Mer­ck cau­tious­ly steps in­to the PD-(L)1/CT­LA-4 check­point fray. But should it ‘go big or go home’ in­stead?

Mer­ck’s strat­e­gy on de­vel­op­ing its PD-1 check­point drug Keytru­da could be sum­ma­rized as: If we have any kind of a shot at a le­git­i­mate tar­get, we’re go­ing to take it. Then we’ll start a com­bo tri­al AS­AP.

Now it’s moved in­to an ear­ly-stage study in what is loom­ing as the next big chal­lenge that will ei­ther dis­tin­guish the lead­ers or set up the next great pit­fall: A PD-(L)1/CT­LA-4 com­bo.

Tim An­der­son

The think­ing be­hind this, out­lined in a note from Bern­stein’s Tim An­der­son, helps il­lus­trate just how in­tense­ly com­pet­i­tive this game of block­busters has be­come, pit­ting Mer­ck $MRK against Bris­tol-My­ers Squibb $BMY (again) and a very am­bi­tious group at As­traZeneca $AZN that has been mak­ing some close­ly-watched in­roads in the field this year.

Mer­ck’s lat­est ear­ly-stage com­bo match­es its in-house CT­LA-4 drug MK-1308 with Keytru­da, its check­point star that has moved in­to a dom­i­nant po­si­tion in the fast-chang­ing field.

Roger Perl­mut­ter, Mer­ck

“(T)here is a dif­fer­en­ti­a­tion that we’re hop­ing for. And it is a mol­e­cule that was ob­tained in part ex­ter­nal­ly and re­fined in­ter­nal­ly,” Mer­ck R&D chief Roger Perl­mut­ter told An­der­son. “We’ve been work­ing on it for some time.”

As An­der­son ob­serves, there is on­ly one CT­LA-4 drug on the mar­ket. That is Bris­tol-My­ers Yer­voy, which is in a com­bi­na­tion study al­ready. As­traZeneca, though, is com­ing up fast with a com­bi­na­tion of Imfinzi and its CT­LA-4 treme­li­mum­ab in their MYS­TIC study, which will ei­ther help them vault ahead or il­lus­trate why there has been grow­ing skep­ti­cism about the com­bo. Yer­voy and CT­LA-4 drugs in gen­er­al have been linked with con­sid­er­able tox­i­c­i­ty, and more re­cent re­ports un­der­score some strong doubts about its fu­ture in check­point com­bos.

Perl­mut­ter ad­mit­ted as much to An­der­son, who thinks that Mer­ck would be bet­ter off shoot­ing for a com­bi­na­tion study with Yer­voy now rather than wait­ing for the ex­per­i­men­tal in-house drug to come along. An­der­son writes:

We have felt that if MRK is go­ing to pur­sue CT­LA4 com­bo – ei­ther as a hedge, or be­cause it gen­uine­ly be­lieves in the op­por­tu­ni­ty – it ei­ther needs to “go big or go home.”  As a com­pound just en­ter­ing first-in-hu­man stud­ies, MK-1308 is far be­hind BMY and AZN.  Un­less MRK be­lieves it has a dif­fer­en­ti­at­ed prod­uct, it is dif­fi­cult to jus­ti­fy de­vel­op­ment of this new mol­e­cule giv­en the sub­stan­tial lead-time ad­van­tage that its two com­peti­tors have in this area.

How­ev­er, MRK’s pur­suit of MK-1308 be­comes eas­i­er to jus­ti­fy if MRK were to si­mul­ta­ne­ous­ly get its feet wet more quick­ly by a com­bi­na­tion study of Keytru­da+Yer­voy (even if on­ly a short­er, quick­er, “prac­tice-en­abling” study, sim­i­lar to what BMY’s CM-568 was sup­posed to be).  This way, Keytru­da would re­main rel­e­vant in the near­er-term in a CT­LA4 com­bi­na­tion set­ting should tri­als like MYS­TIC (AZN) or Check­mate-227 (BMY) show fa­vor­able re­sults.  As long as MRK gen­er­ates clin­i­cal da­ta like this, physi­cians would like­ly feel com­fort­able mix­ing-and-match­ing MRK’s and BMY’s sep­a­rate prod­ucts.  Then, MRK has more time to even­tu­al­ly come in with a CT­LA4 of its own.

