As­traZeneca wants a do-over on MYS­TIC com­bo da­ta. But a change­up in fo­cus won’t end the death watch on this pair­ing

As­traZeneca CEO Pas­cal So­ri­ot’s de­ci­sion to bet big on a check­point R&D strat­e­gy that re­lied heav­i­ly on its in-house com­bo of PD-L1 and CT­LA-4 is start­ing to look like a block­buster los­er. And this week’s push­back on a sub­set of the da­ta re­lat­ed to high tu­mor mu­ta­tion bur­den will like­ly do very lit­tle to change the odds here.

Bioreg­num Opin­ion Col­umn by John Car­roll

Re­searchers for the phar­ma gi­ant $AZN turned up at the Eu­ro­pean So­ci­ety for Med­ical On­col­o­gy Im­muno-On­col­o­gy 2018 Con­gress in Gene­va this week with more stun­ning­ly poor da­ta for the com­bi­na­tion of Imfinzi and treme­li­mum­ab, which was out­per­formed by Imfinzi alone — though the monother­a­py al­so failed to stand out in ad­vanced cas­es of non-small cell lung can­cer.

We al­ready knew that the haz­ard ra­tio for the com­bi­na­tion was a poor 0.85, but Imfinzi’s 24-month over­all sur­vival rate was 38.3% com­pared to an em­bar­rass­ing 35.4% for the PD-L1 plus CT­LA-4 ap­proach.

From As­traZeneca:

Among pa­tients re­ceiv­ing Imfinzi, 40.4% of pa­tients ex­pe­ri­enced a grade 3 or 4 ad­verse event (AE) vs. 47.7% with the Imfinzi plus treme­li­mum­ab com­bi­na­tion and 46.0% with chemother­a­py. 5.4% of pa­tients dis­con­tin­ued Imfinzi due to treat­ment-re­lat­ed AEs vs. 13.2% with the com­bi­na­tion and 9.4% on chemother­a­py.

Chloé Thé­paut

The com­pa­ny’s re­search team, though, was hop­ing to pull a vic­to­ry out of the mouth of de­feat by point­ing to a much bet­ter per­for­mance among pa­tients iden­ti­fied with a high tu­mor mu­ta­tion bur­den — putting them on the ex­act same path that Bris­tol-My­ers Squibb has tried to em­ploy with Op­di­vo plus Yer­voy. In that group there was a 36% drop in risk of death, with a haz­ard ra­tion of 0.64.

That would have to be con­firmed in a new study, though, be­fore reg­u­la­tors would con­sid­er it for ap­proval — which may in turn spur an­oth­er fol­low-up to Bris­tol-My­ers with a change­up in an on­go­ing tri­al to bring that clos­er to re­al­i­ty.

Bris­tol-My­ers’ own ap­proach to carv­ing out mar­ket share among TMB pa­tients, though, has failed to im­press an­a­lysts as more da­ta came out. Cred­it Su­isse in par­tic­u­lar not­ed a sim­i­lar­i­ty in sur­vival ben­e­fit for the low and high TMB groups in Bris­tol-My­ers’ da­ta set, which bodes ill for their mar­ket prospects.

And all of this is play­ing out as Mer­ck con­tin­ues to rack up big gains us­ing a com­bi­na­tion of Keytru­da and chemo in lung can­cer, which in­creas­ing­ly gains strength as the right com­bo to turn to ini­tial­ly to im­prove per­for­mance.

CT­LA-4 al­ready has a bad rep­u­ta­tion for tox­i­c­i­ty and mar­gin­al OS im­prove­ments that’s made it a tar­get for oth­ers look­ing to do bet­ter. Even­tu­al­ly, Yer­voy is like­ly to go down in his­to­ry as the check­point that re­vealed where these ther­a­pies could go. It was a mas­sive­ly im­por­tant start­ing point in a sto­ry that has many chap­ters to come.

Mean­while, the tidal wave of check­points and com­bo tri­als is com­ing up on the hori­zon, with plen­ty of op­por­tu­ni­ties for some­one else to make their mark as As­traZeneca con­tin­ues to fo­cus on MYS­TIC and treme­li­mum­ab.

But that game may al­ready be over, es­pe­cial­ly af­ter an­oth­er read­out for the As­traZeneca com­bo just days ago un­der­scored its fail­ure in head and neck can­cer.

Ear­li­er this week, Chloé Thé­paut, se­nior on­col­o­gy an­a­lyst for Glob­al­Da­ta, put it like this:

Un­less da­ta in fur­ther in­di­ca­tions, such as that ex­pect­ed from the KESTREL tri­al, can demon­strate su­pe­ri­or­i­ty of Imfinzi + treme­li­mum­ab over the stan­dard-of-care, or show im­pres­sive ef­fi­ca­cy or promis­ing safe­ty ver­sus com­pet­ing com­bi­na­tions, it is un­like­ly that As­traZeneca will have a dif­fer­en­ti­a­tion point suf­fi­cient for the com­bi­na­tion to be tak­en up on­to the mar­ket.

