Peter Marks, CBER (MDA USA via Twitter)

Pe­ter Marks on Covid-19 vac­cine ef­fi­ca­cy, EUAs and chal­lenge tri­als

A week af­ter the FDA is­sued guid­ance on vac­cines to pre­vent Covid-19, Pe­ter Marks, di­rec­tor of the Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search, shed light on the rea­son­ing be­hind the agency’s 50% ef­fi­ca­cy thresh­old and where the agency stands on chal­lenge tri­als and emer­gency use au­tho­riza­tions.

Ef­fi­ca­cy and ap­proval

In its guid­ance, FDA said it ex­pect­ed spon­sors to demon­strate a vac­cine is at least 50% ef­fec­tive in a place­bo-con­trolled tri­al, with an ad­just­ed low­er bound of >30%.

Dur­ing a tele­con­fer­ence with the Al­liance for a Stronger FDA on Wednes­day, Marks ex­plained that the 50% fig­ure is based on what the agency could tol­er­ate for ef­fi­ca­cy. “Can we show you some cal­cu­la­tion of how we got there? No,” he said, not­ing that the agency does not typ­i­cal­ly set spe­cif­ic ef­fi­ca­cy tar­gets in its vac­cine guid­ance.

“If you go much low­er than 50% then the low­er bounds of things start to get to a place where vac­cines may have very lit­tle ef­fi­ca­cy,” Marks added. “On the oth­er hand, if we held that num­ber at 70% to 80% … we may not have a vac­cine un­til there’s herd im­mu­ni­ty that’s oc­curred nat­u­ral­ly.”

How­ev­er, Marks said that erad­i­cat­ing the virus will like­ly re­quire a more ef­fec­tive vac­cine. “We’re go­ing to need a vac­cine that’s prob­a­bly in the or­der of 70% ef­fec­tive and 70%, at least, of the pop­u­la­tion is go­ing to need to take it,” he said.

Based on those pa­ra­me­ters, Marks said that piv­otal tri­als for Covid-19 vac­cines will need to be large. “Large means tens of thou­sands of peo­ple, prob­a­bly … some­where be­tween ten to fif­teen thou­sand in­di­vid­u­als in each arm of a ran­dom­ized tri­al to get to the kind of pow­er that you need here.”

Marks could not com­ment on how quick­ly vac­cine could be avail­able but said, “We’re not go­ing to have one in ear­ly fall, it’s go­ing to take months.”

As stat­ed in the agency’s guid­ance, Marks stressed that ac­cel­er­at­ed ap­proval is not ap­pro­pri­ate un­til there are com­pelling sur­ro­gate end­points.

“Giv­en the cur­rent lack of da­ta that we have in­form­ing im­mune cor­re­lates of pro­tec­tion, we’re telling peo­ple that the clin­i­cal de­vel­op­ment pro­gram should pur­sue tra­di­tion­al ap­proval, based on di­rect ev­i­dence of vac­cine ef­fi­ca­cy,” Marks said. “Af­ter a few vac­cines come through the pipeline, we may un­der­stand what a good im­mune cor­re­late of pro­tec­tion is, but we don’t yet know that an­ti­bod­ies are the be-all-end-all of pro­tect­ing against COVID-19.”

Marks al­so ex­pand­ed on whether the agency would con­sid­er is­su­ing an emer­gency use au­tho­riza­tion for a Covid-19 vac­cine.

“We re­al­ly be­lieve that the most like­ly sit­u­a­tion in which an emer­gency use au­tho­riza­tion would be is­sued would be af­ter some in­ter­im analy­sis that shows vac­cine ef­fi­ca­cy and safe­ty, be­fore a for­mal sub­mis­sion is made to the FDA of a li­cen­sure ap­pli­ca­tion and FDA has had a chance to do its nor­mal re­view,” he said.

Chal­lenge tri­als

One of the more eye­brow-rais­ing as­pects of FDA’s guid­ance was a sec­tion dis­cussing the po­ten­tial for chal­lenge tri­als, or con­trol hu­man in­fec­tion mod­els, where­in vol­un­teers are in­ten­tion­al­ly ex­posed to a pathogen. In its guid­ance, FDA sug­gests that such tri­als could be en­ter­tained, “If it is no longer pos­si­ble to demon­strate vac­cine ef­fec­tive­ness by way of con­duct­ing clin­i­cal dis­ease end­point ef­fi­ca­cy stud­ies.”

