FDA ex­perts of­fer a big thumbs up for J&J’s flawed ap­pli­ca­tion for ke­t­a­mine-based de­pres­sion drug — but tri­al fail­ures, safe­ty ques­tions spur con­cerns

J&J may have a deeply flawed ap­pli­ca­tion for its new/old drug to treat ma­jor de­pres­sion, but the re­searchers who turned out to present the case for es­ke­t­a­mine en­coun­tered a re­cep­tive au­di­ence of FDA ex­perts on Tues­day. 

By a wide mar­gin — 14 yes, 2 no and 1 ab­sten­tion — the pan­el con­clud­ed that J&J had of­fered “sub­stan­tial ev­i­dence of the ef­fec­tive­ness of es­ke­t­a­mine,” an in­tranasal ver­sion of a pow­er­ful anes­thet­ic called ke­t­a­mine, bet­ter known in par­ty cir­cles as ‘Spe­cial K.’

The key safe­ty is­sue is the known link be­tween the long­time use of ke­t­a­mine and neu­ro­tox­i­c­i­ty. The re­searchers re­lied on pre­clin­i­cal dog and rat stud­ies to make their case — hard­ly the gold stan­dard on safe­ty da­ta. But the pan­el seemed con­tent that a long-term safe­ty study on a post­mar­ket­ing ba­sis would be enough to war­rant an OK now, with 15 vot­ing that J&J had suc­cess­ful­ly out­lined the safe­ty pro­file for an ini­tial ap­proval. And at least one of the au­thor­i­ties not­ed that cur­rent­ly used de­pres­sion drugs al­so have safe­ty is­sues with long­time use.

The mon­ey ques­tion:

Do the ben­e­fits out­weigh the risks? Yes: 14. No: 2. Ab­stain: 1.

J&J calls es­ke­t­a­mine — which they plan to mar­ket as Spra­va­to — the first drug with a new mech­a­nism of ac­tion in de­pres­sion for some 30 years. Of course, ke­t­a­mine has al­so been used off-la­bel for de­pres­sion for years. It’s an NM­DA drug, with ri­vals in the clin­ic from var­i­ous bio­phar­ma com­pa­nies, in­clud­ing Al­ler­gan.

“Ke­t­a­mine is a nasty drug,” not­ed pan­el mem­ber Steven Meisel, sys­tem di­rec­tor of med­ica­tion safe­ty at Fairview Health Ser­vices/Health­east Care Sys­tem. “It’s been around for 50 years….But ob­vi­ous­ly we’re us­ing low­er dos­es.” Meisel, though, was im­pressed by a sur­vey re­searchers com­plet­ed that high­light­ed just how much these pa­tients need­ed a new ther­a­py.

“You don’t take that pa­tient’s voice as of­ten as you should in this space.”

“The vast ma­jor­i­ty of these pa­tients will take the risks,” he added. “I think that’s very im­por­tant….”

Two of the stud­ies failed to meet the pri­ma­ry out­come, and that raised con­cerns. 

“What prece­dent is set when 2 of 3 short­er ef­fi­ca­cy stud­ies didn’t meet the pri­ma­ry end­point?” Meisel asked. “That’s some­thing the agency has to wres­tle with. “Do we set a prece­dent that may be hard to step back from.”

If the FDA goes ahead and of­fers a for­mal ap­proval, which looks in­creas­ing­ly like­ly in view of the neu­tral in­ter­nal re­view, they’ll be once again over­look­ing the agency’s gold stan­dard on 2 pos­i­tive, well con­trolled stud­ies. But that’s in­creas­ing­ly com­mon, es­pe­cial­ly un­der com­mis­sion­er Scott Got­tlieb.

J&J ex­pe­ri­enced sig­nif­i­cant fail­ures with this pro­gram, and has promis­ing da­ta from one late-stage study and a with­draw­al study, which the ex­perts and in­sid­ers seemed will­ing to ac­cept in lieu of a sec­ond well-con­trolled tri­al.

