Safe­ty fears spur FDA to pause check­point com­bo stud­ies by Bris­tol-My­ers, Cel­gene

Two months af­ter the FDA or­dered Mer­ck to slam the brakes on three Keytru­da com­bo stud­ies tar­get­ing mul­ti­ple myelo­ma, alarmed reg­u­la­tors have fol­lowed up by post­ing a stop sign on en­rolling any new pa­tients in Bris­tol-My­ers Squibb’s three ri­val stud­ies con­cen­trat­ing on the same dis­ease with the same com­bi­na­tion ap­proach­es. And hours lat­er Cel­gene $CELG added that it is be­ing forced to pause 5 com­bo stud­ies us­ing As­traZeneca’s Imfinzi while get­ting slammed with a full hold on one oth­er.

First to be of­fi­cial­ly frozen in place were Mer­ck’s KEYNOTE-183 and KEYNOTE-185 af­ter re­searchers spot­ted a high­er risk of death in the drug arms. Those mul­ti­ple myelo­ma tri­als matched Mer­ck’s block­buster ther­a­py with two drugs from Cel­gene: Po­m­a­lyst and its big drug Revlim­id. The FDA al­so or­dered pa­tients tak­en off of treat­ment in KEYNOTE-023 Co­hort 1, match­ing Keytru­da in com­bi­na­tion with lenalido­mide and dex­am­etha­sone in pa­tients who re­ceived pri­or an­ti-mul­ti­ple myelo­ma treat­ment with an im­munomod­u­la­to­ry (IMiD) treat­ment (lenalido­mide, po­ma­lido­mide or thalido­mide).

Wor­ried by ev­i­dence of safe­ty is­sues, the FDA fol­lowed up Wednes­day evening by or­der­ing a halt to en­roll­ment of new pa­tients in Bris­tol-My­ers’ stud­ies mar­ry­ing Op­di­vo with the same drugs: CA209602 (Check­Mate-602), CA209039 (Check­Mate-039) and CA204142 — al­so mul­ti­ple myelo­ma com­bo stud­ies.

At Cel­gene the dam­age is worse, with a full hold forc­ing re­searchers drop an ear­ly study look­ing at dur­val­um­ab in com­bi­na­tion with lenalido­mide with and with­out low-dose dex­am­etha­sone in mul­ti­ple myelo­ma pa­tients.

Com­bined, therse com­pa­nies have hun­dreds of com­bo stud­ies un­der­way, but reg­u­la­tors clear­ly be­lieve that there’s some oth­er threat to pa­tients in these par­tic­u­lar com­bi­na­tion stud­ies us­ing Cel­gene’s main­stay ther­a­pies. The FDA high­light­ed that con­cern just a week ago, care­ful­ly spelling out their rea­sons for sus­pend­ing the three Mer­ck stud­ies and point­ing out they were hunt­ing down and re­view­ing oth­er, sim­i­lar PD-(L)1 com­bos in the clin­ic.

Bris­tol-My­ers made for a nat­ur­al first stop in that process, with Cel­gene get­ting tagged at vir­tu­al­ly the same time.

The lat­est or­der from the FDA fol­lowed a stun­ning re­ver­sal for Cel­lec­tis, which was slammed with a clin­i­cal hold on Tues­day af­ter the first pa­tient treat­ed in its de­but off-the-shelf CAR-T study died, un­der­scor­ing the un­known risks that still con­front ad­vanced can­cer pa­tients sign­ing up for these ex­per­i­men­tal im­muno-on­col­o­gy tri­als.

Mer­ck and Bris­tol-My­ers are way out front with check­point in­hibitors Keytru­da and Op­di­vo as their PD-1 su­per­stars con­tin­ue to post jaw-drop­ping re­sults in can­cer. Clear­ly, though, as re­searchers con­tin­ue to test the bound­aries of what these new ther­a­pies can do un­ex­pect­ed safe­ty is­sues con­tin­ue to arise, rais­ing ques­tions of just how far de­vel­op­ers should take the drugs.

That same kind of safe­ty is­sue scut­tled Juno’s lead drug, which wound up killing three pa­tients last year af­ter the FDA pre­ma­ture­ly of­fered a green light to re­sume test­ing of its CAR-T af­ter a brief clin­i­cal hold. At this point, reg­u­la­tors ap­pear to be shift­ing their po­si­tion from an en­cour­ag­ing sig­nal to floor it, to a more cau­tious po­si­tion of study­ing safe­ty threats be­fore bar­rel­ing ahead.

For now, safe­ty is still a gray zone in im­muno-on­col­o­gy, as the da­ta con­tin­ues to pour in.

How Pa­tients with Epilep­sy Ben­e­fit from Re­al-World Da­ta

Amanda Shields, Principal Data Scientist, Scientific Data Steward

Keith Wenzel, Senior Business Operations Director

Andy Wilson, Scientific Lead

Real-world data (RWD) has the potential to transform the drug development industry’s efforts to predict and treat seizures for patients with epilepsy. Anticipating or controlling an impending seizure can significantly increase quality of life for patients with epilepsy. However, because RWD is secondary data originally collected for other purposes, the challenge is selecting, harmonizing, and analyzing the data from multiple sources in a way that helps support patients.

Re­gen­eron's Evkeeza shows promise in curb­ing high triglyc­erides, but will ge­net­ic dis­par­i­ties lim­it use?

