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FTR#1168 Bio-Psy-Op Apocalypse Now, Part 24: A Pound of Cure, Part 3

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FTR #1168 This pro­gram was record­ed in one, 60-minute seg­ment.

Intro­duc­tion: Sig­nif­i­cant to the issue of vac­ci­na­tion against Covid-19 is the con­sid­er­a­tion of whether avail­able vac­cines will pre­vent ill­ness in the recip­i­ents, but still leave them capa­ble of spread­ing the dis­ease.

The first major por­tion of the pro­gram con­sists of ana­lyt­i­cal review of the cap­i­tal inter­ests behind BioNTech–the Ger­man cor­po­rate part­ner pro­duc­ing a Covid vac­cine with Pfiz­er.

Head­ed by a Ger­man MD cou­ple whose par­ents were “gas­tar­beit­er” (guest work­ers), BioN­Tech has soared expo­nen­tial­ly in val­ue since the approval of the vac­cine by a num­ber of coun­tries.

A dom­i­nant con­sid­er­a­tion in pow­er pol­i­tics remains the advi­so­ry to “Fol­low the Mon­ey.”

Against the back­ground of I.G. Far­ben and its suc­ces­sor com­pa­nies’ dom­i­nant posi­tion in both the glob­al phar­ma­ceu­ti­cal and chem­i­cal mar­ket, as well as its major posi­tion with­in the remark­able and dead­ly Bor­mann cap­i­tal net­work, the pro­gram explores the cap­i­tal­iza­tion of Uğur Şahin and Özlem Türe­ci’s Ganymed firm and BioN­Tech.

Of para­mount sig­nif­i­cance in both Ganymed (the cou­ple’s ini­tial com­mer­cial ven­ture) and BioN­tech are twin broth­ers Thomas and Andreas Stru­eng­mann.

Key points of analy­sis:

  1. The broth­ers are major play­ers in the phar­ma­ceu­ti­cal and biotech mar­ket.
  2. They keep a pur­pose­ful­ly low pro­fes­sion­al profile–a pro­fes­sion­al behav­ior char­ac­ter­is­tic of the dead­ly Bor­mann net­work.
  3. Thomas was an impor­tant mem­ber of the board of Wack­er Chemie, a major suc­ces­sor to two I.G. Far­ben sub­sidiary com­pa­nies.
  4. Wack­er Chemie has appar­ent­ly obfus­cat­ed its Nazi past.
  5. Andreas ini­ti­at­ed his med­ical career in apartheid South Africa, and the broth­ers’ Hexal firm began its sig­nif­i­cant inter­na­tion­al expan­sion in that coun­try. (The apartheid regime was an off­shoot of the Third Reich.)
  6. Firms that evolved from I.G. Far­ben fig­ure promi­nent­ly in the deal­ings of Hexal, Wack­er Chemie and BioN­Tech (Novar­tis, the Hoechst divi­sion of Sanofi-Aven­tis.)

The bal­ance of the pro­gram presents analy­sis of the pro­found rela­tion­ship between the Bor­mann cap­i­tal net­work and I.G. Far­ben.

Forged dur­ing the clos­ing days of the war, the close coop­er­a­tion between cor­po­rate “masker” Her­mann Schmitz and Bor­mann, the rela­tion­ship built on the dom­i­nant posi­tion of I.G. Far­ben in the Third Reich and its inter­re­lat­ed mil­i­tary and industrial/commercial cam­paigns.

” . . . . If there is any doubt in Europe who in the long run won the peace, there is none what­so­ev­er among the for­mer Ger­man lead­ers dwelling in South Amer­i­ca. It is a good bet that if Her­mann Schmitz were alive today, he would bear wit­ness as to who real­ly won. Schmitz died con­tent­ed, hav­ing wit­nessed the resur­gence of I.G. Far­ben, albeit in altered cor­po­rate forms, a mon­ey machine that con­tin­ues to gen­er­ate prof­its for all the old I.G. share­hold­ers and enor­mous inter­na­tion­al pow­er for the Ger­man cadre direct­ing the work­ings of the suc­ces­sor firms. . . . He was the mas­ter manip­u­la­tor, the cor­po­rate and finan­cial wiz­ard, the magi­cian, who could make mon­ey appear and dis­ap­pear, and reap­pear again. His whole exis­tence was leg­erde­main, played out on the game­board of I.G. Far­ben and his beloved Ger­many. . . Their [Schmitz and Bor­mann] asso­ci­a­tion was close and trust­ing over the years, and it is the con­sid­ered opin­ion of those in their cir­cle that the wealth pos­sessed by Her­mann Schmitz was shift­ed to Switzer­land and South Amer­i­ca, and placed in trust with Bor­mann, the legal heir to Hitler. [Her­mann] Schmitz’s wealth—largely I.G. Far­ben bear­er bonds con­vert­ed to the Big Three suc­ces­sor firms, shares in Stan­dard Oil of New Jer­sey (equal to those held by the Rock­e­fellers), as well as shares in the 750 cor­po­ra­tions he helped Bor­mann estab­lish dur­ing the last year of World War II—has increased in all seg­ments of the mod­ern indus­tri­al world. The Bor­mann orga­ni­za­tion in South Amer­i­ca uti­lizes the vot­ing pow­er of the Schmitz trust along with their own assets to guide the multi­na­tion­als they con­trol, as they keep steady the eco­nom­ic course of the Father­land. . . . ”

After the war, the three main suc­ces­sor firms to I.G.–Hoechst (now a divi­sion of Sanofi-Aven­tis), Bay­er and BASF rose to a pin­na­cle of sales and R & D dom­i­nance.

Review of Dorothy Thomp­son’s 1940 analy­sis of the Third Reich blue­print for world polit­i­cal dom­i­na­tion, pred­i­cat­ed on world eco­nom­ic dom­i­na­tion (includ­ing the exploita­tion of deci­sive car­tel rela­tion­ships with the Wall Street elite; an account of Ber­tels­man­n’s forth­com­ing pur­chase of Simon & Schus­ter, mak­ing this “for­mer” pub­lish­ing house for the SS a “Titan” in Eng­lish-lan­guage pub­lish­ing; a syn­op­tic review of the sce­nario pre­sent­ed in the Nazi tract Ser­pen­t’s Walk.

1a. Sig­nif­i­cant to the issue of vac­ci­na­tion against Covid-19 is the con­sid­er­a­tion of whether avail­able vac­cines will pre­vent ill­ness in the recip­i­ents, but still leave them capa­ble of spread­ing the dis­ease.

“A Vac­cine Pro­tects You, But What About Oth­ers? That’s Where Masks Come In” by Apoor­va Man­davili; The New York Times; 12/09/2020; p. A5.

 The new Covid-19 vac­cines from Pfiz­er and Mod­er­na seem to be remark­ably good at pre­vent­ing seri­ous ill­ness. But it’s unclear how well they will curb the spread of the coro­n­avirus.

Thats’s because the Pfiz­er and Mod­er­na tri­als tracked only how many vac­ci­nat­ed peo­ple became sick with Covid-19. That leaves open the pos­si­bil­i­ty that some vac­ci­nat­ed peo­ple get infect­ed with­out devel­op­ing symp­toms, and could then silent­ly trans­mit the virus—especially if they come in close con­tact with oth­ers or stop wear­ing masks.

If vac­ci­nat­ed peo­ple are silent spread­ers of the virus, they may keep it cir­cu­lat­ing in their com­mu­ni­ties, putting unvac­ci­nat­ed peo­ple at risk.

“A lot of peo­ple are think­ing that once they get vac­ci­nat­ed, they’re not going to have to wear masks any­more,” said Michal Tal, an immu­nol­o­gist at Stan­ford Uni­ver­si­ty, “It’s real­ly going to be crit­i­cal for them to know if they have to keep wear­ing masks, because they could still be con­ta­gious.”

In most res­pi­ra­to­ry infec­tions, includ­ing the new coro­n­avirus, the nose is the main port of entry. The virus rapid­ly mul­ti­plies there, jolt­ing the immune sys­tem to pro­duce a type of anti­bod­ies that are spe­cif­ic to mucosa, the moist tis­sue lin­ing the nose, mouth, lungs and stom­ach. If the same per­son is exposed to the virus a sec­ond time, those anti­bod­ies, as well as immune cells that remem­ber the virus, rapid­ly shut down the virus in the nose before it gets a chance to take hold else­where in the body.

The coro­n­avirus vac­cines, in con­trast, are inject­ed deep into the mus­cles and quick­ly absorbed into the blood, where they stim­u­late the immune sys­tem to pro­duce anti­bod­ies. This appears to be enough pro­tec­tion to keep the vac­ci­nat­ed per­son from get­ting ill.

Some of these anti­bod­ies will cir­cu­late to the nasal mucosa and stand guard there, but it’s not clear how much of the anti­body pool can be mobi­lized, or how quick­ly. If the answer is not much, then virus­es could bloom in the nose—and be sneezed or breathed out to infect oth­ers.

“It’s a race: It depends whether the virus can repli­cate faster, or the immune sys­tem can con­trol it faster,” said Mar­i­on Pep­per, an immu­nol­o­gist at the Uni­ver­si­ty of Wash­ing­ton in Seat­tle. “It’s a real­ly impor­tant ques­tion.” . . . .

. . . . “Pre­vent­ing severe dis­ease is eas­i­est, pre­vent­ing mild dis­ease is hard­er, and pre­vent­ing all infec­tions is the hard­est,” said Deep­ta Bat­tacharya, an immu­nol­o­gist at the Uni­ver­si­ty of Ari­zona. “It’s going to be some­thing less than that in pre­vent­ing all infec­tions, for sure,” Still, he and oth­er experts said they were opti­mistic that the vac­cines would sup­press the virus enough even in the nose and throat to pre­vent immu­nized peo­ple from spread­ing it to oth­ers. . . .

. . . . But some stud­ies have sug­gest­ed that even peo­ple with no symp­toms can have high amounts of coro­n­avirus in their nose, not­ed Dr. Yvonne Mal­don­a­do, who rep­re­sents the Amer­i­can Acad­e­my of Pedi­atrics at meet­ings of the fed­er­al Advi­so­ry Com­mit­tee on Immu­niza­tion Prac­tices. The first per­son con­firmed to be rein­fect­ed with the coro­n­avirus, a 33-year-old man in Hong Kong, also did not have symp­toms, but har­bored enough virus to infect oth­ers.

Vac­ci­nat­ed peo­ple who have a high viral load but don’t have symp­toms “would actu­al­ly, be in some ways, even worse spread­ers because they may be under a false sense of secu­ri­ty,” Dr. Mal­don­a­do said. . . .

1b. The first major sec­tion of the pro­gram con­sists of ana­lyt­i­cal review of the cap­i­tal inter­ests behind BioNTech–the Ger­man cor­po­rate part­ner pro­duc­ing a Covid vac­cine with Pfiz­er.

Head­ed by a Ger­man MD cou­ple whose par­ents were “gas­tar­beit­er” (guest work­ers), BioN­Tech has soared expo­nen­tial­ly in val­ue since the approval of the vac­cine by a num­ber of coun­tries.

A dom­i­nant con­sid­er­a­tion in pow­er pol­i­tics remains the advi­so­ry to “Fol­low the Mon­ey.”

Against the back­ground of I.G. Far­ben and its suc­ces­sor com­pa­nies’ dom­i­nant posi­tion in both the glob­al phar­ma­ceu­ti­cal and chem­i­cal mar­ket, as well as its major posi­tion with­in the remark­able and dead­ly Bor­mann cap­i­tal net­work, the pro­gram explores the cap­i­tal­iza­tion of Uğur Şahin and Özlem Türe­ci’s Ganymed firm and BioN­Tech.

Of para­mount sig­nif­i­cance in both Ganymed (the cou­ple’s ini­tial com­mer­cial ven­ture) and BioN­tech are twin broth­ers Thomas and Andreas Stru­eng­mann.

Key points of analy­sis:

  1. The broth­ers are major play­ers in the phar­ma­ceu­ti­cal and biotech mar­ket.
  2. They keep a pur­pose­ful­ly low pro­fes­sion­al profile–a pro­fes­sion­al behav­ior char­ac­ter­is­tic of the dead­ly Bor­mann net­work.
  3. Thomas was an impor­tant mem­ber of the board of Wack­er Chemie, a major suc­ces­sor to two I.G. Far­ben sub­sidiary com­pa­nies.
  4. Wack­er Chemie has appar­ent­ly obfus­cat­ed its Nazi past.
  5. Andreas ini­ti­at­ed his med­ical career in apartheid South Africa, and the broth­ers’ Hexal firm began its sig­nif­i­cant inter­na­tion­al expan­sion in that coun­try. (The apartheid regime was an off­shoot of the Third Reich.)
  6. Firms that evolved from I.G. Far­ben fig­ure promi­nent­ly in the deal­ings of Hexal, Wack­er Chemie and BioN­Tech (Novar­tis, the Hoechst divi­sion of Sanofi-Aven­tis.)

1c. The I.G. Far­ben com­pa­ny, a core ele­ment of the Third Reich, was cen­tral to Bormann’s plans to secret Germany’s wealth abroad. Note, also, I.G. Farben’s dom­i­nance of the Euro­pean chem­i­cal indus­try, and the opin­ion of Dr. von Schnit­zler that tech­ni­cal depen­dence on I.G. facil­i­ties would con­tin­ue after the war. (To learn more about I.G. Far­ben, see—among oth­er programs–FTR#’s 305, 411, 506, 552. Seri­ous stu­dents should also read Treason’s Peace and The Devil’s Chemists, avail­able for down­load.)

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; p. 28.

 . . . I.G. Far­ben was a for­mi­da­ble ally for Reich­sleit­er Bor­mann in his plans for the post­war eco­nom­ic rebirth of Ger­many. In a tele­phone con­ver­sa­tion with Dr. von Schnit­zler, Bor­mann asked what would the loss of fac­to­ries in France and the oth­er occu­pied coun­tries mean to Ger­man indus­try in gen­er­al and to I.G. in par­tic­u­lar. Dr. von Schnit­zler said he believed the tech­ni­cal depen­dence of these coun­tries on I.G. would be so great that despite Ger­man defeat I.G., in one way or anoth­er, could regain its posi­tion of con­trol of the Euro­pean chem­i­cal busi­ness. “They will need the con­stant tech­ni­cal help of I.G.’s sci­en­tif­ic lab­o­ra­to­ries as they do not own appro­pri­ate instal­la­tions with­in them­selves.” . . . . 

2. Bor­mann and Her­rmann Schmitz then dis­cussed I.G.’s prospects for the post­war peri­od. The cozy rela­tion­ship with pow­er­ful ele­ments with­in the pow­er elites of the West­ern allies was fore­seen by Schmitz as bod­ing well for the company’s future. Schmitz’s pre­dic­tions were rel­a­tive­ly accu­rate. Nei­ther Schmitz nor any of the I.G. Far­ben exec­u­tives were severe­ly pun­ished and the firm’s three suc­ces­sor firms car­ried on effec­tive­ly in the post­war peri­od.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; p. 158.

. . . . The Reich­sleit­er asked Schmitz his views of the future. Schmitz replied, ‘The occu­pa­tion armies will be under­stand­ing in the West, but cer­tain­ly not in the East. I have instruct­ed all Far­ben admin­is­tra­tors and tech­ni­cians to come to the West, where they can be of use in resum­ing our oper­a­tions once the dis­tur­bances of 1945 come to a halt.’ Schmitz added that, while gen­er­al bomb dam­age to the I.G. plants was about 25 per­cent of capac­i­ty, some were untouched. He men­tioned speak­ing with Field Mar­shal Mod­el, who was com­mand­ing the defens­es of the Ruhr. ‘Mod­el had planned to turn our Bay­er-Leberkusen phar­ma­ceu­ti­cal fac­to­ry into an artillery base, but he agreed to make it an open, unde­fend­ed fac­to­ry. Hope­ful­ly, we will get it back untouched.’ ‘What about your board of direc­tors and the essen­tial exec­u­tives? If they are held by the occu­pa­tion author­i­ties, can I.G. con­tin­ue?’ Bor­mann asked. ‘We can con­tin­ue. We have an oper­a­tional plan for such a con­tin­gency, which every­one under­stands. How­ev­er, I don’t believe our board mem­bers will be detained too long. Nor will I. But we must go through a pro­ce­dure of inves­ti­ga­tion before release, so I have been told by our N.W. 7 peo­ple who have excel­lent con­tacts in Wash­ing­ton.” . . . . 

3. The broad­cast details the pro­found rela­tion­ship between I.G. Far­ben and the gov­ern­ment of the Third Reich. Of par­tic­u­lar util­i­ty to the Bor­mann flight cap­i­tal pro­gram was I.G. Farben’s elab­o­rate infra­struc­ture in for­eign coun­tries. Note that, as is seen here, I.G. Far­ben was inex­tri­ca­bly linked with both the gov­ern­ment of the Third Reich and with the Nazi par­ty itself.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; p. 54.

 . . . This, too, report­ed to Mar­tin Bormann.I.G. Farben’s N.W.7 office in Berlin com­piled mil­i­tary and eco­nom­ic data on all coun­tries for the Wehrma­cht. This depart­ment was staffed with men of rec­og­nized abil­i­ty in all branch­es of busi­ness and sci­ence. It was under the direc­tion of Dr. Max Ilgn­er, nephew of Her­mann Schmitz, I.G.’s pres­i­dent, who was known through­out the indus­tri­al world as ‘the mas­ter of finan­cial cam­ou­flage.’ [Empha­sis added.] Far­ben had offices and rep­re­sen­ta­tives in 93 coun­tries, and no social gath­er­ing of busi­ness­men was too small to be cov­ered by an N.W.7 rep­re­sen­ta­tive, whose reports on mar­ket con­di­tions, fac­to­ry instal­la­tions, raw-mate­r­i­al sup­plies, and research were trans­mit­ted imme­di­ate­ly to Berlin and Dr. Ilgn­er. In the Unit­ed States, N.W.7 oper­at­ed through the firm of Chem­ny­co, Inc., an Amer­i­can-formed sub­sidiary. Chem­ny­co sent tremen­dous amounts of infor­ma­tion rang­ing from pho­tographs and blue prints to detailed descrip­tions of entire indus­tri­al com­plex­es and secret process­es. . . . 

4. Of par­tic­u­lar impor­tance for this dis­cus­sion is the fact that I.G. used Ger­man mil­i­tary con­quest to gain effec­tive func­tion­al con­trol of the chem­i­cal indus­try of the con­ti­nent. In para­graph 13, we not­ed Georg von Scnitzler’s pre­dic­tion that I.G.’s tech­ni­cal dom­i­nance would result in the post­war per­pet­u­a­tion of this con­trol. As we will see, this con­trol was main­tained. It is against the back­ground of I.G. Farben’s con­tin­ued dom­i­nance of the Euro­pean chem­i­cal indus­try as well as the post­war per­pet­u­a­tion of the Nazi par­ty appa­ra­tus that the BioN­Tech cap­i­tal­iza­tion rela­tion­ship must be viewed!

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; pp. 55–56.

 . . . This huge orga­ni­za­tion func­tioned as a man­u­fac­tur­ing and research arm of the Ger­man gov­ern­ment, with the respon­si­bil­i­ty of dis­cov­er­ing all pos­si­ble means of increas­ing the mil­i­tary pow­er of Ger­many. More than RM 4.25 bil­lion was invest­ed in new plants, mines, and pow­er instal­la­tions, with oth­er mil­lions going into new research facil­i­ties. . . . So close had Far­ben become to the gov­ern­ment that I.G. always knew in advance all inva­sions planned by Hitler. It was to sup­ply the mate­ri­als nec­es­sary to each con­quest, and when a land had been over­run and sub­ju­gat­ed, the Far­ben experts would han­dle the con­sol­i­da­tion and orga­ni­za­tion of the indus­tri­al facil­i­ties as addi­tion­al sup­ply sources for the Ger­man armed forces. As Ger­man troops swept across Europe and Hitler pro­claimed his vision of a thou­sand-year Third Reich, I.G. Far­ben also dreamed of world empire. This was out­lined with clar­i­ty in a doc­u­ment called Neuord­nung, or ‘New Order,’ that was accom­pa­nied by a let­ter of trans­mit­tal to the Min­istry of Eco­nom­ics. It declared that a new order for the chem­i­cal indus­try of the world should sup­ple­ment Hitler’s New Order. There­fore, the doc­u­ment stat­ed, Far­ben was fit­ting future indus­tri­al plans into such a frame­work. . . . I.G. Far­ben was the major chem­i­cal firm on the Con­ti­nent, and as each coun­try fell to Ger­many its acqui­si­tions of chem­i­cal and dyestuff com­pa­nies were enor­mous. I.G. also increased its invest­ments in these by RM 7 bil­lion. [Empha­sis added.] . . . . 

5. More about I.G. Far­ben, the Third Reich and the devel­op­ment of the remark­able and dead­ly Bor­mann orga­ni­za­tion.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; pp. 56–58.

