Richard Pazdur, FDA's OCE director (Flatiron Health via YouTube)

FDA's OCE makes the case for ac­cel­er­at­ed ap­proval rid­er in user fee reau­tho­riza­tion

Four ex­perts from the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence took to the New Eng­land Jour­nal of Med­i­cine yes­ter­day to make the case for not on­ly im­prov­ing the agency’s abil­i­ty to ex­pe­di­tious­ly pull dan­gling ac­cel­er­at­ed ap­provals when, on the rare oc­ca­sion, con­fir­ma­to­ry tri­als fail, but al­so bet­ter build­ing “qual­i­ty and ef­fi­cien­cy in­to the AA on-ramp.”

The time­ly per­spec­tive ar­rives as Con­gress has ex­act­ly one week left to draft, re­lease and sign off on the reau­tho­rized user fee deals be­fore lay­off no­tices will be sent to drug re­view­ers. That pack­age, which is like­ly to hitch a ride with the con­tin­u­ing res­o­lu­tion, may or may not in­clude sev­er­al pol­i­cy rid­ers (op­posed by Re­pub­li­cans), in­clud­ing one that would al­low the FDA to re­quire con­fir­ma­to­ry tri­als to be un­der­way be­fore an AA is grant­ed, and would im­prove the process by which FDA can with­draw AAs.

The FDA au­thors make clear the need for such an AA rid­er as for on­col­o­gy in­di­ca­tions that have been grant­ed AAs, the me­di­an time to be­gin­ning the with­draw­al process “was longer if the con­fir­ma­to­ry tri­al was ini­ti­at­ed af­ter the ap­proval (see fig­ure). This dif­fer­ence was most strik­ing among with­drawn in­di­ca­tions, with a me­di­an time to with­draw­al of 3.8 years if the con­fir­ma­to­ry tri­al was on­go­ing at the time of AA, as com­pared with 7.3 years if such a tri­al had not been ini­ti­at­ed. De­layed with­drawals in this lat­ter sce­nario rep­re­sent the great­est risk to pa­tients.”

OCE’s Lo­la Fashoyin-Aje, Gau­tam Mehta, Ju­lia Beaver, and Richard Paz­dur al­so of­fer sev­er­al up­front op­tions for those pur­su­ing AAs.

For in­stance, spon­sors could pur­sue a sin­gle ran­dom­ized tri­al, po­ten­tial­ly in an ear­li­er treat­ment set­ting, that could both sup­port AA and ver­i­fy clin­i­cal ben­e­fit, they say, with the ac­cel­er­at­ed ap­proval com­ing on the ba­sis of a planned in­ter­im analy­sis of ORR, and a con­ver­sion to full ap­proval grant­ed on the ba­sis of clin­i­cal ben­e­fit (OS im­prove­ment) at the tri­al’s con­clu­sion.

“This ap­proach would pro­vide a more thor­ough safe­ty as­sess­ment and ear­li­er de­fin­i­tive ev­i­dence of the ben­e­fit–risk bal­ance. It would al­so re­duce the risk of pre­ma­ture­ly halt­ing de­vel­op­ment of a drug with a lim­it­ed over­all re­sponse rate that might nev­er­the­less im­prove over­all sur­vival,” they wrote.

An­oth­er po­ten­tial strat­e­gy for spon­sors would be to agree in ad­vance on the cri­te­ria for at­tain­ing AA, and the cri­te­ria for with­draw­ing the in­di­ca­tion. Spon­sors could then run two con­cur­rent stud­ies: a sin­gle-group AA study ex­am­in­ing the ORR in pa­tients with­out oth­er avail­able ther­a­pies, and a ran­dom­ized tri­al fo­cused on clin­i­cal ben­e­fit in pa­tients who have re­ceived few­er treat­ments.

“If these stud­ies en­rolled pa­tients around the same time, an in­ter­im analy­sis of safe­ty and over­all re­sponse rate in the con­fir­ma­to­ry tri­al could pro­vide sup­port­ive ev­i­dence and greater con­fi­dence for the AA based on the sin­gle-group study,” they ex­plain.

Mov­ing for­ward, OCE’s Fashoyin-Aje et. al. ex­plain how both the at-times de­layed with­draw­al process (the fo­cus on Con­gres­sion­al ef­forts) should not over­shad­ow the lead-up to an ap­proval.

“Pub­lic dis­cus­sion has fo­cused on im­prov­ing the AA off-ramp, sug­gest­ing spe­cif­ic time lim­its for com­plet­ing con­fir­ma­to­ry tri­als, pa­tient en­roll­ment mile­stones for eval­u­at­ing time­ly tri­al com­ple­tion, and al­ter­na­tive pro­ce­dures for with­draw­ing in­di­ca­tions. But equal­ly im­por­tant are pro­ce­dures to build qual­i­ty and ef­fi­cien­cy in­to the AA on-ramp, which should in­clude a prospec­tive com­pre­hen­sive strat­e­gy de­tail­ing plans for AA and the ver­i­fi­ca­tion of clin­i­cal ben­e­fit, with the aim of ex­pe­dit­ing ther­a­peu­tic ad­vances and short­en­ing this pe­ri­od of un­cer­tain­ty,” they con­clud­ed.

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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New in­fla­tion-linked drug re­bates go in­to ef­fect on Sat­ur­day

Beginning tomorrow, biopharma companies can be charged rebates for any new drug price increases rising faster than the rate of inflation.

The new rebates are part of the newly signed Inflation Reduction Act, which introduces this new requirement that manufacturers pay rebates to Medicare for Part D drugs whose price increases exceed inflation, and in January 2023, the same will occur with Part B drugs.

In­dus­try groups call to block WTO IP waiv­er ex­pan­sion to Covid-19 ther­a­peu­tics

The WTO’s TRIPS Council in mid-October is expected to debate whether to extend the IP waiver for Covid-19 vaccines to therapeutics and diagnostics too.

While the Biden administration backed the original vaccine waiver, which critics note has not done much to expand access to vaccines as demand has dried up, US trade officials haven’t offered any perspective yet on whether to expand the waiver to Covid treatments.

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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