Weeks af­ter Keytru­da CRL in high-risk TNBC, Mer­ck claims a win af­ter da­ta ma­ture. How soon will it re­turn to FDA?

There’s been much afoot re­gard­ing Mer­ck’s at­tempts to ex­pand its block­buster Keytru­da drug in­to high-risk, ear­ly-stage triple-neg­a­tive breast can­cer so far in 2021.

In ear­ly Feb­ru­ary, well af­ter Mer­ck had sub­mit­ted its sup­ple­men­tal BLA for the in­di­ca­tion, the FDA’s ODAC unan­i­mous­ly re­buked the phar­ma’s pitch, say­ing the da­ta were too im­ma­ture to be con­clu­sive. FDA can­cer czar Richard Paz­dur took the ex­tra­or­di­nary step of ad­mon­ish­ing Mer­ck dur­ing the meet­ing, say­ing the com­pa­ny should not have as­sumed or hoped for a pos­i­tive re­sult be­fore the piv­otal study read out. A few weeks lat­er, reg­u­la­tors un­sur­pris­ing­ly hand­ed Mer­ck a com­plete re­sponse let­ter.

Now, though, the study has reached the in­ter­im analy­sis check­point. And Mer­ck says it’s a win­ner.

The KEYNOTE-522 study — the same tri­al un­der the mi­cro­scope in Feb­ru­ary’s ad­comm — met its dual pri­ma­ry end­point of event-free sur­vival, Mer­ck an­nounced Thurs­day morn­ing, demon­strat­ing a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in EFS com­pared to the con­trol. Its oth­er pri­ma­ry end­point, patho­log­i­cal com­plete re­sponse, had pre­vi­ous­ly been met.

Roy Baynes

“Now that we are see­ing the da­ta ma­ture af­ter four years to in­clude a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in event-free sur­vival, we look for­ward to work­ing with the FDA and oth­er glob­al au­thor­i­ties,” Roy Baynes, CMO of Mer­ck Re­search Lab­o­ra­to­ries, said in a state­ment.

Mer­ck has been look­ing to ex­pand Keytru­da in­to this TNBC pop­u­la­tion as both a pre-op­er­a­tive (with chemo) and post-op (with­out chemo) treat­ment. The ear­ly da­ta pre­sent­ed at Feb­ru­ary’s ad­comm proved a re­al stick­ing point, with even some pa­tient ad­vo­cates won­der­ing what the rush was all about.

At the time of the last check-in, re­searchers had seen just 53% of tar­get­ed EFS events and 32% of over­all sur­vival events.

It’s not yet clear whether or not the new re­sults will change the agency’s mind re­gard­ing this in­di­ca­tion, giv­en Mer­ck says the EFS da­ta are now good to go. OS is a sec­ondary end­point in this study, and Mer­ck did not dis­close any re­lat­ed in­for­ma­tion in Thurs­day’s an­nounce­ment.

At least one an­a­lyst thinks Thurs­day’s an­nounce­ment will ul­ti­mate­ly set up Mer­ck for a re­bound at the FDA. Bar­clays’ Carter Gould wrote to in­vestors that al­though there were no quan­ti­ta­tive da­ta re­leased, Mer­ck could see a po­ten­tial ap­proval as ear­ly as next year.

“These da­ta should di­rect­ly ad­dress the pan­el’s re­cent con­cern over the lack of ma­ture EFS da­ta, and we would ex­pect Mer­ck to re­file based on these da­ta,” Gould wrote. “This shouldn’t be sur­pris­ing as Mer­ck it­self high­light­ed dur­ing the Ad­Com that the study had 75-95%+ chance of demon­strat­ing a sta­tis­ti­cal­ly sig­nif­i­cant ben­e­fit based on its mod­el­ing as­sump­tions at the time.”

Even though Keytru­da has be­come one of the best-sell­ing drugs on the plan­et, bring­ing in al­most $3.9 bil­lion in this year’s first quar­ter, high-risk TNBC has proven a rare stum­bling block for Mer­ck. Be­fore the ad­comm re­buff, Keytru­da had al­ready come up short to Roche’s ri­val Tecen­triq in pa­tients with PD-L1-ex­press­ing TNBC that have un­re­sectable and lo­cal­ly re­cur­rent or metasta­t­ic tu­mors. Mer­ck even­tu­al­ly gained the thumbs up here last No­vem­ber.

But Tecen­triq pre­vi­ous­ly failed a con­fir­ma­to­ry study for the first-line treat­ment of the PD-L1 group, which may end up putting its ac­cel­er­at­ed ap­proval in jeop­ardy. ODAC vot­ed 7 to 2 in April to main­tain its OK, how­ev­er, as part of the FDA’s broad­er re­view of ac­cel­er­at­ed ap­provals that missed their pri­ma­ry end­points in the con­fir­ma­to­ry fol­low-ups.

So­cial: Va­leriya Zankovych/Shut­ter­stock

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.