“Why can’t we do that for COVID-19?” Marks asked. “Well, there are prob­a­bly a cou­ple rea­sons. One of which is that you don’t have some­thing that cures COVID-19 100% of the time or near 100% of the time.” Marks said there are oth­er is­sues that would need to be worked out be­fore such tri­als would be fea­si­ble, in­clud­ing im­prov­ing our un­der­stand­ing of the dis­ease and de­ter­min­ing which strain of the virus to use.

“This could be a way to­wards re­al­ly fa­cil­i­tat­ing get­ting an an­swer, if we had a res­cue treat­ment and if we knew more about the re­la­tion­ship be­tween car­riage and in­fec­tion, but right now it gives peo­ple some eth­i­cal heart­burn and sci­en­tif­i­cal­ly it’s com­pli­cat­ed,” Marks said.

That said, Marks said FDA would con­sid­er pro­pos­als for chal­lenge tri­als based on what was in the pro­to­col and the cir­cum­stances at the time. “It’s not a ‘no’, it’s a ‘we’ll see,’” he said.

Marks added that it might be more fea­si­ble to con­duct chal­lenge tri­als when there are more ef­fec­tive ther­a­peu­tics avail­able to treat the dis­ease. “If we have mon­o­clon­al an­ti­bod­ies that are re­al­ly good at shut­ting down the dis­ease, that could be a game chang­er.”

Safe­ty and qual­i­ty

Marks said that one of the things that “scares me more than any­thing else is that a third or half of Amer­i­cans are hes­i­tant about tak­ing a vac­cine [for COVID-19].” Marks stressed that part of FDA’s job is to as­sure that an even­tu­al vac­cine is safe and high qual­i­ty.

“For any of these vac­cines tar­get­ing SARS-CoV-2, im­por­tant things for us from the stand­point of our guid­ance… will be things like con­sis­ten­cy of man­u­fac­tur­ing, and the need for man­u­fac­tur­ing process­es and con­trols that have ap­pro­pri­ate steps in them, the need to have fa­cil­i­ties in­spect­ed to pro­duce vac­cines un­der good man­u­fac­tur­ing prac­tices, that’s im­por­tant be­cause we re­al­ly do need to make sure that these are go­ing to be high qual­i­ty prod­ucts that when we say they’re safe, they re­al­ly are,” Marks said.

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The top 100 bio­phar­ma VCs, Bob Brad­way places $2B bet in can­cer, gene edit­ing pi­o­neer's new big idea, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Before diving in, we had some news to share: Endpoints is launching a premium weekly report focusing on all things regulatory. Coverage will be led by our new senior editor, Zachary Brennan, who joins us from POLITICO. Arsalan Arif has more details in his Publisher’s Note.

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Robert Bradway (Photographer: Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Am­gen snaps up can­cer drug play­er Five Prime, adding PhI­II-ready FGFR2b drug in $2B M&A play

Amgen is making a long-awaited move on the M&A side, buying South San Francisco-based Five Prime $FPRX for close to $2 billion and adding a slate of new cancer drugs to the pipeline.

Amgen is paying $38 a share, putting the deal value at $1.9 billion. The stock closed at $21.26 last night, giving investors a 78% premium.

The jewel in the crown of this deal is bemarituzumab, which Amgen describes as a first-in-class, Phase III-ready anti-FGFR2b antibody. Amgen was drawn to the bargaining table by Five Prime’s mid-stage data on gastric cancer, satisfied by PFS and OS data helping to validate FGFR2b as a target. Amgen researchers will now expand on the R&D program in other epithelial cancers, including lung, breast, ovarian and other cancers.

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David Liu (Casey Atkins Photography courtesy Broad Institute)

David Liu has a new big idea: pro­teome edit­ing. It could one day shred tau, RAS and some of the worst dis­ease-caus­ing pro­teins

Before David Liu became famous for inventing new forms of gene editing, he was known around academia in part for a more obscure innovation: a Rube Goldberg-esque system that uses bacteria-infecting viruses to take one protein and turn it into another.

