President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days be­fore Pres­i­dent Joe Biden’s Covid-19 boost­er roll­out is set to go in­to ef­fect, an FDA ad­vi­so­ry com­mit­tee ap­peared on the verge of not rec­om­mend­ing boost­ers for any­one in the US be­fore a last-minute change of word­ing laid the ground­work for old­er adults to have ac­cess to a third dose.

The FDA’s ad­comm on Vac­cines and Re­lat­ed Bi­o­log­i­cal Prod­ucts (VRB­PAC) round­ly re­ject­ed Pfiz­er/BioN­Tech boost­er shots for all in­di­vid­u­als old­er than 16 by a 16-2 vote Fri­day af­ter­noon. Soon af­ter, how­ev­er, the agency posed com­mit­tee mem­bers a new ques­tion lim­it­ing boost­er use to the 65-and-old­er pop­u­la­tion and in­di­vid­u­als at high risk of dis­ease due to oc­cu­pa­tion­al ex­po­sure or co­mor­bidi­ties.

That ques­tion, com­ing rough­ly 45 min­utes af­ter the first, passed through the ad­comm with a unan­i­mous 18-0 vote. This vote cen­tered on an emer­gency use au­tho­riza­tion — not the sup­ple­men­tal BLA for which Pfiz­er had ap­plied.

And at the end of the hear­ing, CBER di­rec­tor Pe­ter Marks asked the pan­el to take an “in­for­mal poll” on whether health-care work­ers and oth­ers at high risk of “oc­cu­pa­tion­al ex­po­sure” be in­clud­ed in the EUA. Here, the pan­el al­so gave a unan­i­mous 18-0 yes.

Af­ter the votes, Pfiz­er vac­cine chief Kathrin Jansen said in a state­ment that the com­pa­ny would con­tin­ue to push for boost­ers in the gen­er­al pop­u­la­tion.

“These da­ta, and the larg­er body of sci­en­tif­ic ev­i­dence pre­sent­ed at the meet­ing, un­der­score our be­lief that boost­ers will be a crit­i­cal tool in the on­go­ing ef­fort to con­trol the spread of this virus,” Jansen said in an emailed state­ment to End­points News. “We thank the com­mit­tee for their thought­ful re­view of the da­ta and will work with the FDA fol­low­ing to­day’s meet­ing to ad­dress the com­mit­tee’s ques­tions, as we con­tin­ue to be­lieve in the ben­e­fits of a boost­er dose for a broad­er pop­u­la­tion.”

Sev­er­al ad­comm mem­bers not­ed through­out the dis­cus­sion pe­ri­od that they’d be open to rec­om­mend­ing boost­ers for small­er high-risk pop­u­la­tions, prompt­ing pan­el chair Arnold Mon­to to ask Marks for mul­ti­ple clar­i­fi­ca­tions on the orig­i­nal, broad vot­ing ques­tion. The ques­tion, re­leased late Thurs­day night, asked whether or not the safe­ty and ef­fi­ca­cy da­ta from Pfiz­er/BioN­Tech’s orig­i­nal Phase III study “sup­port­ed ap­proval” of a boost­er at least six months af­ter the sec­ond dose in those aged 16 and up.

But Mon­to asked if Marks would al­low pan­el mem­bers to con­sid­er da­ta from oth­er re­al-world stud­ies in their votes, to which Marks said the com­mit­tee would be al­lowed to con­sid­er the “to­tal­i­ty of the da­ta.” Then, Mon­to want­ed to know if the ques­tion could be mod­i­fied to al­low com­mit­tee mem­bers to vote on a nar­row­er pop­u­la­tion.

Marks once again an­swered in the af­fir­ma­tive but, in an ex­tra­or­di­nary ex­change, re­ceived sig­nif­i­cant push­back from top vac­cine of­fi­cial Mar­i­on Gru­ber who not­ed that Pfiz­er’s sub­mis­sion cov­ered all in­di­vid­u­als old­er than 16. Gru­ber, along with an­oth­er top vac­cine staffer, Philip Krause, an­nounced their in­tent to re­tire last month af­ter rais­ing con­cerns with boost­ers in the Lancet.

Mon­to then al­lowed Pfiz­er to make a five-minute clos­ing state­ment that was not on the agen­da, in which com­pa­ny ex­ecs pushed for the com­mit­tee to vote on the orig­i­nal ques­tion.

