

    No vac­cine since the 1950s has been approved and licensed with­out com­plet­ing large, prospec­tive, place­bo-con­trolled stud­ies of safe­ty and effec­tive­ness.

    Even if a vac­cine gen­er­ates anti­bod­ies, it does not prove that the vac­cine is effec­tive at pre­vent­ing infec­tion; it only makes it more like­ly that the vac­cine would be effec­tive. Indeed, about half of the vac­cines for oth­er dis­eases that work and are on the mar­ket actu­al­ly lack clear immuno­log­i­cal cor­re­lates for pro­tec­tion, mean­ing they are effec­tive but patients’ anti­bod­ies, immune cells or oth­er mark­ers do not iden­ti­fy whether a patient is pro­tect­ed. Even with the ini­tial tri­als, we are like­ly to have scant data on whether old­er peo­ple will mount an immune reac­tion and be pro­tect­ed.

    Giv­ing peo­ple a false sense of being pro­tect­ed will most like­ly lead to seri­ous out­breaks of the dis­ease as peo­ple reduce their com­pli­ance with phys­i­cal dis­tanc­ing and oth­er pub­lic health mea­sures.

    If only 20,000 par­tic­i­pants receive the vac­cine, seri­ous but rare side effects might be missed. If such harms even­tu­al­ly arise, it could fur­ther erode a frag­ile vac­cine con­fi­dence and threat­en the abil­i­ty to get enough peo­ple vac­ci­nat­ed to estab­lish herd immu­ni­ty. That would be a dis­as­ter.

    We were once in a sit­u­a­tion very sim­i­lar to the cur­rent one. Like Covid-19 today, polio in the 1950s was a hor­rif­ic dis­ease feared by every par­ent. Each sum­mer 1,500 chil­dren died and as many as 30,000 became par­a­lyzed for the rest of their lives. Jonas Salk pro­duced his vac­cine and test­ed it on 700 chil­dren in the Pitts­burgh area. It was safe and pro­duced anti­bod­ies. But proof that it was effec­tive at pre­vent­ing polio was demand­ed. A ran­dom­ized, con­trolled tri­al was required before the vac­cine would be licensed and dis­trib­uted. More than 400,000 chil­dren got the vac­cine and 200,000 got place­bo. Only after this effec­tive­ness tri­al was com­plet­ed was the Salk vac­cine licensed and all chil­dren final­ly pro­tect­ed from the dread­ed dis­ease.

    The F.D.A. must require more than the pro­duc­tion of anti­bod­ies to approve a vac­cine, even for an emer­gency autho­riza­tion, much less licens­ing. Only when the inde­pen­dent data safe­ty and mon­i­tor­ing board com­posed of physi­cians, researchers and bio­sta­tis­ti­cians reviews the accu­mu­lat­ed tri­al data to assess the safe­ty and effec­tive­ness of the vac­cines, should the F.D.A. be allowed to decide on approval.

    ...

    ———–

    “Could Trump Turn a Vac­cine Into a Cam­paign Stunt?” by Ezekiel J. Emanuel and Paul A. Offit; The New York Times; 06/08/2020

    “Giv­en how this pres­i­dent has behaved, this incred­i­bly dan­ger­ous sce­nario is not far-fetched. In a des­per­ate search for a polit­i­cal boost, he could release a coro­n­avirus vac­cine before it had been thor­ough­ly test­ed and shown to be safe and effec­tive.