. . . .The close rela­tion­ship of Far­ben to the Third Reich lead­er­ship was under­scored in oth­er ways. I.G.’s lead­ing offi­cials assist­ed in for­mu­la­tion and exe­cu­tion of eco­nom­ic poli­cies of gov­ern­ment; its pres­i­dent was a mem­ber of the Reich­stag; its lead­ing sci­en­tist was a chief assis­tant to Her­mann Goer­ing under the Four-Year Plan; its sta­tis­ti­cians and econ­o­mists pre­pared intel­li­gence for the Nazi High Com­mand; scores of its tech­ni­cians were at any giv­en time on loan to the air and war min­istries. . . . The con­tact men of N.W.7 through­out the world were called the I.G. Verbindungs­man­ner, the liai­son offi­cers between Far­ben back in Ger­many and the branch­es else­where. These I.G. Verbindungs­man­ner, as well as all oth­er key Far­ben rep­re­sen­ta­tives work­ing beyond the bor­ders of the Third Reich, were mem­bers of the Nation­al Social­ist Ger­man Work­ers Par­ty. . . . So now Mar­tin Bor­mann had at his com­mand not only the Aus­lands-Organ­i­sa­tion but also the I.G. Verbindungs­man­ner of Far­ben, which could be count­ed on to heed his orders when it was time to dis­perse the com­mer­cial assets of the Third Reich. . . . 

6. The vast inter­na­tion­al oper­a­tions of the I.G. Far­ben firm and its var­i­ous sub­sidiary oper­a­tions was a prin­ci­pal ele­ment of the Bor­mann orga­ni­za­tion. I.G. Far­ben chief Her­mann Schmitz dis­cussed I.G.’s involve­ment with the Bor­mann pro­gram.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; pp. 157–158.

. . . . In tes­ti­mo­ny lat­er giv­en to Nurem­berg inves­ti­ga­tors, Schmitz praised Bor­mann for the way he had direct­ed the dis­tri­b­u­tion of Ger­man assets around the world. His own Far­ben orga­ni­za­tion had, of course, con­tributed to the suc­cess of the oper­a­tion. Every region­al rep­re­sen­ta­tive work­ing for Her­mann Schmitz was an excep­tion­al busi­ness­man, or he would not have been with I.G. All had con­tributed sound advice in their areas of com­pe­tence, the regions of the world where they rep­re­sent­ed Far­ben while keep­ing an eye on the sub­sidiaries of the par­ent con­cern and the 700 hid­den cor­po­ra­tions they con­trolled. They had pro­vid­ed assis­tance and con­tin­u­ing guid­ance in estab­lish­ing the 750 new com­pa­nies cre­at­ed on order of Bor­mann, who want­ed more than hid­den assets; Bor­mann want­ed the mon­ey and patents and tech­ni­cians put to work to cre­ate even greater assets that would bol­ster Ger­many in the post­war years. In their meet­ing in the chan­cellery, both men checked over the fig­ures of sums dis­bursed, and they were accu­rate to the pfen­nig. . . .

7. As fore­cast by Dr. Scheid in the August 10, 1944 meet­ing, the cor­po­rate allies of the major Ger­man cor­po­ra­tions, includ­ing and espe­cial­ly those of I.G. Far­ben, proved to be of great val­ue to the suc­cess of the Bor­mann flight cap­i­tal pro­gram.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; p156.

. . . . Pow­er­ful friends of the Bor­mann orga­ni­za­tion in all West­ern coun­tries, includ­ing those sprin­kled in con­trol points through­out the admin­is­tra­tion in Wash­ing­ton and in the finan­cial and bro­ker­age busi­ness­es of Wall Street, the City of Lon­don, and the Paris estab­lish­ment, did not wish a coor­di­nat­ed dri­ve to get at these exter­nal Ger­man assets. They had under­stand­able rea­sons, if you over­look moral­i­ty: the finan­cial ben­e­fits for coop­er­a­tion (col­lab­o­ra­tion had become an old-hat term with the war wind­ing down) were very entic­ing, depend­ing on one’s impor­tance and abil­i­ty to be of ser­vice to the orga­ni­za­tion and the 750 cor­po­ra­tions they were secret­ly manip­u­lat­ing, to say noth­ing of the known multi­na­tion­als such as I.G. Far­ben, Thyssen A.G., and Siemens; and, as a sec­ond rea­son, the phi­los­o­phy of free enter­prise and preser­va­tion of pri­vate prop­er­ty. . . .

8. Note the post­war resus­ci­ta­tion of I.G. Far­ben, in the form of the “Big Three” suc­ces­sor firms that grew out Far­ben. Although offi­cial­ly bro­ken up at the end of World War II, I.G. Far­ben con­tin­ued func­tion­ing in new form. Recent merg­ers (such as the 1996 merg­er of I.G. car­tel affil­i­ates Ciba-Geigy and San­doz to form Novar­tis) indi­cate a new com­ing togeth­er of the old com­po­nents of I.G. Again, pay close atten­tion to the rela­tion­ship between these com­pa­nies and the Bor­mann cap­i­tal net­work.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; p. 282.

. . . . By 1956, the three major multi­na­tion­als (Hoechst, BASF, and Bay­er) reshaped from the 159 com­pa­nies with­in Ger­many that had com­prised I.G. Far­ben were gen­er­at­ing record prof­its for the orig­i­nal 450 major Far­ben stock­hold­ers, who had orga­nized them­selves into the I.G. Far­ben Stock­hold­ers Pro­tec­tive com­mit­tee in Bonn. The Big Three went on expand­ing, tripling cap­i­tal­iza­tion in 1956 from invest­ment funds that poured in from the inter­lock­ing com­pa­nies estab­lished in safe haven coun­tries by Mar­tin Bor­mann and Her­mann Schmitz. There was a return, more vig­or­ous than ever, of the huge, mono­lith­ic indus­tri­al multi­na­tion­als that dom­i­nat­ed the Ger­man econ­o­my before and dur­ing World War II. . . .

9. The enor­mous cor­po­rate wealth and pow­er of the three suc­ces­sor firms is at the dis­pos­al of the Bor­mann cap­i­tal net­work and Under­ground Reich.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; p. 282–283.

. . . . Each of these three spin­offs from I.G. Far­ben today does more busi­ness indi­vid­u­al­ly than did Far­ben at its zenith, when its cor­po­rate struc­ture cov­ered 93 coun­tries. BASF and Bay­er indi­vid­u­al­ly boast world­wide sales of near­ly $10 bil­lion annu­al­ly, while Hoechst, now the world’s largest chem­i­cal com­pa­ny, gen­er­at­ed $16.01 bil­lion in world­wide sales in 1980. Each does more busi­ness than E.I. du Pont de Nemours, with sales of $9.4 bil­lion. The Unit­ed States is, of course, the major mar­ket, one into which these Ger­man cor­po­ra­tions con­tin­ue to pour invest­ment mon­ey for both new cap­i­tal con­struc­tion and cor­po­rate takeovers. Togeth­er, these three multi­na­tion­als assure per­ma­nent pros­per­i­ty for the orig­i­nal 450 Far­ben stock­hold­ers, their banks, and the shad­owy share­hold­ers of the Bor­mann orga­ni­za­tion in South Amer­i­ca who guard and vote the Her­mann Schmitz trust fund through inter­me­di­aries at the annu­al meet­ings of BASF, Bay­er and Hoechst. [Empha­sis added.] . . . . 

10. A sig­nif­i­cant part of the I.G. Far­ben lega­cy, the Her­mann Schmitz Trust is also at the dis­pos­al of the Bor­mann cap­i­tal net­work and the Under­ground Reich.

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; pp. 279–280.

. . . . If there is any doubt in Europe who in the long run won the peace, there is none what­so­ev­er among the for­mer Ger­man lead­ers dwelling in South Amer­i­ca. It is a good bet that if Her­mann Schmitz were alive today, he would bear wit­ness as to who real­ly won. Schmitz died con­tent­ed, hav­ing wit­nessed the resur­gence of I.G. Far­ben, albeit in altered cor­po­rate forms, a mon­ey machine that con­tin­ues to gen­er­ate prof­its for all the old I.G. share­hold­ers and enor­mous inter­na­tion­al pow­er for the Ger­man cadre direct­ing the work­ings of the suc­ces­sor firms. . . . He was the mas­ter manip­u­la­tor, the cor­po­rate and finan­cial wiz­ard, the magi­cian, who could make mon­ey appear and dis­ap­pear, and reap­pear again. His whole exis­tence was leg­erde­main, played out on the game­board of I.G. Far­ben and his beloved Ger­many. . . Their [Schmitz and Bor­mann] asso­ci­a­tion was close and trust­ing over the years, and it is the con­sid­ered opin­ion of those in their cir­cle that the wealth pos­sessed by Her­mann Schmitz was shift­ed to Switzer­land and South Amer­i­ca, and placed in trust with Bor­mann, the legal heir to Hitler. [Her­mann] Schmitz’s wealth—largely I.G. Far­ben bear­er bonds con­vert­ed to the Big Three suc­ces­sor firms, shares in Stan­dard Oil of New Jer­sey (equal to those held by the Rock­e­fellers), as well as shares in the 750 cor­po­ra­tions he helped Bor­mann estab­lish dur­ing the last year of World War II—has increased in all seg­ments of the mod­ern indus­tri­al world. The Bor­mann orga­ni­za­tion in South Amer­i­ca uti­lizes the vot­ing pow­er of the Schmitz trust along with their own assets to guide the multi­na­tion­als they con­trol, as they keep steady the eco­nom­ic course of the Father­land. . . . 

11. In clos­ing, the pro­gram notes the eco­nom­ic and polit­i­cal sig­nif­i­cance of the Bor­mann net­work:

Mar­tin Bor­mann: Nazi in Exile; Paul Man­ning; Copy­right 1981 [HC]; Lyle Stu­art Inc.; ISBN 0–8184-0309–8; pp. 284–285.

. . . . Atop an orga­ni­za­tion­al pyra­mid that dom­i­nates the indus­try of West Ger­many through banks, vot­ing rights enjoyed by major­i­ty share­hold­ers in sig­nif­i­cant car­tels, and the pro­fes­sion­al input of a rel­a­tive­ly young lead­er­ship group of lawyers, invest­ment spe­cial­ists, bankers, and indus­tri­al­ists, he is sat­is­fied that he achieved his aim of help­ing the Father­land back on its feet. To ensure con­ti­nu­ity of pur­pose and direc­tion, a close watch is main­tained on the prof­it state­ments and man­age­ment reports of cor­po­ra­tions under its con­trol else­where. This lead­er­ship group of twen­ty, which is in fact a board of direc­tors, is chaired by Bor­mann, but pow­er has shift­ed to the younger men who will car­ry on the ini­tia­tive that grew from that his­toric meet­ing in Stras­bourg on August 10, 1944. Old Hein­rich Mueller, chief of secu­ri­ty for the NSDAP in South Amer­i­ca, is the most feared of all, hav­ing the pow­er of life and death over those deemed not to be act­ing in the best inter­ests of the orga­ni­za­tion. Some still envi­sion a Fourth Reich. . .What will not pass is the eco­nom­ic influ­ences of the Bor­mann orga­ni­za­tion, whose com­mer­cial direc­tives are obeyed almost with­out ques­tion by the high­est ech­e­lons of West Ger­man finance and indus­try. ‘All orders come from the share­hold­ers in South Amer­i­ca,’ I have been told by a spokesman for Mar­tin Bor­mann. . . . 

12a. We close with Dorothy Thompson’s analy­sis of Germany’s plans for world dom­i­nance by a cen­tral­ized Euro­pean eco­nomic union, uti­liz­ing dom­i­nant cor­po­rate rela­tion­ships with Amer­i­can cor­po­ra­tions to effect con­trol of the Unit­ed States.

Ms. Thomp­son was writ­ing in The New York Her­ald Tri­bune on May 31, 1940! Her com­ments are repro­duced by Tetens on page 92.

Ger­many Plots with the Krem­lin; T.H. Tetens; Hen­ry Schu­man [HC]; 1953; p. 92.

. . . . The Ger­mans have a clear plan of what they intend to do in case of vic­tory. I believe that I know the essen­tial details of that plan. I have heard it from a suf­fi­cient num­ber of impor­tant Ger­mans to cred­it its authen­tic­ity . . . Germany’s plan is to make a cus­toms union of Europe, with com­plete finan­cial and eco­nomic con­trol cen­tered in Berlin. This will cre­ate at once the largest free trade area and the largest planned econ­omy in the world. In West­ern Europe alone . . . there will be an eco­nomic uni­ty of 400 mil­lion per­sons . . . To these will be added the resources of the British, French, Dutch and Bel­gian empires. These will be pooled in the name of Europa Ger­man­i­ca . . .

“The Ger­mans count upon polit­i­cal pow­er fol­low­ing eco­nomic pow­er, and not vice ver­sa. Ter­ri­to­r­ial changes do not con­cern them, because there will be no ‘France’ or ‘Eng­land,’ except as lan­guage groups. Lit­tle imme­di­ate con­cern is felt regard­ing polit­i­cal orga­ni­za­tions . . . . No nation will have the con­trol of its own finan­cial or eco­nomic sys­tem or of its cus­toms. [Ital­ics are mine–D.E.] The Naz­i­fi­ca­tion of all coun­tries will be accom­plished by eco­nomic pres­sure. In all coun­tries, con­tacts have been estab­lished long ago with sym­pa­thetic busi­ness­men and indus­tri­al­ists . . . . As far as the Unit­ed States is con­cerned, the plan­ners of the World Ger­man­ica laugh off the idea of any armed inva­sion. They say that it will be com­pletely unnec­es­sary to take mil­i­tary action against the Unit­ed States to force it to play ball with this sys­tem. . . . Here, as in every oth­er coun­try, they have estab­lished rela­tions with numer­ous indus­tries and com­mer­cial orga­ni­za­tions, to whom they will offer advan­tages in co-oper­a­tion with Ger­many. . . .

13. We have dis­cussed the Nazi tract Ser­pen­t’s Walk in many pro­grams and posts. Ber­tels­mann appears to be cement­ing Under­ground Reich con­trol of Eng­lish lan­guage pub­lish­ing.

“Deal Turns Book Giant Into a Titan” by Alexan­dra Alter and Edmund Lee; The New York Times; 11/25/2020.

The biggest book pub­lish­er in the Unit­ed States is about to get big­ger. Via­com­CBS has agreed to sell Simon & Schus­ter to Pen­guin Ran­dom House for more than $2 bil­lion in a deal that will cre­ate the first mega­pub­lish­er.

Pen­guin Ran­dom House, the largest book pub­lish­er in the Unit­ed States, is owned by the Ger­man media con­glom­er­ate Ber­tels­mann. Adding Simon & Schus­ter, the third largest pub­lish­er, would cre­ate a book behe­moth, a com­bi­na­tion that could trig­ger antitrust con­cerns.

The deal announced on Wednes­day includes pro­vi­sions that would pro­tect Via­com­CBS in the event that a sale is squashed by author­i­ties. Ber­tels­mann would pay what is known as a ter­mi­na­tion fee if the deal does not go through.

The sale of the com­pa­ny will pro­found­ly reshape the pub­lish­ing indus­try, increas­ing­ly a win­ner-take-all busi­ness in which the largest com­pa­nies com­pete for brand-name authors and guar­an­teed best-sell­ers. . . .

Discussion

6 comments for “FTR#1168 Bio-Psy-Op Apocalypse Now, Part 24: A Pound of Cure, Part 3”

  1. The fol­low­ing 64 page book was pub­lished by British Intel­li­gence in 1942 and reveals IG Far­ben’s long term plans for world dom­i­na­tion. It is rel­a­tive­ly easy read­ing:
    https://www.merriam-press.com/sequeltotheapocalypsehowyouhelpedpayforhitlerswar.aspx

    Posted by Socrates | January 14, 2021, 7:44 pm
  2. Here’s a quick update on the rel­a­tive sta­tus of Mod­er­na’s and BioN­Tech in the eyes of the invest­ment com­mu­ni­ty:
    BioN­Tech also report­ed stronger-than-expect­ed quar­ter­ly results, post­ing $6.24 bil­lion in sec­ond quar­ter sales com­pared to ana­lysts expec­ta­tions of $3.83 bil­lion. The com­pa­ny alone is now pro­ject­ed to add 0.5% to Ger­many’s GDP this year. That is a HUGE con­tri­bu­tion to the Ger­many econ­o­my from a sin­gle com­pa­ny. It’s an exam­ple of the kind of news com­ing out of these com­pa­nies that’s trig­gered the 422 per­cent ris­ing BioN­Tech’s stock since the begin­ning of 2021, while Mod­er­na stock is up 333 per­cent. Again, that’s just since the begin­ning of 2021, which does­n’t fac­tor in their enor­mous 2020 growth:

    The New York Post

    Mod­er­na and BioN­Tech shares sky­rock­et amid talk of mRNA treat­ments for can­cer, malar­ia

    By Theo Wayt

    August 9, 2021 | 4:18pm | Updat­ed

    Shares of Mod­er­na and BioN­Tech both sky­rock­et­ed on Mon­day amid grow­ing enthu­si­asm over tech­nol­o­gy used in their coro­n­avirus vac­cines and its poten­tial to help fight oth­er ail­ments like can­cer and malar­ia.

    Monday’s ral­ly came after BioN­Tech told investors on an earn­ings call that it’s push­ing for­ward with plans for human tri­als for flu and malar­ia vac­cines — as well as for can­cer treat­ments.

    The tri­als will rely on mes­sen­ger RNA tech­nol­o­gy, or mRNA — a new type of vac­cine used to pro­tect against the coro­n­avirus that may also have the poten­tial to solve chal­lenges in vac­cine devel­op­ment for oth­er infec­tious dis­eases and can­cer.

    Both BioN­Tech and Mod­er­na cur­rent­ly use mRNA tech­nol­o­gy in their coro­n­avirus vac­cines.

    Shares of Mass­a­chus­setts-based Mod­er­na soared 17 per­cent to end the day at $484.47, while Germany’s BioN­Tech closed 14.9 per­cent high­er at $447.23.

    BioN­Tech also report­ed stronger-than-expect­ed quar­ter­ly results, post­ing $6.24 bil­lion in sec­ond quar­ter sales com­pared to ana­lysts expec­ta­tions of $3.83, accord­ing to Investors Busi­ness Dai­ly. The com­pa­ny expects to deliv­er a whop­ping 2.2 bil­lion dos­es of its COVID-19 vac­cine this year.

    The poten­tial to cure ail­ments that kill mil­lions of humans each year has left investors sali­vat­ing. BioN­Tech stock has risen an eye-water­ing 422 per­cent since the begin­ning of 2021, while Mod­er­na stock is up 333 per­cent, accord­ing to Mar­ket­Watch data.

    The COVID-19 vac­cines are the only mar­ket­ed prod­ucts com­mer­cial­ly avail­able from either com­pa­ny — but Mod­er­na and BioN­Tech have said that mRNA tech­nol­o­gy has the poten­tial to treat can­cer, malar­ia and oth­er dis­eases.

    Pfiz­er, which devel­oped a coro­n­avirus vac­cine along­side BioN­Tech, saw its shares climb a far more mod­est 1.5 per­cent on Mon­day and 24 per­cent since the begin­ning of the year. Pfiz­er is also far more diver­si­fied than its peers with a wide slate of com­mer­cial­ly avail­able drugs.

    In a note shared with The Post, Jef­feries man­ag­ing direc­tor Michael Yee said Mod­er­na “con­tin­ues to trade like the ‘Tes­la of Biotech’” — mean­ing the stock has a mas­sive val­u­a­tion based on high investor expec­ta­tions about its future.

    Mod­er­na is “an inno­va­tion and dis­rup­tion tech­nol­o­gy play,” Yee added, due to the company’s mRNA tech­nol­o­gy hav­ing the poten­tial to sup­plant tra­di­tion­al med­ical treat­ments and cre­ate new vac­cines.

    ...

    ————–

    “Mod­er­na and BioN­Tech shares sky­rock­et amid talk of mRNA treat­ments for can­cer, malar­ia” by Theo Wayt; The New York Post; 08/09/2021

    “In a note shared with The Post, Jef­feries man­ag­ing direc­tor Michael Yee said Mod­er­na “con­tin­ues to trade like the ‘Tes­la of Biotech’” — mean­ing the stock has a mas­sive val­u­a­tion based on high investor expec­ta­tions about its future.

    Mod­er­na is trad­ing like the ‘Tes­la of Biotech’. In oth­er words, investors are bet­ting Mod­er­na owns the keys to the future of med­i­cine.

    At the same BioN­Tech is already exceed­ing those lofty expec­ta­tions, report­ing sec­ond quar­ter sales at $6.24billion com­pared to ana­lyst expec­ta­tions of $3.82. These are the kinds of num­bers that trig­gered 3 and 4‑fold increas­es in these stocks since the start of 2021 alone (so not even count­ing 2020’s mas­sive gains):

    ...
    BioN­Tech also report­ed stronger-than-expect­ed quar­ter­ly results, post­ing $6.24 bil­lion in sec­ond quar­ter sales com­pared to ana­lysts expec­ta­tions of $3.83, accord­ing to Investors Busi­ness Dai­ly. The com­pa­ny expects to deliv­er a whop­ping 2.2 bil­lion dos­es of its COVID-19 vac­cine this year.

    The poten­tial to cure ail­ments that kill mil­lions of humans each year has left investors sali­vat­ing. BioN­Tech stock has risen an eye-water­ing 422 per­cent since the begin­ning of 2021, while Mod­er­na stock is up 333 per­cent, accord­ing to Mar­ket­Watch data.
    ...

    To put BioN­Tech’s wild over-per­for­mance in per­spec­tive, it’s now pro­ject­ed that the com­pa­ny’s alone could lift the Ger­many econ­o­my by 0.5% this year. That is a HUGE impact for a sin­gle com­pa­ny to have on an econ­o­my as large as Ger­many’s, made even more remark­able by the fact that BioN­Tech is basi­cal­ly a start­up. And this is just the start of this lit­tle start­up. So while BioN­Tech has clear­ly made a big impact in the glob­al biotech sec­tor, that impact could end up being dwarfed by the impact BioN­Tech has on the Ger­man econ­o­my in the long-run

    Reuters

    BioN­Tech alone could lift Ger­man econ­o­my by 0.5% this year

    By Reuters Staff
    August 10, 2021 7:34 AM Updat­ed

    BERLIN (Reuters) ‑The devel­op­ment and domes­tic pro­duc­tion of a ground­break­ing COVID-19 vac­cine by Ger­man start-up BioN­Tech could boost eco­nom­ic growth in Europe’s largest econ­o­my by up to 0.5 per­cent­age points this year, an econ­o­mist said on Tues­day.

