Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Car­dio­vas­cu­lar and Re­nal Drugs Ad­vi­so­ry Com­mit­tee will meet next Tues­day to dis­cuss whether Cy­to­ki­net­ics’ po­ten­tial heart drug can safe­ly re­duce the risk of car­dio­vas­cu­lar death and heart fail­ure in pa­tients with symp­to­matic chron­ic heart fail­ure with re­duced ejec­tion frac­tion.

The drug, known as ome­cam­tiv mecar­bil and in de­vel­op­ment for more than 15 years, has seen mixed re­sults, with a first Phase III read­out from No­vem­ber 2020 hit­ting the pri­ma­ry end­point of re­duc­ing the odds of hos­pi­tal­iza­tion or oth­er ur­gent care for heart fail­ure by 8%. But it al­so missed a key sec­ondary end­point an­a­lysts had pegged as key to break­ing in­to the mar­ket.

The FDA on Fri­day made clear the un­cer­tain­ties ahead of the ad­comm, not­ing the “small treat­ment ef­fect” in the piv­otal GALAC­TIC-HF tri­al and adding, “This un­cer­tain­ty is based on both ef­fi­ca­cy and safe­ty con­sid­er­a­tions.”

And de­spite hit­ting on the pri­ma­ry ef­fi­ca­cy, the num­bers “were dri­ven by HF events with no trends of im­prove­ment on CV mor­tal­i­ty. The small treat­ment ef­fect, with a p-val­ue that is not very per­sua­sive for a sin­gle tri­al, with­out es­tab­lished ef­fects on any of the sec­ondary ef­fi­ca­cy end­points, calls in­to ques­tion whether the statu­to­ry re­quire­ment for sub­stan­tial ev­i­dence of ef­fec­tive­ness has been met,” the agency said.

The agency al­so ques­tioned why this sin­gle tri­al re­sult “was not ac­com­pa­nied by con­fir­ma­to­ry ev­i­dence,” adding:

The treat­ment ef­fect ap­peared to fa­vor those with a LVEF <28%, but there is no sci­en­tif­ic ba­sis for this dif­fer­en­tial ef­fect. The ben­e­fit/risk pro­file is fur­ther ten­u­ous, be­cause on­ly 2 ad­di­tion­al ma­jor car­diac is­chemic events per 100 PY are need­ed to negate the po­ten­tial small net ben­e­fit ob­served in the over­all GALAC­TIC-HF pop­u­la­tion.

Cy­to­ki­net­ics, mean­while, laid out its case for ap­proval for its car­diac myosin ac­ti­va­tor, not­ing that the GALAC­TIC-HF tri­al “has the fea­tures of a sin­gle tri­al that could pro­vide sub­stan­tial ev­i­dence of ef­fec­tive­ness as the ba­sis for a sin­gle-tri­al ap­proval.”

While ac­knowl­edg­ing that the “over­all ef­fect size was mod­est,” this pre­spec­i­fied sub­group of LVEF “had the most sta­tis­ti­cal­ly sig­nif­i­cant in­ter­ac­tion ef­fect in both uni­vari­ate and mul­ti­vari­ate analy­ses and is a bi­o­log­i­cal­ly plau­si­ble mod­i­fi­er of the treat­ment ef­fect in pa­tients with re­duced car­diac func­tion giv­en the mech­a­nism of ac­tion of ome­cam­tiv mecar­bil.”

The out­side ex­perts next week will vote once on whether the ben­e­fits of ome­cam­tiv mecar­bil out­weigh its risks for the treat­ment of heart fail­ure with re­duced ejec­tion frac­tion. If an ad­comm mem­ber votes yes, the FDA al­so wants to know if phar­ma­co­ki­net­ic-based dos­ing is es­sen­tial for the safe and ef­fec­tive use.

On the dos­ing strat­e­gy, the FDA not­ed that Cy­to­ki­net­ics ini­tial­ly pro­posed a post-ap­proval dos­ing strat­e­gy based on sched­uled, forced dose titra­tion (i.e., all pa­tients will titrate up to the max­i­mum dose of 50 mg 4 weeks af­ter the start of treat­ment), but then de­cid­ed to go with a PK-guid­ed dos­ing strat­e­gy, such as what was used in the GALAC­TIC-HF tri­al.

But the agency al­so ex­plained how typ­i­cal­ly if di­ag­nos­tic test­ing, such as PK-guid­ed dos­ing, is es­sen­tial for safe and ef­fec­tive use of a ther­a­peu­tic, the test is de­vel­oped along­side the ther­a­peu­tic and brought up for ap­proval si­mul­ta­ne­ous­ly with the drug.

While a close vote may be in the works, Cy­to­ki­net­ics has been build­ing up com­mer­cial op­er­a­tions in case of a po­ten­tial ap­proval. In its first quar­ter earn­ings re­port, the biotech said it’s hired its first field sales staff and is ac­tive­ly re­cruit­ing oth­er po­si­tions to help the launch.

Whether the green light comes through or not, in­vestors’ at­ten­tion has large­ly turned to­ward the next pipeline pro­gram called afi­camten, a myosin in­hibitor de­signed to treat symp­to­matic ob­struc­tive hy­per­trophic car­diomy­opa­thy.