We’ll find out lat­er this year and next how these check­point com­bos line up against the check­point/chemo com­bi­na­tions that have been mov­ing in­to prac­tice. But An­der­son al­so notes that there is a swelling wave of fol­low-up tri­als to watch with IDO and more com­bi­na­tions mov­ing in­to Phase III.

In­di­vid­ual com­bi­na­tion strate­gies have to evolve. Just don’t look for any of the big play­ers, or the sec­ond-gen com­peti­tors lin­ing up, to slow down now.

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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UP­DAT­ED: Stay tuned: Bio­gen’s num­bers are great — it’s their wor­ri­some fu­ture that leaves an­a­lysts skit­tish

Biogen came out with an upbeat assessment of their Q2 numbers today, discounting the arrival of a key rival for its blockbuster Spinraza franchise. But the top execs remain grimly determined to not say much anything new about the sore points that have dragged down its stock, including the future of its big investment in Alzheimer’s or how it plans to invest the considerable cash that the big biotech continues to reap.

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Why wait? Cel­gene re­struc­tures a big Jounce pact — ze­ro­ing in on new I/O path­way with $530M deal and bump­ing ICOS

Celgene’s business team isn’t waiting for the big merger with Bristol-Myers Squibb to go through before syncing its strategy with the new mother ship.

Tuesday evening the big biotech unveiled a $530 million deal — $50 million in upfront cash — to amend their alliance with Jounce Therapeutics $JNCE to gain worldwide rights to JTX-8064, an antibody that targets the LILRB2 receptor on macrophages. Their old, $2.6 billion deal is being scrapped, leaving Jounce with a pipeline that includes the lead drug, the ICOS-targeting vopratelimab.

PACT Phar­ma says it's per­fect­ed the tech to se­lect neoanti­gens for per­son­al­ized ther­a­py — now on­to the clin­ic

At PACT Pharma, the lofty goal to unleash a “tsunami” of T cells personalized for each patient has hinged on the ability to correctly identify the neoantigens that form something of a fingerprint for each tumor, and extract the small group of T cells primed to attack the cancer. It still has a long way to go testing a treatment in humans, but the biotech says it has nailed that highly technical piece of the process.

UP­DAT­ED: My­ovan­t's uter­ine fi­broid drug looks com­pet­i­tive in PhI­II — but can they van­quish mighty Ab­b­Vie?

Vivek Ramaswamy’s Myovant $MYOV has closely matched its positive first round of Phase III data for their uterine fibroid drug relugolix, setting up a head-to-head rivalry with pharma giant AbbVie as the little biotech steers to the market with a planned filing in Q4.

Here’s how Myovant plans to prevail over the AbbVie $ABBV empire.

In the study, 71.2% of women receiving once-daily relugolix combination therapy achieved the clinical response they were looking for, compared to only 14.7% in the control arm. The data comfortably reflected the same outcomes in the first Phase III — 73.4% of women receiving once-daily oral relugolix combination therapy achieved the responder criteria compared with 18.9% of women receiving placebo — which will reassure regulators that they are getting the carefully randomized data that qualifies for the FDA’s gold standard for success.

Lit­tle Mar­i­nus sees its shares eclipsed as the Sage ri­val fails to com­pare on PPD in PhII

The executive team at Sage $SAGE have skirted another potential pitfall on its way to racking up a big future for its depression drug Zulresso.

Little Marinus Pharmaceuticals $MRNS had sought to challenge the Sage drug with an IV formulation — followed by an oral version — of ganaxolone for postpartum depression. But researchers say their Phase II study failed to positively differentiate itself from a placebo at 28 days — leaving them to hold up “clinically meaningful” data within the first day of administration compared to the control arm.

Roche cuts loose Tam­i­flu OTC rights, hand­ing Sanofi the keys as the phar­ma gi­ant dou­bles down on Xofluza

Roche set out to make a better flu medicine than Tamiflu as that franchise was headed to a generic showdown. Now they’ll see just how well Xofluza stacks up against the mainstay drug after handing off over-the-counter rights in the US to Sanofi.

Sanofi $SNY says it will now step in to negotiate a deal with the FDA to steer Tamiflu into the OTC market, a role that could well involve new studies to ease passage of the drug out of doctor’s hands and into the consumer end of the market. And the French pharma giant will have first dibs over “selected” OTC markets around the world as they push ahead.

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.