UP­DAT­ED: Mer­ck, Roche and Bris­tol My­ers nab 4 of 6 pos­i­tive ODAC votes for ‘dan­gling’ ac­cel­er­at­ed ap­provals

What looked at the out­set like a prime op­por­tu­ni­ty for the FDA to cri­tique in­dus­try over failed con­fir­ma­to­ry tri­als for lag­ging ac­cel­er­at­ed ap­provals end­ed up be­ing most­ly a tri­umph for the large bio­phar­ma com­pa­nies.

The FDA’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee vot­ed in fa­vor of keep­ing on the mar­ket four of the six “dan­gling” ac­cel­er­at­ed ap­provals pre­sent­ed to it over the last three days. Even de­spite the failed tri­als, com­pa­nies and their physi­cians raised con­cerns about un­met treat­ment needs and the long du­ra­tion of re­spons­es for the check­point in­hibitors be­fore each of the six votes.

The two ODAC votes that didn’t re­ceive a ma­jor­i­ty of “yes” votes from the out­side ex­perts were Mer­ck’s Keytru­da (pem­brolizum­ab) as a third-line treat­ment for stom­ach can­cer and Bris­tol My­ers Squibb’s Op­di­vo (nivolum­ab) as a sec­ond line treat­ment for liv­er can­cer. In both cas­es, Richard Paz­dur, di­rec­tor of the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence, raised con­cerns with the com­mit­tee, while not­ing the un­in­tend­ed con­se­quences of keep­ing Keytru­da on the mar­ket and ques­tion­ing BMS da­ta (see more be­low).

Leerink se­nior re­search an­a­lyst Daina Gray­bosch said in an in­vestor note on Fri­day, “We be­lieve mar­ket im­pact from the two in­di­ca­tions rec­om­mend­ed for with­draw­al are in­con­se­quen­tial, with a small and shrink­ing num­ber of pa­tients el­i­gi­ble” for Keytru­da as a third-line treat­ment for gas­tric can­cer (~1,000), and as there’s an op­por­tu­ni­ty for Bris­tol My­ers to shift pa­tients from Op­di­vo to the com­bi­na­tion of Op­di­vo and Yer­voy (ip­il­i­mum­ab), which al­so won ac­cel­er­at­ed ap­proval last year as a sec­ond-line treat­ment in he­pa­to­cel­lu­lar car­ci­no­ma (HCC).

Gray­bosch called the FDA “ob­jec­tive, but al­so force­ful in a cou­ple ar­gu­ments with spon­sors” dur­ing the three days, in line with re­cent ob­ser­va­tions from the agency. He al­so not­ed that Paz­dur made a “pow­er­ful case for with­draw­al in two cas­es, which seemed to sway the ODAC vote.”

Over­all, how­ev­er, the main take­away from the last three days seemed to be that if you’re a bio­phar­ma com­pa­ny that has won an ac­cel­er­at­ed ap­proval and your con­fir­ma­to­ry tri­al has failed, it may be un­wise to vol­un­tar­i­ly with­draw that ap­proval. Tak­ing the de­ci­sion to ODAC may end up with a thumbs up to re­main on the mar­ket while fu­ture tri­als are be­ing con­duct­ed.

Some out­side on­col­o­gists raised se­ri­ous con­cerns about main­tain­ing the in­tegri­ty of the ac­cel­er­at­ed ap­proval path­way if com­pa­nies and the FDA don’t get rid of cer­tain drug in­di­ca­tions that have failed in con­fir­ma­to­ry tri­als.

“If the drugs re­main on the mar­ket, the very na­ture of ac­cel­er­at­ed ap­proval should fall in­to ques­tion,” Vinay Prasad, on­col­o­gist at UCSF, told End­points. “Per­haps we can­not re­al­is­ti­cal­ly give con­di­tion­al ap­proval be­cause no one will ever have the courage to pull the drugs.”

Keytru­da in stom­ach can­cer

On Thurs­day morn­ing, ODAC vot­ed 6-2 against keep­ing Keytru­da as a third-line treat­ment for stom­ach can­cer. Pan­elists vot­ing no point­ed to the chang­ing treat­ment land­scape as ear­li­er this month an­oth­er check­point in­hibitor, Bris­tol My­ers Squibb’s Op­di­vo (nivolum­ab), won full ap­proval from the FDA and showed pos­i­tive over­all sur­vival ben­e­fit as a first line treat­ment for stom­ach can­cer.