Late Fri­day ap­proval; Trio of biotechs wind down; Stem cell pi­o­neer finds new fron­tier; Biotech icon to re­tire; and more

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Pfiz­er lays off em­ploy­ees at Cal­i­for­nia and Con­necti­cut sites

Pfizer has laid off employees at its La Jolla, CA, and Groton, CT sites, according to multiple LinkedIn posts from former employees.

The Big Pharma confirmed to Endpoints News it has let go of some employees, but a spokesperson declined to specify how many workers were impacted and the exact locations affected. Earlier this month, the drug developer had confirmed to Endpoints it was sharpening its focus and doing away with some early research on areas such as rare disease, oncology and gene therapies.

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Filip Dubovsky, Novavax CMO

No­vavax gets ready to take an­oth­er shot at Covid vac­cine mar­ket with next sea­son plans

While mRNA took center stage at yesterday’s FDA vaccine advisory committee meeting, Novavax announced its plans to deliver an updated protein-based vaccine based on new guidance.

Vaccines and Related Biological Products Advisory Committee (VRBPAC) members voted unanimously in favor of “harmonizing” Covid vaccine compositions, meaning all future vaccine recipients would receive a bivalent vaccine, regardless of whether they’ve gotten their primary series.

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CBER Director Peter Marks (Susan Walsh/AP Images)

FDA ad­vi­so­ry com­mit­tee votes unan­i­mous­ly in fa­vor of bi­va­lent Covid shots re­plac­ing pri­ma­ry se­ries

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted unanimously in favor of “harmonizing” Covid vaccine compositions, meaning all current vaccine recipients would receive a bivalent vaccine, regardless of whether they’ve gotten their primary series.

The vote marks an effort to clear up confusion around varying formulations and dosing schedules for current primary series and booster vaccines, as well as “get closer to the strains that are circulating,” according to committee member Paul Offit, professor of pediatrics at the Children’s Hospital of Philadelphia.

FDA re­ports ini­tial 'no sig­nal' for stroke risk with Pfiz­er boost­ers, launch­es con­comi­tant flu shot study

The FDA hasn’t detected any potential safety signals, including for stroke, in people aged 65 years and older who have received Pfizer’s bivalent Covid booster, one senior official told members of the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Thursday.

The update comes as the FDA and CDC investigate a “preliminary signal” that may indicate an increased risk of ischemic stroke in older Americans who received Pfizer’s updated shot.

FDA cuts off use for As­traZeneca’s Covid-19 ther­a­py Evusheld

The FDA has stopped use of another drug as a result of the new coronavirus variants. On Thursday, the agency announced that AstraZeneca’s antibody combo Evusheld, which was an important prevention option for many immunocompromised people and others, is no longer authorized.

The FDA said it made its decision based on the fact that Evusheld works on fewer than 10% of circulating variants.

Evusheld was initially given emergency authorization at the end of 2021. However, as Omicron emerged, so did studies that showed Evusheld might not work against the dominant Omicron strain. In October, the FDA warned healthcare providers that Evusheld was useless against the Omicron subvariant BA.4.6. It followed that up with another announcement earlier this month that it did not think Evusheld would work against the latest Omicron subvariant XBB.1.5.

Jake Van Naarden, Loxo@Lilly CEO

Lil­ly en­ters ripe BTK field with quick FDA nod in man­tle cell lym­phoma

Eli Lilly has succeeded in its attempt to get the first non-covalent version of Bruton’s tyrosine kinase, or BTK, inhibitors to market, pushing it past rival Merck.

The FDA gave an accelerated nod to Lilly’s daily oral med, to be sold as Jaypirca, for patients with relapsed or refractory mantle cell lymphoma.

The agency’s green light, disclosed by the Indianapolis Big Pharma on Friday afternoon, catapults Lilly into a field dominated by covalent BTK inhibitors, which includes AbbVie and Johnson & Johnson’s Imbruvica, AstraZeneca’s Calquence and BeiGene’s Brukinsa.

Post-hoc analy­sis: EMA's CHMP re­jects Ipsen's po­ten­tial drug for rare ge­net­ic dis­ease

The European Medicines Agency’s Committee for Medicinal Products for Human Use on Friday rejected Ipsen Pharma’s potential treatment for a rare genetic disease known as fibrodysplasia ossificans progressiva (FOP), which causes extra bone to form outside the skeleton.

The EMA said on its website that it could not draw any firm conclusions on the benefits of the French biopharma’s Sohonos (palovarotene), which selectively targets the retinoic-acid receptor gamma (RARγ), “as the applicant’s conclusion was based on a post-hoc analysis which was neither scientifically nor clinically justified and pre-specified study objectives were not met.”

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FDA ap­proves an­oth­er in­di­ca­tion for Keytru­da, this time in the ad­ju­vant NSCLC set­ting

Merck’s blockbuster cancer treatment Keytruda has been handed another indication by the FDA.

The US regulator announced on Thursday that it has approved Keytruda to serve as an adjuvant treatment for non-small cell lung cancer (NSCLC), which is its fifth indication in NSCLC and 34th indication overall.

According to a Merck release, the approval is based on data from a Phase III trial, dubbed Keynote-091, which measured disease-free survival in patients who received chemotherapy following surgery. The data from Merck displayed that Keytruda cut down on the risk of disease recurrence or death by 27% versus placebo.