FDA slams Spec­trum and On­copep­tides can­cer drugs over ef­fi­ca­cy con­cerns ahead of ODAC meet­ing

The FDA’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee meet­ing on Thurs­day will like­ly be a slaugh­ter for two bio­phar­ma com­pa­nies, Spec­trum Phar­ma­ceu­ti­cals and On­copep­tides, as re­view­ers to­day raised sig­nif­i­cant con­cerns and ques­tions for both spon­sors in brief­ing doc­u­ments re­leased ahead of the meet­ing.

Spec­trum is seek­ing to win an ap­proval for pozi­o­tinib tablets as a treat­ment for pa­tients with pre­vi­ous­ly treat­ed, lo­cal­ly ad­vanced or metasta­t­ic NSCLC har­bor­ing HER2 ex­on 20 in­ser­tion mu­ta­tions. Pozi­o­tinib’s NDA is sup­port­ed by da­ta from a Phase II ZENITH20 tri­al, which showed that the tablets elicit­ed an ORR of 28% (95% CI, 18.9%-38.2%) in this pa­tient pop­u­la­tion, while the me­di­an du­ra­tion of re­sponse (DOR) was 5.1 months (95% CI, 4.2-5.5).

“The ORR and DOR re­sults ob­served in the pri­ma­ry ef­fi­ca­cy pop­u­la­tion en­rolled in ZENITH20 sup­port­ing this NDA may not pro­vide a mean­ing­ful ad­van­tage over avail­able ther­a­pies and may not be like­ly to pre­dict clin­i­cal ben­e­fit,” the FDA said in its brief­ing doc­u­ment. Spec­trum $SP­PI shares were down more than 25% on Tues­day.

The agency al­so not­ed how As­traZeneca and Dai­ichi Sankyo’s En­her­tu was grant­ed ac­cel­er­at­ed ap­proval in Au­gust based on an ORR of 58% (95% CI 43,71) and mDOR 8.7 months (95% CI (7.1, NE).

“The key is­sues for con­sid­er­a­tion in the ben­e­fit-risk as­sess­ment of pozi­o­tinib in­clude the pre­sumed clin­i­cal ben­e­fits of the ap­proval of a tar­get­ed ther­a­py for a rare pa­tient pop­u­la­tion, the in­ad­e­quate dosage op­ti­miza­tion in the con­text of mar­gin­al ef­fi­ca­cy and high tox­i­c­i­ty, and the ac­cept­able trade­offs be­tween the ben­e­fits and risks to pa­tients,” the agency wrote.

FDA al­so not­ed that pozi­o­tinib’s con­fir­ma­to­ry tri­al to ver­i­fy clin­i­cal ben­e­fit “is not well un­der­way and re­sults are not ex­pect­ed un­til at least 2026. Fur­ther­more, the dose se­lect­ed for eval­u­a­tion in the con­fir­ma­to­ry tri­al is 8 mg BID rather than 16 mg QD. This NDA sub­mis­sion may have been pre­ma­ture giv­en the in­ad­e­quate dosage op­ti­miza­tion when con­sid­ered in the con­text of mar­gin­al ef­fi­ca­cy and high tox­i­c­i­ty.”

ODAC will vote on one ques­tion, “Do the cur­rent ben­e­fits of pozi­o­tinib out­weigh its risks for the treat­ment of pa­tients with NSCLC with HER2 ex­on 20 in­ser­tion mu­ta­tions?” The FDA is not re­quired to fol­low the ad­vice of its ad­comms but it of­ten does.

Lat­er on Thurs­day, the FDA will ask ODAC to de­cide the fate of a dan­gling ac­cel­er­at­ed ap­proval, On­copep­tides’ mul­ti­ple myelo­ma drug Pepax­to (mel­pha­lan flufe­namide), which failed to show ben­e­fit in its con­fir­ma­to­ry tri­al. $ON­CO shares were down more than 35% on Tues­day.