It may not be time yet to pre­pare the eu­lo­gy on this one, but it’s al­ready on death watch.

Im­age: Pas­cal So­ri­ot. GET­TY IM­AGES

Hal Barron, GSK

Break­ing the death spi­ral: Hal Bar­ron talks about trans­form­ing the mori­bund R&D cul­ture at GSK in a crit­i­cal year for the late-stage pipeline

Just ahead of GlaxoSmithKline’s Q2 update on Wednesday, science chief Hal Barron is making the rounds to talk up the pharma giant’s late-stage strategy as the top execs continue to woo back a deeply skeptical investor group while pushing through a whole new R&D culture.

And that’s not easy, Barron is quick to note. He told the Financial Times:

I think that culture, to some extent, is as hard, in fact even harder, than doing the science.

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Aca­dia is mak­ing the best of it, but their lat­est PhI­II Nu­plazid study is a bust

Acadia’s late-stage program to widen the commercial prospects for Nuplazid has hit a wall. The biotech reported that their Phase III ENHANCE trial flat failed. And while they $ACAD did their best to cherry pick positive data wherever they can be found, this is a clear setback for the biotech.

With close to 400 patients enrolled, researchers said the drug flunked the primary endpoint as an adjunctive therapy for patients with an inadequate response to antipsychotic therapy. The p-value was an ugly 0.0940 on the Positive and Negative Syndrome Scale, which the company called out as a positive trend.

Their shares slid 12% on the news, good for a $426 million hit on a $3.7 billion market cap at close.

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Some Big Phar­mas stepped up their game on da­ta trans­paren­cy — but which flunked the test?

The nonprofit Bioethics International has come out with their latest scorecard on data transparency among the big biopharmas in the industry — flagging a few standouts while spotlighting some laggards who are continuing to underperform.

Now in its third year, the nonprofit created a new set of standards with Yale School of Medicine and Stanford Law School to evaluate the track record on trial registration, results reporting, publication and data-sharing practice.

Busy Gilead crew throws strug­gling biotech a life­line, with some cash up­front and hun­dreds of mil­lions in biobucks for HIV deal

Durect $DRRX got a badly needed shot in the arm Monday morning as Gilead’s busy BD team lined up access to its extended-release platform tech for HIV and hepatitis B.

Gilead, a leader in the HIV sector, is paying a modest $25 million in cash for the right to jump on the platform at Durect, which has been using its technology to come up with an extended-release version of bupivacaine. The FDA rejected that in 2014, but Durect has been working on a comeback.

In­tec blitzed by PhI­II flop as lead pro­gram fails to beat Mer­ck­'s stan­dard com­bo for Parkin­son’s

Intec Pharma’s $NTEC lead drug slammed into a brick wall Monday morning. The small-cap Israeli biotech reported that its lead program — coming off a platform designed to produce a safer, more effective oral drug for Parkinson’s — failed the Phase III at the primary endpoint.

Researchers at Intec, which has already seen its share price collapse over the past few months, says that its Accordion Pill-Carbidopa/Levodopa failed to prove superior to Sinemet in reducing daily ‘off’ time. 

Cel­gene racks up third Ote­zla ap­proval, heat­ing up talks about who Bris­tol-My­ers will sell to

Whoever is taking Otezla off Bristol-Myers Squibb’s hands will have one more revenue stream to boast.

The drug — a rising star in Celgene’s pipeline that generated global sales of $1.6 billion last year — is now OK’d to treat oral ulcers associated with Behçet’s disease, a common symptom for a rare inflammatory disorder. This marks the third FDA approval for the PDE4 inhibitor since 2014, when it was greenlighted for plaque psoriasis and psoriatic arthritis.

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Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Vlad Coric (Biohaven)

In an­oth­er dis­ap­point­ment for in­vestors, FDA slaps down Bio­haven’s re­vised ver­sion of an old ALS drug

Biohaven is at risk of making a habit of disappointing its investors.

Late Friday the biotech $BHVN reported that the FDA had rejected its application for riluzole, an old drug that they had made over into a sublingual formulation that dissolves under the tongue. According to Biohaven, the FDA had a problem with the active ingredient used in a bioequivalence study back in 2017, which they got from the Canadian drugmaker Apotex.

Apotex, though, has been a disaster ground. The manufacturer voluntarily yanked the ANDAs on 31 drugs — in late 2017 — after the FDA came across serious manufacturing deficiencies at their plants in India. A few days ago, the FDA made it official.

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