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.

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Who are the women su­per­charg­ing bio­phar­ma R&D? Nom­i­nate them for this year's spe­cial re­port

The biotech industry has faced repeated calls to diversify its workforce — and in the last year, those calls got a lot louder. Though women account for just under half of all biotech employees around the world, they occupy very few places in C-suites, and even fewer make it to the helm.

Some companies are listening, according to a recent BIO survey which showed that this year’s companies were 2.5 times more likely to have a diversity and inclusion program compared to last year’s sample. But we still have a long way to go. Women represent just 31% of biotech executives, BIO reported. And those numbers are even more stark for women of color.

Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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When ef­fi­ca­cy is bor­der­line: FDA needs to get more con­sis­tent on close-call drug ap­provals, agency-fund­ed re­search finds

In the exceedingly rare instances in which clinical efficacy is the only barrier to a new drug’s approval, new FDA-funded research from FDA and Stanford found that the agency does not have a consistent standard for defining “substantial evidence” when flexible criteria are used for an approval.

The research comes as the FDA is at a crossroads with its expedited-review pathways. The accelerated approval pathway is under fire as the agency recently signed off on a controversial new Alzheimer’s drug, with little precedent to explain its decision. Meanwhile, top officials like Rick Pazdur have called for a major push to simplify and clarify all of the various expedited pathways, which have grown to be must-haves for sponsors of nearly every newly approved drug.

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Ted White, Verrica CEO

Ver­ri­ca hits an­oth­er bump in the road with CMO re­lat­ed let­ter from FDA

The FDA has rejected Verrica’s new drug application for VP-102 again, with the company pinning the CRL on problems at a CMO that it was partnered with, the company announced Monday.

The FDA didn’t raise issues that directly relate to the manufacturing of VP-102, the company said, but raised “general quality issues” at the CMO’s facility. There were also no clinical concerns, it said, or need to collect more data.

Take­da snaps up the Japan­ese rights to an old Shire cast-off; Boehringer In­gel­heim ac­quires Abexxa Bi­o­log­ics

A week before the FDA is set to decide on Mirum Pharmaceuticals’ lead liver disease drug — an old Shire cast-off called maralixibat — Takeda is swooping in to secure the rights in Japan.

Maralixibat’s roots trace back to Lumena, which was snapped up by Shire for $260 million-plus back in 2014. While the candidate had failed mid-stage studies at Shire, Mirum believes better trial design and patient selection will deliver the wins it needs. The drug is currently in development for Alagille syndrome (a condition called ALGS in which bile builds up in the liver), progressive familial intrahepatic cholestasis (PFIC, which causes progressive liver disease) and biliary atresia (a blockage in the ducts that carry bile from the liver to the gallbladder).

Volker Wagner (L) and Jeff Legos

As Bay­er, No­var­tis stack up their ra­dio­phar­ma­ceu­ti­cal da­ta at #ES­MO21, a key de­bate takes shape

Ten years ago, a small Norwegian biotech by the name of Algeta showed up at ESMO — then the European Multidisciplinary Cancer Conference 2011 — and declared that its Bayer-partnered targeted radionuclide therapy, radium-223 chloride, boosted the overall survival of castration-resistant prostate cancer patients with symptomatic bone metastases.

In a Phase III study dubbed ALSYMPCA, patients who were treated with radium-223 chloride lived a median of 14 months compared to 11.2 months. The FDA would stamp an approval on it based on those data two years later, after Bayer snapped up Algeta and christened the drug Xofigo.

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Mi­rati tri­umphs again in KRAS-mu­tat­ed lung can­cer with a close­ly watched FDA fil­ing now in the cards

After a busy weekend at #ESMO21, which included a big readout for its KRAS drug adagrasib in colon cancer, Mirati Therapeutics is ready to keep the pressure on competitor Amgen with lung cancer data that will undergird an upcoming filing.

In topline results from a Phase II cohort of its KRYSTAL-1 study, adagrasib posted a response rate of 43% in second-line-or-later patients with metastatic non-small cell lung cancer containing a KRAS-G12C mutation, Mirati said Monday.