With big ques­tions still hang­ing over the fate of the vac­cines and drugs now in late-stage de­vel­op­ment for Covid-19, Boehringer In­gel­heim is pulling one of its ear­ly-stage drugs in­to a Phase II tri­al to see if it can help some of the most se­vere­ly af­flict­ed pa­tients.

Put through a safe­ty study last year, re­searchers have been in­trigued by the po­ten­tial of BI 764198 — a TR­PC6 in­hibitor — as a treat­ment for acute res­pi­ra­to­ry dis­tress syn­drome (ARDS), which can cause im­mense dam­age and death for pa­tients ex­posed to the virus.

Clive Wood

As the pan­dem­ic hit, “we start­ed to ask, what are the mech­a­nisms we have in the pipeline, what might help these pa­tients?” says Clive Wood, head of dis­cov­ery re­search at Boehringer. That led them to a drug in de­vel­op­ment for chron­ic kid­ney dis­ease, which shares a path­way that could have an im­pact on the virus.

“We are far from hav­ing a clear path to hav­ing a clear path to the end of this sit­u­a­tion,” says Wood, and that makes it im­por­tant to re­cruit 90 pa­tients for the Phase II, with the abil­i­ty to piv­ot in­to a late-stage reg­is­tra­tion study if it works out.

Even if it doesn’t work out in time for Covid-19, Boehringer’s re­searchers ex­pect that suc­cess could pave the way to oth­er us­es in the fu­ture. Right now, the on­ly thing they know for cer­tain is they need to see if it works. — John Car­roll

Man­u­fac­tur­ing de­lay push­es back the launch of a PhI­II at No­vavax

Though No­vavax $NVAX is near the fore­front of the Covid-19 vac­cine race, it will be start­ing its Phase III tri­al lat­er than an­tic­i­pat­ed.

The com­pa­ny said Tues­day that its late-stage study in the US has been pushed back to the end of No­vem­ber af­ter de­lays in up­scal­ing its man­u­fac­tur­ing process­es. That’s about one month af­ter pre­vi­ous­ly re­port­ed time­lines.

Mean­while, tri­al da­ta from a sep­a­rate Phase III be­ing con­duct­ed in the UK are like­ly com­ing some­time “ear­ly” in the first quar­ter, No­vavax said, adding that the re­sults from this study “are ex­pect­ed to serve as the ba­sis for glob­al li­cen­sure.” No­vavax did not elab­o­rate on what that meant nor how they plan to ap­ply for such “li­cen­sure” in the US.

Ad­di­tion­al­ly, new Phase II da­ta from the com­pa­ny’s on­go­ing Phase I/II tri­al are ex­pect­ed to come Fri­day. In­vestors most­ly greet­ed the news warm­ly, as the com­pa­ny’s shares rose about 3% in Tues­day trad­ing.

While there haven’t been any Covid-19 vac­cine ap­provals or EUAs thus far, there have been a few for treat­ments. The FDA re­cent­ly grant­ed ap­proval for Gilead’s remde­sivir, mar­ket­ed as Vek­lury, in hos­pi­tal­ized pa­tients old­er than 12. That fol­lowed an EUA for the ther­a­py, as well as EUAs for hy­drox­y­chloro­quine and con­va­les­cent plas­ma. Reg­u­la­tors have since re­voked the for­mer’s au­tho­riza­tion.

No­vavax re­ceived a $1.6 bil­lion Warp Speed con­tract in Ju­ly and be­gan its UK Phase III study in late Sep­tem­ber. The biotech is test­ing a two-shot reg­i­men of its low­er, 5 µg dose of pro­tein anti­gen cur­rent­ly in Phase II, plus a 50 µg Ma­trix‑M ad­ju­vant. The shots are be­ing ad­min­is­tered 21 days apart.

Pfiz­er cur­rent­ly leads End­points News’ Covid-19 vac­cine race track­er, with No­vavax com­ing in 8th. — Max Gel­man

CBER di­rec­tor promis­es ‘safe and ef­fec­tive’ vac­cine in op-ed

In an ef­fort to shore up trust in the FDA’s abil­i­ty to au­tho­rize a safe and ef­fec­tive vac­cine, CBER di­rec­tor Pe­ter Marks broke down the EUA process in a USA To­day op-ed. 

“We hope to en­sure pub­lic con­fi­dence in COVID-19 vac­cines by be­ing trans­par­ent about FDA’s de­ci­sion-mak­ing process,” he wrote. “Whether a vac­cine is made avail­able through an EUA or through a tra­di­tion­al ap­proval, FDA will en­sure that it is safe and ef­fec­tive.”