    The Ger­man econ­o­my is seen grow­ing by rough­ly 4% this year fol­low­ing a pan­dem­ic-relat­ed plunge by 4.6% last year. This means that Bion­Tech and its break­through devel­op­ment of a coro­n­avirus vac­cine based on mRNA tech­nol­o­gy could account for rough­ly an eighth of over­all GDP growth in 2021, based on esti­mates by Sebas­t­ian Dul­lien, head of think tank the Macro­eco­nom­ic Pol­i­cy Insti­tute (IMK).

    “I can’t think of anoth­er exam­ple in which a sin­gle com­pa­ny had such an impact on Ger­man GDP,” Dul­lien told Reuters.

    A gov­ern­ment offi­cial said it was absolute­ly plau­si­ble to assume that the BioN­Tech effect on over­all eco­nom­ic growth would eas­i­ly reach up to 0.5 per­cent­age points this year.

    Dul­lien said that as a macro econ­o­mist, he nor­mal­ly does not look at indi­vid­ual com­pa­nies. “Some­times, how­ev­er, there are rare cas­es in which indi­vid­ual com­pa­nies have macro­eco­nom­ic rel­e­vance. BioN­Tech is such a rare exam­ple,” Dul­lien said.

    His cal­cu­la­tions are based on BioNTech’s lat­est earn­ings released on Mon­day which showed the start-up now expects to accrue 15.9 bil­lion euros ($18.63 bil­lion) in rev­enue from the vac­cine this year, up from an ear­li­er esti­mate of 12.4 bil­lion euros.

    That is rough­ly 0.5% of Ger­man GDP, Dul­lien said. In 2020, Germany’s gross domes­tic prod­uct stood at about 3.3 tril­lion euros.

    “Since BioN­Tech pro­cures rel­a­tive­ly few pre­lim­i­nary prod­ucts from abroad, this is almost entire­ly domes­tic added val­ue,” Dul­lien said. “So this has a direct impact on eco­nom­ic growth.”

    In con­trast to Germany’s big car com­pa­nies that pro­duce many vehi­cles out­side the coun­try, BioN­Tech is pro­duc­ing its vac­cine in a fac­to­ry in Mar­burg, in west­ern Ger­many. In addi­tion, it receives licens­ing fees from its U.S. part­ner Pfiz­er.

    BioN­Tech and Pfiz­er got the world’s first approval for a COVID-19 vac­cine at the end of 2020. “The suc­cess of BioN­Tech is impres­sive,” Dul­lien said. “There is an excel­lent research land­scape in Ger­many that has poten­tial for the future.”

    ...

    ————

    “BioN­Tech alone could lift Ger­man econ­o­my by 0.5% this year” by Reuters Staff; Reuters; 08/10/2021

    “His cal­cu­la­tions are based on BioNTech’s lat­est earn­ings released on Mon­day which showed the start-up now expects to accrue 15.9 bil­lion euros ($18.63 bil­lion) in rev­enue from the vac­cine this year, up from an ear­li­er esti­mate of 12.4 bil­lion euros.”

    BioN­Tech’s rev­enue esti­mates just keep ris­ing and that’s just for this year alone. Future rev­enue growth is almost impos­si­ble to mean­ing­ful­ly project giv­en that we’re poten­tial­ly look­ing at decades of bio­med­ical rev­o­lu­tions emerg­ing from this tech­nol­o­gy. It’s the kind of sit­u­a­tion that’s per­fect for gen­er­at­ing stratos­pher­ic stock val­u­a­tions.

    So that’s the update on BioN­Tech and Mod­er­na: they’re now val­ued by investors like com­pa­nies with the poten­tial to rede­fine the biotech sec­tor in the future. And in the case of BioN­Tech, even­tu­al­ly rede­fine Ger­many’s econ­o­my.

    Posted by Pterrafractyl | August 11, 2021, 2:52 pm
  3. Here’s one of those arti­cles that serves as a reminder of the incred­i­ble scope of what’s the­o­ret­i­cal­ly pos­si­ble using the mRNA lipid nanopar­ti­cle deliv­ery sys­tem the Mod­er­na and Pfizer/BioNTech mRNA vac­cines are based on:

    New­ly pub­lished work in the New Eng­land Jour­nal of Med­i­cine demon­strat­ed the effec­tive­ness of a CRISPR-based mRNA drug ther­a­py. And that means this was mRNA that per­ma­nent­ly mod­i­fied the patients DNA. At least the DNA of the liv­er cells that had the spe­cial CRISPR mRNA deliv­ered via the drug. Specif­i­cal­ly, a team at the U.K.’s Roy­al Free Hos­pi­tal, used CRISPR mRNA to deliv­er shut down the gene respon­si­ble for pro­duc­ing a tox­ic pro­tein in patients with transthyretin amy­loi­do­sis. Three of the six peo­ple in the tri­al saw an almost com­plete drop-off in pro­tein pro­duc­tion. That’s a remark­able proof-of-con­cept result for a tri­al like this.

    So while the mRNA vac­cines may not be mod­i­fy­ing peo­ple’s DNA as many fear, that does­n’t mean the same under­ly­ing mRNA tech­nol­o­gy could­n’t be retooled for exact­ly those pur­pos­es in the future. Recall ear­li­er work inves­ti­gat­ing the use of genet­i­cal­ly mod­i­fy­ing skele­tal mus­cles to pro­duce desired anti­bod­ies as an alter­na­tive to tra­di­tion­al vac­cines. Because skele­tal mus­cle cells can live for decades, by strate­gi­cal­ly inject­ing the DNA for these anti­bod­ies into just those cells the body could pro­duc­ing the anti­body for decades to come, mak­ing it effec­tive­ly a one-time life-long treat­ment. It sounds like this approach of using CRISPR mRNA with the mRNA lipid nanopar­ti­cle deliv­ery mech­a­nism could achieve a sim­i­lar result. Tar­get­ed tis­sues could have their DNA per­ma­nent­ly altered.

    One tech­ni­cal obsta­cle that still remains is deliv­er­ing the mRNA to the desired tis­sues. Thus far, research­es have fig­ured out how to do it with liv­er cells. But the researchers believe it could be applied near-term for bone-mar­row, ner­vous-sys­tem, and mus­cle dis­eases. So we might end up see­ing long-term tar­get DNA mod­i­fi­ca­tion med­ical ther­a­pies much soon­er than many expect:

    Time

    MRNA’s Next Chap­ter Has Noth­ing to Do With COVID-19 Vac­cines

    By Jamie Ducharme
    August 2, 2021 7:00 AM EDT

    It’s safe to say that before the devel­op­ment of the Pfiz­er-BioN­Tech and Mod­er­na COVID-19 vac­cines, most peo­ple hadn’t thought about mes­sen­ger RNA, or mRNA, since high school sci­ence class—if ever. The mol­e­cule plays a piv­otal role in the body, car­ry­ing the recipes for mak­ing var­i­ous pro­teins to the parts of cells that pro­duce them. But “mRNA” wasn’t exact­ly a com­mon phrase until Pfiz­er-BioN­Tech and Mod­er­na har­nessed the genet­ic material’s pow­er to teach the body to make a piece of a pro­tein found on the COVID-19 virus’ sur­face, thus train­ing it to fight the real thing, were it to attack.

    The tremen­dous effi­ca­cy of mRNA-based COVID-19 vac­cines has gen­er­at­ed plen­ty of excite­ment about its poten­tial use in vac­cines for oth­er dis­eases. And vac­cines may be just the begin­ning. Last month, researchers used mRNA to deliv­er CRISPR gene-edit­ing tech­nol­o­gy that could per­ma­nent­ly treat a rare genet­ic dis­ease in humans—an advance that experts say has impli­ca­tions far beyond the treat­ment of a sin­gle con­di­tion.

    Med­ical sci­ence research uti­liz­ing CRISPR—a sys­tem that allows sci­en­tists to add, remove or change spe­cif­ic genet­ic infor­ma­tion with­in the body—had already been advanc­ing rapid­ly in recent years. Researchers have shown its poten­tial for revers­ing blind­ness and sick­le cell ane­mia, and to treat genet­ic dis­eases in ani­mals. But new work described in the New Eng­land Jour­nal of Med­i­cine in June marks what researchers are call­ing the first time CRISPR has been shown to treat a genet­ic dis­or­der when direct­ly admin­is­tered to human patients.

    In this case, the tech­nol­o­gy was applied towards a ther­a­py for transthyretin amy­loi­do­sis, a genet­ic dis­ease that caus­es suf­fer­ers’ liv­ers to pro­duce a pro­tein that even­tu­al­ly builds up to tox­ic lev­els. The disease’s preva­lence varies depend­ing on patient demographics—it affects about one in 100,000 Amer­i­cans of Euro­pean descent, but as many as one in every 538 peo­ple in north­ern Por­tu­gal, for example—and can be passed down to future gen­er­a­tions. While there are drugs that can help patients man­age the dis­ease, the goal of the new research was to stop the prob­lem at its source.

    To imag­ine using [CRISPR] as a ther­a­py for peo­ple, you need to fig­ure out how to get these edit­ing tools into the cells you’re try­ing to fix. That’s where mes­sen­ger RNA comes in,” explains Daniel Ander­son, a pro­fes­sor of chem­i­cal engi­neer­ing at the Mass­a­chu­setts Insti­tute of Tech­nol­o­gy and a co-founder of CRISPR Ther­a­peu­tics, which uses CRISPR tech­nol­o­gy to devel­op med­ica­tions. Ander­son was not involved in the research.

    The research team, led by Dr. Julian Gill­more, an amy­loi­do­sis expert at the U.K.’s Roy­al Free Hos­pi­tal, pro­grammed mRNA to deliv­er gene-edit­ing instruc­tions to the liv­er, shut­ting down the part respon­si­ble for pro­duc­ing the tox­ic pro­tein. After a one-time injec­tion of the drug, three of the six peo­ple in the tri­al saw an almost com­plete drop-off in pro­tein pro­duc­tion; the remain­ing three, who received a small­er dose, saw less dra­mat­ic results. It will take a few months to see if that accom­plish­ment trans­lates to symp­tom relief, but the ear­ly find­ings are promis­ing. (The work was fund­ed by phar­ma­ceu­ti­cal com­pa­nies Intel­lia Ther­a­peu­tics and Regen­eron, which pro­duce the injectable CRISPR drug.)

    As Dr. John Leonard, Intellia’s pres­i­dent and CEO, puts it: “mRNA is a way to make CRISPR gene edit­ing come alive. CRISPR is the work­horse; mRNA encodes it.”

    In the­o­ry, the same gen­er­al tech­nol­o­gy could be used to treat con­di­tions beyond transthyretin amy­loi­do­sis. “There are a host of dis­eases in the liv­er where this might work in an anal­o­gous man­ner,” says Dr. Ken­neth Chien, a senior pro­fes­sor of car­di­ol­o­gy research at Sweden’s Karolin­s­ka Insti­tutet and a co-founder of Mod­er­na Ther­a­peu­tics, who was not involved in the research. “The most impor­tant aspect of this is the impli­ca­tions that the tech­nol­o­gy can be repur­posed.”

    Chien has believed in mRNA’s drug-devel­op­ment poten­tial for more than a decade. When Mod­er­na was found­ed in 2010, in fact, its chief goal was to devel­op mRNA-based drugs, not vac­cines. (Chien no longer works at Mod­er­na and is now an advi­sor to the phar­ma­ceu­ti­cal giant AstraZeneca.) He con­tin­ues to work on an mRNA-based drug he hopes could even­tu­al­ly treat heart con­di­tions.

    The tricky part, Leonard says, is fig­ur­ing out how to get a drug into dif­fer­ent tis­sues, since the strat­e­gy for deliv­er­ing CRISPR-based ther­a­peu­tics varies depend­ing on its tar­get. The new research offers a blue­print for liv­er-based con­di­tions, and Leonard believes sim­i­lar approach­es could be used in the near-term for bone-mar­row, ner­vous-sys­tem and mus­cle dis­eases. The list the­o­ret­i­cal­ly grows from there, so long as researchers can fine-tune deliv­ery.

    ...

    ————

    “MRNA’s Next Chap­ter Has Noth­ing to Do With COVID-19 Vac­cines” by Jamie Ducharme; Time; 08/02/2021

    “In the­o­ry, the same gen­er­al tech­nol­o­gy could be used to treat con­di­tions beyond transthyretin amy­loi­do­sis. “There are a host of dis­eases in the liv­er where this might work in an anal­o­gous man­ner,” says Dr. Ken­neth Chien, a senior pro­fes­sor of car­di­ol­o­gy research at Sweden’s Karolin­s­ka Insti­tutet and a co-founder of Mod­er­na Ther­a­peu­tics, who was not involved in the research. “The most impor­tant aspect of this is the impli­ca­tions that the tech­nol­o­gy can be repur­posed.”

    Yes, while the trea­ment for transthyretin amy­loi­do­sis is indeed excit­ing, by far the most impor­tant aspect of this research are the impli­ca­tions for what’s pos­si­ble. Comb­ing CRISPR mRNA with the lipid nanopar­ti­cle deliv­ery sys­tem used in the Mod­er­na and Pfiz­er vac­cines, an entire new modal­i­ty of med­ical appli­ca­tions are pos­si­ble. The tran­sient nature of deliv­ered mRNA can be made per­ma­nent. It’s huge. Half the sub­jects in the tri­al saw an almost com­plete drop off in the gene tar­get­ed for silenc­ing after a singe injec­tion. That’s the kind of study result that will rever­ber­ate through the next few decades of med­ical research:

    ...
    To imag­ine using [CRISPR] as a ther­a­py for peo­ple, you need to fig­ure out how to get theYse edit­ing tools into the cells you’re try­ing to fix. That’s where mes­sen­ger RNA comes in,” explains Daniel Ander­son, a pro­fes­sor of chem­i­cal engi­neer­ing at the Mass­a­chu­setts Insti­tute of Tech­nol­o­gy and a co-founder of CRISPR Ther­a­peu­tics, which uses CRISPR tech­nol­o­gy to devel­op med­ica­tions. Ander­son was not involved in the research.

    The research team, led by Dr. Julian Gill­more, an amy­loi­do­sis expert at the U.K.’s Roy­al Free Hos­pi­tal, pro­grammed mRNA to deliv­er gene-edit­ing instruc­tions to the liv­er, shut­ting down the part respon­si­ble for pro­duc­ing the tox­ic pro­tein. After a one-time injec­tion of the drug, three of the six peo­ple in the tri­al saw an almost com­plete drop-off in pro­tein pro­duc­tion; the remain­ing three, who received a small­er dose, saw less dra­mat­ic results. It will take a few months to see if that accom­plish­ment trans­lates to symp­tom relief, but the ear­ly find­ings are promis­ing. (The work was fund­ed by phar­ma­ceu­ti­cal com­pa­nies Intel­lia Ther­a­peu­tics and Regen­eron, which pro­duce the injectable CRISPR drug.)

    ...

    The tricky part, Leonard says, is fig­ur­ing out how to get a drug into dif­fer­ent tis­sues, since the strat­e­gy for deliv­er­ing CRISPR-based ther­a­peu­tics varies depend­ing on its tar­get. The new research offers a blue­print for liv­er-based con­di­tions, and Leonard believes sim­i­lar approach­es could be used in the near-term for bone-mar­row, ner­vous-sys­tem and mus­cle dis­eases. The list the­o­ret­i­cal­ly grows from there, so long as researchers can fine-tune deliv­ery.
    ...

    Final­ly, note the rather curi­ous twist this promis­ing research cre­ates for Mod­er­na’s and Pfiz­er’s mRNA busi­ness mod­el. As we’ve seen, the cre­ation of mRNA vac­cines was nev­er the orig­i­nal plan. That was a back­up plan Mod­er­na fell back on after it became clear that repeat­ed dos­es of the mRNA ther­a­pies was cre­at­ing too many side-effects. Vac­cines were seen as a way around this because they only require one or two dos­es. The orig­i­nal plan was to cre­ate ther­a­pies that involved reg­u­lar repeat­ed dos­es. A busi­ness mod­el based on sell­ing the treat­ment, not the cure. So as we’ve watched the world embrace mRNA vac­cines and cel­e­brate the promise this tech­nol­o­gy holds, it’s been look­ing like we’re head­ing towards a sce­nario where Mod­er­na and Pfiz­er would final­ly have the momen­tum to over­come saftey con­cerns and start deliv­er­ing mRNA therepeu­tics that involve reg­u­lar dos­ing. But with the CRISPR option now demon­stra­bly avail­able, that busi­ness mod­el faces some inter­est­ing com­pe­ti­tion. Sell­ing the cure is now an option. In oth­er words, while this study is great news for patients, it might not actu­al­ly be the best news for Mod­er­na’s and Pfiz­er’s bot­tom lines:

    ...
    Chien has believed in mRNA’s drug-devel­op­ment poten­tial for more than a decade. When Mod­er­na was found­ed in 2010, in fact, its chief goal was to devel­op mRNA-based drugs, not vac­cines. (Chien no longer works at Mod­er­na and is now an advi­sor to the phar­ma­ceu­ti­cal giant AstraZeneca.) He con­tin­ues to work on an mRNA-based drug he hopes could even­tu­al­ly treat heart con­di­tions.
    ...

    Imag­ine if drug mak­ers had the option of cre­at­ing one-shot drugs. You take one pill and that’s it. You’re cured. Excit­ing, right? But how about the exec­u­tives mak­ing the deci­sions of which drugs to invest in next. How excit­ed would they be about these new won­der drugs? It’s a ques­tion the phar­ma­ceu­ti­cal indus­try is prob­a­bly ask­ing itself these days. In par­tic­u­lar Mod­er­na and Pfiz­er.

    Posted by Pterrafractyl | August 14, 2021, 3:32 pm
  4. Here’s a series of arti­cles relat­ed to the ques­tions that have remained unan­swered so far about whether or not the legal immu­ni­ty grant­ed by the US to vac­cine man­u­fac­tur­ers dur­ing an emer­gency will extend to oth­er coun­tries. First, recall how the US Con­gress passed the Pub­lic Readi­ness and Emer­gency Pre­pared­ness Act in 2005 dur­ing a bird flu out­break that con­ferred legal immu­ni­ty, and just such a emer­gency was declared by then-HHS Sec­re­tary Alex Azar in March of 2020, last­ing until 2024. As a result, the vac­cine man­u­fac­tur­ers have a four year lia­bil­i­ty-free win­dow to devel­op and assess new COVID vac­cine tech­nolo­gies. And while some COVID vac­cines rely on tra­di­tion­al vac­cine tech­nol­o­gy, like the John­son & John­son vac­cine, there’s no deny­ing that the lia­bil­i­ty waiv­er was par­tic­u­lar­ly con­ve­nient for the lia­bil­i­ty-free devel­op­ment of new mRNA tech­nol­o­gy from Mod­er­na and Pfiz­er. It’s like a four-year lia­bil­i­ty-free mass safe­ty tri­al of the mRNA ther­a­peu­tic plat­form.

    A plat­form that goes far beyond vac­cines. Recall the 2016 STAT News arti­cle describ­ing how Mod­er­na start­ed off try­ing to design ther­a­peu­tic mRNA appli­ca­tions involv­ing the reg­u­lar intro­duc­tion of mRNA to cre­ate the prop­er ver­sions of pro­teins but the repeat­ed admin­is­tra­tion of the mRNA nano­lipid par­ti­cles caused too many side-effects for the com­pa­ny to con­tin­ue with that line of research. Mod­er­na instead jumped to mRNA vac­cines due to the fact that vac­cines hope­ful­ly don’t require too many shots. More recent­ly, we’ve learned about lans to use mRNA nano­lipid tech­nol­o­gy to deliv­er CRISPR mRNA that can per­ma­nent­ly alter the DNA of an indi­vid­u­al’s cells.

    Which is all, again, why the four year lia­bil­i­ty-free waiv­er for Mod­er­na and Pfiz­er are like com­mer­cial man­na from heav­en. Because it’s not like the safe­ty infor­ma­tion devel­oped over the next four years are only going to apply to vac­cines. The whole indus­try is going to be point­ing back to the found safe­ty of mRNA vac­cine to jus­ti­fy the ini­tial use of all sorts of oth­er mRNA appli­ca­tions for years to come. At least assum­ing there any major safe­ty issues dis­cov­ered dur­ing this peri­od which, again, is why we real­ly should­n’t be blind­ly trust­ing these vac­cine man­u­fac­tur­ers to con­duct the bulk of the safe­ty assess­ments for the vac­cines. The stakes go far beyond the future of these vac­cines. It’s not an exag­ger­a­tion to say this kind of tech­nol­o­gy rep­re­sents a major new chap­ter in med­i­cine. Pos­si­bly a new chap­ter in the human species if we go bonkers with the DNA mod­i­fi­ca­tion. New pub­lic and pri­vate com­mer­cial bio­med­ical empires are going to be built in the com­ing decades by those who most effec­tive­ly exploit this new tech­nol­o­gy and the stakes almost could­n’t be high­er.

