Stung by pa­tient deaths, a small Juno study points to a Goldilocks for­mu­la for CAR-T

For Juno, the hunt to find just the right mix­ture of T cells along with an ef­fec­tive reg­i­men to prep pa­tients for their CAR-T ther­a­py has had a lethal his­to­ry, tan­gling up de­vel­op­ment time­lines in a way that has ced­ed the lead in the field to ri­val Kite.

Stan­ley Rid­dell

But in a new, small study in­volv­ing one of their most ad­vanced CAR-Ts, an in­ves­tiga­tive team feels that they came up with just the right recipe. And that could have big im­pli­ca­tions for an­oth­er CAR-T pro­gram in which Juno holds high hopes for a come­back.

The drug in­volved in the study is called JCAR014, and the in­ves­ti­ga­tors say that they came up with a one-on-one mix of CD4+ helper cells with CD8+ killer cells that showed a re­mark­able abil­i­ty to wipe out can­cer cells that ex­press CD19, which has been the big ini­tial tar­get for all the play­ers in the van­guard of CAR-T work.

Sig­nif­i­cant­ly, the in­ves­ti­ga­tors al­so con­clud­ed that adding flu­dara­bine to cy­clophos­phamide (Cy/Flu) in a cock­tail to prep pa­tients cre­ates the right en­vi­ron­ment for the T cells to grow in the body. Half of the 18 pa­tients with non-Hodgkin lym­phoma who got the Cy/Flu com­bo had a com­plete re­sponse to the ther­a­py, com­pared to on­ly 8% of the group who re­ceived on­ly cy­clophos­phamide.

The team point­ed out that these re­sults could in­di­cate sim­i­lar out­comes for JCAR017, which is now in ear­ly stud­ies. Juno has tapped JCAR017 as a po­ten­tial “best-in-class” treat­ment for blood can­cers.

The mes­sage helped buoy the com­pa­ny’s stock to­day, send­ing shares up about 3%.

“With the de­fined com­po­si­tion treat­ment, we are able to get more re­pro­ducible da­ta about the ef­fects of the cells — both the ben­e­fi­cial im­pact against the can­cer and any side ef­fects to the pa­tient,” said Fred Hutch clin­i­cal re­searcher Stan Rid­dell, one of the se­nior au­thors of the pa­per, along with Dr. David Mal­oney. “We are then able to ad­just the dose to im­prove what we call the ther­a­peu­tic in­dex — im­pact against the tu­mor, with low­er tox­i­c­i­ty to the pa­tient.”

The ad­di­tion of flu­dara­bine to Juno’s lead CAR-T, JCAR015, was fin­gered for killing four pa­tients, a set­back for the biotech which trig­gered a brief but dam­ag­ing clin­i­cal hold by the FDA. The hold last­ed on­ly days, end­ing with the FDA sign­ing off on the biotech’s de­ci­sion to drop flu­dara­bine. But the hold end­ed up forc­ing Juno to de­lay its ex­pect­ed move to file for their first ap­proval back to 2018. Kite, mean­while, which is us­ing its own mix of T cells and Cy/Flu, has said it ex­pects to take the first batch of da­ta from its lead­ing study to the FDA af­ter an ini­tial re­view that comes in just a mat­ter of weeks.

This new study from Juno al­so rais­es ques­tions about its lead drug, JCAR015. If pa­tient out­comes are sig­nif­i­cant­ly low­ered by the ab­sence of flu­dara­bine, Juno’s first at­tempt at a com­mer­cial en­try against the com­pe­ti­tion could be se­vere­ly af­fect­ed.

CAR-Ts be­came a hot field a cou­ple of years ago, at­tract­ing hun­dreds of mil­lions in new in­vest­ments as the front run­ners raced to ad­vance new reme­dies for can­cer by adding a chimeric anti­gen re­cep­tor to a pa­tient’s T cells and then in­fus­ing them back in­to the pa­tient. But with Juno’s de­rail­ment and a re­cent de­ci­sion by No­var­tis to dis­solve its cell and gene ther­a­py unit and re­ab­sorb it in­to their big on­col­o­gy di­vi­sion, all eyes are on Kite now to see if it can claim the first ap­proval and mar­ket en­try.

The stakes are high.

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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Nooman Haque, head of life sciences and healthcare at Silicon Valley Bank, and John Carroll

I’m head­ed to Lon­don soon for #EU­BIO22. Care to join me?

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.

Up­dat­ed: Al­ny­lam re­in­forces APOL­LO-B patisir­an da­ta be­fore head­ing to the FDA

Weeks after uncorking some mostly positive data for patisiran in transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, Alnylam is bolstering its package with new exploratory and subgroup data before shipping it off to regulators.

The RNAi drug maintained “generally consistent” benefits in efficacy and quality of life across several prespecified subgroups at month 12, Alnylam announced on Friday afternoon, including age, baseline tafamidis use, ATTR amyloidosis type, baseline six-minute walk test score and others.

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Jerome Durso, Intercept Pharmaceuticals CEO

In­ter­cep­t's OCA fails a PhI­II NASH tri­al, rais­ing fresh doubts about its years­long quest for an OK

Intercept Pharmaceuticals has run into another big setback in its yearslong quest to win an approval for OCA in NASH. The biotech put out word Friday morning that its Phase III REVERSE study failed the primary endpoint for the liver disease, sending its share price into a tailspin.

There was no significant improvement in fibrosis among the patients suffering from cirrhosis who were treated with obeticholic acid, with investigators hunting for a minimum 1-stage histological improvement in the disease after 18 months of therapy.

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Vlad Coric, Biohaven CEO (Photo Credit: Andrew Venditti)

As Amy­lyx de­ci­sion waits in the wings, Bio­haven’s ALS drug sinks (again) in plat­form tri­al

The FDA’s decision on Amylyx’s ALS drug is set to come out sometime Thursday. In a space with few drugs, any approval would be a major landmark.

But elsewhere in the ALS field, things are a bit more tepid.

Thursday morning, Biohaven announced that its drug verdiperstat failed its arm of an ALS platform trial led by Massachusetts General Hospital. According to a press release, the drug did not meet its primary endpoint — improvement on an ALS functional status test — or any key secondary endpoints at 24 weeks. The trial had enrolled 167 patients, giving them either verdiperstat or placebo twice a day.

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