FDA busts Mer­ck­'s Keytru­da in triple-neg­a­tive breast can­cer with a CRL — not un­ex­pect­ed giv­en its dis­as­trous ad­comm

Mer­ck and the FDA have en­gaged in a high-noon stand­off over check­point in­hibitor Keytru­da in triple-neg­a­tive breast can­cer af­ter the agency round­ly panned its re­sults in high-risk pa­tients. Now, with a de­ci­sive ad­comm sup­port­ing its crit­i­cisms, the FDA has shown Keytru­da the door in that in­di­ca­tion.

The FDA slapped Keytru­da with a CRL in high-risk triple-neg­a­tive breast can­cer af­ter the agency’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee hand­ed out a rather gen­tle slap­down on the I/O drug’s ap­pli­ca­tion last month, Mer­ck said Mon­day.

Keytru­da’s chances as monother­a­py af­ter a reg­i­men of Keytru­da and chemo and surgery in triple-neg­a­tive breast can­cer were al­ways a long­shot af­ter the FDA of­fered a sting­ing re­buke of the drug’s piv­otal dataset, which it called “ques­tion­able” giv­en im­ma­ture OS da­ta and some wishy-washy ef­fi­ca­cy num­bers, ac­cord­ing to ODAC brief­ing doc­u­ments at the time.

What re­al­ly riled up the agency, how­ev­er, was that they ex­plic­it­ly asked Mer­ck not to sub­mit for ap­proval af­ter ex­press­ing their con­cerns with the ma­tu­ri­ty of the dataset af­ter mul­ti­ple meet­ings. The CRL doesn’t af­fect Keytru­da’s ap­proval as a com­bi­na­tion ther­a­py with chemo in lo­cal­ly ad­vanced, PD-1 ex­press­ing TNBC tu­mors that are metasta­t­ic or can­not be sur­gi­cal­ly re­moved.

The ba­sis for Mer­ck’s sub­mis­sion was KEYNOTE-522, which test­ed Keytru­da as a post-sur­gi­cal monother­a­py fol­low­ing a com­bo of Keytru­da and plat­inum-based chemother­a­py. The study’s event-free sur­vival pri­ma­ry end­point over place­bo was too im­ma­ture to judge — a quick red flag — as re­searchers hadn’t watched pa­tients long enough af­ter treat­ment to de­ter­mine EFS and OS. At the time of third check-in, just 53% of tar­get­ed EFS events had oc­curred and 32% of OS events.

The agency al­so pushed back on the study’s pCR co-pri­ma­ry end­point, which Keytru­da hit, call­ing ef­fi­ca­cy over place­bo “small.”

The 10-0 ODAC vote, how­ev­er, wasn’t a nail in the cof­fin. The ad­vi­so­ry com­mit­tee ad­vo­cat­ed wait­ing out fi­nal safe­ty fig­ures, and Mer­ck said an­oth­er in­ter­im look-in on the KEYNOTE-522 da­ta was com­ing up in the third quar­ter.

Does any of that “wait-and-see” men­tal­i­ty mean the FDA will change its mind and wel­come Keytru­da back in these pa­tients? That’s un­clear. But a win on EFS and OS could be enough to swing a vote giv­en the FDA’s re­cent his­to­ry of re­ward­ing drugs that don’t hit the pri­ma­ry end­point in piv­otal stud­ies. Call­ing an ad­comm on da­ta it seemed nev­er like­ly to ap­prove, how­ev­er, looked a lot like the FDA and OCE di­rec­tor Richard Paz­dur pub­licly putting an overzeal­ous drug­mak­er in the penal­ty box.

Mer­ck, for its part, found the drug’s in­ter­im sur­vival da­ta to show a “strong and durable” trend, the drug­mak­er said in Feb­ru­ary.

Ed­i­tor’s Note: This sto­ry has been up­dat­ed to clar­i­fy de­tails of KEYNOTE-522’s de­sign.

BY­OD Best Prac­tices: How Mo­bile De­vice Strat­e­gy Leads to More Pa­tient-Cen­tric Clin­i­cal Tri­als

Some of the most time- and cost-consuming components of clinical research center on gathering, analyzing, and reporting data. To improve efficiency, many clinical trial sponsors have shifted to electronic clinical outcome assessments (eCOA), including electronic patient-reported outcome (ePRO) tools.

In most cases, patients enter data using apps installed on provisioned devices. At a time when 81% of Americans own a smartphone, why not use the device they rely on every day?

Chris Gibson (Photo By Vaughn Ridley/Sportsfile for Web Summit via Getty Images)

Re­cur­sion founders gin for­tunes as IPO back­ers show­er $436M on one of the biggest boasts in AI -- based on some very small deals

In the AI drug development world, boasting often comes with the territory. Yet few can rival Recursion when it comes to claiming the lead role in what company execs like to call the industrialization of drug development, with promises of continued exponential growth in the number of drugs it has in the pipeline.

On Friday, the Salt Lake City-based biotech translated its unicorn-sized boasts into a killer IPO, pricing more than 24 million shares at the high end of its range and bringing in $436 million — with a large chunk of that promised by some deep-pocket backers.

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Eli Lil­ly asks FDA to re­voke EUA for Covid-19 treat­ment

Eli Lilly on Friday requested that the FDA revoke the emergency authorization for its Covid-19 drug bamlanivimab, which is no longer as effective as a combo therapy because of a rise in coronavirus variants across the US.

