Am­gen's big car­dio­vas­cu­lar bet with Cy­to­ki­net­ics hits PhI­II pri­ma­ry but dra­mat­i­cal­ly dis­ap­points in­vestors

A close­ly watched heart drug from Am­gen and Cy­to­ki­net­ics has both hit the pri­ma­ry end­point on a ma­jor tri­al and dra­mat­i­cal­ly dis­ap­point­ed in­vestors.

In the 8,250-per­son study, the drug re­duced the odds of hos­pi­tal­iza­tion or oth­er ur­gent care for heart fail­ure by 8%, a sta­tis­ti­cal­ly sig­nif­i­cant re­sult. But the drug failed to help high-risk pa­tients live longer, an end­point that an­a­lysts had been fol­low­ing as the key mark­er for whether the drug could make a large im­pact.

“Tri­al tech­ni­cal­ly worked,” Mizuho’s Sal­im Syed wrote in a note to in­vestors, “but failed on what was re­al­ly need­ed here to be a foun­da­tion­al med­i­cine, in my view, which is CV death.”

Cy­to­ki­net­ics shares fell 43% on the news, from $23.66 to $15.33, wip­ing away a ma­jor spike the com­pa­ny had seen in May, when a MyoKar­dia drug with sim­i­lar­i­ties proved suc­cess­ful on mul­ti­ple end­points. Am­gen was down 4.6%, from $257.67 to $245.82.

Fady Ma­lik

The two com­pa­nies have col­lab­o­rat­ed on car­dio­vas­cu­lar R&D since 2007.

A Cy­to­ki­net­ics spokesper­son said in an email that the da­ta are on­ly a few days old and that they hoped sub-group analy­ses set to be un­veiled at the Amer­i­can Heart As­so­ci­a­tion would show how best to use the drug. Syed sug­gest­ed that it was pos­si­ble the in­pa­tient pop­u­la­tion, which is sick­er and rep­re­sent­ed 25% of the tri­al en­roll­ment, had dri­ven the re­sults down.

“Com­pa­ny be­lieves this is still an ap­prov­able drug, say­ing we need to wait for AHA,” he said. “How ef­fec­tive will this drug be com­mer­cial­ly if ap­proved? In my view, with­out CV death ben­e­fit, the drug prob­a­bly won’t be a foun­da­tion­al med­i­cine and do the $4Bn in WW end-user sales that we had orig­i­nal­ly thought (con­sen­sus is ~$3.5Bn). But is it a ze­ro? Maybe not.”

That sub-group da­ta could on­ly yield an ap­proval, though, if they had de­fined the sub-group ahead of time, SVB Leerink’s Ge­of­frey Porges ar­gued.  He said that the study was well-pow­ered to find a re­sult on car­dio­vas­cu­lar death.

“We be­lieve the fu­ture for ome­cam­tiv is high­ly un­cer­tain un­less the com­pa­ny finds a sub­set with clear ben­e­fit (par­tic­u­lar­ly if prospec­tive­ly de­fined),” he said, adding that he ex­pects Am­gen to dis­con­tin­ue oth­er on­go­ing stud­ies.

An­a­lysts raised con­cerns not on­ly about the lack of mor­tal­i­ty da­ta but al­so about the ef­fect size on the pri­ma­ry end­points, which they wide­ly ex­pect­ed to be larg­er. Syed said it “bare­ly” crossed sig­nif­i­cance, with the con­fi­dence in­ter­val ap­proach­ing 1.

Baird’s Bri­an Sko­r­ney com­pared that ef­fect to the 26% re­duc­tion As­traZeneca’s Farx­i­ga saw in a re­cent, 4,700-per­son study, call­ing it “deeply dis­ap­point­ing.” He not­ed Farx­i­ga is avail­able for less than $10,000 per year.