Ob­servers crit­i­cized the FDA in the im­me­di­ate wake of the first vote, pos­ing what they said was an in­flex­i­ble ques­tion giv­en some da­ta has shown the ben­e­fits of boost­ers out­weigh the risk in old­er pop­u­la­tions. Scripps Re­search di­rec­tor Er­ic Topol blast­ed the agency, say­ing the first ques­tion “was set up to fail” in es­sen­tial­ly ask­ing for da­ta that are not yet avail­able.

Through­out the af­ter­noon, pan­elists had ex­pressed se­vere reser­va­tions about rec­om­mend­ing boost­ers for every­one old­er than 16, par­tic­u­lar­ly giv­en the un­known safe­ty risks in young boys and men with re­gards to my­ocardi­tis. It’s an is­sue that harkened back to the orig­i­nal vac­cine ad­comm as well, when pan­elists took is­sue with ap­prov­ing vac­cines for 16- and 17-year-olds.

“I was struck by the FDA’s com­ments on the to­tal­i­ty of da­ta giv­en there’s more da­ta com­ing soon on safe­ty for my­ocardi­tis,” pan­el mem­ber Hay­ley Gans said af­ter the first vote. “It feels like a missed op­por­tu­ni­ty when they con­sid­er these [datasets] large enough even when we have da­ta we could have looked at … it feels like we’re mak­ing de­ci­sions when there’s still da­ta out there.”

Af­ter the first vote con­clud­ed with a re­sound­ing no, FDA of­fi­cials re­turned to com­mit­tee mem­bers with a new ques­tion. Rather than fo­cus on the en­tire gen­er­al pop­u­la­tion, reg­u­la­tors posed the fol­low­ing ques­tion:

Based on the to­tal­i­ty of sci­en­tif­ic ev­i­dence avail­able, in­clud­ing the safe­ty and ef­fec­tive­ness da­ta from clin­i­cal tri­al C4591001, do the known and po­ten­tial ben­e­fits out­weigh the known and po­ten­tial risks of a Pfiz­er-BioN­Tech Covid-19 vac­cine boost­er dose ad­min­is­tered at least 6 months af­ter com­ple­tion of the pri­ma­ry se­ries for use in:

a) In­di­vid­u­als 65 years of age and old­er, and

b) In­di­vid­u­als at high risk of se­vere Covid-19

It’s here where the ma­jor­i­ty of pan­elists seemed to agree, giv­ing the EUA their thumbs up rec­om­men­da­tion.

The ad­comm start­ed off bright and ear­ly at 8:30 a.m. East­ern, with Mon­to wel­com­ing view­ers to the livestream. Af­ter a brief in­tro­duc­tion he soon hand­ed things off to Marks who, in a strik­ing move, di­rect­ed pan­el mem­bers to fo­cus con­ver­sa­tions on the sci­ence rather than con­cerns over vac­cine eq­ui­ty or “op­er­a­tional is­sues re­lat­ed to a boost­er cam­paign.”

Marks’ com­ments came against the back­drop of Gru­ber and Krause’s res­ig­na­tions. The two al­so co-au­thored an ar­ti­cle in the Lancet this week as­sert­ing boost­er dos­es for the gen­er­al pop­u­la­tion are not ap­pro­pri­ate at this stage in the pan­dem­ic, and Gru­ber — who spoke dur­ing the in­tro­duc­tion — not­ed this would like­ly be her last ad­comm ap­pear­ance.

An­oth­er co-au­thor to that pa­per, British sta­tis­ti­cian Jonathan Sterne, gave a pre­sen­ta­tion ear­ly in the ses­sion on the top­ic of “con­found­ables,” or vari­ables that can in­tro­duce or pre­dict both vac­ci­na­tion and Covid-19 out­comes in re­al-world stud­ies. Sterne’s dis­cus­sion drew wide praise among ob­servers on so­cial me­dia, rais­ing ques­tions over how dif­fi­cult it is to de­ter­mine whether wan­ing vac­cine im­mu­ni­ty is pri­mar­i­ly a re­sult of the shots be­com­ing less ef­fec­tive or the Delta vari­ant’s surge.

Sand­wich­ing Sterne were da­ta pre­sen­ta­tions from the CDC and Is­raeli health of­fi­cials, who de­scribed how the pan­dem­ic had pro­gressed in their coun­tries. The Is­raeli pre­sen­ta­tion al­so in­clud­ed da­ta from re­al-world stud­ies dur­ing the coun­try’s Delta surge, which proved no­table giv­en the FDA’s writ­ten ques­tion to pan­el mem­bers asked sole­ly about Pfiz­er’s Phase III study.