    But, again, it was nev­er real­ly clear the lia­bil­i­ty waiv­er passed by the US con­gress was going to apply to the rest of the world. So here’s an update on that front out ot India last week:

    So far, India has been reliant on the AstraZeneca vac­cine, which is being pro­duced with­out a lia­bil­i­ty waiv­er. After months of ques­tions over whether or not the Indi­an gov­ern­ment would grant US vac­cine man­u­fac­tur­ers lia­bil­i­ty waivers, we appear to have an answer. It’s an answer deliv­ered by anony­mous gov­ern­ment sources talk­ing to reporters, so it’s not a defin­i­tive answer. But accord­ing to these anony­mous sources, there will be NO lia­bil­i­ty waivers, although Pfiz­er’s spokesper­son assures us nego­ti­a­tions are ongo­ing. And part of what made this report notable is that it came one day after we got reports that the Indi­an gov­ern­ment expects to receive mil­lions of dos­es of the John­son & John­son vac­cine some time in Novem­ber. So it appears that J&J, with its tra­di­tion­al vac­cine tech­nol­o­gy, has ten­ta­tive­ly arrived at an agree­ment to pro­ceed with­out a lia­bil­i­ty shield, while Mod­er­na and Pfiz­er are con­tin­u­ing to hold out and wait for the sit­u­a­tion to get worse so they can extract a bet­ter deal:

    Reuters

    India govt won’t buy Pfiz­er, Mod­er­na vac­cines amid local out­put ‑sources

    By Neha Aro­ra and Krish­na N. Das, Aftab Ahmed
    Sep­tem­ber 21, 2021 1:12 PM UTC Updat­ed

    NEW DELHI, Sept 21 (Reuters) — Indi­a’s gov­ern­ment will not buy COVID-19 shots from Pfiz­er (PFE.N)/BioNTech (22UAy.DE) and Mod­er­na (MRNA.O), three gov­ern­ment sources told Reuters, main­ly because domes­tic out­put of more afford­able and eas­i­er-to-store vac­cines has jumped.

    That essen­tial­ly means the glob­al­ly pop­u­lar vac­cines, which their mak­ers have pledged not to sell to pri­vate par­ties dur­ing the pan­dem­ic, will not be avail­able for now in the world’s two most pop­u­lous coun­tries — Chi­na and India.

    The Indi­an gov­ern­ment has also declined to meet the U.S. com­pa­nies’ requests for legal pro­tec­tion over any side-effects from the use of their shots, which are cur­rent­ly made only in the Unit­ed States or Europe, two of the sources said.

    No com­pa­ny has received such pro­tec­tion in India.

    “Ear­li­er, there was a short­age, there was a need,” said one of the sources, refer­ring to Indi­a’s appeal to the com­pa­nies in April for vac­cines when infec­tions explod­ed and shots were in short sup­ply.

    “Their price will be high. Why should we take on their con­di­tions?”

    A sec­ond source said: “The gov­ern­ment will not buy Pfiz­er and Mod­er­na vac­cines. They are free to have pri­vate tie-ups after nec­es­sary reg­u­la­to­ry clear­ances. But sov­er­eign indem­ni­ty is clear­ly some­thing we can’t give”.

    A Pfiz­er spokesper­son in India said dis­cus­sions were ongo­ing and it remained com­mit­ted to bring the vac­cine to the coun­try.

    The com­pa­ny reit­er­at­ed that “dur­ing the pan­dem­ic phase, it would sup­ply the COVID-19 vac­cine only to cen­tral gov­ern­ments and supra-nation­al organ­i­sa­tions”.

    ...

    Mod­er­na, through its Indi­an part­ner Cipla (CIPL.NS), already has emer­gency-use autho­ri­sa­tion in India for its vac­cine, which, like the Pfiz­er one, needs ultra-cold stor­age — facil­i­ties that much of India lacks.

    Both vac­cines cost sev­er­al times more than Indi­a’s main shot, Cov­ishield, a licensed ver­sion of the AstraZeneca (AZN.L) drug.

    Indi­a’s month­ly domes­tic out­put has tre­bled since April and will reach 300 mil­lion dos­es in Octo­ber, accord­ing to Health Min­is­ter Man­sukh Man­daviya, who on Mon­day announced a restart of Indi­a’s vac­cine exports from the Octo­ber quar­ter. read more

    ...

    ————

    “India govt won’t buy Pfiz­er, Mod­er­na vac­cines amid local out­put ‑sources” by Neha Aro­ra and Krish­na N. Das, Aftab Ahmed; Reuters; 09/21/2021

    The Indi­an gov­ern­ment has also declined to meet the U.S. com­pa­nies’ requests for legal pro­tec­tion over any side-effects from the use of their shots, which are cur­rent­ly made only in the Unit­ed States or Europe, two of the sources said.”
    .
    Sor­ry, there will be no lia­bil­i­ty shields for side-effects. Not for Mod­er­na, Pfiz­er, or any com­pa­ny in India. Accord­ing to one anony­mous gov­ern­ment source, “sov­er­eign indem­ni­ty is clear­ly some­thing we can’t give.” At the same time, Pfiz­er is telling sources the dis­cus­sion were ongo­ing. At a min­i­mum, there’s an impasse for now:

    ...
    No com­pa­ny has received such pro­tec­tion in India.

    “Ear­li­er, there was a short­age, there was a need,” said one of the sources, refer­ring to Indi­a’s appeal to the com­pa­nies in April for vac­cines when infec­tions explod­ed and shots were in short sup­ply.

    “Their price will be high. Why should we take on their con­di­tions?”

    A sec­ond source said: “The gov­ern­ment will not buy Pfiz­er and Mod­er­na vac­cines. They are free to have pri­vate tie-ups after nec­es­sary reg­u­la­to­ry clear­ances. But sov­er­eign indem­ni­ty is clear­ly some­thing we can’t give”.

    A Pfiz­er spokesper­son in India said dis­cus­sions were ongo­ing and it remained com­mit­ted to bring the vac­cine to the coun­try.
    ...

    .
    So what about the John­son & John­son shot? Did it get a lia­bil­i­ty shield? It did­n’t sound like it, based on that report. But as we learned the day before, Indi­an gov­ern­ment sources were telling reporters that India could receive as man as 43.5 mil­lion dos­es of the J&J shot in Octo­ber. No deal had been signed, but those were the reports were were get­ting a day before reports from anony­mous Indi­an offi­cials indi­cat­ed no com­pa­ny ever would receive a sov­er­eign immu­ni­ty agree­ment. Tak­en togeth­er, it would seem that J&J is going ahead with a sup­ply agree­ment with­out a lia­bil­i­ty shield:

    Reuters

    India set to get first J&J COVID vac­cine dos­es in Octo­ber, says source

    By Neha Aro­ra
    Sep­tem­ber 20, 2021 4:24 PM UTC Updat­ed

    NEW DELHI, Sept 20 (Reuters) — India expects to get its first John­son & John­son (JNJ.N) COVID-19 vac­cine dos­es from next month, filled and fin­ished in India by a part­ner of the U.S. drug­mak­er, a source with knowl­edge of the mat­ter told Reuters on Mon­day.

    It could receive as many as 43.5 mil­lion dos­es of the sin­gle-shot vac­cine in Octo­ber, said the source — a big step towards help­ing India meet its tar­get of pro­duc­ing more than 300 mil­lion dos­es in the month. read more

    India is the world’s biggest cen­tre of vac­cine man­u­fac­tur­ing. Once it has met its own needs, it plans to resume exports, which it stopped in April.

    Indi­a’s drug reg­u­la­tor last month gave emer­gency autho­ri­sa­tion to the J&J vac­cine, whether import­ed or local­ly filled and fin­ished by J&J’s Indi­an part­ner, Bio­log­i­cal E.

    How­ev­er, the Indi­an gov­ern­ment has not yet signed any sup­ply deal with J&J.

    “J&J dos­es are expect­ed from next month,” said the source, who declined to be named as he was not autho­rised to talk to the media. “Bio E will do the for­mu­la­tion and make 5 ml vials.”

    ...

    ————-

    “India set to get first J&J COVID vac­cine dos­es in Octo­ber, says source” by Neha Aro­ra; Reuters; 09/20/2021

    “It could receive as many as 43.5 mil­lion dos­es of the sin­gle-shot vac­cine in Octo­ber, said the source — a big step towards help­ing India meet its tar­get of pro­duc­ing more than 300 mil­lion dos­es in the month. read more”

    It’s not a hard con­fir­ma­tion, but reports like this are typ­i­cal­ly what pre­cedes hard con­fir­ma­tions. On the one hand, con­sid­er­ing that the J&J shot is based on tra­di­tion­al vac­cine tech­nol­o­gy, it would­n’t be a huge sur­prise if the com­pa­ny agreed to sup­ply India with the vac­cine with­out a lia­bil­i­ty shield.

    But Mod­er­na an Pfiz­er, that lia­bil­i­ty shield is look­ing to be an absolute pre­req­ui­site. That’s the sit­u­a­tion described in the fol­low­ing arti­cle from ear­ly August about the Indi­an gov­ern­ment giv­ing its approval for the J&J shot, which points out that the gov­ern­ment approved the Mod­er­na shot back in June but legal wran­gling over the lia­bil­i­ty pro­tec­tion is hold­ing up deliv­er­ies:

    Reuters

    India approves J&J vac­cine; no deliv­ery time­line yet

    August 7, 2021 8:08 AM CDT Updat­ed

    Aug 7 (Reuters) — India has approved John­son & John­son’s (JNJ.N) sin­gle-dose COVID-19 vac­cine for emer­gency use, health min­is­ter Man­sukh Man­daviya said in a tweet on Sat­ur­day, but the com­pa­ny said it was too ear­ly to give a deliv­ery time­line.

    The phar­ma­ceu­ti­cal giant had applied for emer­gency use approval of its vac­cine, the com­pa­ny had said on Fri­day. The shot will be brought to India through a sup­ply agree­ment with home­grown vac­cine mak­er Bio­log­i­cal E Ltd, J&J had said.

    “While we look for­ward to meet­ing our deliv­ery com­mit­ments it is pre­ma­ture for us to spec­u­late on the tim­ing of our vac­cine deliv­er­ies,” the com­pa­ny said in an emailed reply to Reuters.

    Indi­an health author­i­ties have so far approved the use of vac­cines devel­oped by AstraZeneca (AZN.L), Bharat Biotech, Rus­si­a’s Gama­leya Insti­tute and Mod­er­na (MRNA.O).

    Despite the approval of Mod­er­na’s vac­cine in June, not a sin­gle dose has yet arrived due to wran­gling over legal pro­tec­tion sought by the com­pa­ny.

    It is unclear if J&J has reached an agree­ment with the gov­ern­ment over legal con­cerns. Fel­low U.S. com­pa­ny Pfiz­er has yet to seek per­mis­sion for use of its vac­cine in India.

    “This deci­sion was based on topline effi­ca­cy and safe­ty data from the Phase 3 ENSEMBLE clin­i­cal tri­al, which demon­strat­ed our sin­gle-shot vac­cine was 85% effec­tive in pre­vent­ing severe dis­ease across all regions stud­ied, and showed pro­tec­tion against COVID-19 relat­ed hos­pi­tal­iza­tion and death, begin­ning 28 days after vac­ci­na­tion,” J&J said in an emailed state­ment.

    “This is an impor­tant step for­ward in accel­er­at­ing avail­abil­i­ty of our COVID-19 vac­cine to help end the pan­dem­ic.”

    ...

    India has report­ed an aver­age of 30,000 to 40,000 new coro­n­avirus cas­es every day since July. Although dai­ly cas­es have dipped from a high of 400,000 at the peak of the sec­ond wave, the fed­er­al gov­ern­ment has warned that the dan­ger has not yet abat­ed.

    India has admin­is­tered 501 mil­lion vac­cine dos­es, the largest of any coun­try after Chi­na, but lit­tle over 10% of its adult pop­u­la­tion has been inoc­u­lat­ed with both dos­es.

    ————

    “India approves J&J vac­cine; no deliv­ery time­line yet”; Reuters; 08/07/2021

    “Indi­an health author­i­ties have so far approved the use of vac­cines devel­oped by AstraZeneca (AZN.L), Bharat Biotech, Rus­si­a’s Gama­leya Insti­tute and Mod­er­na (MRNA.O).”

    Mod­er­na’s shot got approved. It just did­n’t get lia­bil­i­ty-free approval, which Mod­er­na is con­tin­u­ing to demand. And until that waiv­er is pro­vid­ed, no Mod­er­na shots for India. And note how Pfiz­er had­n’t even sought per­mis­sion to get its vac­cine approved in India:

    ...
    Despite the approval of Mod­er­na’s vac­cine in June, not a sin­gle dose has yet arrived due to wran­gling over legal pro­tec­tion sought by the com­pa­ny.

    It is unclear if J&J has reached an agree­ment with the gov­ern­ment over legal con­cerns. Fel­low U.S. com­pa­ny Pfiz­er has yet to seek per­mis­sion for use of its vac­cine in India.
    ...

    Will the Indi­an gov­ern­ment find any sort of agree­ment with the mRNA vac­cine man­u­fac­tur­ers giv­en the appar­ent hard oppo­si­tion to lia­bil­i­ty pro­tec­tions? Well, as the fol­low­ing arti­cle from late July described, the Indi­an gov­ern­ment appeared to be open to some sort of cre­ative agree­ment involv­ing hav­ing Mod­er­na’s Indi­an part­ner, Cipla, assume some of the lia­bil­i­ties on Mod­er­na’s behalf. Mod­er­na reject­ed the idea:

    Reuters

    Legal wran­gles hold up U.S. vac­cine dona­tions to India

    By Neha Aro­ra and Krish­na N. Das
    July 28, 2021 10:35 AM UTC Updat­ed

    NEW DELHI, July 28 (Reuters) — Two months after India dropped local-tri­al rules for COVID-19 vac­cines approved by devel­oped coun­tries, not a sin­gle dose has arrived as New Del­hi dithers over legal pro­tec­tion sought by com­pa­nies like Pfiz­er (PFE.N) and Mod­er­na (MRNA.O).

    The Unit­ed States has in recent weeks donat­ed mil­lions of vac­cine dos­es to coun­tries such as Bangladesh, Bhutan and South Korea. Sup­plies to India, how­ev­er, are stuck pend­ing con­clu­sion of some “legal require­ments”, accord­ing to the glob­al COVAX vac­cine plat­form through which such dos­es are rout­ed.

    Indi­a’s drugs reg­u­la­tor gave emer­gency use autho­ri­sa­tion to the Mod­er­na vac­cine in June, as the Unit­ed States read­ied dona­tions for India. Fel­low U.S. com­pa­nies Pfiz­er and John­son & John­son (JNJ.N) have not for­mal­ly sought per­mis­sion for the use of their shots in India.

    But India has not met requests for grant­i­ng the man­u­fac­tur­ers indem­ni­ty from law­suits.

    Indi­a’s junior health min­is­ter told par­lia­ment on Tues­day that a team of offi­cials had been formed to engage with the vac­cine mak­ers.

    “This team is in con­tin­u­ous dia­logue with Pfiz­er, Mod­er­na and John­son & John­son to dis­cuss and address var­i­ous issues includ­ing the issue of indem­ni­ty,” Bharati Pravin Pawar said.

    ...

    Vac­cine alliance Gavi, which co-leads the COVAX facil­i­ty, said legal pro­tec­tions for vac­cine sup­pli­ers were manda­to­ry.

    “All facil­i­ty par­tic­i­pants must have signed indem­ni­ty agree­ments with the man­u­fac­tur­ers in ques­tion in order to receive dos­es through COVAX – which would also be true for dos­es received via bilat­er­al deals,” a Gavi spokesper­son said in an email.

    India is heav­i­ly reliant on the AstraZeneca (AZN.L) vac­cine pro­duced by the Serum Insti­tute of India (SII). Bharat Biotech — mak­er of Indi­a’s only approved home-grown shot — is strug­gling to boost sup­ply. read more

    SII has already told the gov­ern­ment that any indem­ni­ty for for­eign vac­cine com­pa­nies should also apply to Indi­an pro­duc­ers.

    One gov­ern­ment source said Mod­er­na’s Indi­an part­ner Cipla (CIPL.NS) had offered to bear some legal respon­si­bil­i­ties for the vac­cine’s use in the coun­try, but that the pro­pos­al had been reject­ed by the U.S. com­pa­ny.

    “The gov­ern­ment can­not give indem­ni­ty to any­one,” the offi­cial said, declin­ing be named as the dis­cus­sions were pri­vate and no deci­sions had been finalised.

    “The gov­ern­ment is say­ing domes­tic com­pa­nies can give indem­ni­ty on behalf of their for­eign part­ners.”

    ...

    India has admin­is­tered 441 mil­lion total vac­cine dos­es, the largest of any coun­try after Chi­na. But only 10% of its adult pop­u­la­tion of about 944 mil­lion peo­ple has been inoc­u­lat­ed with both dos­es, with 47% receiv­ing at least one shot.

    ————

    “Legal wran­gles hold up U.S. vac­cine dona­tions to India” by Neha Aro­ra and Krish­na N. Das; Reuters; 07/28/2021

    “SII has already told the gov­ern­ment that any indem­ni­ty for for­eign vac­cine com­pa­nies should also apply to Indi­an pro­duc­ers.”

    Calls for fair treat­ment by domes­tic sup­pli­ers is one obvi­ous rea­son grant­i­ng lia­bil­i­ty waivers to for­eign vac­cine pro­duc­ers is a touchy top­ic, but even when unfair treat­ment that sounds like a par­tial lia­bil­i­ty waiv­er was pro­posed, Mod­er­na reject­ed the offer. Full lia­bil­i­ty waivers are an absolute demand from the com­pa­ny:

    ...
    One gov­ern­ment source said Mod­er­na’s Indi­an part­ner Cipla (CIPL.NS) had offered to bear some legal respon­si­bil­i­ties for the vac­cine’s use in the coun­try, but that the pro­pos­al had been reject­ed by the U.S. com­pa­ny.

    “The gov­ern­ment can­not give indem­ni­ty to any­one,” the offi­cial said, declin­ing be named as the dis­cus­sions were pri­vate and no deci­sions had been finalised.

    “The gov­ern­ment is say­ing domes­tic com­pa­nies can give indem­ni­ty on behalf of their for­eign part­ners.”
    ...

    So if the vac­cine man­u­fac­tur­ers are demand­ing lia­bil­i­ty pro­tec­tions at the same time the Indi­an gov­ern­ment is repeat­ed­ly insist­ing it’s not going to be grant­i­ng such pro­tec­tions to any­one, what are the real­is­tic paths out of this impasse? Well, as the fol­low­ing arti­cle from back in June describes, there appeared to be a real expec­ta­tion at the time that this impasse could be overcome...with the Indi­an gov­ern­ment capit­u­lat­ing and grant­i­ng the lia­bil­i­ty pro­tec­tions. At least those were the pre­dic­tions we were hear­ing from observers, based in part on the fact that these pro­tec­tions have already been grant­ed by the US, UK, and EU. It was just assumed that India would fol­low suit and sub­mit to those man­u­fac­tur­er demands too. And yet, as the arti­cle also notes, these lia­bil­i­ty waivers that have become pro for­ma dur­ing the pan­dem­ic are his­tor­i­cal­ly unusu­al moves. As Amir Ullah Khan, an econ­o­mist and for­mer pol­i­cy advis­er for the Bill and Melin­da Gates Foun­da­tion, put it, it would be fair for India to hag­gle over indem­ni­ty in nor­mal cir­cum­stances, but not now. “Peo­ple are dying right now, and we don’t have space to bury them. In such a sit­u­a­tion, where there is such a sup­ply prob­lem, it makes no sense to insist on nego­ti­at­ing over indem­ni­ty,” Khan said. It was a sen­ti­ment per­haps put more suc­cinct­ly by K. Sri­nath Red­dy, pres­i­dent of the Pub­lic Health Foun­da­tion of India, who pre­dict­ed the gov­ern­ment would even­tu­al­ly grant indem­ni­ty because the risk of miss­ing out on vac­cines is too high. “It is a seller’s mar­ket,” says Red­dy. And that gives us a snap­shot of how this lia­bil­i­ty bat­tle was look­ing back in June: the expec­ta­tion was that India was acqui­esce to the indus­try demands in part because oth­er coun­tries were already lead­ing the way in sub­mit­ting to the demands but, more impor­tant­ly, because of the urgency of the sit­u­a­tion. It real­ly is a sell­er’s mar­ket, and the sell­ers are behav­ing like they know it:

    For­tune

    India needs Pfiz­er vaccines—but com­pa­ny demand for legal pro­tec­tion is hold­ing things up

    By Biman Mukher­ji
    June 10, 2021 3:12 AM CDT

    In late May, the gov­ern­ment of Indi­an Prime Min­is­ter Naren­dra Modi made a bold promise: to vac­ci­nate every one of India’s 950 mil­lion adults against COVID-19 by the end of the year. But that ambi­tious plan is being held up, in part, by a crit­i­cal issue: whether the gov­ern­ment will pro­tect for­eign vac­cine sup­pli­ers from legal lia­bil­i­ty over vac­cine com­pli­ca­tions.

    V.K. Paul, mem­ber of gov­ern­ment think tank NITI Aayog, sug­gest­ed to reporters last Fri­day that such requests from for­eign com­pa­nies, specif­i­cal­ly Pfiz­er, are delay­ing pur­chase agree­ments for vac­cines that India des­per­ate­ly needs.

    “We are in nego­ti­a­tions with them. There is no deci­sion at the moment,” Paul said. “In prin­ci­pal, they expect [indem­ni­fi­ca­tion] to be giv­en. This has been the case all over the world.”