Pe­ter Marks

In the rough­ly 1,000-word piece, Marks promised that an EUA de­ci­sion will not be rushed. And he ex­plained that the FDA’s min­i­mum rec­om­men­da­tion of 50% ef­fi­ca­cy is just that — a min­i­mum.

“Of course, it is hoped that the vac­cines will pre­vent a much high­er per­cent­age of cas­es, but the 50% fig­ure es­tab­lish­es the min­i­mum ef­fi­ca­cy of a COVID-19 vac­cine that FDA could find ac­cept­able,” he said.

The di­rec­tor al­so men­tioned that con­sid­er­a­tions for an EUA may be dif­fer­ent, de­pend­ing on how a prod­uct will be used. For ex­am­ple, if a drug is in­tend­ed for hos­pi­tal­ized pa­tients who have no oth­er treat­ment, “the po­ten­tial ben­e­fits may out­weigh the risks even if there is un­cer­tain­ty about ef­fec­tive­ness and there are re­al, but ac­cept­able, safe­ty con­cerns,” Marks wrote.

In June, the FDA yanked an EUA for hy­drox­y­chloro­quine as a Covid-19 treat­ment, af­ter de­ter­min­ing the drug is “un­like­ly to be ef­fec­tive.” And in Sep­tem­ber, a pan­el of ex­perts con­vened by the NIH con­clud­ed that there is a lack of da­ta sup­port­ing the safe­ty and ef­fi­ca­cy of an­oth­er coro­n­avirus treat­ment grant­ed an EUA: con­va­les­cent plas­ma.

In the op-ed, Marks said that wouldn’t be the case for a vac­cine:

For a COVID-19 vac­cine that could be ad­min­is­tered to mil­lions of in­di­vid­u­als, in­clud­ing healthy peo­ple, FDA will on­ly is­sue an EUA if a vac­cine has demon­strat­ed clear and com­pelling ef­fi­ca­cy in a large well-de­signed phase 3 clin­i­cal tri­al, much like would be re­quired for a BLA. 

Nor­mal­ly, drug mak­ers take months to an­a­lyze da­ta be­fore sub­mit­ting a BLA, which can be tens of thou­sands of pages long, ac­cord­ing to Marks. “But these are not ‘nor­mal’ times,” he said. “In the Unit­ed States, we have seen many hun­dreds of peo­ple die every day from COVID-19.”

“With high up­take, COVID-19 vac­cines have the po­ten­tial to save many lives in the Unit­ed States that may oth­er­wise be lost. And sav­ing as many lives as is pos­si­ble must be the goal that we strive to achieve to­geth­er,” he wrote. — Nicole De­Feud­is

Sanofi and GSK pledge 200 mil­lion vac­cine dos­es

Sanofi and GSK have agreed to give 200 mil­lion dos­es of their vac­cine can­di­date to the CO­V­AX Fa­cil­i­ty, which is part of a pro­gram set up by CEPI, the WHO and Gavi to eq­ui­tably dis­trib­ute vac­cines around the world.

The idea be­hind CO­V­AX is to give all par­tic­i­pat­ing coun­tries equal ac­cess to vac­cines, re­gard­less of in­come lev­el. As of Oct. 14, more than 180 coun­tries had signed agree­ments to the CO­V­AX Fa­cil­i­ty, in­clud­ing France and the UK. Chi­na joined ear­li­er this month, pledg­ing to make its vac­cines a “glob­al pub­lic good.” One coun­try no­tably off the list is the Unit­ed States.

The Trump ad­min­is­tra­tion has re­fused to join the pro­gram. The US has placed an ini­tial $1.95 bil­lion or­der for 100 mil­lion dos­es of Pfiz­er’s can­di­date, with the op­tion to ac­quire up to 500 mil­lion more down the road. And it placed a $1.5 bil­lion or­der with Mod­er­na for 100 mil­lion dos­es, with an op­tion for an­oth­er 400 mil­lion lat­er. One White House spokesman said the coun­try won’t be “con­strained by mul­ti­lat­er­al or­ga­ni­za­tions in­flu­enced by the cor­rupt World Health Or­ga­ni­za­tion and Chi­na,” ac­cord­ing to a Bloomberg re­port.

CO­V­AX is hop­ing to have 2 bil­lion dos­es avail­able by the end of 2021, “which should be enough to pro­tect high risk and vul­ner­a­ble peo­ple, as well as front­line health­care work­ers,” the GAVI web­site states.

