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.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been insisting for months that a Covid-19 vaccine had to be at least 50% effective – a measure of transparency meant to shore public trust in the agency and in a vaccine that had been brought forward at record speed and record political pressure. But now, with concerns of a Trump-driven authorization arriving before the election, the agency may be raising the bar.

The FDA is set to release new guidance that would raise safety and efficacy requirements for a vaccine EUA above earlier guidance and above the criteria used for convalescent plasma or hydroxychloroquine, The Washington Post reported. Experts say this significantly lowers the odds of an approval before the election on November 3, which Trump has promised despite vocal concerns from public health officials.

Blueprint CEO Jeff Albers (file photo)

Blue­print plots re­turn to FDA with new Ay­vak­it da­ta in rare con­di­tion — and the an­a­lysts cheer

Over a decade after launch, Blueprint Medicines nabbed the first approval for their first drug earlier this year. Now, as they move forward with a Roche-partnered global launch, they’re touting data that could push them into more patients.

The Jeff Albers-led Cambridge biotech released their full pivotal data for Ayvakit in patients with advanced systemic mastocytosis. In one 53-person study, they showed that 76% of patients responded to the drug, 36% had complete responses and that on average their responses lasted for just over 3 years. A smaller, 32-patient study had a 75% response rate and most were still responding after 10.4 months, the last follow-up.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.

Samit Hirawat (Bristol Myers Squibb)

Af­ter bruis­ing re­jec­tion, blue­bird and Bris­tol My­ers Squibb land ide-cel pri­or­i­ty re­view. But will it mat­ter for the CVR?

With the clock all but up, the FDA accepted and handed priority review to Bristol Myers Squibb and bluebird bio’s BCMA CAR-T, keeping a narrow window open for Celgene investors to still cash in on the $9 CVR from the $63 billion Celgene merger.

The acceptance comes five months after the two companies weres slammed with a surprise refuse-to-file that threatened to foreclose the CVR entirely. Today’s acceptance sets the FDA decision date for March 27, 2021 – or precisely 4 days before the CVR deadline of March 31. Given the breakthrough designation and strong pivotal data — 81.5% response rate, 35.2% complete response rate — priority review was largely expected.

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Can a mag­net­ic cell ther­a­py re­place corneal trans­plan­ta­tion? As eight-year jour­ney leads to the clin­ic, two broth­ers un­veil bold vi­sion

Jeff Goldberg was getting acquainted with a brand new way to do corneal transplants when an even newer, even bolder idea hit him.

It was almost 10 years ago, and Goldberg was in his first faculty position at Bascom Palmer Eye Institute at the University of Miami. Scientists had developed a new way to do cornea transplants where instead of sewing a whole donor cornea — a decades-old practice — they were just engrafting the inner layer of cells.

News brief­ing: Tiny Vac­cinex's drug flops in PhII Hunt­ing­ton's tri­al, stock craters; Siol­ta nabs $30M Se­ries B to de­vel­op mi­cro­bio­me drug

Siolta Therapeutics, a microbiome company targeting allergic diseases, raked in a $30 million Series B to develop its lead candidate, STMC-103H. The drug, which has been FDA fast-tracked, is headed for proof-of-concept trials, according to the company. Its various indications include allergic asthma, food allergies, atopic dermatitis, allergic rhinitis, and allergy prevention.

The news comes just after the California-based biotech added a prominent biopharma veteran as an advisor: 20-year Gilead CEO John Martin. The biotech also gained Richard Shames as CMO, who came by way of Protagonist Therapeutics.

Embattled CDC director Robert Redfield (AP Images)

Covid-19 roundup: CDC ad­vi­so­ry com­mit­tee de­lays pri­or­i­ty dis­tri­b­u­tion vote; EU re­port­ed­ly in­dem­ni­fy­ing vac­cine mak­ers

A federal committee that advises the CDC was expected to hold a vote Tuesday on a plan regarding the distribution for initial doses of approved Covid-19 vaccines. But that vote has been scrapped.

The Advisory Committee on Immunization Practices, or ACIP, won’t be voting until the committee members learn more about which vaccines become available first, the Wall Street Journal reported. The vote could potentially wait until a specific vaccine is authorized before recommending how to dole out the first doses.

Anthony Coyle (Repertoire)

Flag­ship's merged biotech Reper­toire nets ex-Pfiz­er CSO An­tho­ny Coyle as R&D chief

Flagship is building a big-name C-suite at its new, $220 million merged biotech.

Repertoire Immune Medicines, which already boasts former Bioverativ chief John Cox as its CEO, announced yesterday that Anthony Coyle, the former Pfizer CSO and the founding CEO of Pandion, will join as their head of R&D.

“As we progress clinical trials for our multi-clonal T cell candidates in immuno-oncology, Tony’s deep expertise in cellular immunology and novel therapeutic development will help us achieve our vision of creating a new class of transformative medicines for patients,” Cox said in a statement.