And then there were 4: Juno adds an­oth­er vic­tim in CAR-T death tal­ly

Juno’s CAR-T drugs didn’t just kill three peo­ple in clin­i­cal tri­als. They ac­tu­al­ly killed 4, as the com­pa­ny notes in its “re­vised” re­marks from last week’s tran­script of a call with com­pa­ny an­a­lysts. And the fol­lowup rais­es the mys­tery of yet an­oth­er case of cere­bral ede­ma trig­gered by se­vere neu­ro­tox­i­c­i­ty, which may or may not have been re­port­ed by Juno.

Here’s the state­ment, post­ed with the tran­script in a fil­ing with the SEC:

Note to Re­vised Re­marks: (Chief Med­ical Of­fi­cer Dr. Mark) Gilbert mis­tak­en­ly said “three” cas­es out of 129 rather than “four” cas­es. The fourth case was a pa­tient treat­ed in the JCAR014 tri­al, which case oc­curred in a young adult pa­tient with r/r ALL who re­ceived flu/cy pre­con­di­tion­ing and a high­er JCAR014 cell dose than is now used on that tri­al. This death was in­clud­ed in the da­ta pre­sent­ed in an oral pre­sen­ta­tion at the Amer­i­can So­ci­ety of Hema­tol­ogy meet­ing in De­cem­ber 2015 and in­clud­ed in Juno’s An­nu­al Re­port on Form 10-K for the fis­cal year end­ed De­cem­ber 31, 2015.

Note to Re­vised Re­marks: As not­ed ear­li­er in the ques­tion and an­swer ses­sion, the FDA al­so re­port­ed an in­stance of cere­bral ede­ma in its data­base out­side of the JCAR015 tri­al. Juno does not know whether that in­stance is the same case of cere­bral ede­ma as Juno is aware of from the JCAR014 tri­al, or if it oc­curred on a tri­al for a non-Juno prod­uct can­di­date.

Juno trig­gered a rout among its in­vestors last week when it stunned the mar­ket with news that its lead CAR-T drug, JCAR015, had killed three peo­ple in clin­i­cal stud­ies, trig­ger­ing a clin­i­cal hold of its piv­otal study by the FDA. The com­pa­ny im­me­di­ate­ly blamed the re­cent ad­di­tion of the chemo drug flu­dara­bine to pre­con­di­tion pa­tients for the cell ther­a­py and of­fered to drop the drug. In one of the fastest re­spons­es by the FDA in the face of mul­ti­ple pa­tient deaths, the agency agreed and lift­ed the hold ear­li­er this week.

The per­son­al­ized brand of CAR-Ts that Juno, Kite, and No­var­tis have been de­vel­op­ing ex­tract im­mune cells from pa­tients, re-en­gi­neer them with a chimeric anti­gen re­cep­tor and then in­ject them back in­to pa­tients, equipped to swarm can­cer cells. These new treat­ments are al­so known to trig­ger cy­tokine re­lease syn­drome, which forced a tem­po­rary pause in the ex­per­i­men­tal work a cou­ple of years ago. But Juno be­lieves that the way that flu­dara­bine was used re­cent­ly caused the neu­ro­tox­i­c­i­ty that trig­gered cas­es of cere­bral ede­ma tracked by in­ves­ti­ga­tors.

Not every­one was as quick as the FDA to buy in­to that the­o­ry, though, as sev­er­al in­ves­ti­ga­tors note that flu­dara­bine has been used reg­u­lar­ly with­out ev­i­dence of cere­bral ede­mas. In ad­di­tion, ri­val Kite Ther­a­peu­tics has used a low dose of flu­dara­bine in its work and has no plans to change as it pur­sues its own piv­otal work.

The FDA, though, is not ex­plain­ing any­thing as of now, de­clin­ing to an­swer some spe­cif­ic ques­tions of mine.

“Cel­lu­lar ther­a­pies, in­clud­ing Chimeric Anti­gen Re­cep­tor (CAR) T-Cell ther­a­pies, hold great promise in the treat­ment of se­ri­ous and life-threat­en­ing dis­eases,” the agency said in a state­ment to End­points. “We there­fore do every­thing pos­si­ble to as­sist spon­sors in ad­vanc­ing clin­i­cal de­vel­op­ment pro­grams in an ef­fort to bring promis­ing ther­a­pies to pa­tients. The FDA rec­og­nizes that in­ves­ti­ga­tion­al prod­ucts in­tend­ed to treat se­ri­ous dis­eases al­so have the po­ten­tial to pose risks to pa­tients. To this end, the FDA con­stant­ly looks at the risk-ben­e­fit pro­file of ex­per­i­men­tal ther­a­pies and when we have con­cerns about the risks, we may place the clin­i­cal tri­als on hold.”

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Mene Pangalos (AstraZeneca via YouTube)

As­traZeneca shuts the PhI­II door for Ion­is' PC­SK9 drug de­spite pos­i­tive PhI­Ib

When Ionis and AstraZeneca unveiled the first round of mid-stage data for their antisense PCSK9 drug, Mene Pangalos, AstraZeneca’s EVP of biopharmaceuticals R&D, underscored the drug’s “potential best-in-class efficacy profile.”

But now that the second batch is in, it appears AZD8233 isn’t hitting the mark after all.

Ionis announced Friday morning that although the candidate, also dubbed ION449, met the primary endpoint in the Phase IIb SOLANO trial, its partners at AstraZeneca have decided not to move it into Phase III studies because the “results did not achieve pre-specified efficacy criteria.”

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Up­dat­ed: Bio­gen throws it­self back in­to mud­dled da­ta ar­gu­ments with more de­tails on its an­ti­sense ALS drug

With a highly watched FDA decision deadline coming in late January, Biogen and Ionis dropped the full data on the Phase III study of their ALS drug tofersen in the New England Journal of Medicine on Wednesday.

Biogen is looking for approval for tofersen in a very small subset of ALS patients — some 2%, according to the paper — who have a SOD1 gene mutation, which has previously been linked to ALS. Tofersen is meant to reduce levels of mutant SOD1 proteins.

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As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

Phil Sharp, Nobel Prize laureate (L), and John Carroll, Endpoints News co-CEO (via Michael Last)

The End­points 11: Fire­side chat with No­bel Prize lau­re­ate Phil Sharp

The following Q&A has been edited for length and clarity.

John Carroll:

We’ve had a chance to talk a little bit before here about some of the things that you’ve done. Just really remarkably, a lot of the things that you’ve done early in your career puts you in the path with some amazing science that has had an absolutely huge impact in terms of what we’re seeing now on drug development and some of the new technologies that are coming out here, and not only the new technologies, but also some of the most remarkable people ever.

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