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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; 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.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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Crit­ics push back on Alzheimer’s As­so­ci­a­tion ad blitz to get Medicare to change its Aduhelm rul­ing: 'Dead wrong'

The latest Alzheimer’s Association advertising campaign encourages people to fight.

Not against the disease or for more research or treatments, but against the Centers for Medicare and Medicaid Services. More specifically, CMS’ recent reimbursement decision to only pay for Biogen and Eisai’s controversial Alzheimer’s drug Aduhelm for patients in clinical trials.

With CMS’ preliminary decision now in a 30-day comment period, patient advocates’ goal is to convince CMS to reverse its decision with a marketing blitz and public pressure.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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