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.

John Hood [file photo]

UP­DATE: Cel­gene and the sci­en­tist who cham­pi­oned fe­dra­tinib's rise from Sanofi's R&D grave­yard win FDA OK

Six years after Sanofi gave it up for dead, the FDA has approved the myelofibrosis drug fedratinib, now owned by Celgene.

The drug will be sold as Inrebic, and will soon land in the portfolio at Bristol-Myers Squibb, which is finalizing a deal to acquire Celgene.

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Ab­b­Vie gets its FDA OK for JAK in­hibitor upadac­i­tinib, but don’t look for this one to hit ex­ecs’ lofty ex­pec­ta­tions

Another big drug approval came through on Friday afternoon as the FDA OK’d AbbVie’s upadacitinib — an oral JAK1 inhibitor that is hitting the rheumatoid arthritis market with a black box warning of serious malignancies, infections and thrombosis reflecting fears associated with the class.

It will be sold as Rinvoq — at a wholesale price of $59,000 a year — and will likely soon face competition from a drug that AbbVie once controlled, and spurned. Reuters reports that a 4-week supply of Humira, by comparison, is $5,174, adding up to about $67,000 a year.

UP­DAT­ED: AveX­is sci­en­tif­ic founder was axed — and No­var­tis names a new CSO in wake of an ethics scan­dal

Now at the center of a storm of controversy over its decision to keep its knowledge of manipulated data hidden from regulators during an FDA review, Novartis CEO Vas Narasimhan has found a longtime veteran in the ranks to head the scientific work underway at AveXis, where the incident occurred. And the scientific founder has hit the exit.

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The top 10 fran­chise drugs in bio­phar­ma his­to­ry will earn a to­tal of $1.4T (tril­lion) by 2024 — what does that tell us?

Just in case you were looking for more evidence of just how important Amgen’s patent win on Enbrel is for the company and its investors, EvaluatePharma has come up with a forward-looking consensus estimate on what the list of top 10 drugs will look like in 2024.

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UP­DAT­ED: Sci­en­tist-CEO ac­cused of im­prop­er­ly us­ing con­fi­den­tial in­fo from uni­corn Alec­tor

The executive team at Alector $ALEC has a bone to pick with scientific co-founder Asa Abeliovich. Their latest quarterly rundown has this brief note buried inside:

On June 18, 2019, we initiated a confidential arbitration proceeding against Dr. Asa Abeliovich, our former consulting co-founder, related to alleged breaches of his consulting agreement and the improper use of our confidential information that he learned during the course of rendering services to us as our consulting Chief Scientific Officer/Chief Innovation Officer. We are in the early stage of this arbitration proceeding and are unable to assess or provide any assurances regarding its possible outcome.

There’s no explicit word in the filing on what kind of confidential info was involved, but the proceeding got started 2 days ahead of Abeliovich’s IPO.

Abeliovich, formerly a tenured associate professor at Columbia, is a top scientist in the field of neurodegeneration, which is where Alector is targeted. More recently, he’s also helped start up Prevail Therapeutics as the CEO, which raised $125 million in an IPO. And there he’s planning on working on new gene therapies that target genetically defined subpopulations of Parkinson’s disease. Followup programs target Gaucher disease, frontotemporal dementia and synucleinopathies.

But this time Abeliovich is the CEO rather than a founding scientist. And some of their pipeline overlaps with Alector’s.

Abeliovich and Prevail, though, aren’t taking this one lying down.

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Chi­na has be­come a CEO-lev­el pri­or­i­ty for multi­na­tion­al phar­ma­ceu­ti­cal com­pa­nies: the trend and the im­pli­ca­tions

After a “hot” period of rapid growth between 2009 and 2012, and a relatively “cooler” period of slower growth from 2013 to 2015, China has once again become a top-of-mind priority for the CEOs of most large, multinational pharmaceutical companies.

At the International Pharma Forum, hosted in March in Beijing by the R&D Based Pharmaceutical Association Committee (RDPAC) and the Pharmaceutical Research and Manufacturers of America (PhRMA), no fewer than seven CEOs of major multinational pharmaceutical firms participated, including GSK, Eli Lilly, LEO Pharma, Merck KGaA, Pfizer, Sanofi and UCB. A few days earlier, the CEOs of several other large multinationals attended the China Development Forum, an annual business forum hosted by the research arm of China’s State Council. It’s hard to imagine any other country, except the US, having such drawing power at CEO level.

As dis­as­ter struck, Ab­b­Vie’s Rick Gon­za­lez swooped in on Al­ler­gan with an of­fer Brent Saun­ders couldn’t say no to

Early March was a no good, awful, terrible time for Allergan CEO Brent Saunders. His big lead drug had imploded in a Phase III disaster and activists were after his hide — or at least his chairman’s title — as the stock price continued a steady droop that had eviscerated share value for investors.

But it was a perfect time for AbbVie CEO Rick Gonzalez to pick up the phone and ask Saunders if he’d like to consider a “strategic” deal.

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CEO Pascal Soriot via Getty Images

As­traZeneca's jug­ger­naut PARP play­er Lyn­parza scoops up an­oth­er dom­i­nant win in PhI­II as the FDA adds a 'break­through' for Calquence

AstraZeneca’s oncology R&D group under José Baselga keeps churning out hits.

Wednesday morning the pharma giant and their partners at Merck parted the curtains on a successful readout for their Phase III PAOLA-1 study, demonstrating statistically significant improvement in progression-free survival for women with ovarian cancer in a first-line maintenance setting who added their PARP Lynparza to Avastin. This is their second late-stage success in ovarian cancer, which will help stave off rivals like GSK.

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ICER blasts FDA, PTC and Sarep­ta for high prices on DMD drugs Em­flaza, Ex­ondys 51

ICER has some strong words for PTC, Sarepta and the FDA as the US drug price watchdog concludes that as currently priced, their respective new treatments for Duchenne muscular dystrophy are decidedly not cost-effective.

The final report — which cements the conclusions of a draft issued in May — incorporates the opinion of a panel of 17 experts ICER convened in a public meeting last month. It also based its analysis of Emflaza (deflazacort) and Exondys 51 (eteplirsen) on updated annual costs of $81,400 and over $1 million, respectively, after citing “incorrect” lower numbers in the initial calculations.