The ac­cel­er­at­ed ap­proval first came in Sep­tem­ber 2017, but the FDA not­ed in its pre­sen­ta­tion Thurs­day that two fol­low-up tri­als did not con­firm the ben­e­fit that was ini­tial­ly seen.

Poo­ja Bha­gia, VP of on­col­o­gy re­search at Mer­ck, coun­tered that these two stud­ies were eval­u­at­ing Keytru­da as first- and sec­ond-line treat­ments for stom­ach can­cer. She al­so ex­plained how four on­go­ing Phase 3 tri­als (three of which are ei­ther ful­ly en­rolled or greater than 90% en­rolled) have the po­ten­tial to con­firm clin­i­cal ben­e­fit of Keytru­da in stom­ach can­cer be­fore the end of 2024.

Pe­ter En­zinger of the Dana Far­ber Can­cer In­sti­tute and a paid con­sul­tant to Mer­ck and oth­er physi­cians raised con­cerns about the lack of treat­ment op­tions in the third line, es­pe­cial­ly since Keytru­da is the on­ly im­munother­a­py avail­able.

But Paz­dur, FDA’s head of on­col­o­gy, shift­ed the tone of the morn­ing meet­ing and of­fered the agency’s per­spec­tive, stress­ing the un­in­tend­ed con­se­quences of keep­ing Keytru­da in this in­di­ca­tion as physi­cians might see check­point in­hibitors as op­tions in the first or third line, even though pos­i­tive over­all sur­vival re­sults have on­ly been seen in the first line with Op­di­vo.

And as more re­ceive check­point in­hibitors in the first line set­ting, few­er will re­ceive it in the third line set­ting, Steven Lemery, act­ing di­rec­tor of FDA’s Di­vi­sion of On­col­o­gy 3, added. He al­so not­ed im­mune-re­lat­ed ad­verse events with Keytru­da, how most pa­tients do not ben­e­fit from Keytru­da in this in­di­ca­tion, and he ques­tioned the rel­e­vance of the four pro­posed con­fir­ma­to­ry tri­als for this third-line in­di­ca­tion as they all are study­ing Keytru­da in com­bo with chemo.

“Many of these po­ten­tial con­fir­ma­to­ry tri­als won’t be avail­able for years. Would we grant this in­di­ca­tion at this time? The de­fin­i­tive an­swer is no,” Paz­dur said.

He al­so stressed that even if Keytru­da is pulled for this in­di­ca­tion, pa­tients who might be caught in lim­bo be­tween treat­ments may still be able to ac­cess Keytru­da be­cause the FDA can set up an ex­pand­ed ac­cess pro­to­col.

Keytru­da in HCC

The sit­u­a­tion turned against the FDA again in the af­ter­noon, al­though the agency isn’t oblig­ed to fol­low the ad­vice of its ad­vi­so­ry com­mit­tees.

In the first ses­sion, ODAC vot­ed unan­i­mous­ly, 8-0, to main­tain Keytru­da’s ac­cel­er­at­ed ap­proval for pa­tients with he­pa­to­cel­lu­lar car­ci­no­ma (HCC), a com­mon type of liv­er can­cer, as a sec­ond line treat­ment.

Mer­ck first won that ac­cel­er­at­ed ap­proval in No­vem­ber 2018, and the com­pa­ny made the case for why Keytru­da should re­main on the mar­ket as, even with the new ap­proval in the first line set­ting for the com­bi­na­tion of ate­zolizum­ab and be­va­cizum­ab, and the two new sec­ond-line ac­cel­er­at­ed ap­provals in this in­di­ca­tion, there’s a need for an­ti-PD-1 monother­a­py in the sec­ond line set­ting.

The FDA ar­gued that the treat­ment land­scape changed af­ter the ate­zolizum­ab-be­va­cizum­ab com­bo was ap­proved in the first-line set­ting.

Richard Finn, a pro­fes­sor of med­i­cine at UCLA and paid con­sul­tant for Mer­ck, said there does not seem to be any ben­e­fit to pulling this ac­cel­er­at­ed ap­proval for Keytru­da while two oth­er con­fir­ma­to­ry re­sults are ex­pect­ed soon. One of those re­sults from a tri­al in Asia is ex­pect­ed to read out in June or Ju­ly, and is in the same set­ting as the ac­cel­er­at­ed ap­proval.

