Should J&J win an OK for a flawed de­pres­sion drug af­ter no­table tri­al fail­ures? FDA re­view of­fers a path for­ward

Should the FDA ig­nore its gold stan­dard and ap­prove J&J’s top drug prospect es­ke­t­a­mine with­out sol­id sup­port­ing ev­i­dence from two well-con­trolled stud­ies? Even af­ter it failed in oth­er stud­ies and presents some se­ri­ous safe­ty is­sues to deal with?

In an in­ter­nal re­view post­ed on­line this morn­ing, reg­u­la­tors posed those ques­tions to an ex­pert com­mit­tee this morn­ing pick­ing up the phar­ma gi­ant’s pitch for their ver­sion of the par­ty drug ke­t­a­mine. Their an­swer may well in­flu­ence the en­tire field of de­pres­sion drug re­search, where fail­ures are far more com­mon than suc­cess.

J&J has a lot rid­ing on this one. The phar­ma gi­ant has tapped es­ke­t­a­mine as one of its top late-stage ef­forts, putting it in a line­up of po­ten­tial block­busters the com­pa­ny is push­ing to beef up rev­enue.

The agency has al­ready blessed J&J with its break­through ther­a­py des­ig­na­tion for es­ke­t­a­mine, im­pressed by the mid-stage da­ta that was pro­duced to show how its in­tranasal ther­a­py brought swift re­lief to pa­tients suf­fer­ing from deep de­pres­sion.

That as­pect of the drug is well known. Ke­t­a­mine — known in par­ty cir­cles as Spe­cial K  — is a horse tran­quil­iz­er that al­so has pro­duced a fast ef­fect in a long range of aca­d­e­m­ic stud­ies over the years. In com­ing up with its own ver­sion, J&J is look­ing to keep the swift im­pact and lose the hal­lu­cino­genic qual­i­ties that make it a con­trolled sub­stance.

De­pres­sion, though, is a mass mar­ket, and the bar on an ap­proval is high, as Richard Pops could tell you af­ter Alk­er­mes was re­peat­ed­ly slapped down on ‘5461. An­ti­de­pres­sants on the mar­ket, though, are of­ten used ran­dom­ly, in se­quence, to find one that can pro­duce an ef­fect — of­ten tak­ing weeks to be­gin work­ing.

For its stud­ies, J&J re­searchers re­cruit­ed heav­i­ly pre-treat­ed pa­tients in des­per­ate need of a ther­a­py. They were start­ed on a new an­ti­de­pres­sant plus es­ke­t­a­mine, fig­ur­ing that an­ti­de­pres­sants usu­al­ly act so slow­ly it wouldn’t in­ter­fere with es­ke­t­a­mine’s fast ac­tion.

As the re­view notes, J&J has pos­i­tive re­sults from “the flex­i­ble-dose tri­al in adults younger than 65 years of age and the ran­dom­ized with­draw­al study.” With­draw­al stud­ies, though, are gen­er­al­ly not rec­og­nized as a well con­trolled study that qual­i­fies as one of the 2 typ­i­cal­ly need­ed stud­ies for an ap­proval.

Then there were the fail­ures — which, by the way, are quite com­mon in de­pres­sion. One rea­son why J&J ran 5 stud­ies is to give them­selves bet­ter odds at suc­cess, rather than re­strict­ing them­selves to 2 piv­otals.

In the fixed-dose study of adults younger than 65 years of age, the pre­spec­i­fied analy­sis plan dic­tat­ed that ef­fi­ca­cy of the 84-mg dose would be eval­u­at­ed first, fol­lowed by eval­u­a­tion of the 56-mg dose. How­ev­er, the 84-mg dose did not sep­a­rate from place­bo and the test­ing se­quence end­ed there. The geri­atric study in­clud­ed flex­i­ble dos­es rang­ing from 28 to 84 mg; the ef­fect of es­ke­t­a­mine in the com­bined dose group was not sta­tis­ti­cal­ly su­pe­ri­or to place­bo (1-sided p = 0.029).

The safe­ty pro­file is al­so far from be­nign, in­clud­ing se­da­tion, dis­so­cia­tive be­hav­ior and in­creased blood pres­sure as pri­ma­ry con­cerns. And none of that was new to the R&D team when they start­ed the work.

To get an OK here will al­so clear­ly re­quire a de­tailed risk mit­i­ga­tion plan, and the FDA wants its ex­perts to weigh in on that as well. The pro­posed REMS in­cludes 2 hours of mon­i­tor­ing af­ter the drug is giv­en to the pa­tient. There will be no dis­tri­b­u­tion of the drug to pa­tients — to avoid abuse — and the plan now is to in­clude a pa­tient reg­istry to track risks.

The FDA’s in­ter­nal re­view nei­ther sug­gests an ap­proval is war­rant­ed or that the pan­el should vote no. The agency has al­ready proved its will­ing­ness to forego the 2-tri­al stan­dard, at least in oth­er dis­eases. The big ques­tion is whether the ex­perts will go for a new and clear­ly im­per­fect drug to add for a group of pa­tients with nowhere else to turn. Un­der those cir­cum­stances, J&J seems to have pret­ty good odds of suc­cess in a field bet­ter known for re­peat­ed set­backs.

Image courtesy of The Janssen Pharmaceutical Companies of Johnson & Johnson.