“While cross-tri­al com­par­isons al­ways should be tak­en with a grain of salt as pa­tient pop­u­la­tions and clin­i­cal end­points of­ten slight­ly dif­fer,” he said,  “we be­lieve the top-line re­sults from GALAC­TIC-HF sug­gest ome­cam­tiv mecar­bil is un­like­ly to be a com­mer­cial­ly at­trac­tive prod­uct even if it should gain ap­proval (which we view as un­like­ly.)”

The drug, ome­cam­tiv mecar­bil, works by tar­get­ing myosin, a pro­tein that con­verts chem­i­cal en­er­gy in­to me­chan­i­cal force in the heart. The drug was sup­posed to ac­ti­vate the pro­tein, help­ing the heart con­tract.

MyoKar­dia’s drug, mava­camten, al­so tar­get­ed myosin but in­hib­it­ed it, help­ing cor­rect a rare car­diomy­opa­thy. The com­pa­ny, ac­quired this week by Bris­tol My­ers Squibb, al­so has a myosin ac­ti­va­tor in Phase II.

David Reese

This would not be the first sig­nif­i­cant dis­ap­point­ment for Cy­to­ki­net­ics, a com­pa­ny that has worn the vi­cis­si­tudes of biotech over its 23-year his­to­ry. The South San Fran­cis­co-based com­pa­ny in­vest­ed in two ALS drugs over the last decade, but strug­gled to hit key end­points in tri­als for the dif­fi­cult-to-treat con­di­tions. One ALS drug, relde­sem­tiv, is still in de­vel­op­ment and set to en­ter Phase III this year.

In pub­lic state­ments, nei­ther ex­ec­u­tives from Am­gen and Cy­to­ki­net­ics tout­ed the study as a suc­cess nor in­di­cat­ed whether they would sub­mit for FDA ap­proval. Cy­to­ki­net­ics’ R&D chief Fady Ma­lik said the tri­al “pro­vides in­sight” and that “they look for­ward to fur­ther da­ta analy­ses.” Am­gen R&D chief David Reese said sim­ply they “fur­ther the un­der­stand­ing of treat­ing heart fail­ure.”

“The out­comes ob­served in GALAC­TIC-HF fur­ther the un­der­stand­ing of treat­ing heart fail­ure, a dev­as­tat­ing dis­ease in which half of heart fail­ure pa­tients will die with­in five years of ini­tial hos­pi­tal­iza­tion,” Reese said. “At Am­gen, we re­main com­mit­ted to de­vel­op­ing and de­liv­er­ing trans­for­ma­tive med­i­cines that im­prove the lives of pa­tients with car­dio­vas­cu­lar dis­ease.”

Full da­ta will be pre­sent­ed at the AHA in No­vem­ber, but the ear­ly read­out al­so spells bad news for one oth­er com­pa­ny, Roy­al­ty Phar­ma.  In 2017, the com­pa­ny  paid $90 mil­lion for a 4.5% roy­al­ty.

Cor­rec­tion: An ear­li­er ver­sion of this ar­ti­cle mis­stat­ed the terms of a roy­al­ty deal with RTW. It does not cov­er ome­cam­tiv mecar­bil.

How Pa­tients with Epilep­sy Ben­e­fit from Re­al-World Da­ta

Amanda Shields, Principal Data Scientist, Scientific Data Steward

Keith Wenzel, Senior Business Operations Director

Andy Wilson, Scientific Lead

Real-world data (RWD) has the potential to transform the drug development industry’s efforts to predict and treat seizures for patients with epilepsy. Anticipating or controlling an impending seizure can significantly increase quality of life for patients with epilepsy. However, because RWD is secondary data originally collected for other purposes, the challenge is selecting, harmonizing, and analyzing the data from multiple sources in a way that helps support patients.

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When Regeneron scored an early approval for lipid lowering antibody Evkeeza back in February, the drugmaker cracked open a new pathway to lower abnormally high cholesterol levels. Now, Regeneron is chasing high triglycerides as well with some promising mid-stage data — but will genetic restrictions limit the drug’s use?

