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.

Com­mu­ni­cat­ing the val­ue of pre­ci­sion med­i­cine

By Natasha Cowan, Content Marketing Manager at Blue Latitude Health.
Many stakeholders are confused by novel precision medicines, including patients and healthcare professionals. So, how can industry help them to navigate this complexity?

Precision medicine represents a new paradigm in healthcare. It embodies the shift from treating many patients with the same therapy, to having the tools to identify the best treatment for every patient.

Mer­ck buys a fledg­ling neu­rode­gen­er­a­tive biotech spawned by an old GSK dis­cov­ery al­liance. What’s up with that?

Avalon Ventures chief Jay Lichter has a well-known yen for drug development programs picked up in academia. And what he found in Haoxing Xu’s lab at the University of Michigan pricked his interest enough to launch one of his umbrella biotechs in San Diego.
Xu’s work laid the foundation for Avalon to launch Calporta, which has been working on finding small molecule agonists of TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1) for lysosomal storage disorders. And that pathway, they believe, points to new approaches on major market neurodegenerative diseases like Parkinson’s, ALS and Alzheimer’s.

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In­vestors could emerge from Neil Wood­ford de­ba­cle with £1B loss, in­ter­nal analy­sis re­veals

When Link Fund Solutions announced that it is closing Woodford Equity Income Fund permanently and kicking out Neil Woodford, it was implied that investors probably won’t get back everything they entrusted to the fund manager. But nobody knew just how much they would lose.

An internal analysis commissioned by Link suggested that the collective loss could amount to £1 billion — out of a fund last valued at £3.1 billion — Citywire has revealed.

GSK's asth­ma bi­o­log­ic Nu­cala scores in rare blood dis­or­der study

GlaxoSmithKline’s asthma drug Nucala, which received a resounding FDA rejection for use in chronic obstructive pulmonary disease (COPD) last year, has shown promise in a rare blood disorder.

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Spe­cial re­port: Twen­ty ex­tra­or­di­nary women in bio­phar­ma R&D who worked their way to the top

What differentiates a woman leader in biopharma R&D from a man?

Not much, except there are fewer of them in senior posts. Data suggest women are not more risk-averse, family-oriented or less confident than their male counterparts — indeed the differences between the two sexes are negligible. But a glance at the top R&D positions in Big Pharma leaves little doubt that upward migration in the executive ranks of biopharma R&D is tough.

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FDA Vas­cepa re­view spot­lights new safe­ty sig­nals, pos­si­ble min­er­al oil spoil­er as Amarin hunts a block­buster ap­proval

An in-house FDA review of Amarin’s Vascepa raises a set of hurdles the biotech will have to clear if the biotech expects to get the long-awaited FDA approval that could set it on a path to superstar status. But it appears that Amarin has survived another potential setback without introducing a major new threat to its prospects.

The stakes don’t get much higher, with analysts saying a win this week for Amarin could lead to billions in new sales — provided the agency stamps it with an OK. And investors liked what they say in the FDA review this morning, bumping the stock $AMRN 17%.

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FDA puts Sol­id Bio’s lead gene ther­a­py pro­gram on hold — again — af­ter an­oth­er pa­tient is hurt by SGT-001

Solid Biosciences continues to be plagued by safety issues.

Close to 18 months after the gene therapy biotech was able to quickly shed an FDA hold on their lead Duchenne muscular dystrophy program for SGT-001, regulators have stepped back in to force another halt after another patient was hit hard by a set of serious adverse events remarkably similar to the first set.

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FDA slaps a hold on an AML tri­al as Mark­er scraps a fail­ing ovar­i­an can­cer pro­gram, sink­ing shares

The FDA has placed a hold on a Phase II AML trial from the small immuno-oncology biotech Marker Therapeutics. Marker disclosed the issue two weeks after responding to FDA concerns, adding it to the Q3 release Tuesday. The company also announced it was scrapping a Phase II ovarian cancer program it determined was unlikely to succeed.

The agency’s concern centers around two reagents used in manufacturing for their trial for acute myeloid leukemia patients who have received a stem cell transplant. The reagents are from third parties and not present in the final product, Marker said.

Eli Lil­ly-backed biotech grabs $100M to dis­patch an­ti­body-oligonu­cleotide con­ju­gates af­ter mus­cu­lar dy­s­tro­phy

Hold up your hand. Make a fist. Now open it. And again.

If you can do it fully and with ease, then the proteins in your hand are likely working properly. If you can’t then they may not be. In people with myotonic muscular dystrophy, something more atomic is going on.

In those folks, the problem is RNA. Certain base pairs repeat far beyond normal, up to 11,000 superfluous letters in some cases. The extended strands form “clumps.” Proteins misform and can’t function properly. They often allow one movement but not the reverse, a condition called myotonia that gives the dystrophy its name.