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.

MedTech clinical trials require a unique regulatory and study design approach and so engaging a highly experienced CRO to ensure compliance and accurate data across all stages is critical to development milestones.

In­no­v­a­tive MedTech De­mands Spe­cial­ist Clin­i­cal Tri­al Reg­u­la­to­ry Af­fairs and De­sign

Avance Clinical is the Australian CRO for international biotechs providing world-class clinical research services with FDA-accepted data across all phases. With Avance Clinical, biotech companies can leverage Australia’s supportive clinical trials environment which includes no IND requirement plus a 43.5% Government incentive rebate on clinical spend. The CRO has been delivering clinical drug development services for international biotechs for FDA and EMA regulatory approval for the past 24 years. The company has been recognized for the past two consecutive years with the prestigious Frost & Sullivan CRO Best Practices Award and a finalist in Informa Pharma’s Best CRO award for 2022.

Illustration: Kim Ryu for Endpoints News

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