Pro­tect­ing the glob­al phar­ma­ceu­ti­cal in­no­va­tion ecosys­tem – what’s at stake?

We are living in a new era of healthcare that is rapidly advancing progress impacting patient outcomes and experiences. We’ve seen a remarkable pace of transformational innovation, applied research, and advanced clinical development over the last decade.

Despite this tremendous progress, there is much more work to be done, and patients are counting on us – now more than ever – to continue that momentum. At the heart of our industry is a focus on developing and delivering medicines for some of the world’s most challenging diseases, including those that have few or no effective treatments today.

Mi­rati’s drug sitra­va­tinib flops PhI­II in com­bo with Op­di­vo for cer­tain lung can­cer

Mirati Therapeutics’ path to a second drug approval will likely have to wait. The San Diego biotech company said Wednesday that its investigational lung cancer drug failed a Phase III trial testing it in combination with Bristol Myers Squibb’s Opdivo.

The drug, sitravatinib, and Opdivo weren’t better than the chemo drug docetaxel at keeping patients alive, Mirati said in a press release. The spectrum-selective kinase inhibitor missed the primary goal of overall survival in patients with second- or third-line advanced non-squamous, non-small cell lung cancer.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

End­points 20(+2) un­der 40, 2023; Bio­phar­ma's high­est-paid CEOs; N-of-1 CRISPR sto­ry goes on af­ter tragedy; 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.

We will be off Monday in observance of Memorial Day — and when we get back, it will be a straight march to ASCO, BIO and more. Enjoy the (long) weekend!

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

Rich Horgan (R) with his late brother, Terry

Rich Hor­gan spear­head­ed a gene ther­a­py for his broth­er. The tri­al end­ed in tragedy, but the work con­tin­ues for more pa­tients

Rich Horgan’s quest to create a custom gene therapy for his brother, Terry, ended in tragedy. But Horgan doesn’t believe it’s the end of the story.

Terry, a 27-year-old patient with Duchenne muscular dystrophy, died last October just eight days after receiving the therapy in a clinical trial in which he was the only participant. The case raised questions about the safety of certain gene therapies and what would happen to other drug programs under a nonprofit that Horgan created, called Cure Rare Disease.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

Bio­phar­ma's 20 high­est-paid CEOs of 2022, each bring­ing in $20M+ pay­days

Even in a down year for much of the biopharma market, 20 CEOs brought in pay packages valued at more than $20 million, an Endpoints News analysis found.

Endpoints collected data on more than 350 CEO compensation packages, covering a wide range of pharma, biotech, and life sciences companies. All told, the 20 largest earners made over $725 million in 2022 — an average package of $36.4 million. Three brought in paydays over $50 million, and one CEO broke the $100 million mark.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

FDA ap­proves Lex­i­con’s heart-fail­ure drug af­ter de­feat in di­a­betes

The FDA on Friday approved Lexicon’s heart failure drug sotagliflozin following a string of setbacks for the pharma company, including an FDA rejection in diabetes and the loss of a development deal with Sanofi.

The dual SGLT1 and SGLT2 inhibitor will be marketed as Inpefa and is a once-daily tablet. It’s been approved to reduce the risk of cardiovascular death and heart failure-related hospitalization or urgent visits in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. The label spans the range of left ventricular ejection fraction, including preserved ejection fraction and reduced ejection fraction, as well as patients with or without diabetes, Lexicon said Friday.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

The 20(+2) un­der 40: Your guide to the next gen­er­a­tion of biotech lead­ers

This year’s list of 20 biotech leaders under the age of 40 includes a huge range of ambitions. Some of our honorees are planning to create the next big drug giant. Others are pushing the bounds of AI. One is working to revolutionize TB testing. All are compelling talents who are still young in age, but already far along in achievement.

And, as in years past, we went over. The 20 are actually 22 because of two double profiles that reflect how important teamwork is in the industry. As one of our honorees, Joe Illingworth of DJS Antibodies, told me in our interview, “It takes a village to raise a biotech.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

Eu­ro­pean Com­mis­sion to re­ceive few­er Pfiz­er-BioN­Tech vac­cine dos­es un­der amend­ed con­tract

The European Commission has made a few changes to its vaccine contract with Pfizer and BioNTech, reducing the dose volume while extending the delivery timeline to cope with “evolving public health needs.”

The Commission previously struck a contract in May 2021 for 900 million doses, with the option to purchase another 900 million. Of those, 450 million were expected to be delivered in 2023, though an amendment now calls for fewer doses. While neither the Commission nor Pfizer and BioNTech have revealed an exact amount, an unnamed source told Reuters that the amendment reduces the remaining expected doses by about a third.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.

EMA rec­om­mends re­vok­ing au­tho­riza­tion of No­var­tis' sick­le cell drug

The European Medicines Agency’s committee for medicinal products for human use (CHMP) on Friday recommended revoking the marketing authorization for Novartis’ treatment for a painful complication related to sickle cell, after a recent study did not confirm its clinical benefit.

CHMP’s review looked at results of the STAND study, finding that Adakveo (crizanlizumab) did not reduce the number of painful crises leading to a healthcare visit, and patients treated with Adakveo had slightly more painful crises on average, with a subsequent healthcare visit, over the first year of treatment, compared with those on placebo.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 170,300+ biopharma pros reading Endpoints daily — and it's free.