    That’s the gener­ic sce­nario that seems all too plau­si­ble: In a des­per­ate search for a polit­i­cal boost, Trump basi­cal­ly pres­sures the FDA into approv­ing a vac­cine before the elec­tion. A sce­nario the vac­cine man­u­fac­tur­ers show no incli­na­tion to resist. As they note, Mod­er­na isn’t the only com­pa­ny talk­ing about deliv­er­ing a vac­cine before fall. Astra Zeneca has been mak­ing those kinds of bold pledges too:

    ...
    There are 123 can­di­date Covid-19 vac­cines in devel­op­ment, and 10 are in human tri­als. Many have not even been test­ed, or only per­func­to­ri­ly test­ed, in ani­mals. In July, the Nation­al Insti­tutes of Health is plan­ning to begin ran­dom­ized phase III tri­als to test whether some of the 10 vac­cines pre­vent infec­tion with coro­n­avirus. Some phar­ma­ceu­ti­cal com­pa­nies are plan­ning to start their own tri­als at about the same time. Astra Zeneca has already men­tioned it plans to begin deliv­ery of its vac­cine in Octo­ber.

    ...

    One high­ly unlike­ly pos­si­bil­i­ty is that recruit­ment of vol­un­teers in a coro­n­avirus “hot spot” would be so rapid that it would allow for an ade­quate assess­ment of the vaccine’s safe­ty and effec­tive­ness very quick­ly.

    There is anoth­er sce­nario that is far more omi­nous: Three months after the N.I.H. tri­als begin in July — so, mid Octo­ber — stud­ies reveal many patients are devel­op­ing high lev­els of anti­bod­ies to the coro­n­avirus with­out severe side effects. As the White House did with its relent­less pro­mo­tion of hydrox­y­chloro­quine as a cure, it would bad­ger the F.D.A. to per­mit use of the vac­cine. More pres­sure would come from drug com­pa­nies, some of whom may spend up to $1 bil­lion on research and are intense­ly com­pet­ing for pres­tige and glo­ry. They are plan­ning to begin man­u­fac­tur­ing their vac­cine can­di­dates at-risk — that is, before com­plet­ed stud­ies show­ing their vac­cine is actu­al­ly effec­tive.

    Cog­nizant of the fate of Rick Bright — the head of the Bio­med­ical Advanced Research and Devel­op­ment Author­i­ty, who was sum­mar­i­ly demot­ed when he resist­ed the president’s wish­es to ramp up pur­chase of hydrox­y­chloro­quine — the F.D.A. could issue an Emer­gency Use Autho­riza­tion for one or more vac­cines. These autho­riza­tions only require that the F.D.A. finds it “rea­son­able to believe” that a vac­cine “may be effec­tive” in pre­vent­ing a life-threat­en­ing dis­ease for it to be put on the mar­ket, with­out being for­mal­ly licensed.

    An emer­gency autho­riza­tion would allow Mr. Trump to hold his news con­fer­ence and declare vic­to­ry. But like Pres­i­dent George W. Bush’s “Mis­sion Accom­plished” procla­ma­tion, it has the poten­tial to be a trav­es­ty. Mil­lions of vac­cines could be dis­trib­uted with­out proof that the vac­cine can pre­vent dis­ease or trans­mis­sion.

    ...

    And note their warn­ings about the sam­ple sizes need­ed to detect rare side-effects and the impor­tance of find­ing those rare effects: Even if they’re rare and there­fore don’t impact a huge por­tion of the pop­u­lace, if we miss those rare effect and a bunch of peo­ple are harmed by these vac­cines that’s only going to erode already frag­ile pub­lic con­fi­dence in vac­cines in gen­er­al and fuel the anti-vaxxer crowd:

    ...
    Even if a vac­cine gen­er­ates anti­bod­ies, it does not prove that the vac­cine is effec­tive at pre­vent­ing infec­tion; it only makes it more like­ly that the vac­cine would be effec­tive. Indeed, about half of the vac­cines for oth­er dis­eases that work and are on the mar­ket actu­al­ly lack clear immuno­log­i­cal cor­re­lates for pro­tec­tion, mean­ing they are effec­tive but patients’ anti­bod­ies, immune cells or oth­er mark­ers do not iden­ti­fy whether a patient is pro­tect­ed. Even with the ini­tial tri­als, we are like­ly to have scant data on whether old­er peo­ple will mount an immune reac­tion and be pro­tect­ed.

