J&J’s big block­buster hope­ful es­ke­t­a­mine scores high for ma­jor de­pres­sion — but side ef­fects haunt re­sults

Can a horse tran­quil­iz­er and no­to­ri­ous par­ty drug be rein­vent­ed as a safe and ef­fec­tive break­through ther­a­py to swift­ly treat ma­jor de­pres­sion and sui­ci­dal think­ing?

J&J $JNJ has been work­ing on that task for years and is now ham­mer­ing away at a piv­otal late-stage pro­gram. This week they’re rolling out some de­tailed Phase II re­sults that un­der­score the po­ten­tial, as well as the prob­lems, that seem in­ex­tri­ca­bly linked to this drug.

Hus­sei­ni Man­ji

J&J’s team took ke­t­a­mine — Spe­cial K as it’s called in cer­tain so­cial cir­cles — and cre­at­ed an in­tranasal ver­sion dubbed es­ke­t­a­mine. The phar­ma gi­ant picked up its first break­through des­ig­na­tion for this drug more than four years ago. And the phar­ma gi­ant be­lieves it’s a block­buster to be, one of the biggest po­ten­tial earn­ers in its late-stage pipeline.

Re­searchers took three dos­es of es­ke­t­a­mine in­to a Phase II study with 126 pa­tients, sep­a­rat­ing them in­to three dose groups. And the drug per­formed as they had ex­pect­ed, of­fer­ing a quick up­take over a two-week study with a dose-de­pen­dent re­ac­tion that of­fered fast re­lief for ma­jor de­pres­sive dis­or­der, as tracked in a com­mon­ly used tri­al as­sess­ment tool.

The good news: By day 8 there was a ma­jor im­prove­ment in the MADRS score for the high dose, more than twice what was reg­is­tered in the low-dose group — which was al­so still clin­i­cal­ly sig­nif­i­cant. Over a two-month fol­lowup, the re­sponse ap­peared to im­prove.

The bad news: Among the side ef­fects was “per­cep­tu­al changes/dis­so­cia­tive symp­toms,” which ran at more than twice the rate seen in the place­bo arm. One in four of the pa­tients tak­ing the drug ex­pe­ri­enced dis­so­cia­tive symp­toms. Se­da­tion was an­oth­er com­mon symp­tom. The dis­so­cia­tive symp­toms oc­curred short­ly af­ter dos­ing and gen­er­al­ly re­solved af­ter a cou­ple of hours. In oth­er words, the Phase II ver­sion of this drug still car­ries risks linked to Spe­cial K.

Aca­d­e­m­ic groups have been re­search­ing straight ke­t­a­mine in hu­mans for years, and their re­sults gen­er­al­ly match, with a rapid lift­ing of de­pres­sion, even among the pa­tients who ap­pear re­sis­tant to any­thing else avail­able. It is an amaz­ing­ly ef­fec­tive treat­ment, and would be an un­am­bigu­ous boon with­out the side ef­fects. It’s al­so tran­sient, with a dose ef­fect that wears off rel­a­tive­ly quick­ly, re­quir­ing re­peat­ed dos­ing to re­main ef­fec­tive.

That re­peat­ed dos­ing, and the longterm im­pact of a ver­sion of a drug that’s been used to in­duce schiz­o­phrenic symp­toms in healthy vol­un­teers, hasn’t been stud­ied so close­ly.

Cur­rent­ly, as any­one with de­pres­sion will tell you, the crop of de­pres­sion drugs avail­able is wild­ly in­con­sis­tent and of­ten tran­sient in na­ture. Ke­t­a­mine works on NM­DA re­cep­tors, and that in turn has led to a surge of new drug de­vel­op­ment pro­grams, in­clud­ing a late-stage ef­fort at Al­ler­gan af­ter that com­pa­ny ac­quired Nau­rex for $560 mil­lion up­front. Sage has al­so at­tract­ed wide­spread in­ter­est in its own ap­proach for de­pres­sion.

Who­ev­er wins this race, if it is won, will have ac­cess to an enor­mous mar­ket, even if its side ef­fects lim­it the drug to a group of the most se­vere­ly af­flict­ed pa­tients.

“If ap­proved by the FDA,” says J&J’s Hus­sei­ni Man­ji, “es­ke­t­a­mine would be one of the first new ap­proach­es to treat re­frac­to­ry ma­jor de­pres­sive dis­or­der avail­able to pa­tients in the last 50 years.”

But the very size of the mar­ket al­so rais­es the bar on safe­ty and ef­fi­ca­cy. And that ju­ry will re­main out un­til Phase III da­ta are com­plete.

Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive piv­otal for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma.

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

We don’t know what the data are yet, but DREAMM-2 falls on the heels of a promising set of data delivered 5 months ago for DREAMM-1. There investigators noted that complete responses among treatment-resistant patients rose to 15% in the extra year’s worth of data to look over, with a median progression-free survival rate of 12 months, up from 7.9 months reported earlier. The median duration of response was 14.3 months.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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Why would Am­gen want to buy Alex­ion? An­a­lysts call hot­ly ru­mored takeover un­like­ly, but seize the mo­ment

A rumor that Amgen is closing in on buyout deal for Alexion has sparked a guessing game on just what kind of M&A strategy Amgen is pursuing and how much Alexion is worth.

Mizuho analyst Salim Syed first lent credence to the report out of the Spanish news outlet Intereconomía, which said Amgen is bidding as much as $200 per share. While the source may be questionable, “the concept of this happening doesn’t sound too crazy to me,” he wrote.