“Giv­en the po­ten­tial detri­ment in over­all sur­vival, fail­ure to demon­strate a pro­gres­sion-free sur­vival ben­e­fit, and lack of an ap­pro­pri­ate dose, is the ben­e­fit-risk pro­file of mel­pha­lan flufe­namide fa­vor­able for the cur­rent­ly in­di­cat­ed pa­tient pop­u­la­tion?” is the vot­ing ques­tion for this one.

It’s been a rocky jour­ney for Pepax­to, as last Oc­to­ber, On­copep­tides de­cid­ed to pull it from the mar­ket af­ter the tri­al fail­ure, on­ly to de­cide three months lat­er that it won’t pull the drug, with­out much ex­pla­na­tion for the about-face. The Eu­ro­pean Med­i­cines Agency in June rec­om­mend­ed ap­proval for Pepax­ti (mel­pha­lan flufe­namide) for the treat­ment of mul­ti­ple myelo­ma, which is a rare can­cer of the bone mar­row.

Now it ap­pears that On­copep­tides is try­ing to make a case that the con­fir­ma­to­ry tri­al showed ben­e­fit, even as the FDA in Ju­ly alert­ed pa­tients and health­care pro­fes­sion­als that the con­fir­ma­to­ry tri­al for mel­pha­lan flufe­namide had been halt­ed, as the com­bi­na­tion of it and dex­am­etha­sone showed an in­creased risk of death.

Ahead of Thurs­day’s dis­cus­sion, the FDA makes clear in its side-by-side brief­ing doc­u­ments that it “does not agree with the Ap­pli­cant’s po­si­tion that the re­sults of the OCEAN tri­al con­firm the clin­i­cal ben­e­fit of mel­pha­lan flufe­namide…At this time, the over­all avail­able ev­i­dence in­di­cates a po­ten­tial for harm, un­cer­tain clin­i­cal ben­e­fit and sug­gests that the over­all ben­e­fit-risk pro­file of mel­pha­lan flufe­namide is un­fa­vor­able.”

While On­copep­tides con­duct­ed a re­vised PFS analy­sis “which in­di­cat­ed a mar­gin­al PFS sig­nif­i­cance,” the agency said the “re­sults of analy­ses of oth­er ef­fi­ca­cy end­points such as ORR and DOR were ei­ther not sta­tis­ti­cal­ly sig­nif­i­cant or pro­vid­ed for a mag­ni­tude of ef­fect that would not be con­sid­ered clin­i­cal­ly mean­ing­ful.”

But the agency did say that ad­di­tion­al dose ex­plo­ration to iden­ti­fy a tol­er­a­ble dose for Pepax­to with dos­ing based on weight or body sur­face area is war­rant­ed.

Justin Klee (L) and Joshua Cohen, Amylyx co-CEOs (Cody O'Loughlin/The New York Times; courtesy Amylyx)

Ad­vo­cates, ex­perts cry foul over Amy­lyx's new ALS drug, cit­ing is­sues with price, PhI­II com­mit­ment

Not 24 hours after earning the first ALS drug approval in five years, Amylyx Pharmaceuticals’ Relyvrio is already drawing scrutiny. And it’s coming from multiple fronts.

In an investor call Friday morning, Amylyx revealed that it would charge about $158,000 per year, a price point that immediately drew backlash from ALS advocates and some outside observers. The cost reveal had been highly anticipated in the immediate hours after Thursday evening’s approval, though Amylyx only teased Relyvrio would cost less than previously approved drugs.

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Pi­o­neer­ing Click Chem­istry in Hu­mans

Reimagining cancer treatments

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, which is nearly one in six deaths. Recently, we have seen incredible advances in novel cancer therapies such as immune checkpoint inhibitors, cell therapies, and antibody-drug conjugates that have revamped cancer care and improved survival rates for patients.

Despite this significant progress in therapeutic targeting, why are we still seeing such a high mortality rate? The reason is that promising therapies are often limited by their therapeutic index, which is a measure of the effective dose of a drug, relative to its safety. If we could broaden the therapeutic indices of currently available medicines, it would revolutionize cancer treatments. We are still on the quest to find the ultimate cancer medicine – highly effective in several cancer types, safe, and precisely targeted to the tumor site.

