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.

BiTE® Plat­form and the Evo­lu­tion To­ward Off-The-Shelf Im­muno-On­col­o­gy Ap­proach­es

Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

Pfiz­er’s Doug Gior­dano has $500M — and some ad­vice — to of­fer a cer­tain breed of 'break­through' biotech

So let’s say you’re running a cutting-edge, clinical-stage biotech, probably public, but not necessarily so, which could see some big advantages teaming up with some marquee researchers, picking up say $50 million to $75 million dollars in a non-threatening minority equity investment that could take you to the next level.

Doug Giordano might have some thoughts on how that could work out.

The SVP of business development at the pharma giant has helped forge a new fund called the Pfizer Breakthrough Growth Initiative. And he has $500 million of Pfizer’s money to put behind 7 to 10 — or so — biotech stocks that fit that general description.

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Ken Frazier, AP Images

Why Mer­ck wait­ed, and what they now bring to the Covid-19 fight

Nicholas Kartsonis had been running clinical infectious disease research at Merck for almost 2 years when, in mid-January, he got a new assignment: searching the pharma giant’s vast libraries for something that could treat the novel coronavirus.

The outbreak was barely two weeks old when Kartsonis and a few dozen others got to work, first in small teams and then in a larger task force that sucked in more and more parts of the sprawling company as Covid-19 infected more and more of the globe. By late February, the group began formally searching for vaccine and antiviral candidates to license. Still, while other companies jumped out to announce their programs and, eventually and sometimes controversially, early glimpses at human data, Merck remained silent. They made only a brief announcement about a data collection partnership in April and mentioned vaguely a vaccine and antiviral search in their April 28 earnings call.

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Gilead re­leas­es an­oth­er round of murky remde­sivir re­sults

A month after the NIH declared the first trial on remdesivir in Covid-19 a success, Gilead is out with new results on their antiviral. But although the study met one of its primary endpoints, the data are likely to only add to a growing debate over how effective the drug actually is.

In a Phase III trial, patients given a 5-day dose of remdesivir were 65% more likely to show “clinical improvement” compared to an arm given standard-of-care. The trial, though, gave little indication for whether the drug had an impact on key endpoints such as survival or time-to-recovery. And in a surprising twist, a 10-day dosing arm of remdesivir didn’t lead to a statistically significant improvement over standard of care.

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Mark Genovese (Stanford via Twitter)

Gilead woos fil­go­tinib clin­i­cal in­ves­ti­ga­tor from Stan­ford to lead the charge on NASH, in­flam­ma­to­ry dis­eases

With an FDA OK for the use of filgotinib in rheumatoid arthritis expected to drop any day now, Gilead has recruited a new leader from academia to lead its foray into inflammatory diseases.

Mark Genovese — a longtime Stanford professor and most recently the clinical chief in the division of immunology and rheumatology — was the principal investigator in FINCH 2, one of three studies that supported Gilead’s NDA filing. In his new role as SVP, inflammation, he will oversee the clinical development of the entire portfolio.

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Bris­tol My­ers Squib­b's just-launched MS drug Zeposia makes the cut in key ul­cer­a­tive col­i­tis tri­al

In March, Zeposia became the third oral S1P modulator to secure US approval for multiple sclerosis. Now, the drug has succeeded in a key ulcerative colitis study.

The immunomodulator, akin to others in its class, controls lymphocyte trafficking by limiting the white blood cells to the lymphatic system, in the lymph nodes, and thwarting their ability to jam up lymph nodes — precluding their ability to penetrate the bloodstream and the central nervous system.

Stephen Isaacs, Aduro president and CEO (Aduro)

Once a high fly­er, a stag­ger­ing Aduro is auc­tion­ing off most of the pipeline as CEO Stephen Isaacs hands off the shell to new own­ers

After a drumbeat of failure, setbacks and reorganizations over the last few years, Aduro CEO Stephen Isaacs is handing over his largely gutted-out shell of a public company to another biotech company and putting up some questionable assets in a going-out-of-business sale.

Isaacs —who forged a string of high-profile Big Pharma deals along the way — has wrapped a 13-year run at the biotech with one program for kidney disease going to the new owners at Chinook Therapeutics. A host of once-heralded assets like their STING agonist program partnered with Novartis (which dumped their work on ADU-S100 after looking over weak clinical results), the Lilly-allied cGAS-STING inhibitor program and the anti-CD27 program out-licensed to Merck will all be posted for auction under a strategic review process.

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Hill­house re­casts spot­light on Chi­na's biotech scene with $160M round for Shang­hai-based an­ti­body mak­er

Almost two years after first buying into Genor Biopharma’s pipeline of cancer and autoimmune therapies, Hillhouse Capital has led a $160 million cash injection to push the late-stage assets over the finish line while continuing to fund both internal R&D and dealmaking.

The Series B has landed right around the time Genor would have listed on the Hong Kong stock exchange, according to plans reported by Bloomberg late last year. Insiders had said that the company was looking to raise about $200 million.

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Novus Ther­a­peu­tics plunges deep in­to pen­ny stock ter­ri­to­ry af­ter failed ear tri­al

After a more than 15-year run, a California-based biotech is exploring options, including a sale, after its lead experimental therapy failed an exploratory mid-stage study in patients with middle ear infections characterized by a build-up of fluid behind the eardrum.

The company, initially called Tokai Pharmaceuticals but which subsequently changed its name to Novus Therapeutics in 2017, saw its shares more than halve on Monday after the drug — OP0201— did not pass muster as an adjunct therapy to oral antibiotics in infants and children aged 6 to 24 months with acute otitis media (OM).