With hits and miss­es in first piv­otal tri­als, J&J con­fi­dent­ly maps a path to the FDA with its ma­jor de­pres­sion med es­ke­t­a­mine

J&J re­searchers rolled out da­ta from the first two piv­otal tri­als of their an­ti-de­pres­sion drug es­ke­t­a­mine to­day, blaz­ing a trail that they say leads straight to an FDA fil­ing in a mat­ter of months with a ground­break­ing ap­proach to treat­ing ma­jor de­pres­sion.

The da­ta are mixed, with some hits and miss­es, as you’ll see fur­ther be­low as I set out the da­ta points. But there are some im­por­tant caveats to note about the num­bers for a low-dose, in­tranasal for­mu­la­tion of a pow­er­ful anes­thet­ic and fre­quent­ly abused par­ty drug — bet­ter known as Spe­cial K — which will in­vite a very care­ful ex­am­i­na­tion by reg­u­la­tors.

First, and fore­most, the FDA doesn’t re­quire per­fec­tion in de­pres­sion stud­ies, a field where a high place­bo re­sponse is a vir­tu­al giv­en. Be­cause these were hard-to-treat pa­tients, they couldn’t re­serve sole­ly a place­bo for the con­trol arm of the stud­ies. One group re­ceived es­ke­t­a­mine in a nasal spray with an ac­tive de­pres­sion drug while the con­trol arm was giv­en an ac­tive de­pres­sion drug — invit­ing a high re­sponse in the con­trol group, which they got.

Nev­er­the­less, they still beat the con­trol group re­sponse in the first key Phase III. And the in­ves­ti­ga­tors say that stud­ies read­ing out in the next few months will com­plete a pic­ture of pos­i­tive re­sults that reg­u­la­tors will not be able to re­ject for these pa­tients.

“We be­lieve with these stud­ies that we’re go­ing to meet that hur­dle,” says David Hough, Janssen’s clin­i­cal tri­al leader for es­ke­t­a­mine.


The first study among pa­tients with hard-to-treat ma­jor de­pres­sion hit a clear­ly sta­tis­ti­cal­ly sig­nif­i­cant re­sult for the com­mon­ly used Mont­gomery-Ås­berg De­pres­sion Rat­ing Scale, or MADRS. And a low dose ver­sion used in el­der­ly pa­tients missed sta­tis­ti­cal sig­nif­i­cance — they hit a p-val­ue of 0.029 in a tri­al that set the bar for sig­nif­i­cance at 0.025.

The first study al­so missed a key sec­ondary: on­set of clin­i­cal ef­fect in 24 hours main­tained through 28 days in a rel­a­tive­ly short tri­al. And be­cause of that miss they couldn’t for­mal­ly present da­ta on the next two sec­on­daries.

Two oth­er key mea­sures scored for the es­ke­t­a­mine com­bo.

  • There was a 69.3% re­sponse rate in the es­ke­t­a­mine/de­pres­sion drug com­bo group ver­sus a (very high) 52% in the con­trol group at 28 days.
  • The re­mis­sion rate at day 28 was 52.5% for the es­ke­t­a­mine com­bo and 31% for the es­ke­t­a­mine and place­bo nasal spray group.

“This is not gar­den va­ri­ety de­pres­sion,” says Hough. The pa­tients in these stud­ies had tried and failed any­where from two to 5 dif­fer­ent de­pres­sion meds.

Among the side ef­fects of the es­ke­t­a­mine com­bi­na­tion, re­searchers found that some pa­tients suf­fered from dis­so­ci­a­tion, not un­ex­pect­ed in a drug that at high dos­es is some­times used to in­duce schiz­o­phrenic be­hav­ior in clin­i­cal tri­als. J&J’s ap­proach to that will be to pro­vide this drug on­ly un­der care­ful su­per­vi­sion in a clin­i­cal set­ting. That might com­pli­cate mar­ket­ing, if ap­proved, but in a time of wide­spread opi­oid abuse, J&J knows there will be care­ful clin­i­cal re­stric­tions on dis­tri­b­u­tion.

If ap­proved, Hough says the plan would be to use the drug twice a week ini­tial­ly for 4 weeks and then start low­er­ing the fre­quen­cy un­til they get the right main­te­nance lev­el.

If they can win here, they add, this will be the first new drug for treat­ment-re­sis­tant cas­es of ma­jor de­pres­sion in decades.

“We were very pleased,” says Hough, who’s prep­ping the roll­out on more promis­ing da­ta from three more stud­ies.

Over the years a host of aca­d­e­mics have re­peat­ed­ly seen ke­t­a­mine score high for swift if tem­po­rary treat­ment of de­pres­sion and sui­ci­dal think­ing. But its pow­er­ful ef­fects over­all pre­vent its use. That’s what set J&J down this path with a low-dose ver­sion of the drug, while Al­ler­gan and oth­ers are test­ing NM­DA drugs that mim­ic par­tic­u­lar as­pects of the par­ty drug, look­ing for a nar­row hit on de­pres­sion with­out the il­lic­it side ef­fects.

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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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive PhI­II 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.

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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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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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

Am­gen, Al­ler­gan biosim­i­lar of Roche's block­buster Rit­ux­an clears an­oth­er US piv­otal study 

Novartis $NVS may have given up, but Amgen $AMGN and Allergan $AGN are plowing ahead with their knockoff of Roche’s blockbuster biologic Rituxan in the United States.

Their copycat, ABP 798, was found to have a clinically equivalent impact as Rituxan — meeting the main goal of the study involving CD20-positive B-cell non-Hodgkin’s lymphoma patients. This is the second trial supporting the profile of the biosimilar. In January, it came through with positive PK results in patients with rheumatoid arthritis.

BeiGene and Mus­tang nail down spe­cial FDA sta­tus for top drugs; Roche bags added cov­er­age for Hem­li­bra

→ BeiGene $BGNE is getting a boost in its drive to field a rival to Imbruvica. The FDA has offered an accelerated review to zanubrutinib, a BTK inhibitor that has posted positive results for mantle cell lymphoma. The PDUFA date lands on February 27, 2020. The drug scored breakthrough status at the beginning of the year.

→ BeiGene isn’t the only biopharma company to gain special regulatory status today. Mustang Bio $MBIO and St. Jude Children’s Research Hospital announced that MB-107, a lentiviral gene therapy for the treatment of X-linked severe combined immunodeficiency, also known as bubble boy disease, has been granted Regenerative Medicine Advanced Therapy status.