    Indem­ni­fy­ing vac­cine mak­ers from lia­bil­i­ty is an unusu­al move that has become pro for­ma dur­ing the pan­dem­ic. Such legal pro­tec­tion incen­tivizes man­u­fac­tur­ers to get vac­cines to mar­ket as fast as pos­si­ble and low­ers the price they charge for dos­es while shield­ing cor­po­ra­tions from hav­ing to pay dam­ages for vac­cine com­pli­ca­tions unless they result from will­ful neg­li­gence. It’s what man­u­fac­tur­ers have asked for, and the U.S., the U.K., and Euro­pean Union—eager to get life­sav­ing jabs into arms—have all grant­ed the demand.

    These gov­ern­ments and oth­ers have deter­mined that the issue is a no-brain­er, giv­en the sever­i­ty of the pan­dem­ic, so pub­lic health experts in India are puz­zled as to why Naren­dra Modi’s admin­is­tra­tion has yet to come to the same con­clu­sion.

    Naushad Forbes, past pres­i­dent of the Con­fed­er­a­tion of Indi­an Indus­try, is con­fi­dent India will even­tu­al­ly grant man­u­fac­tur­ers indem­ni­ty, “but we will do it at a leisure­ly pace,” he says. “I am unable to under­stand why there are these delays.”

    ...

    An Indi­an Min­istry of Finance report on Wednes­day called for step­ping up the immu­niza­tion dri­ve to cov­er 700 mil­lion peo­ple by Sep­tem­ber to speed up the country’s eco­nom­ic recov­ery.

    India is well suit­ed to car­ry out a mas­sive vac­ci­na­tion cam­paign. It’s the world’s largest sup­pli­er of vac­cines, and two of its biggest man­u­fac­tur­ers, the Serum Insti­tute of India and Bharat Biotech, announced in March that they would ful­fill domes­tic need before pro­duc­ing any jabs for export. Still, sup­ply of the three jabs India has approved—the Serum Insti­tute of India’s Cov­ishield ver­sion of the AstraZeneca vac­cine, Bharat Biotech’s Cov­ax­in, and Russia’s Sput­nik V—have run short as mil­lions of Indi­ans have flocked to vac­ci­na­tion cen­ters.

    To boost sup­ply, the gov­ern­ment said ear­li­er this month it would approve some for­eign vac­cines even if man­u­fac­tur­ers hadn’t con­duct­ed tri­als in India, a stan­dard process that can take months, if not years, to com­plete.

    But so far, India has grant­ed approval to only one for­eign-made vaccine—Sputnik V—despite being in talks with Pfiz­er and John­son & John­son. A spokesman for Dr Reddy’s Lab­o­ra­to­ries, the Indi­an com­pa­ny that import­ed the Russ­ian-made vac­cine, did not com­ment on whether the com­pa­ny had sought indem­ni­ty.

    “Pfizer’s dis­cus­sions with the gov­ern­ment of India are ongo­ing, and we are hope­ful to bring the Pfiz­er-BioN­Tech COVID-19 vac­cine for use in the coun­try,” a com­pa­ny spokesman said in a writ­ten response to For­tune.

    A John­son & John­son spokesper­son said the com­pa­ny is engaged in talks with the Indi­an gov­ern­ment to sup­ply vac­cines.

    “[The man­u­fac­tur­ers] have vac­cine stocks avail­able with them. The price lev­els are also not unrea­son­able. The only thing com­ing in the way is indem­ni­ty,” Forbes said.

    Indus­try exec­u­tives, who asked not to be named, say nego­ti­a­tions between the gov­ern­ment and vac­cine mak­ers are part­ly hung up on whether law­suits that do arise will be tried in Indi­an or inter­na­tion­al courts. Indi­an pol­i­cy­mak­ers are also con­cerned about appear­ing to grant the for­eign com­pa­nies too many con­ces­sions.

    Amir Ullah Khan, an econ­o­mist and for­mer pol­i­cy advis­er for the Bill and Melin­da Gates Foun­da­tion, said that it would be fair for India to hag­gle over indem­ni­ty in nor­mal cir­cum­stances, but not now.

    “Peo­ple are dying right now, and we don’t have space to bury them. In such a sit­u­a­tion, where there is such a sup­ply prob­lem, it makes no sense to insist on nego­ti­at­ing over indem­ni­ty,” he said.

    Pay­out pro­gram

    Khan sug­gests that the gov­ern­ment waive the legal lia­bil­i­ty for vac­cine mak­ers for a lim­it­ed peri­od, such as six months to one year. Dur­ing that time, the gov­ern­ment should pro­vide com­pen­sa­tion to any­one who expe­ri­ences unin­ten­tion­al adverse side effects. This, he notes, is the strat­e­gy employed by the U.S., which has some of the world’s tough­est prod­uct lia­bil­i­ty and safe­ty laws.

    The U.S. intro­duced a vac­cine com­pen­sa­tion scheme that pays par­ties who are injured by the vac­cines. Health care experts say the tac­tic sat­is­fies drug­mak­ers’ indem­ni­ty demands and gives the pub­lic recourse if they suf­fer irrepara­ble harm from the jabs, though such pro­grams are noto­ri­ous­ly stingy with pay­outs.

    ...

    K. Sri­nath Red­dy, pres­i­dent of the Pub­lic Health Foun­da­tion of India, expects the gov­ern­ment to grant indem­ni­ty because the risk of miss­ing out on vac­cines is too high.

    “It is a seller’s mar­ket,” he says.

    ————

    “India needs Pfiz­er vaccines—but com­pa­ny demand for legal pro­tec­tion is hold­ing things up” by Biman Mukher­ji; For­tune; 06/10/2021

    Naushad Forbes, past pres­i­dent of the Con­fed­er­a­tion of Indi­an Indus­try, is con­fi­dent India will even­tu­al­ly grant man­u­fac­tur­ers indem­ni­ty, “but we will do it at a leisure­ly pace,” he says. “I am unable to under­stand why there are these delays.””

    Some­one had to blink, and the vac­cine man­u­fac­tur­ers were open­ly express­ing con­fi­dence that it would be the Indi­an gov­ern­ment who did the blink­ing. Peo­ple are dying, after all, who can the gov­ern­ment jus­ti­fy any such delays? That was the nar­ra­tive we got from the indus­try. A nar­ra­tive that con­ve­nient­ly ignores the moral lia­bil­i­ty of the man­u­fac­tur­ers dur­ing an emer­gency. And a nar­ra­tive that con­ve­nient­ly ignores the gen­uine­ly nov­el nature of the vac­cine tech­nol­o­gy in the case of mRNA vac­cines. As we’ve sub­se­quent­ly seen, J&J seems to be mov­ing for­ward with its tra­di­tion­al vac­cine tech­nol­o­gy with­out the lia­bil­i­ty pro­tec­tions. And AstraZeneca must have come to some sort of arrange­ment. It’s Mod­er­na and Pfiz­er where we’re see­ing the intense indus­try resis­tance:

    ...
    V.K. Paul, mem­ber of gov­ern­ment think tank NITI Aayog, sug­gest­ed to reporters last Fri­day that such requests from for­eign com­pa­nies, specif­i­cal­ly Pfiz­er, are delay­ing pur­chase agree­ments for vac­cines that India des­per­ate­ly needs.

    “We are in nego­ti­a­tions with them. There is no deci­sion at the moment,” Paul said. “In prin­ci­pal, they expect [indem­ni­fi­ca­tion] to be giv­en. This has been the case all over the world.”

    Indem­ni­fy­ing vac­cine mak­ers from lia­bil­i­ty is an unusu­al move that has become pro for­ma dur­ing the pan­dem­ic. Such legal pro­tec­tion incen­tivizes man­u­fac­tur­ers to get vac­cines to mar­ket as fast as pos­si­ble and low­ers the price they charge for dos­es while shield­ing cor­po­ra­tions from hav­ing to pay dam­ages for vac­cine com­pli­ca­tions unless they result from will­ful neg­li­gence. It’s what man­u­fac­tur­ers have asked for, and the U.S., the U.K., and Euro­pean Union—eager to get life­sav­ing jabs into arms—have all grant­ed the demand.

    These gov­ern­ments and oth­ers have deter­mined that the issue is a no-brain­er, giv­en the sever­i­ty of the pan­dem­ic, so pub­lic health experts in India are puz­zled as to why Naren­dra Modi’s admin­is­tra­tion has yet to come to the same con­clu­sion.
    ...

    And note the par­tic­u­lar stick­ing point: con­cern over whether or not law­suits could be brought in Indi­an courts vs inter­na­tion­al courts. It’s the kind of stick­ing point that should be rais­ing ques­tions about the close­ness between inter­na­tion­al courts and multi­na­tion­al com­pa­nies:

    ...
    Indus­try exec­u­tives, who asked not to be named, say nego­ti­a­tions between the gov­ern­ment and vac­cine mak­ers are part­ly hung up on whether law­suits that do arise will be tried in Indi­an or inter­na­tion­al courts. Indi­an pol­i­cy­mak­ers are also con­cerned about appear­ing to grant the for­eign com­pa­nies too many con­ces­sions.

    Amir Ullah Khan, an econ­o­mist and for­mer pol­i­cy advis­er for the Bill and Melin­da Gates Foun­da­tion, said that it would be fair for India to hag­gle over indem­ni­ty in nor­mal cir­cum­stances, but not now.

    “Peo­ple are dying right now, and we don’t have space to bury them. In such a sit­u­a­tion, where there is such a sup­ply prob­lem, it makes no sense to insist on nego­ti­at­ing over indem­ni­ty,” he said.

    ...

    Khan sug­gests that the gov­ern­ment waive the legal lia­bil­i­ty for vac­cine mak­ers for a lim­it­ed peri­od, such as six months to one year. Dur­ing that time, the gov­ern­ment should pro­vide com­pen­sa­tion to any­one who expe­ri­ences unin­ten­tion­al adverse side effects. This, he notes, is the strat­e­gy employed by the U.S., which has some of the world’s tough­est prod­uct lia­bil­i­ty and safe­ty laws.
    ...

    Will India grant vac­cine man­u­fac­tur­ers a more lim­it­ed lia­bil­i­ty? Or per­haps adopt a strat­e­gy sim­i­lar to the US where the gov­ern­ment pro­vides com­pen­sa­tion in the event of an adverse side effect? We’ll see. Those con­fi­dent pre­dic­tions of a lia­bil­i­ty waiv­er still haven’t panned out and it sure sound­ed like the anony­mous Indi­an gov­ern­ment sources were adamant that no com­pa­ny would end up being grant­ed immu­ni­ty. It’s a sell­er’s mar­ket, after all. And a lot can change in a sit­u­a­tion like this. Espe­cial­ly the virus.

    Posted by Pterrafractyl | September 28, 2021, 2:05 pm
  5. If there’s been one area of unam­bigu­ous good news on the Coro­n­avirus front of late it’s been in the area of ther­a­peu­tics, with not just one but two new drugs on the cusp of emer­gency approval that appear to demon­strate sig­nif­i­cant effi­ca­cy against the virus. Mer­ck­’s new drug, mol­nupi­ravir, reduced hos­pi­tal­iza­tions by 50% and pre­vent­ed deaths entire­ly. Pfiz­er’s Paxlovid also pre­vent­ed deaths entire­ly and reduced hos­pi­tal­iza­tions by a stun­ning 89%. That’s a block­buster drug. The kind of block­buster drug the world has been clam­or­ing for ever since the out­break of the pan­dem­ic.

    And that brings us back to a ques­tion that has lin­gered over the glob­al response to the pan­dem­ic from the very begin­ning: to what extent is Big Phar­ma influ­enc­ing the glob­al quest for emer­gency ther­a­peu­tics? Are cheap­er options being passed over for expen­sive nov­el ther­a­peu­tics? It’s been a ques­tion raised repeat­ed­ly in the sto­ry of Gilead­’s Remde­sivir and the per­sis­tent push­ing of the drug by the US gov­ern­ment despite high­ly lim­it­ed pos­i­tive results. As we’ve seen, Gilead has already made bil­lions of dol­lars in sales to gov­ern­ments for a drug that costs over $3000/patient with ques­tion­able ben­e­fits.

    But then there’s the endur­ing mys­tery of the “Thai cock­tail”. Name­ly, the mys­tery of why those seem­ing­ly mirac­u­lous reports of incred­i­ble recov­er­ies for sev­er­ly ill patients giv­en large dos­es of oseltamivir (Tam­i­flu) com­bined with an anti-HIV pro­tease inhibitor mix of lopinavir and riton­avir were large­ly just ignored by the glob­al health com­mu­ni­ty. Why has there be almost no reports on any inves­ti­ga­tions into this treat­ment option? We’ve nev­er received an answer to this day.

    So when we learn that Pfiz­er’s not Paxlovid drug (actu­al­ly Paxlovid + riton­avir) works in a man­ner high­ly sim­i­lar to lopinavir, we again have to ask the ques­tion: what has there been basi­cal­ly no inter­est in using this exist­ing well-under­stood drug? Lopinavir is a pro­tease inhibitor tar­get­ing HIV. Plaxlovid tar­gets SARS-CoV­‑2. What are the dif­fer­ences in effi­ca­cy when tak­en ear­ly on in the infec­tion? You’d think this would have been asked by now. But as we’ll see, nope that basic ques­tion of how lopinavir works ear­ly on in a COVID infec­tion has yet to be asked. There was basi­cal­ly a sin­gle study on severe­ly ill patients that did­n’t pan out (note, this study did NOT include Tam­i­flu) and that’s been it. The world real­ly has con­tin­ued to ignore the “Thai Cock­tail” mys­tery even as we’re now learn­ing the new Pfiz­er’s block­buster drug is a “Thai cock­tail” bio­chem­i­cal-cousin. Why is that? It’s one of the many ques­tions still lin­ger­ing over this sto­ry:

    STAT News

    8 lin­ger­ing ques­tions about the new Covid pills from Mer­ck and Pfiz­er

    By STAT Staff
    Nov. 15, 2021

    The past two months have brought extreme­ly good news in the fight against Covid-19. Two dif­fer­ent oral treat­ments have proved effec­tive at both pre­vent­ing peo­ple new­ly diag­nosed with Covid-19 from enter­ing the hos­pi­tal and from dying.

    “We’re accel­er­at­ing our path out of this pan­dem­ic,” Pres­i­dent Biden said after data on the sec­ond Covid pill became avail­able. The wide avail­abil­i­ty of oral drugs could make Covid-19 less lethal, mak­ing it less risky for peo­ple to return to in-per­son work and to their nor­mal lives.

    The first results, from Mer­ck and Ridge­back Ther­a­peu­tics, were released in Octo­ber and will be con­sid­ered by an advi­so­ry pan­el to the Food and Drug Admin­is­tra­tion in Decem­ber. That could lead to an emer­gency use autho­riza­tion in the U.S. by the end of the year. That drug, mol­nupi­ravir, reduced hos­pi­tal­iza­tions by 50% and pre­vent­ed deaths entire­ly a large ran­dom­ized clin­i­cal tri­al when it was giv­en with­in five days of when symp­toms began. The pill is giv­en as a five-day course dur­ing which patients take a total of 40 pills.

    In Novem­ber, Pfiz­er announced that its Covid pill, Paxlovid, reduced hos­pi­tal­iza­tions by 89% and also pre­vent­ed deaths in its own large ran­dom­ized study. As with the Mer­ck drug, Paxlovid is giv­en as a five-day course. It must be giv­en with a sec­ond med­i­cine, a boost­er, called riton­avir, which is made by Abb­Vie, anoth­er large drug firm. The Pfiz­er reg­i­men involves tak­ing 30 pills over a five-day peri­od.

    Though the topline results are sim­i­lar, the med­i­cines could have dif­fer­ent risks and ben­e­fits. The com­pa­nies have only issued data in press releas­es, not sci­en­tif­ic arti­cles, and doc­tors need to know a lot more about both. Here is an overview of what we still don’t know about the Covid pills and when we might learn it.

    Which one works bet­ter?

    At the head­line lev­el, Pfizer’s pill reduced the risk of hos­pi­tal­iza­tion and death by 89%, while Mer­ck showed a reduc­tion of 50%. But nei­ther firm has dis­closed detailed data from its piv­otal stud­ies, and the tri­als were not iden­ti­cal­ly designed.

    The stud­ies enrolled sim­i­lar pop­u­la­tions — unvac­ci­nat­ed peo­ple with mild to mod­er­ate Covid-19 and at least one risk fac­tor for severe dis­ease — but they had slight­ly dif­fer­ent mea­sures of effi­ca­cy. Pfizer’s 89% fig­ure comes from patients who start­ed get­ting its pill, Paxlovid, with­in three days of their first Covid-19 symp­toms. Merck’s 50% applies to patients who began treat­ment with­in five days. In the Paxlovid study, patients who start­ed treat­ment with­in five days saw an 85% improve­ment in hos­pi­tal­iza­tion or death ver­sus place­bo. Mer­ck has not shared data on patients who got its drug with­in three days of symp­tom onset.

    What the stud­ies had in com­mon was 100% effi­ca­cy against death, regard­less of when patients start­ed treat­ment. Merck’s study count­ed eight deaths among patients on place­bo, and Pfizer’s observed 10.

    On the safe­ty side, the rate of side effects in both stud­ies was sim­i­lar between the treat­ment groups and place­bo groups. In each study, few­er patients in the treat­ment group left the study due to side effects com­pared to those in the place­bo group. Nei­ther com­pa­ny has dis­closed detailed data on the type and sever­i­ty of side effects.

    Each treat­ment is admin­is­tered twice a day for five total days, amount­ing to 10 dos­es in total. Pfizer’s drug is co-admin­is­tered with a com­mon antivi­ral called riton­avir.

    Would they work bet­ter in com­bi­na­tion? And would the com­pa­nies allow that to hap­pen?

    The­o­ret­i­cal­ly, yes. And it’s unlike­ly.

    Com­bi­na­tions of antivi­ral drugs are the stan­dard treat­ment for peo­ple with HIV because it reduces the risk of resis­tance caused by muta­tions in the virus. Since the Pfiz­er and Mer­ck pills attack SARS-CoV­‑2 dif­fer­ent­ly, using them in com­bi­na­tion might offer the same pro­tec­tive ben­e­fit for patients with Covid, said Céline Gounder, a physi­cian and infec­tious dis­ease expert at New York University’s Gross­man School of Med­i­cine.

    “The chal­lenge is that since these drugs are devel­oped by dif­fer­ent com­pa­nies, nei­ther Mer­ck nor Pfiz­er is incen­tivized to run a com­bi­na­tion ther­a­py tri­al,” said Gounder. “How­ev­er, the Nation­al Insti­tutes of Health or oth­ers could do that, and I think it’s real­ly impor­tant that they start to devel­op a com­bi­na­tion ther­a­py.”

    Nahid Bhadelia, the found­ing direc­tor of the Cen­ter for Emerg­ing Infec­tious Dis­eases Pol­i­cy and Research at Boston Uni­ver­si­ty, also sup­ports the idea of clin­i­cal tri­als to test com­bi­na­tion treat­ments. Com­bi­na­tion ther­a­py is stan­dard in HIV because patients are treat­ed chron­i­cal­ly — the virus is nev­er ful­ly cleared. SARS-CoV­‑2 is cleared in most peo­ple, but it’s also a faster-evolv­ing virus.

    “The patients that we see the most evo­lu­tion in are immuno­com­pro­mised who have pro­longed infec­tions with SARS-Cov­‑2,” she said.

    In an inter­view with STAT after Pfizer’s data were announced, the company’s head of research and devel­op­ment, Mikael Dol­sten, argued that Pfizer’s antivi­ral is potent enough to pro­tect against new strains and already has strong effi­ca­cy, and that com­bin­ing the drugs would only add the poten­tial for more side effects.

    Will the antivi­ral be avail­able for vac­ci­nat­ed patients with break­through infec­tions?

    Both com­pa­nies con­duct­ed their stud­ies entire­ly in patients who were at high risk of com­pli­ca­tions if they caught Covid and who also had not been vac­ci­nat­ed. That leads to a big ques­tion for pol­i­cy­mak­ers: Should those who have been vac­ci­nat­ed, but who devel­op a break­through infec­tion of SARS-CoV­‑2, be giv­en the pills?

    Right now that is a ques­tion with­out data. A third antivi­ral pill, from the biotech firm Atea and the large drug firm Roche, failed to prove it was effec­tive in its own study, and Wall Street ana­lysts sus­pect the rea­son is that the com­pa­nies includ­ed vac­ci­nat­ed patients in the research. For those who have received the vac­cine, hos­pi­tal­iza­tion and death are much less like­ly. This means that it is hard­er for a drug to show effi­ca­cy, because there are few­er infec­tions to pre­vent.

    So reg­u­la­tors and pub­lic health offi­cials will have to make a judge­ment on the risks and ben­e­fits of the Covid pills for peo­ple with break­through infec­tions — with­out direct data in these pop­u­la­tions.

    Pfiz­er is run­ning a clin­i­cal tri­al, with results due next year, that does include vac­ci­nat­ed patients, and the company’s exec­u­tives have expressed con­fi­dence based on the results so far that the treat­ment should work. Both Mer­ck and Pfiz­er are also run­ning stud­ies to show that the drugs can pre­vent peo­ple from devel­op­ing symp­toms if they take the antivi­rals after they are exposed to the virus.

    Do the drugs work the same way?

    No, not real­ly. While both drugs inter­fere with the process the coro­n­avirus uses to repro­duce itself, each drug inter­feres at a very dif­fer­ent point.

