Check­Mate-227: Bris­tol-My­ers Squibb has a MYS­TIC-sized prob­lem on its hands

Ja­mi Ru­bin, Gold­man Sachs

No­body knows how to put a top ex­ec on the spot quite like Gold­man Sach’s Ja­mi Ru­bin.

The high-pro­file an­a­lyst has a well-earned rep for go­ing straight for the jugu­lar, and that was on full dis­play Thurs­day night as she went at Bris­tol-My­ers Squibb’s lat­est po­ten­tial Achilles heel in im­muno-on­col­o­gy: Its Check­Mate 227 tri­al that in­cludes a matchup of Op­di­vo and the CT­LA-4 drug Yer­voy in front-line lung can­cer.

With the spec­tac­u­lar MYS­TIC fail on every­one’s mind Thurs­day, and the com­pa­ny’s stock fresh­ly pum­meled by the im­pli­ca­tions of As­traZeneca’s prat­fall on its own PD-L1/CT­LA-4 com­bo, she said, “it’s very hard to walk away from MYS­TIC feel­ing warm and fuzzy about 227.”

None of this, of course, was un­ex­pect­ed at Bris­tol-My­ers, which is acute­ly sen­si­tive to just how im­por­tant Op­di­vo is to its fu­ture. Bris­tol-My­ers had al­ready re­placed its R&D chief af­ter a key fail­ure of its own in lung can­cer, which gave Mer­ck a big ad­van­tage that it’s now cap­i­tal­iz­ing on with a front-line OK for a com­bi­na­tion of Keytru­da and chemo. By the time Ru­bin tack­led the ele­phant in the room, Bris­tol-My­ers CEO Gio­van­ni Caforio had al­ready drawn a dis­tinc­tion be­tween MYS­TIC and 227. He told an­a­lysts:

Gio­van­ni Caforio, Bris­tol-My­ers Squibb CEO

(O)ur Check­Mate 227 is a first-line, non-small cell lung can­cer pro­gram, not just one tri­al, in­ves­ti­gat­ing sev­er­al im­por­tant sci­en­tif­ic ques­tions. In study 227 we have at least three dis­crete op­por­tu­ni­ties for suc­cess. We will be able to eval­u­ate the com­bi­na­tion of Op­di­vo plus Yer­voy, we will eval­u­ate Op­di­vo plus chemo in PDL-1 neg­a­tive pa­tients and we will be avail­able to eval­u­ate Op­di­vo plus chemo in all com­ers. Ad­di­tion­al­ly, as you know, we are test­ing two cy­cles of chemo with the com­bi­na­tion of Op­di­vo and Yer­voy.

It’s al­so im­por­tant to rec­og­nize that MYS­TIC tri­al and Check­Mate 227 are very dif­fer­ent tri­als. First, the dose and sched­ules are dif­fer­ent. In 227, we be­lieve we have op­ti­mized the dose and the sched­ule. Sec­ond, the tri­al sizes are very dif­fer­ent. 227 en­rolled over 2,200 pa­tients, with 1,200 pa­tients in the PDL-1 pos­i­tive por­tion alone. In con­trast, MYS­TIC en­rolled rough­ly 1,100 pa­tients in all com­ers, and its pri­ma­ry end­point was eval­u­at­ed in a sub­set of that pop­u­la­tion. While the MYS­TIC re­sults are im­por­tant da­ta and we look for­ward to see­ing more, it’s very dif­fi­cult to read across tri­als.

New R&D chief Thomas Lynch went fur­ther af­ter Ru­bin’s com­ment, not­ing that Yer­voy has a proven sur­vival ben­e­fit that could log­i­cal­ly be ex­pect­ed to con­tin­ue in a com­bo with Op­di­vo. And he al­so un­der­scored the op­tions the com­pa­ny has to go in dif­fer­ent di­rec­tions, adding that there are a cou­ple of new moves in R&D to come up with a bet­ter CT­LA-4.

But Bris­tol-My­ers is now fac­ing a tough chal­lenge win­ning over an­a­lysts. Not­ed Leerink’s Sea­mus Fer­nan­dez:

While 2Q pro­vid­ed en­cour­ag­ing growth for BMY’s key fran­chis­es, we are up­dat­ing our DCF-based price tar­get to $61/shr (from $66/shr pre­vi­ous­ly) to re­flect in­creased un­cer­tain­ty fol­low­ing the fail­ure of AZN’s MYS­TIC (Imfinzi (dur­val­um­ab; an­ti-PD-L1) + treme­li­mum­ab (an­ti-CT­LA-4)) and the po­ten­tial read through to BMY’s I/O com­bo of Op­di­vo + Yer­voy (ip­il­i­mum­ab; an­ti-CT­LA-4) in the PDL1+ group in the on­go­ing Check­Mate-227 tri­al.

As­traZeneca CEO Pas­cal So­ri­ot has been plagued all year long by the in­tense fo­cus that has been cen­tered on MYS­TIC. And he’ll have to spend the rest of the year ex­plain­ing how the com­pa­ny plans to move on from the first big end­point flop.

That’s not a po­si­tion that Bris­tol-My­ers Squibb wants to be in. But ex­ecs don’t have much choice. Brad Lon­car, an in­vestor who runs the $CN­CR im­munother­a­py ETF, has been track­ing quar­ter­ly PD-(L)1 sales, and the lat­est up­date to­day shows why the fo­cus on 227 isn’t go­ing away.

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We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

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Traditionally, peanut allergies are managed by avoidance, but the threat of accidental exposure cannot be nullified. Some allergists have devised a way to dose patients off-label with peanut protein derived from supermarket products to wean them off their allergies. But the idea behind Aimmune’s product was to standardize the peanut protein, and track the process of desensitization — so when accidental exposure in the real world invariably occurs, patients are less likely to experience a life-threatening allergic reaction.

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Lisa M. DeAngelis, MSKCC

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His replacement, who now will be in charge of MSK’s cutting-edge research work as well as the cancer care delivered by hundreds of practitioners, is Lisa M. DeAngelis. DeAngelis had been chair of the neurology department and co-founder of MSK’s brain tumor center and was moved in to the acting CMO role in the wake of Baselga’s departure.

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The mR­NA uni­corn Mod­er­na has more ear­ly-stage hu­man da­ta it wants to show off — reach­ing new peaks in prov­ing the po­ten­tial

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The whole hand, of course, has yet to be dealt. And there’s no telling who gets to walk with a share of the pot. But any cards on display at this point — especially after being accused of keeping its deck under lock and key — will attract plenty of attention from some very wary, and wired, observers.

“In terms of the complexity and unmet need,” says Tal Zaks, the chief medical officer, “this is peak for what we’ve accomplished.”

Moderna has two Phase I studies it wants to talk about now.

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Sanofi’s unhappiness was already apparent when the company — now under new CEO Paul Hudson — posted a statement back in July that they were dropping the deal. But it wasn’t that simple. 

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An analyst at BMO Capital Markets, he’d meet with biotech or pharmaceutical heads for their IPO or secondary funding and his brain, trained on a biology degree and six years at Merck and Endo, would spring with questions: Why this biomarker? Why this design? Why not this endpoint? Not that he could do anything about it. These execs were coming for clinical money; their decisions had been made and finalized long ago.