FDA’s Steve Lemery not­ed that if this larg­er study in Asia is neg­a­tive, it’s un­clear if an­oth­er tri­al could be use­ful as a con­fir­ma­to­ry study as there would then be two neg­a­tive con­fir­ma­to­ry tri­als against place­bo. He al­so not­ed that while some pa­tients did see long du­ra­tion of re­sponse, most pa­tients do not ben­e­fit from the treat­ment. And he raised ques­tions, giv­en the chang­ing treat­ment land­scape, if Keytru­da would win ac­cel­er­at­ed ap­proval in this sec­ond line set­ting to­day.

Op­di­vo in HCC

In the late af­ter­noon ses­sion, ODAC vot­ed 5 to 4 to not main­tain Bris­tol My­ers Squibb’s Op­di­vo’s (nivolum­ab) in­di­ca­tion for the monother­a­py use of nivolum­ab in pa­tients pre­vi­ous­ly treat­ed with so­rafenib pend­ing the con­duct or com­ple­tion of ad­di­tion­al tri­al(s).

Pan­elist An­tho­ny Sung, as­sis­tant pro­fes­sor of med­i­cine at Duke Uni­ver­si­ty School of Med­i­cine, vot­ed “no” and said he didn’t think the da­ta was there on the whole. Su­san Ha­l­abi, a pro­fes­sor of bio­sta­tis­tics at Duke, al­so vot­ed no and said that al­though there’s an un­met need, she wasn’t con­vinced there was a clin­i­cal ben­e­fit.

Back in Sep­tem­ber 2017, Bris­tol My­ers Squibb’s Op­di­vo (nivolum­ab) won ac­cel­er­at­ed ap­proval as a sec­ond-line treat­ment for HCC. Two years lat­er, a con­fir­ma­to­ry study did not meet sta­tis­ti­cal sig­nif­i­cance in its pri­ma­ry end­point of over­all sur­vival and oth­er treat­ments for this in­di­ca­tion made their way to the mar­ket.

As seen with Keytru­da in the pri­or ses­sion, the al­tered treat­ment land­scape was a ques­tion for Op­di­vo, part­ly be­cause the drug al­so won an­oth­er, sep­a­rate ac­cel­er­at­ed ap­proval in com­bi­na­tion with Yer­voy (ip­il­i­mum­ab) last March for the same set­ting — pa­tients with HCC who have been pre­vi­ous­ly treat­ed with so­rafenib.

Bris­tol My­ers dis­cussed the sig­nif­i­cant un­met need in the sec­ond line treat­ment space for HCC and some long re­sponse rates with Op­di­vo.

An­tho­ny El-Khoueiry, as­so­ciate pro­fes­sor of med­i­cine at the Uni­ver­si­ty of South­ern Cal­i­for­nia, said Op­di­vo of­fers a more fa­vor­able ben­e­fit-risk pro­file than sec­ond-line an­ti-VEGF tar­get­ed op­tions.

Lemery pre­sent­ed again for FDA, ex­plain­ing the failed con­fir­ma­to­ry tri­al and not­ing that the agency found the com­bo of Op­di­vo and Yer­voy to be “high­ly rel­e­vant” giv­en the con­sid­er­ably low­er re­sponse rate for monother­a­py.

But Thomas Abrams, an as­so­ci­at­ed pro­fes­sor at Har­vard Med­ical School and paid Mer­ck con­sul­tant, said the com­bo treat­ment is re­al­ly re­served for the fit­ter pa­tients who failed a TKI (ty­ro­sine ki­nase in­hibitor) in the first line. For monother­a­py with Op­di­vo, Abrams said the pa­tients have more co­mor­bidi­ties, and “they re­al­ly are two dif­fer­ent pa­tient pop­u­la­tions.”

FDA’s Paz­dur again weighed in, claim­ing that BMS is es­sen­tial­ly try­ing to make the case for Op­di­vo as a monother­a­py for those who can­not tol­er­ate the Op­di­vo and Yer­voy com­bi­na­tion. But when Paz­dur pressed BMS on da­ta around the re­sponse rate for this pop­u­la­tion, BMS said it didn’t have the da­ta.