    Merck’s drug throws a wrench into the works quite ear­ly. After some­one takes mol­nupi­ravir, the drug is trans­formed into some­thing uncan­ni­ly sim­i­lar to one of RNA’s chem­i­cal build­ing blocks.

    The mod­i­fi­ca­tion is so sub­tle that not only will the coro­n­avirus use mol­nupi­ravir in place of oth­er build­ing blocks when it repli­cates itself, but coro­n­avirus­es’ unusu­al proof­read­ing mech­a­nism can’t even pick up on the imposter com­pound. Over time, the drug will encour­age the virus to intro­duce even more mis­takes.

    “Ulti­mate­ly, this leads to what’s known as error cat­a­stro­phe. It’s intro­duc­ing so many dif­fer­ent muta­tions that, even­tu­al­ly, noth­ing fur­ther can hap­pen,” said Kather­ine Seley-Radtke, a med­i­c­i­nal chemist at the Uni­ver­si­ty of Mary­land, Bal­ti­more Coun­ty. “You’ve got this com­plete­ly mutat­ed RNA.”

    Pfizer’s drug, Paxlovid, acts at a com­plete­ly dif­fer­ent point in the virus’ repro­duc­tive process.

    “It’s apples and oranges,” said Ronald Swanstrom, a bio­chem­istry pro­fes­sor at the Uni­ver­si­ty of North Car­oli­na School of Med­i­cine.

    Unlike mol­nupi­ravir, Paxlovid allows the strings of viral RNA to be assem­bled cor­rect­ly. It even allows those strings to be used to cre­ate viral pro­teins, which are ini­tial­ly pro­duced in one big chunk. Like a bolt of fab­ric before it’s cut to a cloth­ing pat­tern, this pro­tein needs to be chopped down to size before it can work.

    That cut­ting is what Paxlovid pro­hibits. The drug is designed to bind to a par­tic­u­lar­ly impor­tant point in an enzyme called a pro­tease which slices up pro­teins. With­out a func­tion­ing pro­tease, the virus can’t cre­ate func­tion­al copies; no work­ing virus, no prob­lem.

    Pro­tease inhibitors have been used for decades to cre­ate more than a dozen drugs for HIV and hepati­tis C; in some cas­es, they’ve also been used as can­cer drugs.

    “There’s a long his­to­ry of med­i­c­i­nal chem­istry tar­get­ing pro­teas­es,” said Bryan Dick­in­son, a chem­i­cal biol­o­gist at the Uni­ver­si­ty of Chica­go.

    Paxlovid is designed with a SARS-CoV-2-spe­cif­ic pro­tease in mind, so it works more specif­i­cal­ly on this coro­n­avirus than mol­nupi­ravir.

    But Paxlovid can’t work as well if it’s tak­en on its own. The body’s defense mech­a­nisms will get rid of any­thing that it doesn’t rec­og­nize — includ­ing drugs, which can be digest­ed by enzymes in a person’s liv­er. Anoth­er drug called riton­avir blocks the liv­er enzyme that would like­ly chew up Paxlovid, which gives the lat­ter drug the space it needs to work.

    How do they com­pare with mon­o­clon­al anti­bod­ies?

    Regen­eron Phar­ma­ceu­ti­cals and Eli Lil­ly have each won FDA autho­riza­tion for anti­body com­bi­na­tion ther­a­pies that keep recent­ly diag­nosed Covid-19 patients from hos­pi­tal­iza­tion and death. In a Phase 3 study enrolling recent­ly diag­nosed patients at high risk for severe dis­ease, Regeneron’s treat­ment reduced the risk of hos­pi­tal­iza­tion or death by 70% com­pared to place­bo. In a sim­i­lar study, Lilly’s ther­a­py showed an 87% reduc­tion.

    The biggest dif­fer­ence is one of con­ve­nience. The anti­body treat­ments are admin­is­tered intra­venous­ly in a one-time, rough­ly hour-long process (Regeneron’s is autho­rized for sub­cu­ta­neous injec­tion when an IV pro­ce­dure is not fea­si­ble). That could make the treat­ments from Pfiz­er and Mer­ck, tak­en oral­ly at home, prefer­able to patients unable to vis­it an infu­sion cen­ter.

    There’s also a dif­fer­ence in cost. Regen­eron and Lil­ly have signed deals with the fed­er­al gov­ern­ment to sell their treat­ments at about $1,250 per dose. Merck’s agree­ment with the U.S. works out to about $700 for a five-day course of mol­nupi­ravir. Pfiz­er is still nego­ti­at­ing con­tracts but is expect­ed to set a sim­i­lar price for Paxlovid.

    How easy will they be to get?

    A pill is a huge leap in terms of logis­ti­cal ease over infused ther­a­pies like mon­o­clon­al anti­bod­ies. For those treat­ments, not only did peo­ple have to make their way to clin­ics for their infu­sions, but hos­pi­tals and oth­er facil­i­ties had to set up places where peo­ple who were active­ly infec­tious could come get treat­ed with­out risk­ing oth­ers’ health. (The oth­er antivi­ral autho­rized to treat Covid-19, Gilead’s remde­sivir, is an infu­sion and approved only for hos­pi­tal­ized patients, but some data indi­cate that if it were to be giv­en to patients ear­li­er in their infec­tions, it could have a greater effect. If its approval ever cov­ered out­pa­tients, how­ev­er, it would still run into the same logis­ti­cal chal­lenges of an infused ther­a­py.)

    Still, the Covid pills come with a key chal­lenge of their own. They’re most effec­tive when giv­en ear­ly in the infec­tion, so peo­ple need to be able to get test­ed and get their pre­scrip­tion rapid­ly. And the U.S. test­ing land­scape is still lim­it­ed. PCR tests can take days to return a result, and though the Biden admin­is­tra­tion has upped its effort to expand the avail­abil­i­ty of at-home rapid tests, find­ing one at a store is still hit or miss — suc­cess feels like scor­ing this hol­i­day season’s hottest gift. Any delay in get­ting diag­nosed under­cuts the pow­er of these pills; even a day or two has real impli­ca­tions for a treat­ment meant to clear out an acute infec­tion like Covid-19.

    Will it affect a patient’s DNA?

    This is real­ly a ques­tion only for Merck’s mol­nupi­ravir, since it works by sneak­ing sub­tly cor­rupt­ed parts into the coronavirus’s RNA sequence.

    Once the virus has mutat­ed too much, it can’t work — mis­sion accom­plished. But there’s a the­o­ret­i­cal chance that mol­nupi­ravir could also influ­ence nor­mal human DNA when it repli­cates, too. If muta­tions hap­pen dur­ing that process, it could spell real trou­ble.

    Mer­ck did some tests dur­ing molnupiravir’s devel­op­ment to check this pos­si­bil­i­ty out. In two dif­fer­ent types of ani­mal stud­ies using high­er and longer dos­es than are giv­en to humans, Merck’s sci­en­tists didn’t see any increased risk of unwant­ed muta­tions.

    “We are very con­fi­dent in the safe­ty pro­file of mol­nupi­ravir based on our pre­clin­i­cal and clin­i­cal data,” exec­u­tive vice pres­i­dent Dean Li told investors in an Octo­ber con­fer­ence call, accord­ing to a tran­script in the finan­cial data­base Sen­tieo.

    But UNC’s Swanstrom isn’t com­plete­ly con­vinced that the tests Mer­ck did were sen­si­tive enough. In August, he and his col­leagues pub­lished a paper in the Jour­nal of Infec­tious Dis­eases show­ing that a key metabo­lite of mol­nupi­ravir could mutate DNA in ani­mal cells.

    Giv­en these results, Swanstrom said he would be par­tic­u­lar­ly inter­est­ed in see­ing a long-term study of peo­ple who took mol­nupi­ravir to con­tin­ue to mon­i­tor this poten­tial effect over the next 10 or 20 years.

    “This thing is going to go into thou­sands of peo­ple. And are we just going to ignore the fact that there’s this poten­tial risk?” he said. “The risk could be zero. It could be no worse than going to get a den­tal X‑ray — or it could do some­thing more. But unless we find out, you know, we’re going to learn this les­son the hard way, way lat­er than we should.”

    ...

    ————

    “8 lin­ger­ing ques­tions about the new Covid pills from Mer­ck and Pfiz­er” by STAT Staff; STAT News; 11/15/2021

    “Though the topline results are sim­i­lar, the med­i­cines could have dif­fer­ent risks and ben­e­fits. The com­pa­nies have only issued data in press releas­es, not sci­en­tif­ic arti­cles, and doc­tors need to know a lot more about both. Here is an overview of what we still don’t know about the Covid pills and when we might learn it.”

    We don’t know very much about these drugs, and what we do know has come in the form of cor­po­rate press releas­es. But those press releas­es were excit­ing enough that emer­gency autho­riza­tion is expect­ed soon­er rather than lat­er. There’s just one catch: both drugs are more effec­tive when giv­en ear­li­er in the infec­tion. In oth­er words, these two drugs do NOT appear to be the sil­ver-bul­let for severe infec­tions after they’ve devel­oped, but they may be sil­ver-bul­lets at pre­vent­ing those severe infec­tions from devel­op­ing in the first place. It real­ly is legit­i­mate­ly good news even if it’s not the best pos­si­ble news:

    ...
    The first results, from Mer­ck and Ridge­back Ther­a­peu­tics, were released in Octo­ber and will be con­sid­ered by an advi­so­ry pan­el to the Food and Drug Admin­is­tra­tion in Decem­ber. That could lead to an emer­gency use autho­riza­tion in the U.S. by the end of the year. That drug, mol­nupi­ravir, reduced hos­pi­tal­iza­tions by 50% and pre­vent­ed deaths entire­ly a large ran­dom­ized clin­i­cal tri­al when it was giv­en with­in five days of when symp­toms began. The pill is giv­en as a five-day course dur­ing which patients take a total of 40 pills.

    In Novem­ber, Pfiz­er announced that its Covid pill, Paxlovid, reduced hos­pi­tal­iza­tions by 89% and also pre­vent­ed deaths in its own large ran­dom­ized study. As with the Mer­ck drug, Paxlovid is giv­en as a five-day course. It must be giv­en with a sec­ond med­i­cine, a boost­er, called riton­avir, which is made by Abb­Vie, anoth­er large drug firm. The Pfiz­er reg­i­men involves tak­ing 30 pills over a five-day peri­od.

    ...

    Which one works bet­ter?

    At the head­line lev­el, Pfizer’s pill reduced the risk of hos­pi­tal­iza­tion and death by 89%, while Mer­ck showed a reduc­tion of 50%. But nei­ther firm has dis­closed detailed data from its piv­otal stud­ies, and the tri­als were not iden­ti­cal­ly designed.

    ...

    Still, the Covid pills come with a key chal­lenge of their own. They’re most effec­tive when giv­en ear­ly in the infec­tion, so peo­ple need to be able to get test­ed and get their pre­scrip­tion rapid­ly. And the U.S. test­ing land­scape is still lim­it­ed. PCR tests can take days to return a result, and though the Biden admin­is­tra­tion has upped its effort to expand the avail­abil­i­ty of at-home rapid tests, find­ing one at a store is still hit or miss — suc­cess feels like scor­ing this hol­i­day season’s hottest gift. Any delay in get­ting diag­nosed under­cuts the pow­er of these pills; even a day or two has real impli­ca­tions for a treat­ment meant to clear out an acute infec­tion like Covid-19.
    ...

    It’s worth not­ing that, as these drugs haven’t been seen as effec­tive for already severe­ly ill patients, they won’t be replac­ing Gilead­’s Remde­sivir, which is still used for severe­ly ill patients despite the ques­tion­able results. So it’s worth com­par­ing the expect­ed costs of these two new drugs to Remde­sivir’s $3000+ cost: It’s look­ing like around $700 both both drugs for a five day course. So these aren’t incred­i­bly afford­able drugs, but still a frac­tion of the cost of Remde­sivir:

    ...
    There’s also a dif­fer­ence in cost. Regen­eron and Lil­ly have signed deals with the fed­er­al gov­ern­ment to sell their treat­ments at about $1,250 per dose. Merck’s agree­ment with the U.S. works out to about $700 for a five-day course of mol­nupi­ravir. Pfiz­er is still nego­ti­at­ing con­tracts but is expect­ed to set a sim­i­lar price for Paxlovid.
    ...

    And what about the pos­si­bil­i­ty of com­bin­ing these two drugs? Well, that’s very pos­si­bly even more effec­tive, but we’ll prob­a­bly nev­er find out. Why? Because Pfiz­er and Mer­ck don’t have an incen­tive to do so. Keep in mind that this kind of behav­ior only encour­ages the devel­op­ment of drug-resis­tant strains. That’s one of the big advan­tages of mul­ti-drug ther­a­pies. But nope, max­i­mum prof­its are the pri­ma­ry motive here:

    ...
    Would they work bet­ter in com­bi­na­tion? And would the com­pa­nies allow that to hap­pen?

    The­o­ret­i­cal­ly, yes. And it’s unlike­ly.

    Com­bi­na­tions of antivi­ral drugs are the stan­dard treat­ment for peo­ple with HIV because it reduces the risk of resis­tance caused by muta­tions in the virus. Since the Pfiz­er and Mer­ck pills attack SARS-CoV­‑2 dif­fer­ent­ly, using them in com­bi­na­tion might offer the same pro­tec­tive ben­e­fit for patients with Covid, said Céline Gounder, a physi­cian and infec­tious dis­ease expert at New York University’s Gross­man School of Med­i­cine.

    “The chal­lenge is that since these drugs are devel­oped by dif­fer­ent com­pa­nies, nei­ther Mer­ck nor Pfiz­er is incen­tivized to run a com­bi­na­tion ther­a­py tri­al,” said Gounder. “How­ev­er, the Nation­al Insti­tutes of Health or oth­ers could do that, and I think it’s real­ly impor­tant that they start to devel­op a com­bi­na­tion ther­a­py.”

    ...

    In an inter­view with STAT after Pfizer’s data were announced, the company’s head of research and devel­op­ment, Mikael Dol­sten, argued that Pfizer’s antivi­ral is potent enough to pro­tect against new strains and already has strong effi­ca­cy, and that com­bin­ing the drugs would only add the poten­tial for more side effects.
    ...

    So how con­fi­dent should we be in the safe­ty of these drugs giv­en that they’re new and bound for emer­gency approval? Well, on the one hand, we are told that the side effects were no worse than for the place­bo group in their tri­als. That’s what that the com­pa­nies are telling us. But when we look at the actu­al mech­a­nism for how Mer­ck­’s molupi­ravir works, it’s hard­er to take those assur­ances at face val­ue. Because it turns out monupi­ravir works by induc­ing muta­tions. Yes, ide­al­ly those muta­tions will only be impact­ing virus­es attempt­ing to repli­cate. But there’s no guar­an­tee the drug isn’t induc­ing muta­tions in cel­lu­lar DNA too, some­thing that could take 10 to 20 years to real­ly test. Long-term tests that obvi­ous­ly haven’t hap­pened yet. But Mer­ck­’s con­fi­dent assess­ment o the long-term safe­ty of the drug is more or less being accept­ed. It’s good to be a phar­ma giant:

    ...
    On the safe­ty side, the rate of side effects in both stud­ies was sim­i­lar between the treat­ment groups and place­bo groups. In each study, few­er patients in the treat­ment group left the study due to side effects com­pared to those in the place­bo group. Nei­ther com­pa­ny has dis­closed detailed data on the type and sever­i­ty of side effects.

    ...

    Will it affect a patient’s DNA?

    This is real­ly a ques­tion only for Merck’s mol­nupi­ravir, since it works by sneak­ing sub­tly cor­rupt­ed parts into the coronavirus’s RNA sequence.

    Once the virus has mutat­ed too much, it can’t work — mis­sion accom­plished. But there’s a the­o­ret­i­cal chance that mol­nupi­ravir could also influ­ence nor­mal human DNA when it repli­cates, too. If muta­tions hap­pen dur­ing that process, it could spell real trou­ble.

    Mer­ck did some tests dur­ing molnupiravir’s devel­op­ment to check this pos­si­bil­i­ty out. In two dif­fer­ent types of ani­mal stud­ies using high­er and longer dos­es than are giv­en to humans, Merck’s sci­en­tists didn’t see any increased risk of unwant­ed muta­tions.

    ...

    But UNC’s Swanstrom isn’t com­plete­ly con­vinced that the tests Mer­ck did were sen­si­tive enough. In August, he and his col­leagues pub­lished a paper in the Jour­nal of Infec­tious Dis­eases show­ing that a key metabo­lite of mol­nupi­ravir could mutate DNA in ani­mal cells.

    Giv­en these results, Swanstrom said he would be par­tic­u­lar­ly inter­est­ed in see­ing a long-term study of peo­ple who took mol­nupi­ravir to con­tin­ue to mon­i­tor this poten­tial effect over the next 10 or 20 years.

    “This thing is going to go into thou­sands of peo­ple. And are we just going to ignore the fact that there’s this poten­tial risk?” he said. “The risk could be zero. It could be no worse than going to get a den­tal X‑ray — or it could do some­thing more. But unless we find out, you know, we’re going to learn this les­son the hard way, way lat­er than we should.”
    ...

    But it’s the mech­a­nism for Paxlovid that is of par­tic­u­lar inter­est here in rela­tion to the ques­tion of whether or not oth­er cheap­er and more read­i­ly avail­able treat­ments were effec­tive­ly ignored in favor of nov­el pro­pri­etary (and there­fore more exten­sive, but less safe­ty-test­ed) alter­na­tives: It turns out Paxlovid is a pro­tease inhibitor. Specif­i­cal­ly, a pro­tease inhibitor designed with a SARS-CoV­‑2 spe­cif­ic pro­tease in mind. So, in the­o­ry, this could be a high­ly effec­tive treat­ment and it turns out that, yes, it is a high­ly effec­tive treat­ment if giv­en with­in the first few days of an infec­tion:

    ...
    Unlike mol­nupi­ravir, Paxlovid allows the strings of viral RNA to be assem­bled cor­rect­ly. It even allows those strings to be used to cre­ate viral pro­teins, which are ini­tial­ly pro­duced in one big chunk. Like a bolt of fab­ric before it’s cut to a cloth­ing pat­tern, this pro­tein needs to be chopped down to size before it can work.

    That cut­ting is what Paxlovid pro­hibits. The drug is designed to bind to a par­tic­u­lar­ly impor­tant point in an enzyme called a pro­tease which slices up pro­teins. With­out a func­tion­ing pro­tease, the virus can’t cre­ate func­tion­al copies; no work­ing virus, no prob­lem.

    Pro­tease inhibitors have been used for decades to cre­ate more than a dozen drugs for HIV and hepati­tis C; in some cas­es, they’ve also been used as can­cer drugs.

    “There’s a long his­to­ry of med­i­c­i­nal chem­istry tar­get­ing pro­teas­es,” said Bryan Dick­in­son, a chem­i­cal biol­o­gist at the Uni­ver­si­ty of Chica­go.

    Paxlovid is designed with a SARS-CoV-2-spe­cif­ic pro­tease in mind, so it works more specif­i­cal­ly on this coro­n­avirus than mol­nupi­ravir.

    But Paxlovid can’t work as well if it’s tak­en on its own. The body’s defense mech­a­nisms will get rid of any­thing that it doesn’t rec­og­nize — includ­ing drugs, which can be digest­ed by enzymes in a person’s liv­er. Anoth­er drug called riton­avir blocks the liv­er enzyme that would like­ly chew up Paxlovid, which gives the lat­ter drug the space it needs to work.
    ...

    And that brings to back to the mys­tery of the “Thai cock­tail” ther­a­py from ear­ly on in the pan­dem­ic. Recall the reports of sick elder­ly patients show­ing a remark­able recov­ery when giv­en the “thai cock­tail” mix of oseltamivir (Tam­i­flu) com­bined with an anti-HIV pro­tease inhibitor mix of lopinavir and riton­avir. Part of the mys­tery was whether or not this cock­tail real­ly did have the abil­i­ty to clear the infec­tion as these mirac­u­lous-sound­ing reports sug­gest­ed. But there was a sec­ond, much larg­er mys­tery: why is the the glob­al health com­mu­ni­ty show­ing so lit­tle inter­est in these reports, but a near uni­form focus on Remde­sivir as the ther­a­peu­tic almost all of the offi­cial hopes were being placed on. This was the state of affairs back in Feb­ru­ary of 2020, when the world bare­ly seemed to know what it was deal­ing with and before remde­sivir proved to be a dis­ap­point­ment. It implic­it­ly raised a pair of ques­tions at the time:

    1. Would the “Thai cock­tail” approach ever be mean­ing­ful­ly test­ed?

    2. Would any of the even­tu­al­ly dis­cov­ered effec­tive ther­a­peu­tics work using a sim­i­lar drug mech­a­nism?

    So the ques­tion of just how big of an oppor­tu­ni­ty did the world pass up when it more or less ignored the “Thai cock­tail” reports in favor of un unproven Remde­sivir remains an open ques­tion to this day. For exam­ple, take a look at the fol­low NY Times piece that is con­stant­ly track­ing the range of COVID ther­a­pies and what the over­all sci­en­tif­ic estab­lish­ment has assessed on their effec­tive­ness. It’s a con­stant­ly update piece that’s pre­sum­ably giv­ing us a rea­son­ably up-to-date sum­ma­ry of what stud­ies have actu­al­ly been con­duct­ed on these ther­a­pies. And as we can see, while the full “Thai Cock­tail” does­n’t appear to have been test­ed, the lopinavir + riton­avir com­bi­na­tion alone has indeed been test­ed. With not very promis­ing results. But as we’ll also see, these not very promis­ing results were found in stud­ies con­duct­ed on sev­er­ly ill patients and the stud­ies them­selves stat­ed they could not rule out the pos­si­bil­i­ty of the drug com­bo work­ing on patients not yet sick enough to be hos­pi­tal­ized or new­ly exposed to the virus. In oth­er words, the ques­tion of whether or not a lopinavir + riton­avir com­bo could work in a man­ner sim­i­lar to the Paxlovid + riton­avir com­bo has nev­er actu­al­ly been asked.