“With the growing prevalence of variants in the U.S. that bamlanivimab alone may not fully neutralize, and with sufficient supply of etesevimab, we believe now is the right time to complete our planned transition and focus on the administration of these two neutralizing antibodies together,” Daniel Skovronsky, Lilly’s CSO, said in a statement.

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Covid-19 vac­cine halt drags on, an FDA ap­point­ment at long last, the great CRO con­sol­i­da­tion, 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.

Conference season is upon us, and while we’d much prefer to be wandering down the hallways and presentation rooms in person, the team is ready to cover the most consequential data coming out of these scientific meetings. Get in touch early if you have news to share.

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Ex­clu­sive in­ter­view: Pe­ter Marks on why full Covid-19 vac­cine ap­provals could be just months away

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, took time out of his busy schedule last Friday to discuss with Endpoints News all things related to his work regulating vaccines and the pandemic.

Marks, who quietly coined the name “Operation Warp Speed” before deciding to stick with his work regulating vaccines at the FDA rather than join the Trump-era program, has been the face of vaccine regulation for the FDA throughout the pandemic, and is usually spotted in Zoom meetings seated in front of his wife’s paintings.

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Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Natalie Holles was five months into her tenure as Audentes CEO and working to smooth out a $3 billion merger when the world crashed in.

Holles and her team received word on the morning of May 5 that, hours before, a patient died in a trial for their lead gene therapy. They went into triage mode, alerting the FDA, calling trial investigators to begin to understand what happened, and, the next day, writing a letter to alert the patient community so they would be the first to know. “We wanted to be as forthright and transparent as possible,” Holles told me late last month.

The brief letter noted two other patients also suffered severe reactions after receiving a high dose of the therapy and were undergoing treatment. One died a month and a half later, at which point news of the deaths became public, jolting an emergent gene therapy field and raising questions about the safety of the high doses Audentes and others were now using. The third patient died in August.

“It was deeply saddening,” Holles said. “But I was — we were — resolute and determined to understand what happened and learn from it and get back on track.”

Eleven months have now passed since the first death and the therapy, a potential cure for a rare and fatal muscle-wasting disease called X-linked myotubular myopathy, is back on track, the FDA having cleared the company to resume dosing at a lower level. Audentes itself is no more; last month, Japanese pharma giant Astellas announced it had completed working out the kinks of the $3 billion merger and had restructured and rebranded the subsidiary as Astellas Gene Therapies. Holles, having successfully steered both efforts, departed.

Still, questions about precisely what led to the deaths of the 3 boys still linger. Trial investigators released key details about the case last August and December, pointing to a biological landmine that Audentes could not have seen coming — a moment of profound medical misfortune. In an emerging field that’s promised cures for devastating diseases but also seen its share of safety setbacks, the cases provided a cautionary tale.

Audentes “contributed in a positive way by giving a painful but important example for others to look at and learn from,” Terry Flotte, dean of the UMass School of Medicine and editor of the journal Human Gene Therapy, told me. “I can’t see anything they did wrong.”

Yet some researchers say they’re still waiting on Astellas to release more data. The company has yet to publish a full paper detailing what happened, nor have they indicated that they will. In the meantime, it remains unclear what triggered the events and how to prevent them in the future.

“Since Audentes was the first one and we don’t have additional information, we’re kind of in a holding pattern, flying around, waiting to figure out how to land our vehicles,” said Jude Samulski, professor of pharmacology at UNC’s Gene Therapy Center and CSO of the gene therapy biotech AskBio, now a subsidiary of Bayer.

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As­traZeneca-Alex­ion merg­er slides through FTC re­view af­ter sup­posed M&A crack­down pos­es no bar­ri­ers

The AstraZeneca-Alexion megamerger received a good sign Friday, despite warning signs of the tides turning against large M&A pharma deals.

US regulators at the FTC have cleared the acquisition for approval, AstraZeneca announced, all but signing off on the deal to go through once it officially closes in the third quarter. AstraZeneca originally said it was planning to buy out Alexion back in December for $39 billion.

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J&J faces CDC ad­vi­so­ry com­mit­tee again next week to weigh Covid-19 vac­cine risks

The CDC’s Advisory Committee on Immunization Practices punted earlier this week on deciding whether or not to recommend lifting a pause on the administration of J&J’s Covid-19 vaccine, but the committee will meet again in an emergency session next Friday to discuss the safety issues further.

The timing of the meeting likely means that the J&J vaccine will not return to the US market before the end of next week as the FDA looks to work hand-in-hand with the CDC to ensure the benefits of the vaccine still outweigh the risks for all age groups.

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David Stack, Pacira Biosciences CEO

In high­ly un­usu­al move, Paci­ra sues med­ical jour­nal for li­bel over its non-opi­oid painkiller

A New Jersey biotech whose only approved drug is used as a painkiller after surgeries is suing a scientific journal, its editors and a handful of authors for libel after the publication printed numerous papers and editorials that the company says discredited the drug.

Pacira Biosciences filed the complaint against the American Society of Anesthesiologists in the US District Court for New Jersey on Wednesday afternoon. A February issue of the group’s journal Anesthesiology printed three articles and other content full of “bias” that “seriously disparaged” the drug Exparel, Pacira claimed.