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.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Albert Bourla, Pfizer CEO (Efren Landaos/Sipa USA/Sipa via AP Images)

Pfiz­er makes an­oth­er bil­lion-dol­lar in­vest­ment in Eu­rope and ex­pands again in Michi­gan

Pfizer is continuing its run of manufacturing site expansions with two new large investments in the US and Europe.

The New York-based pharma giant’s site in Kalamazoo, MI, has seen a lot of attention over the past year. As a major piece of the manufacturing network for Covid-19 vaccines and antivirals, Pfizer is gearing up to place more money into the site. Pfizer announced it will place $750 million into the facility, mainly to establish “modular aseptic processing” (MAP) production and create around 300 jobs at the site.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Vas Narasimhan, Novartis CEO (Thibault Camus/AP Images, Pool)

No­var­tis bol­sters Plu­vic­to's case in prostate can­cer with PhI­II re­sults

The prognosis is poor for metastatic castration-resistant prostate cancer (mCRPC) patients. Novartis wants to change that by making its recently approved Pluvicto available to patients earlier in their course of treatment.

The Swiss pharma giant unveiled Phase III results Monday suggesting that Pluvicto was able to halt disease progression in certain prostate cancer patients when administered after androgen-receptor pathway inhibitor (ARPI) therapy, but without prior taxane-based chemotherapy. The drug is currently approved for patients after they’ve received both ARPI and chemo.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Nkarta CEO Paul Hastings at Endpoints' #BIO22 panel (J.T. MacMillan Photography for Endpoints News)

Nkar­ta un­der­scores safe­ty of CAR-NK, boasts ear­ly re­spons­es

The first generation of personalized CAR-T therapies made big waves in the treatment of lymphoma for their stunning efficacy. Nkarta is hoping its off-the-shelf natural killer cell approach will stand out on safety — while keeping some of those impressive numbers on responses.

In a new update from its Phase I dose escalation study, the South San Francisco-based biotech reported that seven out of 10 patients treated with the highest doses of its NK cell therapy, NKX019, achieved a complete response, translating to a complete response rate of 70%.

Pfiz­er-backed Me­di­ar Ther­a­peu­tics ropes in an­oth­er Big Phar­ma in­vestor

A biotech centered on treating fibrosis — born out of Mass General and Brigham and Women’s Hospital — has received a financial boost.

According to an SEC filing, the company has raised $31,761,186 in its latest funding round, which includes 17 investors. The filing lists six names attached to the company, including Meredith Fisher, a partner at Mass General Brigham Ventures and Mediar’s acting CEO.

Sekar Kathiresan, Verve Therapeutics CEO

Verve re­veals let­ter from FDA that lays out con­di­tions to lift base edit­ing tri­al hold

We now know why Verve’s lead candidate was placed on hold last month by US regulators.

In an SEC filing, Verve laid out the FDA’s conditions for lifting the hold on its lead therapy, VERVE-101. That includes submitting preclinical data about potency differences in human versus non-human cells, risks of gene editing germline cells, and off-target analyses in non-hepatocyte cell types.

The FDA also wants clinical data from the ongoing Heart-1 trial, and to modify the trial protocol in the US to add additional contraceptive measures and increase the length of a staggering interval between the dosing of participants.

Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



Talk therapy didn’t help Lily with attention deficit hyperactivity disorder, or ADHD. But a video game did.

As the 10-year-old zooms through icy waters and targets flying creatures on the snow-capped planet Frigidus, she builds attention skills, thanks to Akili Interactive Labs’ video game EndeavorRx. She’s now less anxious and scattered, allowing her to stay on a low dose of ADHD medication, according to her mom Violet Vu.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Rick Modi, Affinia Therapeutics CEO

Ver­tex-part­nered gene ther­a­py biotech Affinia scraps IPO plans

Affinia Therapeutics has ditched its plans to go public in a relatively closed-door market that has not favored Nasdaq debuts for the drug development industry most of this year. A pandemic surge in 2020 and 2021 opened the doors for many preclinical startups, which caught Affinia’s attention and gave the gene therapy biotech confidence in the beginning days of 2022 to send in its S-1.

But on Friday, Affinia threw in the S-1 towel and concluded now is not the time to step onto Wall Street. The biotech has put out few public announcements since the spring of this year. Endpoints News picked the startup as one of its 11 biotechs to watch last year.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.