    Paxlovid is turn­ing out to be wild­ly effec­tive. And yes, it was designed specif­i­cal­ly for SAR-CoV­‑2, which pre­sum­ably explains in part its effec­tive­ness. But con­sid­er­ing those ear­ly mir­a­cle reports on the “Thai cock­tail”, it seems rather absurd that this obvi­ous pos­si­bil­i­ty of lopinavir + riton­avir ear­ly in the infec­tion was nev­er actu­al­ly tak­en to tri­al. And at this point it remains unclear if that tri­al will indeed take place:

    The New York Times

    Coro­n­avirus Drug and Treat­ment Track­er

    By Carl Zim­mer, Kather­ine J. Wu and Jonathan Corum
    Updat­ed Nov. 16, 2021

    When the Covid-19 pan­dem­ic emerged in ear­ly 2020, bio­med­ical researchers scram­bled to find treat­ments and drugs that could save the lives of peo­ple infect­ed with the coro­n­avirus. Some of these inves­ti­ga­tions have been clear suc­cess­es, lead­ing to mil­lions of saved lives. Some are still ongo­ing, hav­ing yet to yield strong evi­dence of effec­tive­ness. Oth­er drugs and treat­ments have failed the test of sci­ence and have been aban­doned. Mean­while, fake claims and pseu­do­science have pro­mot­ed bogus cures.

    Below is an updat­ed list of 33 of the most talked-about drugs and treat­ments for Covid-19. For each entry, we review the evi­dence for or against its use, based on pub­lished sci­en­tif­ic find­ings and con­sul­ta­tion with experts.

    We are fol­low­ing 33 coro­n­avirus treat­ments for effec­tive­ness and safe­ty:

    This list pro­vides a snap­shot of the lat­est research on the coro­n­avirus, but does not con­sti­tute med­ical endorse­ments. Always con­sult your doc­tor about treat­ments for Covid-19. You can also con­sult the Covid-19 Treat­ment Guide­lines from the Nation­al Insti­tutes of Health and the World Health Organization’s “liv­ing guide­line” for Covid-19 drugs. Both of these doc­u­ments are reg­u­lar­ly updat­ed based on new research.

    For the cur­rent sta­tus of vac­cine devel­op­ment, see our Coro­n­avirus Vac­cine Track­er.

    ...

    Antivi­rals

    Antivi­rals can stop virus­es such as H.I.V. and hepati­tis C from hijack­ing our cells. Sci­en­tists are search­ing for antivi­rals that work against the new coro­n­avirus. One is now approved for Covid-19, and two oth­ers have shown promis­ing results in Phase 3 clin­i­cal tri­als.

    Remde­sivir

    * WIDELY USED
    * F.D.A. APPROVED
    * EVIDENCE IN CELLS, ANIMALS AND HUMANS

    Remde­sivir, made by Gilead Sci­ences under the brand Vek­lury, is the first — and so far only — drug to gain full approval from the F.D.A. for the treat­ment of Covid-19. Gilead suc­ceed­ed in launch­ing clin­i­cal tri­als ear­ly in the pan­dem­ic, and their results were encour­ag­ing. With few oth­er options to choose from, remde­sivir went into wide­spread use after its approval in Octo­ber 2020. Since then, how­ev­er, sci­en­tists have raised ques­tions about how firm the results of these tri­als were, and about how wide­ly remde­sivir should be pre­scribed. And in the time since remdesivir’s approval, oth­er drugs, such as mon­o­clon­al anti­bod­ies and new antivi­rals, have emerged with the poten­tial to be eas­i­er to give to patients and more effec­tive against Covid-19.

    Remde­sivir was orig­i­nal­ly test­ed as an antivi­ral against Ebo­la and Hepati­tis C. The mol­e­c­u­lar stops virus­es by insert­ing itself into their genes, cre­at­ing muta­tions that leave the virus­es unable to repli­cate. While remedesivir worked against virus­es in dish­es of cells, clin­i­cal tri­als deliv­ered lack­lus­ter results.

    Nev­er­the­less, Gilead decid­ed to try it out on coro­n­avirus­es when the Covid-19 pan­dem­ic emerged. After promis­ing results on cells, a large clin­i­cal tri­al was then launched, which found that the drug reduced the recov­ery time of peo­ple hos­pi­tal­ized with Covid-19 from 15 to 11 days.

    The F.D.A. respond­ed quick­ly to this data in May 2020 by issu­ing an emer­gency autho­riza­tion for remdesivir’s use in crit­i­cal­ly ill patients who need sup­ple­men­tal oxy­gen. In August, they expand­ed that approval after anoth­er study found that patients with less severe forms of Covid-19 seemed to ben­e­fit mod­est­ly from a five-day treat­ment course of remde­sivir. The revised approval per­mit­ted the use of the drug on all patients hos­pi­tal­ized with Covid-19, regard­less of how severe their dis­ease is. The move was crit­i­cized by some experts who said the F.D.A. had expand­ed remdesivir’s use with­out enough strong evi­dence to back the change.

    When for­mer Pres­i­dent Trump devel­oped Covid-19 in Octo­ber he received a five-day course of remde­sivir. The F.D.A. gave full approval to the drug soon after­wards, on Oct. 22, for use in patients 12 years and old­er. The reg­u­la­to­ry suc­cess was immense­ly lucra­tive for Gilead, which made $2.8 bil­lion on remde­sivir in 2020 alone.

    Yet many experts grew skep­ti­cal of remdesivir’s ben­e­fits. For one thing, the ini­tial tri­als failed to show sta­tis­ti­cal­ly sig­nif­i­cant evi­dence that remde­sivir actu­al­ly pre­vents deaths from Covid-19. The World Health Orga­ni­za­tion fueled more skep­ti­cism when they pub­lished a glob­al ran­dom­ized tri­al that found remde­sivir had lit­tle or no effect on the length of hos­pi­tal­iza­tion, the risk of going onto a ven­ti­la­tor, or over­all mor­tal­i­ty.

    In the wake of these results, the WHO issued guide­lines rec­om­mend­ing against using remde­sivir. The Nation­al Insti­tutes of Health only sug­gests using remde­sivir with patients who are hos­pi­tal­ized and requir­ing oxy­gen. They rec­om­mend against start­ing severe­ly ill patients on a course of the drug.
    Updat­ed Oct. 26

    Mol­nupi­ravir

    * PROMISING EVIDENCE
    * EVIDENCE IN CELLS, ANIMALS AND HUMANS
    * EMERGENCY USE AUTHORIZATION

    Mol­nupi­ravir (also known as MK-4482 and pre­vi­ous­ly as EIDD-2801) is an antivi­ral orig­i­nal­ly designed to fight the flu. Ridge­back Bio­ther­a­peu­tics and Mer­ck are col­lab­o­rat­ing to devel­op it as a treat­ment for Covid-19. Unlike remde­sivir, which has to be giv­en intra­venous­ly, mol­nupi­ravir can be swal­lowed as a pill. That could make it eas­i­er to use as a means to stop the dis­ease ear­ly in its pro­gres­sion.

    In ear­ly stud­ies in human lung cells and on ani­mals mol­nupi­ravir pro­duced promis­ing results against the new coro­n­avirus. In Octo­ber 2020, the com­pa­nies start­ed two Phase 2/3 tri­als to see if it could reduce mor­tal­i­ty and speed recov­ery in patients.

    In April, Mer­ck and Ridge­back announced that it would end their tri­al of mol­nupi­ravir in hos­pi­tal­ized patients because the data showed it was unlike­ly to help. But in Octo­ber 2021, they announced that a tri­al on high-risk out­pa­tients had deliv­ered promis­ing results. Mol­nupi­ravir reduced the risk of hos­pi­tal­iza­tion and death by half. A week after unveil­ing these results, Mer­ck and Ridge­back sub­mit­ted an appli­ca­tion for emer­gency autho­riza­tion for the pill. The F.D.A. will host a pub­lic meet­ing to review their appli­ca­tion at the end of Novem­ber. The fed­er­al gov­ern­ment has now com­mit­ted to pur­chase a total of approx­i­mate­ly 3.1 mil­lion cours­es of mol­nupi­ravir, for approx­i­mate­ly $2.2 bil­lion.

    On Nov. 4, the Unit­ed King­dom became the first coun­try to grant emer­gency autho­riza­tion for the use of mol­nupi­ravir. Adults with mild-to-mod­er­ate Covid-19 that have at least one risk fac­tor for devel­op­ing severe ill­ness are now eli­gi­ble to receive the drug.

    Updat­ed Nov. 10

    Paxlovid (also known as PF-07321332)

    * PROMISING EVIDENCE
    * EVIDENCE IN CELLS, ANIMALS AND HUMANS

    Pfiz­er devel­oped a drug in the ear­ly 2000s as a poten­tial treat­ment for SARS, which is caused by the coro­n­avirus SARS-CoV. At the start of the Covid-19 pan­dem­ic, they retooled it to work against SARS-CoV­‑2, which has a sim­i­lar biol­o­gy. In addi­tion, they mod­i­fied the drug, orig­i­nal­ly designed to be giv­en intra­venous­ly, as a pill. When mice were giv­en the drug oral­ly, it reached high enough lev­els in the body to block the coro­n­avirus. Paxlovid, as the drug is now known, went into clin­i­cal tri­als in March 2021, fol­lowed by a larg­er Phase 3 tri­al in July.

    In Novem­ber, Pfiz­er announced that Paxlovid cut the risk of hos­pi­tal­iza­tion or death by 89 per­cent when giv­en with­in three days after the start of symp­toms. They have yet to make the detailed results of the tri­al pub­lic. On Nov. 16, Pfiz­er announced it had applied to the Food and Drug Admin­is­tra­tion to autho­rize Paxlovid for emer­gency use. If the F.D.A. autho­rized the drug, it could become avail­able to high-risk patients with­in a few months.

    In Sep­tem­ber, false claims cir­cu­lat­ed on social media that peo­ple who took the Pfiz­er-BioN­Tech vac­cine would have to take Pfizer’s antivi­ral drug twice a day. The vac­cine is high­ly effec­tive at pre­vent­ing infec­tions and severe dis­ease. Paxlovid is an entire­ly sep­a­rate drug, which blocks the virus from repli­cat­ing inside cells.

    Updat­ed Nov. 16

    Favipi­ravir (also known as Avi­gan)

    * TENTATIVE OR MIXED EVIDENCE
    * EVIDENCE IN CELLS, ANIMALS AND HUMANS

    Orig­i­nal­ly designed to beat back influen­za, favipi­ravir blocks a virus’s abil­i­ty to copy its genet­ic mate­r­i­al. Some small stud­ies sug­gest­ed that the drug might clear the coro­n­avirus from the air­way, lead­ing to a num­ber of coun­tries, includ­ing Japan, Kenya, Rus­sia, Sau­di Ara­bia, and Thai­land, to approve favipi­ravir for Covid-19. But these deci­sions may have been too hasty; the evi­dence from clin­i­cal tri­als has proven dis­ap­point­ing. The qual­i­ty of many of the stud­ies has been very low, either because they only recruit­ed small num­bers of patients or were not ran­dom­ized enough. The Cana­di­an com­pa­ny Appili Ther­a­peu­tics ran a Phase 3 tri­al in which they gave the drug to 1,231 new­ly diag­nosed vol­un­teers. In Novem­ber 2021 the com­pa­ny announced that favipi­ravir did not speed up recov­ery from Covid-19.

    ...

    Lopinavir and riton­avir

    * NOT PROMISING
    * EVIDENCE IN CELLS AND HUMANS

    Twen­ty years ago, the F.D.A. approved this com­bi­na­tion of drugs to treat H.I.V. Researchers found that they also stop the coro­n­avirus from repli­cat­ing in cul­tures of cells. But sub­se­quent clin­i­cal tri­als in patients proved dis­ap­point­ing. In ear­ly July, the World Health Orga­ni­za­tion sus­pend­ed tri­als on patients hos­pi­tal­ized for Covid-19. They didn’t rule out stud­ies to see if the drugs could help patients not sick enough to be hos­pi­tal­ized, or to pre­vent peo­ple exposed to the new coro­n­avirus from falling ill. The N.I.H. Covid treat­ment guide­lines rec­om­mend against using lopinavir and riton­avir in both hos­pi­tal­ized and non­hos­pi­tal­ized patients. The drug could also still have a role to play in cer­tain com­bi­na­tion treat­ments.

    Updat­ed March 1

    ...

    ————

    “Coro­n­avirus Drug and Treat­ment Track­er” by Carl Zim­mer, Kather­ine J. Wu and Jonathan Corum; The New York Times; 11/16/2021

    “Twen­ty years ago, the F.D.A. approved this com­bi­na­tion of drugs to treat H.I.V. Researchers found that they also stop the coro­n­avirus from repli­cat­ing in cul­tures of cells. But sub­se­quent clin­i­cal tri­als in patients proved dis­ap­point­ing. In ear­ly July, the World Health Orga­ni­za­tion sus­pend­ed tri­als on patients hos­pi­tal­ized for Covid-19. They didn’t rule out stud­ies to see if the drugs could help patients not sick enough to be hos­pi­tal­ized, or to pre­vent peo­ple exposed to the new coro­n­avirus from falling ill. The N.I.H. Covid treat­ment guide­lines rec­om­mend against using lopinavir and riton­avir in both hos­pi­tal­ized and non­hos­pi­tal­ized patients. The drug could also still have a role to play in cer­tain com­bi­na­tion treat­ments.”

    What will those even­tu­al stud­ies on mod­er­ate­ly ill patients reveal? Or will those stud­ies now nev­er take place as a result of the dis­cov­ery of Paxlovid? We’ll even­tu­al­ly, belat­ed, find out. But just to under­score how it’s open­ly rec­og­nized that the lopinavir + riton­avir treat­ment has poten­tial yet to be explored, here’s an excerpt of a review arti­cle on exact­ly that top­ic from Feb­ru­ary 2021. The con­clu­sion of the review­ers? That while no clear evi­dence of the drug com­bo’s effec­tive­ness against SARS-CoV­‑2 exists yet, it deserves fur­ther eval­u­a­tion in par­tic­u­lar dur­ing the ear­ly stages of the dis­ease:

    Bio­med­ical Jour­nal
    Vol­ume 44, Issue 1, Feb­ru­ary 2021, Pages 43–53
    Review Arti­cle

    Lopinavir/ritonavir: Repur­pos­ing an old drug for HIV infec­tion in COVID-19 treat­ment

    Pao­la Magro, Isabel­la Zanel­la, Mar­ta Pescaro­lo, Francesco Castel­li, Euge­nia Quiros-Roldan

    Received 28 Sep­tem­ber 2020, Accept­ed 5 Novem­ber 2020, Avail­able online 10 Novem­ber 2020.
    https://doi.org/10.1016/j.bj.2020.11.005

    Abstract

    Cur­rent­ly, there is no spe­cif­ic antivi­ral treat­ment for COVID-19. How­ev­er, drugs pre­vi­ous­ly devel­oped to treat oth­er viral infec­tions are being test­ed to ver­i­fy if they might also be effec­tive against SARS-CoV­‑2, the virus that caus­es COVID-19. Twen­ty years ago, the F.D.A. approved Lopinavir/ritonavir (LPV/r) to treat HIV infec­tion. LPV and riton­avir were ini­tial­ly pur­posed to inhib­it 3‑chy­motrypsin-like pro­tease (3CLpro) of SARS-CoV and MERS-CoV and pre­lim­i­nary promis­ing data on its effi­ca­cy for treat­ing peo­ple infect­ed with those virus­es were avail­able. There­fore, due to the high genet­ic sim­i­lar­i­ties among those virus­es and SARS-CoV­‑2, ear­ly dur­ing COVID-19 pan­dem­ic LPV/r was also pro­posed as one emer­gency treat­ment. We reviewed data from the lit­er­a­ture about LPV/r treat­ment and SARS-CoV­‑2 infec­tion, main­ly focused on the effi­ca­cy and safe­ty of this drugs for COVID-19 treat­ment. We can con­clude that although up to date no clear ben­e­fit has been observed with the LPV/r treat­ment beyond stan­dard care, its effi­ca­cy against SARS-COV‑2 infec­tion deserves fur­ther eval­u­a­tions, par­tic­u­lar­ly dur­ing the very ear­ly phase of the dis­ease.

    ...

    Con­clu­sions

    As we have described above, there are no con­clu­sive results about LPV/r effi­ca­cy for treat­ing COVID-19 and its use is cur­rent­ly only per­mit­ted in the course of clin­i­cal exper­i­men­ta­tion. On Sep­tem­ber 1st 2020, 67 stud­ies reg­is­tered in the data­base of the U.S Nation­al Library of Med­i­cine, cur­rent­ly ongo­ing, include LPV/r for the treat­ment of COVID-19 (https://clinicaltrials.gov).

    Although up to date no clear ben­e­fit was observed with the LPV/r treat­ment beyond stan­dard care, its effi­ca­cy against SARS-COV‑2 infec­tion is still under eval­u­a­tion.

    In con­sid­er­a­tion of the actu­al bipha­sic mod­els of the patho­gen­e­sis of COVID-19, which hypoth­e­size a viro­log­ic-dri­ven dam­age in the first days of dis­ease and a sec­ond phase of inflam­ma­tion-dri­ven pathol­o­gy [80], stud­ies of LPV/r effi­ca­cy focused on patients dur­ing very ear­ly phase of dis­ease may help to dis­cern the use­ful­ness of this drug in the actu­al emer­gency con­text.

    Up to date nei­ther of “old” (and prob­a­bly nei­ther of any “new”) drugs are cer­tain­ly able to cure “all” patients with COVID-19 by revers­ing the dis­ease or halt­ing its wors­en­ing. How­ev­er, more com­plex ther­a­peu­tic approach­es based on using com­bi­na­tions of drugs that have dif­fer­ent tar­gets and thus affect dif­fer­ent path­ways and mech­a­nisms com­pro­mised by the dis­ease might sig­nif­i­cant­ly improve patients’ con­di­tions and slow down the dis­ease pro­gres­sion.

    ...

    ————-

    “Lopinavir/ritonavir: Repur­pos­ing an old drug for HIV infec­tion in COVID-19 treat­ment” by Pao­la Magro, Isabel­la Zanel­la, Mar­ta Pescaro­lo, Francesco Castel­li, Euge­nia Quiros-Roldan; Bio­med­ical Jour­nal; Vol­ume 44, Issue 1, Feb­ru­ary 2021, Pages 43–53

    “In con­sid­er­a­tion of the actu­al bipha­sic mod­els of the patho­gen­e­sis of COVID-19, which hypoth­e­size a viro­log­ic-dri­ven dam­age in the first days of dis­ease and a sec­ond phase of inflam­ma­tion-dri­ven pathol­o­gy [80], stud­ies of LPV/r effi­ca­cy focused on patients dur­ing very ear­ly phase of dis­ease may help to dis­cern the use­ful­ness of this drug in the actu­al emer­gency con­text.”

    First we had the mir­a­cle reports of the “Thai cock­tail” in Feb­ru­ary of 2020, fol­lowed by noth­ing oth­er than a long-term study on lopinavir + riton­avir alone on severe­ly ill patients and end­less rec­om­men­da­tions that it be tried out on the new­ly infect­ed. And then, a year and a half after those “Thai cock­tail” reports, we learn that the bio­chem­i­cal­ly-relat­ed Paxlovid — which oper­ates on the same under­ly­ing prin­ci­ple of lopinavir, but is more specif­i­cal­ly tar­get­ed to SARS-CoV­‑2 — has indeed been run through those exact same types of tri­als and found to be wild­ly effec­tive. So what’s the actu­al sto­ry here? Did the globe pass over what could have been a wild­ly effec­tive treat­ment? Again, we don’t know but those tri­als nev­er actu­al­ly hap­pened, still to this day.

    But on the plus side, at least if Mer­ck­’s mol­nupi­ravir ends up induc­ing all sorts of dan­ger­ous muta­tions, the con­se­quences prob­a­bly won’t be felt for anoth­er cou­ple of decades.

    Posted by Pterrafractyl | November 24, 2021, 6:33 pm
  6. Here’s a pair of updates on the hunt for effec­tive covid ther­a­peu­tics. First, it turns out Mer­ck­’s new ‘block­buster’ drug, mol­nupi­ravir, does­n’t have quite the effi­ca­cy against pro­tect­ing against death as first adver­tised. Instead of the ini­tial­ly report­ed 50 per­cent reduc­tion in hos­pi­tal­iza­tions and deaths, Mer­ck pro­vid­ed updat­ed infor­ma­tion on its clin­i­cal tri­al, reveal­ing just a 30 per­cent reduc­tion. It’s a pret­ty big drop, espe­cial­ly in com­par­i­son to Pfiz­er’s new Paxlovid drug that can appar­ent­ly cause an 89% reduc­tion. It’s also the kind of update that could and should weigh the costs and ben­e­fits of approv­ing the drug for emer­gency autho­riza­tion.

    It sounds like the plan for the US FDA is to have a com­mit­tee of out­side experts review the mate­ri­als on mol­nupi­ravir and make a judge­ment. The FDA is ask­ing the pan­el to review safe­ty con­cerns involv­ing the poten­tial for birth defects and oth­er issues that could arise should the drug end up intro­duc­ing muta­tions in human DNA too. Recall how mol­nupi­ravir works by induc­ing muta­tions into the viral repli­ca­tion process, so con­cerns over whether or not the drug could induce muta­tions in human cells are ground­ed in that fact.