Land­mark Amy­lyx OK spurs de­bate; Some... pos­i­tive? Alzheimer's da­ta; Can­cer tri­al bot­tle­neck; Sanofi's CRISPR bet; 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.

After brief stops in Paris and Boston, John Carroll and the Endpoints crew are staying on the road in October with their return for a live/streaming EUBIO22 in London. The hybrid event fireside chats and panels on mRNA, oncology and the crazy public market. We hope you can join him there.

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Joshua Cohen (L) and Justin Klee, Amylyx co-CEOs

Up­dat­ed: Af­ter long and wind­ing road, FDA ap­proves Amy­lyx's ALS drug in vic­to­ry for pa­tients and ad­vo­ca­cy groups

For just the third time in its 116-year history, the FDA has approved a new treatment for Lou Gehrig’s disease, or ALS.

US regulators gave the thumbs-up to the drug, known as Relyvrio, in a massive win for patients and their families. The approval, given to Boston-area biotech Amylyx Pharmaceuticals, comes after two years of long and contentious debates over the drug’s effectiveness between advocacy groups and FDA scientists, following the readout of a mid-stage clinical trial in September 2020.

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Up­dat­ed: Al­ny­lam re­in­forces APOL­LO-B patisir­an da­ta be­fore head­ing to the FDA

Weeks after uncorking some mostly positive data for patisiran in transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, Alnylam is bolstering its package with new exploratory and subgroup data before shipping it off to regulators.

The RNAi drug maintained “generally consistent” benefits in efficacy and quality of life across several prespecified subgroups at month 12, Alnylam announced on Friday afternoon, including age, baseline tafamidis use, ATTR amyloidosis type, baseline six-minute walk test score and others.

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Nooman Haque, head of life sciences and healthcare at Silicon Valley Bank, and John Carroll

I’m head­ed to Lon­don soon for #EU­BIO22. Care to join me?

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.

#AAO22: J&J’s first look at com­mon eye dis­ease port­fo­lio pads the case for PhII of gene ther­a­py

CHICAGO — While the later-stage drug developers in the geographic atrophy field are near the finish line, Johnson & Johnson’s Janssen is taking a more deliberate route, with a treatment that it hopes to be a one-time fix.

The Big Pharma will take its Hemera Biosciences-acquired gene therapy into a Phase II study later this year in patients with GA, a common form of age-related macular degeneration that impacts about five million people worldwide. To get there, Janssen touted early-stage safety data at the American Academy of Ophthalmology annual conference Saturday morning, half a day after competitors Apellis and Iveric Bio revealed their own more-detailed Phase III analyses.

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Jerome Durso, Intercept Pharmaceuticals CEO

In­ter­cep­t's OCA fails a PhI­II NASH tri­al, rais­ing fresh doubts about its years­long quest for an OK

Intercept Pharmaceuticals has run into another big setback in its yearslong quest to win an approval for OCA in NASH. The biotech put out word Friday morning that its Phase III REVERSE study failed the primary endpoint for the liver disease, sending its share price into a tailspin.

There was no significant improvement in fibrosis among the patients suffering from cirrhosis who were treated with obeticholic acid, with investigators hunting for a minimum 1-stage histological improvement in the disease after 18 months of therapy.

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Bo Cumbo, new Solid Bio CEO

Sol­id Bio gets a new CEO, $75M cash and drops lead drug as big in­vestors ju­ry-rig a merg­er deal

Three months after Endpoints News broke the story that gene therapy outfit AavantiBio had gutted its CMC group in a reorganization, the biotech’s CEO has helped engineer a merger with struggling penny stock player Solid Bio. And he’s going to remain in charge of the combined operation, as Solid founder Ilan Ganot steps aside.

The merger news this morning features some high-profile investors.

Perceptive Advisors, RA Capital Management and Bain Capital Life Sciences are leading a $75 million raise to add to the pool of cash Solid will have after the tie-up. That will leave Solid $215 million in cash as Bain’s Adam Koppel jumps on the board — enough to pay for ops and get through some key data milestones on their way into 2025.

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