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.

Norbert Bischofberger. Kronos

Backed by some of the biggest names in biotech, Nor­bert Bischof­berg­er gets his megaround for plat­form tech out of MIT

A little over a year ago when I reported on Norbert Bischofberger’s jump from the CSO job at giant Gilead to a tiny upstart called Kronos, I noted that with his connections in biotech finance, that $18 million launch round he was starting off with could just as easily have been $100 million or more.

With his first anniversary now behind him, Bischofberger has that mega-round in the bank.

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Chas­ing Roche's ag­ing block­buster fran­chise, Am­gen/Al­ler­gan roll out Avastin, Her­ceptin knock­offs at dis­count

Let the long battle for biosimilars in the cancer space begin.

Amgen has launched its Avastin and Herceptin copycats — licensed from the predecessors of Allergan — almost two years after the FDA had stamped its approval on Mvasi (bevacizumab-awwb) and three months after the Kanjinti OK (trastuzumab-anns). While the biotech had been fielding biosimilars in Europe, this marks their first foray in the US — and the first oncology biosimilars in the country.

Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Seer adds ex-FDA chief Mark Mc­Clel­lan to the board; Her­cules Cap­i­tal makes it of­fi­cial for new CEO Scott Bluestein

→ On the same day it announced a $17.5 million Series C, life sciences and health data company Seer unveiled that it had lured former FDA commissioner and ex-CMS administrator Mark McClellan on to its board. “Mark’s deep understanding of the health care ecosystem and visionary insights on policy reform will be crucial in informing our thinking as we work to bring our liquid biopsy and life sciences products to market,” said Seer chief and founder Omid Farokhzad in a statement.

Daniel O'Day

No­var­tis hands off 3 pre­clin­i­cal pro­grams to the an­tivi­ral R&D mas­ters at Gilead

Gilead CEO Daniel O’Day’s new task hunting up a CSO for the company isn’t stopping the industry’s dominant antiviral player from doing pipeline deals.

The big biotech today snapped up 3 preclinical antiviral programs from pharma giant Novartis, with drugs promising to treat human rhinovirus, influenza and herpes viruses. We don’t know what the upfront is, but the back end has $291 million in milestones baked in.

Vas Narasimhan, AP Images

On a hot streak, No­var­tis ex­ecs run the odds on their two most im­por­tant PhI­II read­outs. Which is 0.01% more like­ly to suc­ceed?

Novartis CEO Vas Narasimhan is living in the sweet spot right now.

The numbers are running a bit better than expected, the pipeline — which he assembled as development chief — is performing and the stock popped more than 4% on Thursday as the executive team ran through their assessment of Q2 performance.

Year-to-date the stock is up 28%, so the investors will be beaming. Anyone looking for chinks in their armor — and there are plenty giving it a shot — right now focus on payer acceptance of their $2.1 million gene therapy Zolgensma, where it’s early days. And CAR-T continues to underperform, but Novartis doesn’t appear to be suffering from it.

So what could go wrong?

Actually, not much. But Tim Anderson at Wolfe pressed Narasimhan and his development chief John Tsai to pick which of two looming Phase III readouts with blockbuster implication had the better odds of success.

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On a glob­al romp, Boehringer BD team picks up its third R&D al­liance for Ju­ly — this time fo­cused on IPF with $50M up­front

Boehringer Ingelheim’s BD team is on a global deal spree. The German pharma company just wrapped its third deal in 3 weeks, going back to Korea for its latest pipeline pact — this time focused on idiopathic pulmonary fibrosis.

They’re handing over $50 million to get their hands on BBT-877, an ATX inhibitor from Korea’s Bridge Biotherapeutics that was on display at a science conference in Dallas recently. There’s not a whole lot of data to evaluate the prospects here.

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Servi­er scoots out of an­oth­er col­lab­o­ra­tion with Macro­Gen­ics, writ­ing off their $40M

Servier is walking out on a partnership with MacroGenics $MGNX — for the second time.

After the market closed on Wednesday MacroGenics put out word that Servier is severing a deal — inked close to 7 years ago — to collaborate on the development of flotetuzumab and other Dual-Affinity Re-Targeting (DART) drugs in its pipeline.

MacroGenics CEO Scott Koenig shrugged off the departure of Servier, which paid $20 million to kick off the alliance and $20 million to option flotetuzumab — putting a heavily back-ended $1 billion-plus in additional biobuck money on the table for the anti-CD123/CD3 bispecific and its companion therapies.