Es­ke­t­a­mine is one of J&J’s top late-stage drugs, which the phar­ma gi­ant be­lieves has block­buster mar­ket po­ten­tial. By all ap­pear­ances, they’ll soon be able to ex­plore just how big this drug can be.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Lat­est on ul­tra-rare dis­ease ap­proval; Pos­i­tive, if mixed, signs for Bio­gen's ALS drug; Clay Sie­gall finds a new job; and more

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FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

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FDA spells out how can­cer drug de­vel­op­ers can use one tri­al for both ac­cel­er­at­ed and full ap­provals

The FDA’s Oncology Center of Excellence has been a bright spot within the agency in terms of speeding new treatments to patients. That flexibility was on full display this morning as FDA released new draft guidance spelling out exactly how oncology drug developers can fulfill both the accelerated and full approval’s requirements with just a single randomized controlled trial.

While Congress recently passed legislation that will allow FDA to require confirmatory trials to be recruiting and ongoing prior to granting an accelerated approval, the agency is now making clear that the initial trial used to win the AA, if designed appropriately, can also serve as the trial for converting the accelerated approval into a full approval.

Clay Siegall, Morphimmune CEO

Up­dat­ed: Ex-Seagen chief Clay Sie­gall emerges as CEO of pri­vate biotech

Clay Siegall will be back in the CEO seat, taking the helm of a private startup working on targeted cancer therapies.

It’s been almost a year since Siegall resigned from Seagen, the biotech he co-founded and led for more than 20 years, in the wake of domestic violence allegations by his then-wife. His eventual successor, David Epstein, sold the company to Pfizer in a $43 billion deal unveiled last week.

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Eu­ro­pean doc­tors di­al up dig­i­tal com­mu­ni­ca­tion with phar­mas, but still lean to­ward in-per­son med meet­ings, study finds

As in-person sales rep access declines in the big five European countries, a corresponding uptick in virtual rep access is happening. It’s not surprising, but it does run counter to pharma companies’ assessment – along with long-held sales rep sway in Europe – that in-person access hadn’t changed.

CMI Media Group and Medscape’s recent study reports that 75% of physicians in the EU5 countries of Spain, Germany, Italy, France and the UK already limit engagements with pharma sales reps, and 25% of those surveyed plan to decrease time with reps.

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Judge al­lows ex­pert tes­ti­mo­ny in GSK tri­al al­leg­ing Zan­tac link to can­cer

A California judge will allow a plaintiff in a state court case to introduce expert testimony connecting a potential carcinogen in former blockbuster medicine Zantac to cancer.

The order was handed down on Thursday from state judge Evelio Grillo, who is now allowing both parties to introduce expert testimony in an upcoming trial after what’s known as a Sargon hearing, where a judge determines the admissibility of expert witnesses and expert opinions.

No­vo Nordisk oral semaglu­tide tri­al shows re­duc­tion in blood sug­ar, plus weight loss

Novo Nordisk is testing higher levels of its oral version of its GLP-1, semaglutide, and its type 2 diabetes trial results released today show reductions in blood sugar as well as weight loss.

In the Phase IIIb trial, Novo compared its oral semaglutide in 25 mg and 50 mg doses with the 14 mg version that’s currently the maximum approved dose. The trial looked at how the doses compared when added to a stable dose of one to three oral antidiabetic medicines in people with type 2 diabetes who were in need of an intensified treatment.

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Ly­me vac­cine test com­ple­tion is pushed back by a year as Pfiz­er, Val­ne­va say they'll ad­just tri­al

Valneva and Pfizer have adjusted the end date for the Phase III study of their investigational Lyme disease vaccine, pushing it back by a year after issues at a contract researcher led to thousands of US patients being dropped from the test.

In a March 20 update to clinicaltrials.gov, Valneva and Pfizer moved the primary completion date on the trial, called VALOR, from the end of 2024 to the end of 2025.

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