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I still remember the uncertainty in the air last year when nobody was sure whether ASCO would cancel their in-person meeting. But it’s now back again for the second virtual conference, and Endpoints News is here for it. Check out our 2-day event reviewing the landscape of cancer R&D and send news our way.

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As­traZeneca's Farx­i­ga missed big on Covid-19 study, but it's tak­ing SGLT2 safe­ty da­ta as a sil­ver lin­ing

AstraZeneca hasn’t seen many setbacks in recent months for SGLT2 inhibitor Farxiga, which broke ground in heart failure and kidney disease regardless of diabetes diagnosis. But the British drugmaker had to admit defeat in taking Farxiga into Covid-19, but follow-up results add a bit of a silver lining to that trial’s safety data.

Of hospitalized Covid-19 patients dosed with AstraZeneca’s Farxiga, 11.2% experienced an organ failure or died after 30 days of therapy compared with 13.8% of those given placebo, according to follow-up data from the DARE-19 study revealed Sunday at the virtual American College of Cardiology meeting.

Pfiz­er, Bris­tol My­er­s' Eliquis flops in post-heart surgery pa­tients, spurring an 'un­ex­plained sig­nal' in cer­tain deaths

Pfizer and Bristol Myers Squibb’s non-warfarin blood thinner Eliquis has raced out to become the most prescribed drug of its class on the market — even overtaking warfarin’s long-time lead. But in tricky-to-treat patients after a valve replacement, an investigator-sponsored study couldn’t turn up benefit and raised a troubling safety signal.

Eliquis failed to show benefit over standard of care in preventing serious clinical outcomes after a transaortic valve replacement (TAVR) and was linked to an “unexplained signal” in a subset of populations with a higher rate of non-CV deaths who did not need blood thinners apart from the surgery, according to data presented Saturday at the virtual American College of Cardiology meeting.

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Biogen announced that the candidate, an experimental treatment for a rare and progressive form of blindness called X-linked retinitis pigmentosa (XLRP), failed to sufficiently improve vision in patients’ treated eye — patients only received an injection in one eye — after a year, on a standard scale, compared to their untreated eye. The company said they saw “positive trends” on several secondary endpoints, including visual acuity, but declined to say whether the trial actually hit any of those endpoints.

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Michael Dell (Richard Drew, AP Images)

'Dude, you're get­ting a Del­l' — as a new deep-pock­et biotech in­vestor

What happens when you marry longtime insiders in the global biotech VC game with the family fund of tech billionaire Michael Dell, a synthetic biology legend out of MIT and Harvard and the former director of the NCI?

Today, the answer is a newly financed, $200 million biotech SPAC now cruising the industry for a top player interested in finding a short cut to Nasdaq.

Orion Biotech Opportunities priced their blank check company today, raising $200 million with Dell’s multibillion-dollar MSD group’s commitment on investing another $20 million in a forward-purchase agreement.

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Bris­tol My­ers backs up its case for heart drug mava­camten as FDA weighs app in car­diomy­opa­thy

When Bristol Myers Squibb signed off on its $13 billion acquisition of MyoKardia back in October, it was making a big bet that lead drug mavacamten could prove a game changer in cardiac myopathy. Now, with the drug up for FDA review, Bristol Myers is backing up its case with new quality of life data.

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Vas Narasimhan (Photographer: Simon Dawson/Bloomberg via Getty Images)

No­var­tis whiffs on En­tresto study af­ter heart at­tacks — but that does­n't mean it's go­ing down qui­et­ly

If Novartis learned one thing from its interaction with the FDA over its latest heart failure approval for Entresto, it was that missing a primary endpoint may not be the nail in the coffin. Now, Entresto has missed again on a late-stage study in high-risk heart patients, and it’s already sowing the seeds for a path forward regardless.

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