    Giv­ing peo­ple a false sense of being pro­tect­ed will most like­ly lead to seri­ous out­breaks of the dis­ease as peo­ple reduce their com­pli­ance with phys­i­cal dis­tanc­ing and oth­er pub­lic health mea­sures.

    If only 20,000 par­tic­i­pants receive the vac­cine, seri­ous but rare side effects might be missed. If such harms even­tu­al­ly arise, it could fur­ther erode a frag­ile vac­cine con­fi­dence and threat­en the abil­i­ty to get enough peo­ple vac­ci­nat­ed to estab­lish herd immu­ni­ty. That would be a dis­as­ter.

    ...

    The F.D.A. must require more than the pro­duc­tion of anti­bod­ies to approve a vac­cine, even for an emer­gency autho­riza­tion, much less licens­ing. Only when the inde­pen­dent data safe­ty and mon­i­tor­ing board com­posed of physi­cians, researchers and bio­sta­tis­ti­cians reviews the accu­mu­lat­ed tri­al data to assess the safe­ty and effec­tive­ness of the vac­cines, should the F.D.A. be allowed to decide on approval.
    ...

    And that’s all why this ini­tial pre­lim­i­nary good news from Mod­er­na’s ani­mal stud­ies on the COVID vac­cine is poten­tial­ly bad news: when one of the biggest dan­gers is the pre­emp­tive abuse of pre­lim­i­nary good news by Trump good news becomes poten­tial­ly cat­a­stroph­ic news.

    So over­all, the good news is that Mod­er­na’s COVID vac­cine does­n’t appear to trig­ger ADE in lab rats with sub-pro­tec­tive immune respons­es. The bad news is that if this good news is used by Trump to push a pre­ma­ture release of the vac­cine before the human clin­i­cal tri­als are com­plet­ed it’s going to effec­tive­ly turn every­one who gets the vac­cine into a lab rat. It’s going to be a real­ly, real­ly, real­ly large human clin­i­cal safe­ty tri­al and every­one will be enrolled.

    Posted by Pterrafractyl | June 13, 2020, 1:21 pm
  2. Mod­er­na is launch­ing its Phase III coro­n­avirus vac­cine tri­al today with 30,000 peo­ple. This is the tri­al that’s going to deter­mine if the vac­cine actu­al­ly works in a mean­ing­ful way. If it works it will prob­a­bly be approved for wide­spread use so the stakes are quite high. Espe­cial­ly since, as we’ve seen, this Phase III tri­al is tak­ing place at the same time the Phase II safe­ty tri­als are still ongo­ing along with ani­mal safe­ty exper­i­ments.

    It’s that con­text that brings us to a STAT News arti­cle from last week that rec­om­mend­ed to mem­bers of the House Ener­gy and Com­merce Over­sight and Inves­ti­ga­tions Sub­com­mit­tee six burn­ing ques­tions they should ask for coro­n­avirus vac­cine man­u­fac­tur­ers dur­ing the com­mit­tee hear­ing that took place last Tues­day.

    Exec­u­tives from a num­ber of dif­fer­ent com­pa­nies rac­ing to devel­op a SARS-CoV­‑2 vac­cine appeared before the com­mit­tee to take ques­tions about their plans to both devel­op a safe vac­cine and mas­sive­ly scale up pro­duc­tion to make it avail­able to the pub­lic and there was one par­tic­u­lar rec­om­mend­ed ques­tion for the vac­cine man­u­fac­tur­ers that real­ly stood out in part because it’s so rarely asked amidst this unprece­dent­ed vac­cine race: so in 2005 the US passed a law that shields vac­cine and drug devel­op­ers from lia­bil­i­ty if a drug or vac­cine devel­oped in response to a health emer­gency caus­es injuries to the peo­ple who receive it. If that lia­bil­i­ty pro­tec­tion was not in place would these com­pa­nies be pur­su­ing this vac­cine? And per­haps more impor­tant­ly, since this is glob­al pan­dem­ic that needs to be addressed at a glob­al lev­el to tru­ly be fixed, will US vac­cine man­u­fac­tur­ers make the vac­cines they devel­op avail­able in coun­tries that don’t offer them the same lia­bil­i­ty shield?

