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.

Pi­o­neer­ing Click Chem­istry in Hu­mans

Reimagining cancer treatments

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, which is nearly one in six deaths. Recently, we have seen incredible advances in novel cancer therapies such as immune checkpoint inhibitors, cell therapies, and antibody-drug conjugates that have revamped cancer care and improved survival rates for patients.

Despite this significant progress in therapeutic targeting, why are we still seeing such a high mortality rate? The reason is that promising therapies are often limited by their therapeutic index, which is a measure of the effective dose of a drug, relative to its safety. If we could broaden the therapeutic indices of currently available medicines, it would revolutionize cancer treatments. We are still on the quest to find the ultimate cancer medicine – highly effective in several cancer types, safe, and precisely targeted to the tumor site.

Justin Klee (L) and Joshua Cohen, Amylyx co-CEOs (Cody O'Loughlin/The New York Times; courtesy Amylyx)

Ad­vo­cates, ex­perts cry foul over Amy­lyx's new ALS drug, cit­ing is­sues with price, PhI­II com­mit­ment

Not 24 hours after earning the first ALS drug approval in five years, Amylyx Pharmaceuticals’ Relyvrio is already drawing scrutiny. And it’s coming from multiple fronts.

In an investor call Friday morning, Amylyx revealed that it would charge about $158,000 per year, a price point that immediately drew backlash from ALS advocates and some outside observers. The cost reveal had been highly anticipated in the immediate hours after Thursday evening’s approval, though Amylyx only teased Relyvrio would cost less than previously approved drugs.

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Land­mark Amy­lyx OK spurs de­bate; Some... pos­i­tive? Alzheimer's da­ta; Can­cer tri­al bot­tle­neck; Sanofi's CRISPR bet; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

After brief stops in Paris and Boston, John Carroll and the Endpoints crew are staying on the road in October with their return for a live/streaming EUBIO22 in London. The hybrid event fireside chats and panels on mRNA, oncology and the crazy public market. We hope you can join him there.

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Joshua Cohen (L) and Justin Klee, Amylyx co-CEOs

Up­dat­ed: Af­ter long and wind­ing road, FDA ap­proves Amy­lyx's ALS drug in vic­to­ry for pa­tients and ad­vo­ca­cy groups

For just the third time in its 116-year history, the FDA has approved a new treatment for Lou Gehrig’s disease, or ALS.

US regulators gave the thumbs-up to the drug, known as Relyvrio, in a massive win for patients and their families. The approval, given to Boston-area biotech Amylyx Pharmaceuticals, comes after two years of long and contentious debates over the drug’s effectiveness between advocacy groups and FDA scientists, following the readout of a mid-stage clinical trial in September 2020.

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#AAO22: J&J’s first look at com­mon eye dis­ease port­fo­lio pads the case for PhII of gene ther­a­py

CHICAGO — While the later-stage drug developers in the geographic atrophy field are near the finish line, Johnson & Johnson’s Janssen is taking a more deliberate route, with a treatment that it hopes to be a one-time fix.

The Big Pharma will take its Hemera Biosciences-acquired gene therapy into a Phase II study later this year in patients with GA, a common form of age-related macular degeneration that impacts about five million people worldwide. To get there, Janssen touted early-stage safety data at the American Academy of Ophthalmology annual conference Saturday morning, half a day after competitors Apellis and Iveric Bio revealed their own more-detailed Phase III analyses.

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Some­one old, some­one new: Mod­er­na pro­motes CTO, raids No­var­tis for re­place­ment amid pipeline push

Moderna CEO Stéphane Bancel made clear on the last quarterly call that “now is not the time to slow down.” On Thursday, he made a bit more room in the cockpit.

The company unveiled a new executive role on Thursday, promoting former chief technical operations and quality officer Juan Andres to president of strategic partnerships and enterprise expansion, and poaching a former Novartis exec to take his place.

#AAO22 conference in Chicago (Photo credit: Associate editor Kyle LaHucik)

#AAO22: In bid for first FDA nod in ge­o­graph­ic at­ro­phy, Apel­lis claims an­oth­er first in eye dis­ease field

CHICAGO — Eight weeks before patients and industry find out if the FDA approves the first treatment for geographic atrophy, an advanced form of age-related macular degeneration, the biotech behind the drug is out with some new data on a secondary endpoint.

In what study investigator Charles Wykoff called the “first direct evidence of function preservation by slowing GA growth” in an investigational treatment, Apellis Pharmaceuticals’ drug pegcetacoplan led to less loss of retinal sensitivity versus sham  within 250 microns on either side of the GA lesion over 24 months.

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BioCryst's new website for its HAE unbranded campaign encourages patients to take charge of treatment decisions.

BioCryst launch­es aware­ness cam­paign around man­age­ment of rare vas­cu­lar dis­ease

While hereditary angioedema (HAE) is rare, treatment options for the condition have become much more common. So BioCryst Pharmaceuticals is taking a new angle in its recently launched HAE awareness campaign encouraging patients to take control of their disease management.

“Hereditary angioedema (HAE) isn’t the author of your story — you are … #cHAEngetheplan. Not the goal,” the US campaign website advises.

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EMA makes new rec­om­men­da­tions for Im­bru­vi­ca, med­i­cines with ter­li­pressin over res­pi­ra­to­ry and car­dio­vas­cu­lar risks

The EMA is handing out a new recommendation surrounding J&J and AbbVie’s cancer drug Imbruvica and some medicines containing terlipressin.

On Friday, the EMA’s safety committee (PRAC) stated that it has taken new measures to reduce the risk of respiratory failure and sepsis when medicines containing terlipressin that are used to treat people with hepatorenal syndrome (HRS-1), particularly for patients with advanced acute-on-chronic liver disease or advanced kidney failure.