Susan Galbraith, AstraZeneca EVP, Oncology R&D

Can­cer pow­er­house As­traZeneca rolls the dice on a $75M cash bet on a buzzy up­start in the on­col­o­gy field

After establishing itself in the front ranks of cancer drug developers and marketers, AstraZeneca is putting its scientific shoulder — and a significant amount of cash — behind the wheel of a brash new upstart in the biotech world.

The pharma giant trumpeted news this morning that it is handing over $75 million upfront to ally itself with Scorpion Therapeutics, one of those biotechs that was newly birthed by some top scientific, venture and executive talent and bequeathed with a fortune by way of a bankroll to advance an only hazily explained drug platform. And they are still very much in the discovery and preclinical phase.

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Lat­est news on Pfiz­er's $3B+ JAK1 win; Pacts over M&A at #JPM22; 2021 by the num­bers; Bio­gen's Aduhelm reck­on­ing; The sto­ry of sotro­vimab; 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.

For those of you who attended #JPM22 in any shape or form, we hope you had a fruitful time. Regardless of how you spent the past hectic week, may your weekend be just what you need it to be.

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A $3B+ peak sales win? Pfiz­er thinks so, as FDA of­fers a tardy green light to its JAK1 drug abroc­i­tinib

Back in the fall of 2020, newly crowned Pfizer chief Albert Bourla confidently put their JAK1 inhibitor abrocitinib at the top of the list of blockbuster drugs in the late-stage pipeline with a $3 billion-plus peak sales estimate.

Since then it’s been subjected to serious criticism for the safety warnings associated with the class, held back by a cautious FDA and questioned when researchers rolled out a top-line boast that their heavyweight contender had beaten the champ in the field of atopic dermatitis — Dupixent — in a head-to-head study.

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Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Rob Califf ad­vances as Biden's FDA nom­i­nee, with a close com­mit­tee vote

Rob Califf’s second confirmation process as FDA commissioner is already much more difficult than his near unanimous confirmation under the Obama administration.

The Senate Health Committee on Thursday voted 13-8 in favor of advancing Califf’s nomination to a full Senate vote. Several Democrats voted against Califf, including Sen. Bernie Sanders and Sen. Maggie Hassan. Several other Democrats who aren’t on the committee, like West Virginia’s Joe Manchin and Ed Markey of Massachusetts, also said Thursday that they would not vote for Califf. Markey, Hassan and Manchin all previously expressed reservations about the prospect of Janet Woodcock as an FDA commissioner nominee too.

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Michel Vounatsos, Biogen CEO (World Economic Forum/Ciaran McCrickard)

Bio­gen vows to fight CM­S' draft cov­er­age de­ci­sion for Aduhelm be­fore April fi­nal­iza­tion

Biogen executives made clear in an investor call Thursday they are not preparing to run a new CMS-approved clinical trial for their controversial Alzheimer’s drug anytime soon.

As requested in a draft national coverage decision from CMS earlier this week, Biogen and other anti-amyloid drugs will need to show “a meaningful improvement in health outcomes” for Alzheimer’s patients in a randomized, placebo-controlled trial to get paid for their drugs, rather than just the reduction in amyloid plaques that won Aduhelm its accelerated approval in June.

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CRO own­er pleads guilty to ob­struct­ing FDA in­ves­ti­ga­tion in­to fal­si­fied clin­i­cal tri­al da­ta

The co-owner of a Florida-based clinical research site pleaded guilty to lying to an FDA investigator during a 2017 inspection, revealing that she falsely portrayed part of a GlaxoSmithKline pediatric asthma study as legitimate, when in fact she knew that certain data had been falsified, the Department of Justice said Wednesday.

Three other employees — Yvelice Villaman Bencosme, Lisett Raventos and Maytee Lledo — previously pleaded guilty and were sentenced in connection with falsifying data associated with the trial at the CRO Unlimited Medical Research.

‘Skin­ny la­bels’ on gener­ics can save pa­tients mon­ey, re­search shows, but re­cent court de­ci­sions cloud fu­ture

New research shows how generic drug companies can successfully market a limited number of approved indications for a brand name drug, prior to coming to market for all of the indications. But several recent court decisions have created a layer of uncertainty around these so-called “skinny” labels.

While courts have generally allowed generic manufacturers to use their statutorily permitted skinny-label approvals, last summer, a federal circuit court found that Teva Pharmaceuticals was liable for inducing prescribers and patients to infringe GlaxoSmithKline’s patents through advertising and marketing practices that suggested Teva’s generic, with its skinny label, could be employed for the patented uses.

A patient in Alaska receiving an antibody infusion to prevent Covid hospitalizations in September. All but one of these treatments has been rendered useless by Omicron (Rick Bowmer/AP Images)

How a tiny Swiss lab and two old blood sam­ples cre­at­ed one of the on­ly ef­fec­tive drugs against Omi­cron (and why we have so lit­tle of it)

Exactly a decade before a novel coronavirus broke out in Wuhan, Davide Corti — a newly-minted immunologist with frameless glasses and a quick laugh — walked into a cramped lab on the top floor of an office building two hours outside Zurich. He had only enough money for two technicians and the ceiling was so low in parts that short stature was a job requirement, but Corti believed it’d be enough to test an idea he thought could change medicine.

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