    They’re the kinds of ques­tions that indi­rect­ly ask a ques­tion vac­cine and drug devel­op­ers undoubt­ed­ly have asked them­selves many times but would pre­fer not to answer in pub­lic: just how much are they rely­ing on this lia­bil­i­ty shield when mak­ing cost/benefit analy­ses involv­ing patient safe­ty. Keep in mind that Health and Human Ser­vices sec­re­tary Alex Azar announced back in March that the pan­dem­ic qual­i­fied as the kind of pub­lic health emer­gency that waived lia­bil­i­ty for vac­cine and drug devel­op­ers so this 2005 rule is cur­rent­ly in effect.

    And sure, the com­pa­nies would obvi­ous­ly pre­fer it if there are no neg­a­tive side-effects from their prod­ucts. But how much do they real­ly care if there are side-effects thanks to that lia­bil­i­ty shield? We’re talk­ing about prof­it-max­i­miz­ing enti­ties, after all.

    Plus, as we’ve already seen with Mod­er­na’s hunt for an COVID mRNA vac­cine, it’s not just a hunt for a vac­cine that can stop the virus. It’s also a hunt to estab­lish the safe­ty of mRNA tech­nol­o­gy in humans for the first time ever. An entire indus­try of new med­i­cine that rely on this mRNA ther­a­peu­tic approach but it’s nev­er actu­al­ly been estab­lished that this is safe and, as we’ve seen, the phar­ma­ceu­ti­cal indus­try has been try­ing and fail­ing to devel­op the tech­nol­o­gy with­out side-effects for years now. They just can’t avoid the side-effects thus far. So that makes this pan­dem­ic an incred­i­ble oppor­tu­ni­ty specif­i­cal­ly for mRNA vac­cine man­u­fac­tur­ers to get that untest­ed tech­nol­o­gy wide­ly rolled out to the pub­lic while avoid­ing lia­bil­i­ty if there are unfore­seen (or fore­seen and ignored) neg­a­tive side-effects. And that per­verse­ly could encour­age the mRNA vac­cine man­u­fac­tur­ers to take even greater risks with the pub­lic’s safe­ty because this is the kind of oppor­tu­ni­ty that could estab­lish mRNA tech­nol­o­gy as a safe and effec­tive plat­form that could be used for all sorts of oth­er prod­ucts but this pre­cious lia­bil­i­ty shield fades away as soon as a viable com­peti­tor vac­cine gets devel­oped.

    Unfor­tu­nate­ly, it does­n’t sound like these ques­tions were actu­al­ly asked dur­ing the hear­ing so these ques­tions remain urgent open burn­ing ques­tions:

    STAT News

    6 burn­ing ques­tions Con­gress could push Covid-19 vac­cine mak­ers to answer today

    By Dami­an Garde and Helen Bran­swell

    July 20, 2020

    Some drug com­pa­nies say we’ll have a coro­n­avirus vac­cine by the win­ter. Oth­ers say that’s an irre­spon­si­ble pre­dic­tion. Some promise to for­go prof­its on a vac­cine, but oth­ers believe they’re enti­tled to their mon­e­tary due.

    Now, law­mak­ers can force the indus­try to get its sto­ry straight. On Tues­day, exec­u­tives from five drug com­pa­nies lead­ing the vac­cine race are due at a con­gres­sion­al hear­ing to talk about their progress in devel­op­ing a prod­uct the entire world des­per­ate­ly needs. Rep­re­sen­ta­tives from AstraZeneca, John­son & John­son, Mer­ck, Mod­er­na, and Pfiz­er will appear in front of the House Ener­gy and Com­merce Over­sight and Inves­ti­ga­tions Sub­com­mit­tee.

