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.

Charles Baum, Mirati CEO

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Michel Vounatsos, Biogen CEO (via YouTube)

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Stephen Hahn, FDA commissioner (AP Images)

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Biond­Vax stock im­plodes af­ter a big PhI­II gam­ble for its uni­ver­sal flu vac­cine fails

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