FDA rais­es big safe­ty is­sues in No­var­tis’ CAR-T re­view, but spot­lights post-mar­ket­ing path for­ward

The FDA’s in-house re­view of No­var­tis’ ground­break­ing CAR-T ther­a­py ti­s­agen­le­cleu­cel (CTL019) came out this morn­ing, care­ful­ly out­lin­ing the ef­fi­ca­cy tracked in Phase II and hon­ing in on the agency’s big con­cern: How do ex­perts in the field view the se­ri­ous safe­ty is­sues re­main and what would be the best way to track and con­tain them once mar­ket­ing be­gins?

“The over­all ef­fec­tive­ness of this prod­uct is not the pri­ma­ry is­sue for con­sid­er­a­tion by this Com­mit­tee,” states the re­view doc­u­ment. But the Phase II study in pa­tients with B-cell acute lym­phoblas­tic leukemia raised a host of is­sues on short-term and po­ten­tial­ly lethal dan­gers, from a high though fa­mil­iar rate of cy­tokine re­lease syn­drome to the neu­ro­log­i­cal con­di­tions that CRS can trig­ger.

The FDA, while tak­ing a mea­sured look at the dan­gers with­out con­demn­ing them, is al­so clear­ly alarmed about the prospect of long-term risks that have yet to be ful­ly ex­plored – in­clud­ing the risk of new ma­lig­nan­cies. But the agency couched the dis­cus­sion on a risk-mit­i­ga­tion strat­e­gy which ex­perts will be ex­pect­ed to weigh in on, keep­ing the fo­cus on an ap­proval.

In the re­view, the FDA not­ed:

In ad­di­tion to the short-term safe­ty is­sues not­ed above, po­ten­tial long-term safe­ty con­cerns with ti­s­agen­le­cleu­cel in­clude the po­ten­tial for gen­er­a­tion of repli­ca­tion-com­pe­tent retro­virus (RCR) and the po­ten­tial for in­ser­tion­al mu­ta­ge­n­e­sis to cause new ma­lig­nan­cies (geno­tox­i­c­i­ty). The safe­ty as­sess­ments in Study B2202 did not iden­ti­fy risks from clon­al out­growth and vec­tor me­di­at­ed de­layed ad­verse events (e.g., sec­ondary leukemias). How­ev­er, most study sub­jects have not been fol­lowed for very long, thus lim­it­ing the abil­i­ty to as­sess the risk of de­layed events. The po­ten­tial for geno­tox­i­c­i­ty from in­ser­tion­al mu­ta­ge­n­e­sis is a con­cern with im­munother­a­py prod­ucts that re­quire gam­maretro­vi­ral and lentivi­ral trans­duc­tion. There­fore, post-mar­ket­ing con­sid­er­a­tions for long-term safe­ty mon­i­tor­ing may be nec­es­sary to ad­dress the po­ten­tial safe­ty con­cern.

The pan­el will al­so get to vote on whether the ben­e­fits of this drug jus­ti­fy the risks.

The agency’s safe­ty con­cerns un­der­score the promise as well as the pit­falls of CAR-T. The ef­fec­tive­ness of these drugs in treat­ing late-stage liq­uid can­cers has raised the ex­cit­ing pos­si­bil­i­ty of a break­through ap­proach. But ear­ly on in clin­i­cal stud­ies pa­tients al­so died from cy­tokine re­lease syn­drome, forc­ing in­ves­ti­ga­tors to change their re­cruit­ing stan­dards to lim­it – but not erase – the dan­ger. Lat­er a slate of pa­tient deaths from cere­bral ede­ma forced Juno to dump its lead drug and move to a back­up in the pipeline.

The FDA re­cent­ly called ex­perts in­to the FDA to help reg­u­la­tors un­der­stand the risks as­so­ci­at­ed with CAR-T in the lead­up to this first pan­el re­view and mar­ket­ing de­ci­sion. Kite will be next up with its lead ther­a­py as the two com­pa­nies an­gle for ear­ly mar­ket ad­van­tage.

No­var­tis to­day re­mains in the lead of a tight race.

Da­ta Lit­er­a­cy: The Foun­da­tion for Mod­ern Tri­al Ex­e­cu­tion

In 2016, the International Council for Harmonisation (ICH) updated their “Guidelines for Good Clinical Practice.” One key shift was a mandate to implement a risk-based quality management system throughout all stages of a clinical trial, and to take a systematic, prioritized, risk-based approach to clinical trial monitoring—on-site monitoring, remote monitoring, or any combination thereof.