    Peo­ple weary of the con­straints Covid-19 is plac­ing on lives are pin­ning a lot of hopes on the promis­es those com­pa­nies have made, par­tic­u­lar­ly when it comes to when a vac­cine might be ready. But there are still loom­ing ques­tions, from who will get a suc­cess­ful vac­cine first to how much it might cost.

    Here are six burn­ing ques­tions the pan­el could pose.
    0
    Can you tru­ly make Covid-19 vac­cines for wide­spread deploy­ment in the U.S. by Jan­u­ary 2021?

    Most of the man­u­fac­tur­ers in the hunt for Covid-19 vac­cines are mak­ing very bold promis­es about how quick­ly vac­cines will be ready to be deployed and how rapid­ly they’ll be able to pro­duce their vac­cines to the kind of scale need­ed to com­bat the pan­dem­ic. Many are promis­ing tens, even hun­dreds of mil­lions of dos­es by ear­ly 2021, and some even pre­dict they can scale to the bil­lion-dose range with­in the next cal­en­dar year.

    But in a recent inter­view with Har­vard pro­fes­sor Tsedal Nee­ley, Mer­ck CEO Ken Fra­zier warned that these pre­dict­ed time­lines are doing “a grave dis­ser­vice to the pub­lic.”

    For one thing, he said, vac­cine devel­op­ment takes time. The fastest vac­cine ever devel­oped before now was the mumps vac­cine, which took four years.

    Cut­ting cor­ners is a risky busi­ness, Fra­zier sug­gest­ed: “If you’re going to use a vac­cine in bil­lions of peo­ple, you bet­ter know what that vac­cine does.”

    Implied in the state­ment is the risk that any prob­lems that might arise from use of the vac­cines would throw fuel on the fire of the anti-vac­cine move­ment, which is already sow­ing doubts about the safe­ty of these fast-tracked Covid-19 vac­cines.

    Fra­zier also warned that giv­ing peo­ple the sense a vac­cine may be com­ing soon allows politi­cians to down­play oth­er tools that can sup­press spread of the dis­ease, such as “[wear­ing] the damn masks.”

    Will you com­mit to a price for your vac­cine?

    The most press­ing ques­tion fac­ing the drug indus­try is how soon it can come up with an effec­tive vac­cine. But right behind that is just how much it’ll cost. And the indus­try could answer now by com­mit­ting to a price before a vac­cine is approved.

    The U.S. gov­ern­ment has some lever­age for such a demand. With the excep­tion of Pfiz­er, each of the com­pa­nies at the table has received sub­stan­tial fed­er­al fund­ing to sup­port its vac­cine devel­op­ment. Through the government’s Oper­a­tion Warp Speed project, tax­pay­ers are on the line for more than $3 bil­lion in research sup­port, and the Nation­al Insti­tutes of Health is pick­ing up the tab for at least three mas­sive vac­cine stud­ies.

    So, what does the Amer­i­can pub­lic get in exchange? Some man­u­fac­tur­ers have promised to sell their vac­cines on a not-for-prof­it basis, at least for the extent of the pan­dem­ic. Oth­ers have not. Either way, it’s look­ing increas­ing­ly like­ly that the nov­el coro­n­avirus will not sim­ply van­ish once the cur­rent cri­sis sub­sides, mean­ing there will demand for vac­cines for years to come. If that’s the case, will com­pa­nies come to charge what­ev­er the mar­ket will bear? Or are they will­ing to make pric­ing com­mit­ments now?

    How are you going to release the data?

    Since the start of the cri­sis, news about vac­cine tri­als has made glob­al head­lines, moved mar­kets, and seeped into pol­i­tics. But the process of dis­sem­i­nat­ing that data has been incon­sis­tent. In May, Mod­er­na put out a press release with vague pos­i­tive lan­guage about its ear­ly-stage tri­al, frus­trat­ing experts who want­ed more. Pfiz­er chose to upload its data to a preprint serv­er, where sci­en­tif­ic papers are post­ed with­out peer review, while AstraZeneca is hold­ing out for pub­li­ca­tion in the Lancet.