When Regeneron scored an early approval for lipid lowering antibody Evkeeza back in February, the drugmaker cracked open a new pathway to lower abnormally high cholesterol levels. Now, Regeneron is chasing high triglycerides as well with some promising mid-stage data — but will genetic restrictions limit the drug’s use?

Regeneron’s Evkeeza (evinacumab) cut median triglyceride levels by more than 800 mg/dL (57%) in patients with a rare disorder causing abnormally high triglyceride levels compared with an overall increase of 50 mg/dL (1.8%) in participants on placebo, according to Phase II data presented Sunday at the virtual American College of Cardiology meeting.

$DNA is once again on NYSE; FDA clears Soliris chal­lenger for the mar­ket; Flag­ship’s think­ing big again with eR­NA; 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.

I still remember the uncertainty in the air last year when nobody was sure whether ASCO would cancel their in-person meeting. But it’s now back again for the second virtual conference, and Endpoints News is here for it. Check out our 2-day event reviewing the landscape of cancer R&D and send news our way.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 105,400+ biopharma pros reading Endpoints daily — and it's free.

As­traZeneca's Farx­i­ga missed big on Covid-19 study, but it's tak­ing SGLT2 safe­ty da­ta as a sil­ver lin­ing

AstraZeneca hasn’t seen many setbacks in recent months for SGLT2 inhibitor Farxiga, which broke ground in heart failure and kidney disease regardless of diabetes diagnosis. But the British drugmaker had to admit defeat in taking Farxiga into Covid-19, but follow-up results add a bit of a silver lining to that trial’s safety data.

Of hospitalized Covid-19 patients dosed with AstraZeneca’s Farxiga, 11.2% experienced an organ failure or died after 30 days of therapy compared with 13.8% of those given placebo, according to follow-up data from the DARE-19 study revealed Sunday at the virtual American College of Cardiology meeting.

Pfiz­er, Bris­tol My­er­s' Eliquis flops in post-heart surgery pa­tients, spurring an 'un­ex­plained sig­nal' in cer­tain deaths

Pfizer and Bristol Myers Squibb’s non-warfarin blood thinner Eliquis has raced out to become the most prescribed drug of its class on the market — even overtaking warfarin’s long-time lead. But in tricky-to-treat patients after a valve replacement, an investigator-sponsored study couldn’t turn up benefit and raised a troubling safety signal.

Eliquis failed to show benefit over standard of care in preventing serious clinical outcomes after a transaortic valve replacement (TAVR) and was linked to an “unexplained signal” in a subset of populations with a higher rate of non-CV deaths who did not need blood thinners apart from the surgery, according to data presented Saturday at the virtual American College of Cardiology meeting.

Vas Narasimhan (Photographer: Simon Dawson/Bloomberg via Getty Images)

No­var­tis whiffs on En­tresto study af­ter heart at­tacks — but that does­n't mean it's go­ing down qui­et­ly

If Novartis learned one thing from its interaction with the FDA over its latest heart failure approval for Entresto, it was that missing a primary endpoint may not be the nail in the coffin. Now, Entresto has missed again on a late-stage study in high-risk heart patients, and it’s already sowing the seeds for a path forward regardless.

Novartis’ Entresto couldn’t best standard-of-care ramipril in staving off a composite of deaths and heart failure events in patients with left ventricular systolic dysfunction and/or pulmonary congestion who have had a prior heart attack, according to topline data from the Phase III PARADISE-MI study revealed Saturday at the virtual American College of Cardiology meeting.

Michael Dell (Richard Drew, AP Images)

'Dude, you're get­ting a Del­l' — as a new deep-pock­et biotech in­vestor

What happens when you marry longtime insiders in the global biotech VC game with the family fund of tech billionaire Michael Dell, a synthetic biology legend out of MIT and Harvard and the former director of the NCI?

Today, the answer is a newly financed, $200 million biotech SPAC now cruising the industry for a top player interested in finding a short cut to Nasdaq.

Orion Biotech Opportunities priced their blank check company today, raising $200 million with Dell’s multibillion-dollar MSD group’s commitment on investing another $20 million in a forward-purchase agreement.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Gene ther­a­py from Bio­gen's $800M buy­out flops in mid-stage study, deal­ing blow to new am­bi­tions

The #2 candidate from Biogen’s $800 million ocular gene therapy buyout has failed in a mid-stage trial, dealing an early blow to the big biotech’s plans to revitalize its pipeline with new technologies.

Biogen announced that the candidate, an experimental treatment for a rare and progressive form of blindness called X-linked retinitis pigmentosa (XLRP), failed to sufficiently improve vision in patients’ treated eye — patients only received an injection in one eye — after a year, on a standard scale, compared to their untreated eye. The company said they saw “positive trends” on several secondary endpoints, including visual acuity, but declined to say whether the trial actually hit any of those endpoints.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 105,400+ biopharma pros reading Endpoints daily — and it's free.

In­cyte’s PD-(L)1 in­hibitor head­ed for an ODAC show­down next month

The FDA’s Oncologic Drugs Advisory Committee will spend a half day on June 24 reviewing Incyte’s PD-(L)1 inhibitor retifanlimab as a treatment for locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) for those who have progressed on or who are intolerant of platinum-based chemotherapy.

The eighth PD-(L)1 entrant in January nabbed a priority review and an orphan designation from the FDA, which sets the agency’s final decision date as July 25.