Mer­ck scraps Covid-19 vac­cine pro­grams af­ter they fail to mea­sure up on ef­fi­ca­cy in an­oth­er ma­jor set­back in the glob­al fight

After turning up late to the vaccine development game in the global fight against Covid-19, Merck is now making a quick exit.

The pharma giant is reporting this morning that it’s decided to drop development of 2 vaccines — V590 and V591 — after taking a look at Phase I data that simply don’t measure up to either the natural immune response seen in people exposed to the virus or the vaccines already on or near the market.

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Jackie Fouse, Agios CEO

Agios scores its sec­ond pos­i­tive round of da­ta for its lead pipeline drug — but that won't an­swer the stub­born ques­tions that sur­round this pro­gram

Agios $AGIO bet the farm on its PKR activator drug mitapivat when it recently decided to sell off its pioneering cancer drug Tibsovo and go back to being a development-stage company — for what CEO Jackie Fouse hoped would be a short stretch before they got back into commercialization.

On Tuesday evening, the bellwether biotech flashed more positive topline data — this time from a small group of patients in a single-arm study. And the executive team plans to package this with its earlier positive results from a controlled study to make its case for a quick OK.

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Adeno-associated virus-1 illustration; the use of AAVs resurrected the gene therapy field, but companies are now testing the limits of a 20-year-old technology (File photo, Shutterstock)

Af­ter 3 deaths rock the field, gene ther­a­py re­searchers con­tem­plate AAV's fu­ture

Nicole Paulk was scrolling through her phone in bed early one morning in June when an email from a colleague jolted her awake. It was an article: Two patients in an Audentes gene therapy trial had died, grinding the study to a halt.

Paulk, who runs a gene therapy lab at the University of California, San Francisco, had planned to spend the day listening to talks at the American Association for Cancer Research annual meeting, which was taking place that week. Instead, she skipped the conference, canceled every work call on her calendar and began phoning colleagues across academia and industry, trying to figure out what happened and why. All the while, a single name hung in the back of her head.

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George Yancopoulos (L) and Len Schleifer (Regeneron)

Re­gen­eron touts pos­i­tive pre­lim­i­nary im­pact of its Covid an­ti­body cock­tail, pre­vent­ing symp­to­matic in­fec­tions in high-risk group

Regeneron flipped its cards on an interim analysis of the data being collected for its Covid-19 antibody cocktail used as a safeguard against exposure to the virus. And the results are distinctly positive.

The big biotech reported Tuesday morning that their casirivimab and imdevimab combo prevented any symptomatic infections from occurring in a group of 186 people exposed to the virus through a family connection, while the placebo arm saw 8 of 223 people experience symptomatic infection. Symptomatic combined with asymptomatic infections occurred in 23 people among the 223 placebo patients compared to 10 of the 186 subjects in the cocktail arm.

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Hal Barron, GSK via YouTube

What does $29B buy you in Big Phar­ma? In Glax­o­SmithK­line’s case, a whole lot of un­com­fort­able ques­tions about the pipeline

Talk about your bad timing.

A little over a week ago, GSK R&D chief Hal Barron marked his third anniversary at the research helm by taking a turn at the virtual podium during JP Morgan to make the case that he and his team had built a valuable late-stage pipeline capable of churning out more than 10 blockbusters in the next 5 years.

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Vir's CMO says he's sur­prised that a low dose of their he­pati­tis B drug ap­pears promis­ing in ear­ly slice of da­ta — shares soar

Initial topline data from a Phase I study of a new therapeutic for chronic hepatitis B virus was so promising that it surprised even the CMO of the company that produces it.

Vir Biotechnology on Tuesday announced that its VIR-3434 molecule reduced the level of virus surface antigens present in a blinded patient cohort after eight days of the trial with just a single 6 mg dose. Six of the eight patients in the cohort were given the molecule, and the other two a placebo—all six who received the molecule saw a mean antigen reduction of 1.3 log10 IU/mL, Vir said.

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David Marek, Myovant

My­ovant beefs up da­ta pack­age in NDA #3, boost­ing its case for longterm dos­ing of Pfiz­er-part­nered re­l­u­golix

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Look­ing to win over some skep­ti­cal an­a­lysts, Rhythm beats the drum on in­ter­im da­ta in PhII bas­ket study for ad­di­tion­al in­di­ca­tions

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