Since 2011, Liu’s lab has used the system, called PACE, to dream up fantastical new proteins: DNA base editors far more powerful than the original; more versatile forms of the gene editor Cas9; insecticides that kill insecticide-resistant bugs; enzymes that slide synthetic amino acids into living organisms. But they struggled throughout to master one of the most common and powerful proteins in the biological world: proteases, a set of Swiss army knife enzymes that cut, cleave or shred other proteins in everything from viruses to humans.

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The 2021 top 100 bio­phar­ma in­vestors: As the pan­dem­ic hit and IPOs boomed, VCs swung in­to ac­tion like nev­er be­fore

The global pandemic may have roiled economies, killed hundreds of thousands and throttled entire industries, but the only effect it had on biopharma venture investing was to help turbocharge the field to giddy new heights.

Below you’ll find the new top 100 venture investors in the industry, ranked by the number of deals they were publicly involved in, as tracked by DealForma chief Chris Dokomajilar. The numbers master then calculated the estimated amount of money they put into each deal — divvying up the cash by the number of players — to indicate how they managed their syndicates.

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Bruce Cozadd, Jazz CEO (Jazz Pharmaceuticals)

Jazz CEO Bruce Cozadd cam­paigned for 6 months to buy GW Phar­ma. A 90% pre­mi­um sealed the deal — along with $17.6M in ‘re­ten­tion’ in­cen­tives

Jazz CEO Bruce Cozadd didn’t beat around the bush.

In his first video meeting with GW Pharma chief Justin Gover last July 8, he offered to pay $172 a share to get the company, which had beaten the odds in getting its remarkable cannabinoid drug Epidiolex across the regulatory finish line for epilepsy. GW’s stock closed at $129 that day.

Cozadd had already done his homework on the financing to make sure he could swing it the way he wanted. He just needed to do some due diligence before making the non-binding bid firm.

Covid-19 roundup: RE­COV­ERY tri­al halts re­cruit­ment for colchicine study af­ter find­ing ‘no con­vinc­ing ev­i­dence’; Italy blocks As­traZeneca vac­cine ship­ment meant for Aus­tralia

It may be the end of the road for colchicine, an inexpensive oral anti-inflammatory drug commonly used to treat gout, as a potential Covid-19 treatment — at least in hospitalized patients.

The UK’s RECOVERY trial put out the word on Friday that it’s halting enrollment in its colchicine study after a data monitoring committee saw “no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any pre-specified subgroup.”

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One of biotech’s earliest SPAC investors is back with another blank-check company, less than a month after his last effort announced its intent to merge.

Rajiv Shukla is intending to take a third lucky winner public with Alpha Healthcare Acquisition III, filing to go public Thursday with a $150 million raise penciled in. The move comes just a couple of weeks after Shukla’s second SPAC said it would jump to Nasdaq in tandem with Laura Niklason’s Humacyte in a $255 million new investment.

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Paul Hudson, Getty Images

How does Paul Hud­son's $13.5M comp pack­age stack up against oth­er CEOs? He's in the 'first quar­tile'

Paul Hudson arrived at Sanofi like a hurricane, chopping off duds in the pipeline, shaking up the C-suite, striking big M&A deals and jumping into the Covid-19 vaccine race — all in an attempt to reboot a pharma giant notorious for its setbacks.

Now, we’re getting a look at what the CEO brought home in his first year on the job.

When all is said and done, Hudson will have made about $6.7 million in 2020, about $2.5 million of which has already been paid. The bigger figure includes a $2.3 million bonus that’s subject to approval at an April meeting, and another $1.8 million in variable compensation that has yet to be paid.

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Brii Bio joins the NIH grave­yard along­side GSK, Lil­ly af­ter flop­ping an­ti­body study in hos­pi­tal­ized Covid-19 pa­tients

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An antibody cocktail from Brii Biosciences failed to show a trend toward clinical benefit in the NIH’s ACTIV-3 trial, and as a result, did not meet criteria for further enrollment. As such, the NIH shut down the study subgroup evaluating the program Thursday, which contains the two Brii antibodies dubbed BRII-196 and BRII-198.