Soon af­ter came the heavy hit­ters: Pfiz­er and the FDA. Much of the ar­gu­ments as­sert­ed here matched up with how they each in­ter­pret­ed the da­ta in the brief­ing doc­u­ments re­leased ear­li­er this week. In a mi­nor point of con­tention dur­ing the hear­ing, Mon­to cut off Pfiz­er’s pre­sen­ter who went over his al­lot­ted time when try­ing to re­it­er­ate find­ings from Is­raeli stud­ies.

Af­ter these pre­sen­ta­tions and the open com­ment pe­ri­od, pan­elists be­gan their Q&A ses­sion with Pfiz­er and the FDA. The first ques­tion de­liv­ered some fire­works, with Gru­ber giv­ing Krause the op­por­tu­ni­ty to ques­tion Pfiz­er on the sta­tis­ti­cal mod­els used in a re­al-world study in Is­rael.

Krause claimed there was a dis­crep­an­cy be­tween the ef­fi­ca­cy Pfiz­er re­port­ed us­ing a spe­cif­ic mod­el, which said ef­fi­ca­cy af­ter 8 months fell to 58% to 61%, but num­bers cal­cu­lat­ed through a dif­fer­ent math­e­mat­i­cal process us­ing cas­es per per­son-years re­sult­ed in 93% ef­fi­ca­cy. These dis­parate fig­ures, Krause said, came from the same num­ber of cas­es in a study by Cal­i­for­nia health care com­pa­ny Kaiser Per­ma­nente.

When giv­en time to re­spond, how­ev­er, Pfiz­er be­gan ex­pe­ri­enc­ing tech­ni­cal dif­fi­cul­ties. Ex­ecs from the Big Phar­ma os­ten­si­bly had three mi­cro­phone lines open at the same time, per the ad­comm’s tech­ni­cal mod­er­a­tor, prompt­ing an un­sched­uled break to fix the is­sue. Af­ter the feed re­turned, Mon­to moved the pan­el on to the next ques­tion.

Pan­elists con­tin­ued pep­per­ing Pfiz­er with ques­tions about the risks of my­ocardi­tis in younger pa­tients and whether Pfiz­er should tai­lor its boost­er shots to spe­cif­ic vari­ants. Ques­tions al­so arose about how Is­raeli of­fi­cials have clas­si­fied se­vere Covid-19, with the CDC pre­sen­ter say­ing they use a loos­er de­f­i­n­i­tion than the Unit­ed States.

Then things moved to the dis­cus­sion pe­ri­od when things start­ed to grow more chaot­ic. Ul­ti­mate­ly, the pan­el land­ed on rec­om­mend­ing an EUA for in­di­vid­u­als 65 and old­er and at high risk for se­vere Covid-19. The ball now moves back to the FDA’s court, and it’s not im­me­di­ate­ly clear how long it will take for the agency to make an EUA de­ci­sion.

For a look at all End­points News coro­n­avirus sto­ries, check out our spe­cial news chan­nel.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

So — that pig-to-hu­man trans­plant; Po­ten­tial di­a­betes cure reach­es pa­tient; Ac­cused MIT sci­en­tist lash­es back; 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.

We’re incredibly excited to welcome Beth Bulik, seasoned pharma marketing reporter, to the team. You can find much of her work in our new Marketing channel — and in her weekly newsletter, Endpoints PharmaRx, which will launch in early November. Add it to your subscriptions here.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data are messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data are exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Pfiz­er pitch­es its Covid-19 vac­cine for younger chil­dren ahead of ad­comm next week

Pfizer will present its case to the FDA’s vaccine adcomm next week, seeking authorization for a lower-dose version of its Covid-19 vaccine for kids ages 5 through 12, which the Biden administration said will likely begin rolling out early next month.

Two primary doses of the 10 µg vaccine (the dose for those ages 12 and up is 30 μg) given 3 weeks apart in this group of children “have shown a favorable safety and tolerability profile, robust immune responses against all variants of concern including Delta, and vaccine efficacy of 90.7% against laboratory-confirmed symptomatic COVID-19,” the company said in briefing documents ahead of next Tuesday’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.

No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Boost­er bo­nan­za: FDA en­dors­es 'mix-and-match' scheme, and Mod­er­na and J&J too

The FDA late Wednesday signed off on authorizing the use of heterologous — or what FDA calls a “mix and match” of a primary vaccine series and different booster doses — for all currently available Covid-19 vaccines, in addition to separately authorizing Moderna and J&J boosters.

On the mix-and-match approach, which FDA officials insisted isn’t too confusing in a press conference, the agency offered the example of an 18-year-old who received the J&J shot at least two months ago and may now receive a single booster of the J&J, a half dose of the Moderna, or the Pfizer-BioNTech booster.