FDA de­lays its de­ci­sion on Bris­tol My­er­s' $13B heart drug an­oth­er three months

Last week, Bris­tol My­ers Squibb marched out long-term da­ta for its heart drug mava­camten ahead of what ex­ecs had hoped would be a pos­i­tive FDA de­ci­sion in Jan­u­ary. But reg­u­la­tors are say­ing they need a bit more time to think.

The FDA has ex­tend­ed mava­camten’s PDU­FA date three months, from Jan. 28 to April 28, Bris­tol My­ers an­nounced on Fri­day. The news came just a few days af­ter in­de­pen­dent drug pric­ing watch­dog ICER raised con­cerns about the can­di­date’s long-term safe­ty in its fi­nal ev­i­dence re­port.

Mava­camten, a myosin in­hibitor, was the cen­ter­piece of BMS’ $13 bil­lion MyoKar­dia buy­out last Oc­to­ber. The phar­ma gi­ant’s shoot­ing for an ini­tial in­di­ca­tion in symp­to­matic ob­struc­tive hy­per­trophic car­diomy­opa­thy, or oHCM: a con­di­tion in which the mus­cu­lar wall be­tween the two bot­tom cham­bers of the heart be­comes thick­er than nor­mal, block­ing blood flow out of the heart.

In an ab­stract at the Amer­i­can Heart As­so­ci­a­tion con­fer­ence, BMS said HCM pa­tients who took mava­camten saw a “sus­tained re­duc­tion” of a hor­mone called NT-proB­NP through Week 48. High­er than nor­mal NT-proB­NP lev­els are in­dica­tive of heart fail­ure.

How­ev­er, the com­pa­ny re­port­ed that nine pa­tients paused treat­ment be­cause their left ven­tric­u­lar ejec­tion frac­tions (a mea­sure­ment of how much blood is be­ing pumped out of the heart’s left ven­tri­cle) were too low. Eight of the pa­tients re­sumed treat­ment at a low­er dose af­ter re­cov­ery, while one dis­con­tin­ued the tri­al per­ma­nent­ly, the com­pa­ny said.

BMS says the FDA re­quest­ed more time to “re­view in­for­ma­tion per­tain­ing to up­dates to the pro­posed Risk Eval­u­a­tion Mit­i­ga­tion Strat­e­gy (REMS),” and that no ad­di­tion­al da­ta or stud­ies have been re­quest­ed.

Mizuho’s Sal­im Syed spec­u­lat­ed that the de­lay seems to be mol­e­cule-spe­cif­ic, and not class-spe­cif­ic, not­ing that no pa­tients saw EF be­low 40% in Cy­to­ki­net­ics’ Phase II study for its myosin in­hibitor afi­camten (al­so known as CK-274). In that drug’s dose-range find­ing tri­al, one pa­tient ex­pe­ri­enced a tran­sient de­crease in LVEF that re­quired dose ad­just­ment, but not dose in­ter­rup­tion, Cy­to­ki­net­ics said.

Samit Hi­rawat

Ejec­tion frac­tion is con­sid­ered nor­mal if it’s in the range of 50% to 70%. Of the sev­en mava­camten pa­tients who ex­pe­ri­enced EF be­low 50% in the Phase III EX­PLOR­ER-HCM tri­al, one pa­tient had an EF be­low 40%.

“This is the pri­ma­ry rea­son we be­lieve the REMS is mol­e­cule-spe­cif­ic and should be treat­ed as such ⁠— these are clear­ly two dif­fer­ent safe­ty datasets,” Syed said in a note to in­vestors on Fri­day. “The PDU­FA de­lay should al­so be help­ful to­ward en­rolling US pa­tients in CK-274’s Ph3 SE­QUOIA-HCM study, where ‘start-up ac­tiv­i­ties’ are ‘un­der­way.’

While ICER not­ed that mava­camten may de­liv­er im­por­tant ben­e­fits for HCM pa­tients with few­er side ef­fects than oth­er drugs, the or­ga­ni­za­tion sug­gest­ed more da­ta are nec­es­sary to as­sess long-term safe­ty:

While mava­camten im­proved phys­i­o­log­ic pa­ra­me­ters and symp­toms in the EX­PLOR­ER tri­al, the avail­able da­ta are most­ly short term, and symp­to­matic HOCM, once it ap­pears, can last a life­time. Clin­i­cal ex­perts dif­fered on whether the re­duc­tions in ejec­tion frac­tion with mava­camten re­flect­ed ben­e­fi­cial im­prove­ments in car­diac func­tion, in­clud­ing healthy re­mod­el­ing, or wor­ri­some changes that could be as­so­ci­at­ed with clin­i­cal harm with longer ob­ser­va­tion times.

Bris­tol My­ers re­mains con­fi­dent in the drug, with CMO Samit Hi­rawat stat­ing: “We look for­ward to con­tin­u­ing to work close­ly with the FDA to bring this im­por­tant med­i­cine to pa­tients.”

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; 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.

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Usama Malik

Ex-Im­munomedics CFO charged with in­sid­er trad­ing, faces up to 20 years in prison af­ter al­leged­ly tip­ping off girl­friend and rel­a­tives of a PhI­II suc­cess

The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Pfiz­er, Am­gen and Janssen seek fur­ther clar­i­ty on FDA's new ben­e­fit-risk guid­ance

Three top biopharma companies are seeking more details from the FDA on how the agency conducts its benefit-risk assessments for new drugs and biologics.

While Pfizer, Amgen and Janssen praised the agency for further spelling out its thinking on the subject in a new draft guidance, including a discussion of patient experience data as part of the assessment, the companies said the FDA could’ve included more specifics in the 20-page draft document.

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Janet Woodcock (AP Images)

Janet Wood­cock plots her fu­ture at FDA, with se­nior ad­vi­sor role to fall back on if Califf wins con­fir­ma­tion

Acting FDA commissioner Janet Woodcock has been the face of just about every drug approval decision at the agency since the turn of the century. Since the pandemic began, she’s moved between the top of the drugs center to the head of therapeutics at Operation Warp Speed, leading the drive for work on Covid-targeted mAbs and antivirals.

Looking forward — and pending a quick Senate confirmation to cement Rob Califf’s return to the top of FDA early next year — Woodcock’s role at the agency will again be in flux.

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Richard Pazdur (via AACR)

Ac­cel­er­at­ed ap­proval re­forms need mean­ing­ful con­fir­ma­to­ry tri­al im­prove­ments, pro­fes­sors write in Sci­ence

Outside of Covid-19, 2021 has been the year of the accelerated approval.

Beginning last spring, FDA openly challenged six “dangling” accelerated approvals (hadn’t confirmed their clinical benefit yet), three of which were later pulled by the companies.

Then in June, FDA pulled out the accelerated approval pathway, seemingly out of nowhere, to sign off on Biogen’s controversial Alzheimer’s drug Aduhelm. It hadn’t even been mentioned at the drug’s adcomm.

Vas Narasimhan, Novartis CEO (Thibault Camus/Pool via AP Images)

With gener­ic com­pe­ti­tion heat­ing up, Vas Narasimhan out­lines No­var­tis' growth plans at R&D day

Thursday marks Novartis’ annual R&D day, and with it comes CEO Vas Narasimhan’s attempt to spotlight the company’s pipeline strategy and emerging stars.

The biggest question entering Thursday’s presentation dealt with how the big biopharma will make up revenues from upcoming generic competition — Novartis says within the next five years, generics will eat away roughly $9 billion in sales. To offset this, Narasimhan outlined a strategy for 4% growth or higher until 2026, focusing on six key medicines he believes will see multibillion dollar profits during this time.

In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.