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

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

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Pfiz­er, Am­gen and Janssen seek fur­ther clar­i­ty on FDA's new ben­e­fit-risk guid­ance

Three top biopharma companies are seeking more details from the FDA on how the agency conducts its benefit-risk assessments for new drugs and biologics.

While Pfizer, Amgen and Janssen praised the agency for further spelling out its thinking on the subject in a new draft guidance, including a discussion of patient experience data as part of the assessment, the companies said the FDA could’ve included more specifics in the 20-page draft document.

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Usama Malik

Ex-Im­munomedics CFO charged with in­sid­er trad­ing, faces up to 20 years in prison af­ter al­leged­ly tip­ping off girl­friend and rel­a­tives of a PhI­II suc­cess

The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Ab­b­Vie tacks on a new warn­ing to Rin­voq la­bel as safe­ty frets crimp JAK class

The safety problems that continue to plague the JAK class as new data highlight some severe side effects are casting a large shadow over AbbVie’s Rinvoq.

As a result of a recent readout highlighting major adverse cardiac events (MACE), malignancy, mortality and thrombosis with Xeljanz a couple of months ago, AbbVie put out a notice late Friday afternoon that it is adding the new class risks to its label for their rival drug.

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Biospec­i­men M&A: Dis­cov­ery ac­quires Al­bert Li's he­pa­to­cyte project; PhI­II tri­al on Bay­er's Nube­qa reached pri­ma­ry end­point

Discovery Life Sciences has acquired what claims to be the Maryland-based host of the world’s largest hepatocyte inventory, known as IVAL, to help researchers select more effective and safer drug candidates in the future.

The combined companies will now serve a wider range of drug research and development scientists, according to Albert Li, who founded IVAL in 2004 and is set to join the Discovery leadership team as the CSO of pharmacology and toxicology.

Re­searchers move clos­er to de­ci­pher­ing blood clots from As­traZeneca, J&J's Covid-19 vac­cines

Researchers may be nearing an answer for the mysterious and life-threatening blood clots that appeared on very rare occasions in people who received the J&J or AstraZeneca Covid-19 vaccine.

The new work builds on an early hypothesis researchers in Norway put forward last spring, when the cases first cropped up. They proposed the events were similar to blood clots that can occur in a small subset of patients who receive heparin, one of the most commonly used blood thinners.

Ed Kaye, Stoke Therapeutics CEO

Stoke touts ear­ly signs of ef­fi­ca­cy for Dravet syn­drome drug

Two and a half years after driving his antisense oligonucleotide platform to Wall Street, Stoke Therapeutics CEO Ed Kaye is painting a fuller picture of the company’s first clinical data. And though the trial wasn’t powered to detect statistical significance, Kaye says the readout shows early signs of efficacy in kids with a rare, drug-resistant form of epilepsy

STK-001 was well-tolerated in single and multiple doses in 22 Dravet syndrome patients between the ages of 2 and 18 years old, Stoke announced on Friday. What’s more, 12 of the 17 evaluable patients at the time (70.6%) saw reductions from baseline in convulsive seizure frequency, according to the company.