“You’re ad­vo­cat­ing for a new in­di­ca­tion, please pro­vide the re­sponse rate – not anec­do­tal in­for­ma­tion,” Paz­dur said.

Leerink’s Gray­bosch said ODAC’s vote to with­draw nivolum­ab from this in­di­ca­tion “seemed some­what un­fair as ODAC vot­ed unan­i­mous­ly ear­li­er to keep ac­cel­er­at­ed ap­proval for pem­brolizum­ab in the same in­di­ca­tion. Three dif­fer­ences, how­ev­er, were that Mer­ck did share ORR [over­all re­sponse rate] da­ta for pem­brolizum­ab in pa­tients who would be con­sid­ered in­el­i­gi­ble for be­va­cizum­ab, placed more em­pha­sis on com­pa­ra­ble ef­fi­ca­cy in 2L to TKIs, and has an on­go­ing, ran­dom­ized tri­al that could con­firm monother­a­py ef­fi­ca­cy.”

Last two days

Thurs­day’s meet­ing fol­lowed three oth­er votes on Tues­day and Wednes­day to main­tain Keytru­da and Tecen­triq ac­cel­er­at­ed ap­provals in oth­er in­di­ca­tions.

On Wednes­day morn­ing, ODAC vot­ed 5-3 in fa­vor of keep­ing Keytru­da’s ac­cel­er­at­ed ap­proval alive as a first line blad­der can­cer treat­ment for those who are cis­platin-in­el­i­gi­ble and car­bo­platin-in­el­i­gi­ble, even af­ter a Mer­ck con­fir­ma­to­ry tri­al failed.

And on Wednes­day af­ter­noon, ODAC vot­ed 10-1 in fa­vor of keep­ing Genen­tech’s Tecen­triq (ate­zolizum­ab) as a first-line treat­ment of cis­platin-in­el­i­gi­ble pa­tients with ad­vanced/metasta­t­ic blad­der can­cer pend­ing fi­nal over­all sur­vival re­sults from a con­fir­ma­to­ry tri­al, known as IMvig­or130.

Com­mit­tee mem­bers on Tues­day al­so vot­ed 7-2 to main­tain the ac­cel­er­at­ed ap­proval for Tecen­triq plus Abrax­ane (nab-pa­cli­tax­el) in metasta­t­ic triple neg­a­tive breast can­cer while ad­di­tion­al con­fir­ma­to­ry tri­als are on­go­ing.

These votes add to four oth­er vol­un­tary ac­cel­er­at­ed ap­proval with­drawals for Op­di­vo and Keytru­da as third-line treat­ments in small cell lung can­cer, and Tecen­triq and As­traZeneca’s Imfinzi (dur­val­um­ab) as sec­ond-line treat­ments for blad­der can­cer.

Look­ing for­ward

The FDA is not ob­lig­at­ed to fol­low the ad­vice of ODAC, but the agency will be faced with some dif­fi­cult de­ci­sions, par­tic­u­lar­ly on the prece­dent that might be set if some com­pa­nies are al­lowed to con­duct or wait for an ad­di­tion­al con­fir­ma­to­ry tri­al to read out be­fore their ac­cel­er­at­ed ap­proval in­di­ca­tions are pulled or con­vert­ed to a full ap­proval.

Al­though none of the drugs will be pulled en­tire­ly from the mar­ket, mean­ing all can be used off-la­bel for these in­di­ca­tions no mat­ter what hap­pens, this three-day meet­ing may push the FDA, and pos­si­bly even Con­gress, to re­assess the ac­cel­er­at­ed ap­proval path­way over­all and what should oc­cur when a con­fir­ma­to­ry tri­al fails.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Troy Wilson, Kura CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.

Kenneth Galbraith, incoming Zymeworks CEO

Zymeworks re­places half its C-suite, aims to lay off 25% of to­tal work­force as new CEO takes over

New Zymeworks CEO Kenneth Galbraith is aiming to hit the ground running when his tenure officially begins next month, but he’ll be doing so with a much different looking team.

In a lengthy press release outlining the biotech’s 2022 goals, Galbraith said Zymeworks will be laying off at least 25% of its staff over the course of the year. Half of its C-suite will also be replaced immediately as Galbraith looks to remake the company in his image after Ali Tehrani, Zymeworks’ founder and CEO since 2003, stepped down two weeks ago.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.