    Dis­turbing­ly, Mer­ck is tak­ing the stance that the drug is not capa­ble of induc­ing genet­ic changes in human cells. And yet, as the arti­cle notes, Mer­ck had the men in the tri­al had to abstain for het­ero­sex­u­al inter­course or agree to use con­tra­cep­tion and women of child-bear­ing age also had to use birth con­trol. So the com­pa­ny clear­ly had inter­nal con­cerns about the poten­tial for the drug trig­ger­ing muta­tions in the DNA of these vol­un­teers, and yet the com­pa­ny is telling the world that the drug isn’t capa­ble of any of that. It’s a pret­ty big red flag about Mer­ck­’s good faith here.

    But the FDA asked the pan­el to not just review the issue of induc­ing muta­tions in humans but also weigh in on con­cerns over whether the drug could encour­age the virus to mutate. Again, the drug lit­er­al­ly works by induc­ing muta­tions in the virus, so this seems like a very rea­son­able con­cern. We’ll see what con­clu­sions this pan­el arrives on on that mat­ter, but the fact that this pan­el is meet­ing right as a new glob­al pan­ic over a new high­ly mutat­ed strain is get­ting under­way should make this a pret­ty press­ing issue for the pan­el to inves­ti­gate. Because as we’re going to see in the sec­ond arti­cle below, this new strain emerg­ing out of South Africa is loaded with a large num­ber of muta­tions, espe­cial­ly in the spike pro­tein. And at least some of these muta­tions are known to enhance the innate immu­ni­ty of the virus and could poten­tial­ly lead to strains that both escape vac­cines but also escape exist­ing immune built up on peo­ple’s bod­ies. It’s poten­tial­ly a very big deal. The kind of big deal that prompt­ed mul­ti­ple coun­tries to shut trav­el from not just South Africa but a num­ber of its neigh­bors.

    Ok, first, here’s a report on Mer­ck­’s dis­ap­point­ing mol­nupi­ravir update, prompt­ing next week’s review. A review that will cov­er not just the drug’s safe­ty but whether or not the drug is induc­ing muta­tions in both humans and the virus itself:

    Reuters

    Mer­ck­’s COVID-19 pill sig­nif­i­cant­ly less effec­tive in new analy­sis

    By Man­as Mishra and Michael Erman
    Novem­ber 26, 2021 8:50 PM UTC
    Updat­ed

    Nov 26 (Reuters) — Mer­ck & Co (MRK.N) said on Fri­day updat­ed data from its study of its exper­i­men­tal COVID-19 pill showed the drug was sig­nif­i­cant­ly less effec­tive in cut­ting hos­pi­tal­iza­tions and deaths than pre­vi­ous­ly report­ed.

    The drug­mak­er said its pill showed a 30% reduc­tion in hos­pi­tal­iza­tions and deaths, based on data from 1,433 patients. In Octo­ber, its data showed a rough­ly 50% effi­ca­cy, based on data from 775 patients. The drug, mol­nupi­ravir, was devel­oped with part­ner Ridge­back Bio­ther­a­peu­tics.

    The low­er effi­ca­cy of Mer­ck­’s drug could have big impli­ca­tions in terms of whether coun­tries con­tin­ue to buy the pill. Inter­im data from 1,200 par­tic­i­pants in Pfiz­er Inc’s (PFE.N) tri­al for its exper­i­men­tal pill, Paxlovid, showed an 89% reduc­tion in hop­si­tal­iza­tions and deaths.

    Mer­ck­’s shares fell 3.5% to $79.39 in morn­ing trad­ing.

    Mer­ck released the data before the U.S Food and Drug Admin­is­tra­tion pub­lished a set of doc­u­ments on Fri­day intend­ed to brief a pan­el of out­side experts who will meet on Tues­day to dis­cuss whether to rec­om­mend autho­riz­ing the pill.

    The agen­cy’s staff did not make their own rec­om­men­da­tion as to whether the pill should be autho­rized.

    FDA staff asked the pan­el to dis­cuss whether the ben­e­fits of the drug out­weigh the risks and whether the pop­u­la­tion for whom the drug should be autho­rized should be lim­it­ed.

    They also asked the com­mit­tee to weigh in on con­cerns over whether the drug could encour­age the virus to mutate, and how those con­cerns could be mit­i­gat­ed.

    ...

    The two exper­i­men­tal drugs have dif­fer­ent mech­a­nisms of action. Mer­ck­’s is designed to intro­duce errors into the genet­ic code of the virus. Pfiz­er’s drug, part of a class known as pro­tease inhibitors, is designed to block an enzyme the coro­n­avirus needs in order to mul­ti­ply.

    Mer­ck filed for a U.S. autho­riza­tion of mol­nupi­ravir on Oct. 11, fol­low­ing the inter­im data, and sub­mit­ted the updat­ed data to the FDA this week. read more

    The mol­nupi­ravir arm of the study had a hos­pi­tal­iza­tion and death rate of 6.8%, accord­ing to the updat­ed data. The place­bo group had a hos­pi­tal­iza­tion and death rate of 9.7%.

    One patient in the mol­nupi­ravir arm died, ver­sus nine in the place­bo group.

    The Unit­ed King­dom con­di­tion­al­ly approved mol­nupi­ravir, brand­ed as Lagevrio, ear­li­er this month.

    Mer­ck expects to pro­duce 10 mil­lion cours­es of the treat­ment by the end of this year, with at least 20 mil­lion set to be man­u­fac­tured in 2022. It has a con­tract with the U.S. gov­ern­ment to sup­ply as many as 5 mil­lion cours­es at a price of $700 per course. Sev­er­al oth­er coun­tries have already secured mil­lions of cours­es of the pill.

    Mer­ck has said data shows mol­nupi­ravir is not capa­ble of induc­ing genet­ic changes in human cells, but men enrolled in its tri­als had to abstain from het­ero­sex­u­al inter­course or agree to use con­tra­cep­tion. Women of child-bear­ing age also had to use birth con­trol.

    Still, the FDA said in its brief­ing doc­u­ment that there are safe­ty con­cerns about poten­tial birth defects from the drug and asked the pan­el to dis­cuss whether the drug should be avail­able to preg­nant women.

    ————–

    “Mer­ck­’s COVID-19 pill sig­nif­i­cant­ly less effec­tive in new analy­sis” by Man­as Mishra and Michael Erman; Reuters; 11/26/2021

    The drug­mak­er said its pill showed a 30% reduc­tion in hos­pi­tal­iza­tions and deaths, based on data from 1,433 patients. In Octo­ber, its data showed a rough­ly 50% effi­ca­cy, based on data from 775 patients. The drug, mol­nupi­ravir, was devel­oped with part­ner Ridge­back Bio­ther­a­peu­tics.”

    What role might mol­nupi­ravir play with just a 30% reduc­tion in hos­pi­tal­iza­tions and deaths? That depends, in part on all the costs that come with that pro­tec­tion. Costs like the poten­tial to induce muta­tions in the patients them­selves. It’s an obvi­ous con­cern based on the mech­a­nism for the drug. And yet Mer­ck insists there’s no dan­ger while tak­ing steps dur­ing its tri­al that clear­ly point towards con­cerns about the risk of muta­tions caus­ing birth defects. The com­pa­ny is giv­ing us an implau­si­ble blan­ket denial. That’s omi­nous:

    ...
    FDA staff asked the pan­el to dis­cuss whether the ben­e­fits of the drug out­weigh the risks and whether the pop­u­la­tion for whom the drug should be autho­rized should be lim­it­ed.

    ...

    The two exper­i­men­tal drugs have dif­fer­ent mech­a­nisms of action. Mer­ck­’s is designed to intro­duce errors into the genet­ic code of the virus. Pfiz­er’s drug, part of a class known as pro­tease inhibitors, is designed to block an enzyme the coro­n­avirus needs in order to mul­ti­ply.

    ...

    Mer­ck has said data shows mol­nupi­ravir is not capa­ble of induc­ing genet­ic changes in human cells, but men enrolled in its tri­als had to abstain from het­ero­sex­u­al inter­course or agree to use con­tra­cep­tion. Women of child-bear­ing age also had to use birth con­trol.

    Still, the FDA said in its brief­ing doc­u­ment that there are safe­ty con­cerns about poten­tial birth defects from the drug and asked the pan­el to dis­cuss whether the drug should be avail­able to preg­nant women.
    ...

    But per­haps more omi­nous is the poten­tial for mol­nupi­ravir to induce muta­tions in the virus itself, poten­tial­ly cre­at­ing high­ly mutat­ed new vari­ants:

    ...
    They also asked the com­mit­tee to weigh in on con­cerns over whether the drug could encour­age the virus to mutate, and how those con­cerns could be mit­i­gat­ed.
    ...

    Don’t for­get, if mol­nupi­ravir does­n’t kill the virus all it man­aged to do is cre­ate a viable high­ly mutat­ed ver­sion. It’s like turn­ing each patient on the drug into a human ver­sion of those viral pas­sage exper­i­ments on fer­rets shown to cre­ate pow­er­ful new strains of virus­es capa­ble of jump­ing species. And that brings us to the dis­turb­ing new reports out of South Africa about the lat­est poten­tial night­mare vari­ant. A vari­ant with an unusu­al num­ber of muta­tions con­cen­trat­ed in the spike pro­tein, includ­ing muta­tions known to enhance the virus’s innate immu­ni­ty and escape the immune sys­tem. While the num­ber of cas­es is tiny so far, they’re in such a tight clus­ter that fears are we’re see­ing the start of the new glob­al wave. As a result, coun­tries like the UK and Israel have already cut off trav­el from South Africa and some of its neigh­bors. But, again, we’re just in the ini­tial stages of this so we real­ly don’t yet have a good idea of what this new vari­ant is capa­ble of and how effec­tive cur­rent vac­cines will be. It’s a game of wait and see. Wait and see and cut off trav­el in the mean time:

    The New York Times

    South Africa detects a new vari­ant, prompt­ing new inter­na­tion­al trav­el restric­tions.

    By Lynsey Chutel, Andrés R. Martínez and Mike Ives

    Pub­lished Nov. 25, 2021
    Updat­ed Nov. 26, 2021, 3:09 a.m. ET

    Sci­en­tists in South Africa on Thurs­day iden­ti­fied a con­cern­ing new coro­n­avirus vari­ant with muta­tions that one sci­en­tist said marked a “big jump in evo­lu­tion,” prompt­ing sev­er­al coun­tries to quick­ly lim­it trav­el from the region.

    With­in hours, Britain, Israel and Sin­ga­pore had restrict­ed trav­el from South Africa and some neigh­bor­ing coun­tries, cit­ing the threat of the new vari­ant. By Fri­day, mar­kets were down in Japan in response to the dis­cov­ery, and offi­cials in Aus­tralia and in New Zealand said that they were mon­i­tor­ing the new vari­ant close­ly.

    The Euro­pean Com­mis­sion will also pro­pose restrict­ing air trav­el to the bloc from south­ern Africa based on con­cerns over the vari­ant, Ursu­la von der Leyen, the commission’s pres­i­dent, said in a Twit­ter post on Fri­day. She referred to it by its sci­en­tif­ic name, B.1.1.529.

    The @EU_Commission will pro­pose, in close coor­di­na­tion with Mem­ber States, to acti­vate the emer­gency brake to stop air trav­el from the south­ern African region due to the vari­ant of con­cern B.1.1.529.— Ursu­la von der Leyen (@vonderleyen) Novem­ber 26, 2021

    In the past two days, sci­en­tists detect­ed the vari­ant after observ­ing an increase in infec­tions in South Africa’s eco­nom­ic hub sur­round­ing Johan­nes­burg. So far, 22 pos­i­tive cas­es have been iden­ti­fied in the coun­try, accord­ing to South Africa’s Nation­al Insti­tute for Com­mu­ni­ca­ble Dis­eases. Two cas­es were detect­ed in Hong Kong, both appar­ent­ly linked to some­one who had trav­eled from South Africa. No cas­es have been detect­ed yet in Britain.

    A num­ber of vari­ants have emerged since the onset of the pan­dem­ic. One under­ly­ing con­cern about them is whether they will stymie the fight against the virus or lim­it the effec­tive­ness of vac­cines. South African sci­en­tists will meet with the World Health Orga­ni­za­tion tech­ni­cal team on Fri­day to dis­cuss the new vari­ant, and the author­i­ties will assign it a let­ter of the Greek alpha­bet.

    ...

    In Decem­ber 2020, South Africa was the first nation to report the appear­ance of the Beta vari­ant, which has now spread to near­ly 70 coun­tries. Sci­en­tists have been con­cerned that some clin­i­cal tri­als have shown that vac­cines offer less pro­tec­tion against the Beta vari­ant. Since then, the more vir­u­lent and aggres­sive Delta vari­ant has spread all over the world and is believed to be fuel­ing the lat­est surge in cas­es.

    The vari­ant has also been iden­ti­fied in Botswana. The country’s health min­istry con­firmed in a state­ment that four cas­es of the new vari­ant were detect­ed in peo­ple who were all ful­ly vac­ci­nat­ed. All four were test­ed before their planned trav­el.

    With over 1,200 new infec­tions, South Africa’s dai­ly infec­tion rate is much low­er than in Ger­many, where new cas­es are dri­ving a wave. How­ev­er, the den­si­ty of muta­tions on this new vari­ant rais­es fears that it could be high­ly con­ta­gious, lead­ing sci­en­tists to sound the alarm ear­ly.

    “This vari­ant did sur­prise us, it has a big jump in evo­lu­tion, many more muta­tions than we expect­ed, espe­cial­ly after a very severe third wave of Delta,” said Tulio de Oliveira, direc­tor of the KwaZu­lu-Natal Research and Inno­va­tion Sequenc­ing Plat­form.

    The B1.1.529 vari­ant has a “very unusu­al con­stel­la­tion of muta­tions,” with more than 30 muta­tions in the spike pro­tein alone, Mr. de Oliveira said. On the ACE2 recep­tor — the pro­tein that helps to cre­ate an entry point for the coro­n­avirus to infect human cells — the new vari­ant has 10 muta­tions. In com­par­i­son, the Beta vari­ant has three, the Delta vari­ant has two, said Mr. de Oliveira.

    Sci­en­tists are still unclear on how effec­tive exist­ing vac­cines will be against the new vari­ant, which dis­plays muta­tions that might resist neu­tral­iza­tion.

    The vari­ant shares sim­i­lar­i­ties with the Lamb­da and Beta vari­ants, which are asso­ci­at­ed with an innate eva­sion of immu­ni­ty, said Richard Les­sells, an infec­tious dis­eases spe­cial­ist at the KwaZu­lu-Natal Research and Inno­va­tion Sequenc­ing Plat­form.

    “All these things are what give us some con­cern that this vari­ant might have not just enhanced trans­mis­si­bil­i­ty, so spread more effi­cient­ly, but might also be able to get around parts of the immune sys­tem and the pro­tec­tion we have in our immune sys­tem,” Mr. Les­sells said.

    The new vari­ant has large­ly been detect­ed among young peo­ple, the cohort that also has the low­est vac­ci­na­tion rate in South Africa. Just over a quar­ter of those ages between 18 and 34 in South Africa are vac­ci­nat­ed, said Dr. Joe Phaahla, the country’s min­is­ter of health.

    While cas­es of the new vari­ant are main­ly con­cen­trat­ed in the country’s eco­nom­ic hub, par­tic­u­lar­ly in the cap­i­tal, Pre­to­ria, it is “only a mat­ter of time” before the virus spreads across the coun­try as schools close and fam­i­lies pre­pare to trav­el for the hol­i­day sea­son, Mr. Phaahla said.

    ———–

    “South Africa detects a new vari­ant, prompt­ing new inter­na­tion­al trav­el restric­tions.” By Lynsey Chutel, Andrés R. Martínez and Mike Ives; The New York Times; 11/25/2021

    With­in hours, Britain, Israel and Sin­ga­pore had restrict­ed trav­el from South Africa and some neigh­bor­ing coun­tries, cit­ing the threat of the new vari­ant. By Fri­day, mar­kets were down in Japan in response to the dis­cov­ery, and offi­cials in Aus­tralia and in New Zealand said that they were mon­i­tor­ing the new vari­ant close­ly.”

    It’s a dark reminder that we’re still in a sit­u­a­tion where a sin­gle bad report about a nasty new strain can end up lead­ing to a coun­try effec­tive­ly get­ting quar­an­tined by the rest of the world over night. To some extent it’s a reflec­tion of the ongo­ing dan­gers of this virus. But it’s also a reflec­tion of just how much we are still forced to rely emer­gency ad hoc pol­i­cy based large­ly on fears of what might hap­pen because we still don’t real­ly know what this virus is ful­ly capa­ble of. This is still only SARS-CoV­‑2 ver­sion 1.0 or 2.0. We don’t know what ver­sion 10.0 of the virus is going to be capa­ble of and whether or not any exist­ing vac­cines or drugs will work at all. But what we do know is that when a new ver­sion of the virus shows up, the more mutat­ed it is the more poten­tial it has to be a night­mare strain. That’s what’s dri­ving a lot of this response: the com­bi­na­tion of not yet under­stand­ing what this virus is capa­ble of but rec­og­nize the signs that it could be a par­tic­u­lar­ly nasty strain, with over 30 muta­tions on the spike pro­tein alone. It’s an omi­nous mutant:

    ...
    With over 1,200 new infec­tions, South Africa’s dai­ly infec­tion rate is much low­er than in Ger­many, where new cas­es are dri­ving a wave. How­ev­er, the den­si­ty of muta­tions on this new vari­ant rais­es fears that it could be high­ly con­ta­gious, lead­ing sci­en­tists to sound the alarm ear­ly.

    This vari­ant did sur­prise us, it has a big jump in evo­lu­tion, many more muta­tions than we expect­ed, espe­cial­ly after a very severe third wave of Delta,” said Tulio de Oliveira, direc­tor of the KwaZu­lu-Natal Research and Inno­va­tion Sequenc­ing Plat­form.

    The B1.1.529 vari­ant has a “very unusu­al con­stel­la­tion of muta­tions,” with more than 30 muta­tions in the spike pro­tein alone, Mr. de Oliveira said. On the ACE2 recep­tor — the pro­tein that helps to cre­ate an entry point for the coro­n­avirus to infect human cells — the new vari­ant has 10 muta­tions. In com­par­i­son, the Beta vari­ant has three, the Delta vari­ant has two, said Mr. de Oliveira.

    Sci­en­tists are still unclear on how effec­tive exist­ing vac­cines will be against the new vari­ant, which dis­plays muta­tions that might resist neu­tral­iza­tion.

    The vari­ant shares sim­i­lar­i­ties with the Lamb­da and Beta vari­ants, which are asso­ci­at­ed with an innate eva­sion of immu­ni­ty, said Richard Les­sells, an infec­tious dis­eases spe­cial­ist at the KwaZu­lu-Natal Research and Inno­va­tion Sequenc­ing Plat­form.

    “All these things are what give us some con­cern that this vari­ant might have not just enhanced trans­mis­si­bil­i­ty, so spread more effi­cient­ly, but might also be able to get around parts of the immune sys­tem and the pro­tec­tion we have in our immune sys­tem,” Mr. Les­sells said.
    ...

    What kind of new night­mare mutant will mol­nupi­ravir end up cre­at­ing once it gets thrown at a patient with this already-mutat­ed strain? Let’s hope we nev­er find out. But we’re prob­a­bly going find out any­way, espe­cial­ly if that review pan­el ends up approv­ing the drug for emer­gency use next week.

    It’s also worth recall­ing one of the pri­ma­ry tools we have at our dis­pos­al for poten­tial­ly pre­vent­ing the devel­op­ment of mutant strains: drug com­bi­na­tions. As the world learned in its bat­tle with HIV — a virus high­ly prone to muta­tions — you real­ly need a com­bi­na­tion of two or three drugs at once if you want to avoid the devel­op­ment of drug-resis­tant strains of HIV. A sim­i­lar prin­ci­ple is going to apply for SARS-CoV­‑2, which means the world real­ly does need to be scram­bling for as many dif­fer­ent ther­a­peu­tics as pos­si­ble to be used in as many com­bi­na­tions as we can safe­ly dis­cov­er. Recall the con­cerns about actu­al­ly see­ing clin­i­cal tri­als on drug com­bi­na­tions take place because it would involve rival Phar­ma giants team­ing up and poten­tial­ly reduc­ing their prof­its.

    And that’s all part of what’s going to make the sto­ry of mol­nupi­ravir so inter­est­ing to watch play out: it’s a drug that, when used on its own, might actu­al­ly end up cre­at­ing more dev­as­tat­ing ver­sions of the virus. And yet those dan­gers might be mit­i­gat­ed sig­nif­i­cant­ly if the drug is tak­en in com­bi­na­tion with oth­er ther­a­peu­tics like Paxlovid that are simul­ta­ne­ous­ly attack­ing the virus in oth­er ways. At least the dan­gers of cre­at­ing a new viral strain. The dan­gers of induc­ing muta­tions in the patients will still poten­tial­ly be there, but those may be rel­a­tive­ly small dan­gers in com­par­i­son when faced with the prospect of a dead­ly coro­n­avirus infec­tion. There’s a num­ber of red flags warn­ing us about mol­nupi­ravir, and a num­ber of oth­er red flags telling us we’re going to maybe need it any­way.

    Posted by Pterrafractyl | November 26, 2021, 5:45 pm

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