Thomas Tri­om­phe

Sanofi and GSK en­tered their ad­ju­vant­ed re­com­bi­nant pro­tein-based can­di­date in a Phase I/II study on Sept. 3, and an­tic­i­pate the first cut of da­ta in ear­ly De­cem­ber. The com­pa­nies are hop­ing the re­sults sup­port the launch a piv­otal Phase III tri­al be­fore the end of the year. If all goes ac­cord­ing to plan, they think a re­quest for ap­proval could come in the first half of 2021.

“The com­mit­ment we are an­nounc­ing to­day for the CO­V­AX Fa­cil­i­ty can help us to­geth­er stand a bet­ter chance of bring­ing the pan­dem­ic un­der con­trol,” Sanofi Pas­teur ex­ec­u­tive VP and glob­al head Thomas Tri­om­phe said in a state­ment. “This mo­ment al­so re­flects our long-term com­mit­ment to glob­al health and en­sures our COVID-19 vac­cines are af­ford­able and ac­ces­si­ble to those most at risk, every­where in the world.” — Nicole De­Feud­is

Vac­ci­nol­o­gist Paul Of­fit calls for more ef­fi­ca­cy da­ta 

In the next cou­ple months, drug mak­ers will like­ly sub­mit EUA ap­pli­ca­tions for Covid-19 vac­cines, renowned vac­ci­nol­o­gist Paul Of­fit pre­dicts.

This could come at the be­gin­ning of a “twindem­ic” — par­al­lel flu and coro­n­avirus out­breaks, he added. The ques­tion is, what will be re­quired for emer­gency au­tho­riza­tion?

“Per­mis­sion is be­ing giv­en to vac­ci­nate 150 mil­lion Amer­i­cans es­sen­tial­ly, which is ob­vi­ous­ly some­thing we’ve nev­er dealt with be­fore,” Of­fit, di­rec­tor of the Chil­dren’s Hos­pi­tal of Philadel­phia’s Vac­cine Ed­u­ca­tion Cen­ter and in­ven­tor of the ro­tavirus vac­cine, said in a JA­MA Net­work in­ter­view.

Paul Of­fit

“How much un­cer­tain­ty are we will­ing to live with know­ing that we’re fac­ing a virus that’s brought us to our knees?” he asked lat­er.

Of­fit said he’s con­cerned the pub­lic will see emer­gency au­tho­riza­tion as “flim­sy,” or based on a lack of ev­i­dence, af­ter what hap­pened with hy­drox­y­chloro­quine and the “con­va­les­cent plas­ma fi­as­co.”

“I think where the rub­ber’s go­ing to meet the road here is how we han­dle these in­ter­im analy­ses,” he said in the in­ter­view.

Pfiz­er and BioN­Tech, cur­rent­ly in the lead for an EUA, an­nounced in their tri­al pro­to­col that their first in­ter­im analy­sis would oc­cur when 32 par­tic­i­pants are in­fect­ed. Mod­er­na will hold its first in­ter­im analy­sis at 53 events. And As­traZeneca is plan­ning to con­duct an analy­sis when 75 pa­tients get sick. Re­searchers would then com­pare how many in­fec­tions oc­curred in the vac­cine arm, ver­sus the place­bo arm.

“I’d like to think that we’re go­ing to be re­al­ly loathe to ap­prove this or to rec­om­mend ap­proval through emer­gency use au­tho­riza­tion with just 34 or 60 par­tic­i­pants get­ting sick,” Of­fit said.

In NIH AC­TIV tri­als, sta­tis­ti­cians want­ed to see 147 in­fec­tions if the vac­cine was ad­min­is­tered in a 2:1 ra­tio to place­bo, or 160 in­fec­tions in a 1:1 sce­nario, Of­fit said. “That’s where I’m com­ing from,” he added.

“If dreams could come true, all I ask is this: Let’s have at least 150 par­tic­i­pants that got sick,” Of­fit said. “That’s all I ask.” — Nicole De­Feud­is

DC District Court Judge Christopher Cooper today granted Vanda Pharma’s request to require the FDA to disclose more info on the complete response letter for its sleep disorder drug Hetlioz.

The melatonin receptor agonist is approved by the FDA to treat non-24-hour sleep-wake disorder, a circadian rhythm disorder. But in 2018 Vanda filed a supplemental application to market Hetlioz as a treatment for jet lag, which the FDA rejected in August 2019, with few details on what Vanda needed to correct course, according to the company.