    A work­ing vac­cine is key to restor­ing any­thing resem­bling nor­mal­cy, and the pub­lic is des­per­ate for infor­ma­tion on the process. But with­out stan­dard­iz­ing the cur­rent sys­tem, the pub­lic is left to parse press releas­es, rumors, and, worst of all, Twit­ter. Can the com­pa­nies devel­op­ing vac­cines estab­lish a sys­tem where­by the world gets clear, time­ly updates on their progress?

    Who’s going to get the vac­cine?

    The sec­ond a coro­n­avirus vac­cine proves to be safe and effec­tive, the entire world is going to be call­ing its man­u­fac­tur­er. The U.S. has already moved to secure mil­lions of future dos­es, and the Euro­pean Union is report­ed­ly nego­ti­at­ing to do the same, but what’s the plan for the world at large?

    Scal­ing up man­u­fac­tur­ing is a time-con­sum­ing process, mean­ing drug mak­ers will be deal­ing with a con­strained sup­ply in the months fol­low­ing a vaccine’s approval. Beyond the wealthy nations that are already lock­ing in bids, how can coun­tries in the devel­op­ing world ensure they get access?

    That may seem like a ques­tion beyond the scope of a House hear­ing, but the U.S. has a pub­lic health inter­est in vac­cines being wide­ly avail­able. With an econ­o­my deeply reliant on glob­al trade — and trav­el — the U.S. will be at risk of anoth­er Covid-19 out­break as long as the virus per­sists any­where in the world.

    How do lia­bil­i­ty pro­tec­tions fac­tor into your accel­er­at­ed time­line?

    Some man­u­fac­tur­ers are sug­gest­ing that there may be enough data to war­rant emer­gency use autho­riza­tions as soon as Octo­ber. If that hap­pens, vac­cines des­tined for use in poten­tial­ly bil­lions of peo­ple will be deployed after mere months of human test­ing.

    In the U.S., man­u­fac­tur­ers are shield­ed from lia­bil­i­ty if a vac­cine or drug devel­oped in response to a health emer­gency caus­es injuries to peo­ple who receive it. That pro­tec­tion comes from the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act of 2005.

    If that pro­tec­tion were not in place, would vac­cine man­u­fac­tur­ers be will­ing to roll out vac­cines on such a slight evi­dence base? Will they make them avail­able to coun­tries that don’t offer sim­i­lar pro­tec­tion against lia­bil­i­ty?

    Are you hav­ing prob­lems scal­ing up pro­duc­tion of your can­di­date vac­cines?

    The major man­u­fac­tur­ers are all mak­ing vac­cine “at-risk,” mean­ing they are already work­ing to pro­duce at com­mer­cial scale, even before they deter­mine whether their vac­cine can­di­date actu­al­ly works. The goal is to have large amounts avail­able for use as soon as the Food and Drug Admin­is­tra­tion green-lights a vac­cine. If some can­di­dates fail to clear the FDA’s bar, that prod­uct will be destroyed.

    ...

    ————-

    “6 burn­ing ques­tions Con­gress could push Covid-19 vac­cine mak­ers to answer today” by Dami­an Garde and Helen Bran­swell; STAT News; 07/20/2020

    Some man­u­fac­tur­ers are sug­gest­ing that there may be enough data to war­rant emer­gency use autho­riza­tions as soon as Octo­ber. If that hap­pens, vac­cines des­tined for use in poten­tial­ly bil­lions of peo­ple will be deployed after mere months of human test­ing.”

    Emer­gency use autho­riza­tions for these vac­cines could come as soon as Octo­ber accord­ing to some of the vac­cine man­u­fac­tur­ers. Keep in mind that emer­gency use autho­riza­tions imply the safe­ty stud­ies won’t have been com­plet­ed by that point. So the indus­try is clear­ly very keen on get­ting these vac­cines into peo­ple ASAP. But it’s the large-scale use of the vac­cine that could come lat­er where many of the rar­er side-effects would be expect­ed to man­i­fest and it’s at that point that the lia­bil­i­ty shield from the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act of 2005 becomes invalu­able for these com­pa­nies. So would these com­pa­nies still be pur­su­ing these vac­cines with­out the lia­bil­i­ty pro­tec­tion? And what about coun­tries with­out sim­i­lar lia­bil­i­ty pro­tec­tions? Are they going to be blocked from receiv­ing the vac­cine unless they extend the pro­tec­tions? These are the kinds of ques­tions that are going to become more and more impor­tant the clos­er we get to reach­ing a point where a vac­cine has been approved for large-scale use:

    ...
    In the U.S., man­u­fac­tur­ers are shield­ed from lia­bil­i­ty if a vac­cine or drug devel­oped in response to a health emer­gency caus­es injuries to peo­ple who receive it. That pro­tec­tion comes from the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act of 2005.

    If that pro­tec­tion were not in place, would vac­cine man­u­fac­tur­ers be will­ing to roll out vac­cines on such a slight evi­dence base? Will they make them avail­able to coun­tries that don’t offer sim­i­lar pro­tec­tion against lia­bil­i­ty?
    ...

    But these are also the of course the kinds of ques­tions that we would­n’t real­ly expect these com­pa­nies to hon­est­ly answer any­way. That’s why, while it’s kind of sad that these ques­tions did­n’t actu­al­ly get asked of the phar­ma­ceu­ti­cal exec­u­tives dur­ing the con­gres­sion­al hear­ing last week, it’s not like they were going to give mean­ing­ful answers any­way. They’re real­ly ques­tions con­gress and the pub­lic should be ask­ing itself. Espe­cial­ly before we all start inject­ing these vac­cines.

    It’s also worth keep­ing in mind anoth­er night­mar­ish sce­nario we could be lurch­ing towards: polls show around a third of Amer­i­cans won’t take the vac­cine even when it’s devel­oped, which to some extent reflects the deep anti-vac­cine skep­ti­cism that per­vades the US soci­ety, espe­cial­ly among right-wing vot­ers who have been bing­ing on Alex Jones-style far right con­spir­a­cy the­o­ries for the last decade (or, increas­ing­ly, just bing­ing on main­stream con­ser­v­a­tive media that has now main­streamed Alex Jones). Now imag­ine a sit­u­a­tion where a vac­cine does get rushed to the pub­lic and there are real­ly are wide­spread side-effects. That expe­ri­ence is going to cre­ate the kind of anti-vaxxer sen­ti­ment and gen­er­al dis­trust of sci­ence in this soci­ety that could last gen­er­a­tions, espe­cial­ly if the man­u­fac­tur­ers man­age make a wild prof­it and escape lia­bil­i­ties at the same time. In oth­er words, if Oper­a­tion Warp Speed moves too fast and peo­ple get hurt while investors remain untouched it could end up warp­ing the US pub­lic’s abil­i­ty to trust pub­lic health experts — by trans­lat­ing legit­i­mate con­cerns about the for-prof­it nature of the US’s econ­o­my into gener­ic con­cerns about the safe­ty of vac­cines — with all sorts of con­se­quences dur­ing future pan­demics.

    So that’s all some­thing that’s going to be increas­ing­ly impor­tant to keep in mind as we get clos­er and clos­er to rolling out a vac­cine: It’s gen­er­al­ly assumed that phar­ma­ceu­ti­cal com­pa­nies won’t know­ing­ly release a prod­uct they don’t know is safe due to con­cerns about pos­si­ble legal lia­bil­i­ties but those lia­bil­i­ties don’t exist in this case. Big gam­bles can be tak­en with mas­sive upsides and min­i­mal down­sides. At least min­i­mal down­sides for the investors.

    Posted by Pterrafractyl | July 27, 2020, 3:34 pm

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