In stag­ger­ing set­back, tox­ic re­ac­tion kills Cel­lec­tis’ first CAR-T pa­tient, forc­ing tri­al halt

The FDA has forced Cel­lec­tis $CLLS to slam the brakes on two clin­i­cal tri­als of its off-the-shelf ver­sion of a CAR-T ther­a­py af­ter their first pa­tient was killed by a lethal­ly tox­ic re­ac­tion to treat­ment.

Ac­cord­ing to the biotech, which is based in Paris with R&D op­er­a­tions in New York, a 78-year-old pa­tient suf­fer­ing from blas­tic plas­ma­cy­toid den­drit­ic cell neo­plasm (BPD­CN) died eight days af­ter re­ceiv­ing the biotech’s first dose of the cell ther­a­py. He ex­pe­ri­enced a lethal re­ac­tion as cy­tokine re­lease syn­drome hit, along with a grade 4 case of cap­il­lary leak syn­drome. A sep­a­rate study which al­so treat­ed one pa­tient is un­der­way for acute myeloid leukemia.

The com­pa­ny’s stock was ham­mered by the bad news, drop­ping about 30% in pre-mar­ket trad­ing and shed­ding more than $400 mil­lion of its mar­ket cap.

Sig­nif­i­cant­ly, nei­ther of the first two pa­tients treat­ed with UCART123 ex­pe­ri­enced graft ver­sus host dis­ease, one of the chief fears in­volved in an al­lo­gene­ic ther­a­py that takes do­nat­ed pa­tient cells then adapts them in­to a ready-to-use ther­a­py, by­pass­ing a com­plex step re­quired by the first CAR-Ts.

The FDA ap­proved the first per­son­al­ized CAR-T from No­var­tis just days ago, and Kite is ex­pect­ed to get an OK of its own soon. But the move by the FDA to slap a hold on these off-the-shelf ther­a­pies rais­es a host of thorny ques­tions for Cel­lec­tis.

Juno $JUNO was al­so forced to halt a study of its lead CAR-T last year — one of the pi­o­neer­ing au­tol­o­gous ver­sions that ex­tracts pa­tient cells and then adapts them be­fore re­in­fus­ing them in­to pa­tients — af­ter pa­tients died from cere­bral ede­ma. Then in an as­ton­ish­ing­ly short pe­ri­od of just a few days, reg­u­la­tors agreed to let re­searchers pro­ceed with the piv­otal tri­al af­ter a ques­tion­able change-up in the pre­con­di­tion­ing reg­i­men used to pre­pare pa­tients for the cell ther­a­py. Al­most im­me­di­ate­ly af­ter treat­ment re­sumed, three more pa­tients died fol­lowed by a tri­al halt and the sub­se­quent de­ci­sion to scrap a drug Juno and the FDA clear­ly didn’t com­plete­ly un­der­stand.

An­dre Chouli­ka

Will that dead­ly mis­take by reg­u­la­tors force them to be ex­tra sen­si­tive to this quick and ear­ly death in the UCART123 stud­ies? Or will reg­u­la­tors be quick to green-light this new ther­a­py back in­to the study, con­fi­dent that years of treat­ing CRS — a com­mon re­ac­tion among pa­tients re­ceiv­ing CAR-T ther­a­py — can be man­aged?

Cel­lec­tis spelled out the down­ward spi­ral ex­pe­ri­enced by its first pa­tient.

About a week ago, Cel­lec­tis re­ports, the da­ta safe­ty mon­i­tor­ing board sug­gest­ed low­er­ing the dose — to 6.25×104 UCART123 cells per kilo­gram — in both stud­ies and cap­ping cy­clophos­phamide to a to­tal dose of 4g over three days. But the FDA fol­lowed up by de­mand­ing a halt to the BPD­CN study along with the sep­a­rate study on acute myeloid leukemia, which has al­so seen one pa­tient treat­ed. That pa­tient ex­pe­ri­enced a grade 3 case of CRS and a grade 4 case of cap­il­lary leak syn­drome — both of which re­solved with­in a few days.

Cap­il­lary leak syn­drome is a con­di­tion in which leaky blood ves­sels can cause a po­ten­tial­ly lethal drop in blood pres­sure.

In the ab­sence of any sim­ple ex­pla­na­tion, in­vestors like Biren Amin at Jef­feries spec­u­lat­ed on caus­es and de­fects. His note:

We think there is a chance that CRS events could be mit­i­gat­ed up­on low­er­ing the dose of UCART123 be­yond the DSMB rec­om­men­da­tion and treat­ing CRS symp­toms more ag­gres­sive­ly, al­though ul­ti­mate­ly we look to more in­for­ma­tion. These events may be par­tial­ly due to the UCART123 cells be­ing from a healthy donor but, giv­en the dearth of da­ta, we think CLLS needs to ap­proach through a more holis­tic ap­proach and utliliz­ing key re­search on safe­ty from au­tol­o­gous CAR-T tri­als over the last 3-4 years. How­ev­er, we be­lieve the Grd 3 in­fec­tion (po­ten­tial­ly a re­sult of a neu­tropenic state) and Grd 4 CLS events have the po­ten­tial to be tar­get spe­cif­ic. For the lat­ter, we note that sAEs in­volv­ing CLS has been re­port­ed for Stem­line’s (STML, NC) CD123-di­rect­ed SL-401 ther­a­peu­tic. It’s un­clear if CLLS al­so re­quired pa­tients in their stud­ies to have nor­mal ejec­tion frac­tions and cer­tain pre-spec­i­fied al­bu­min lev­els at time of study en­try.

Cel­lec­tis will get ham­mered by in­vestors to­day, par­tic­u­lar­ly as the en­thu­si­asm for all things CAR-T seen in the past few days has swelled every­one’s stock price. Cel­lec­tis shares have soared past the $32 mark. The safe­ty is­sue will chal­lenge CEO An­dré Chouli­ka, a fierce and un­abashed pro­po­nent of all things Cel­lec­tis.

“Cel­lec­tis is the first com­pa­ny do­ing CAR-T,” he told me dur­ing an in­ter­view at AS­CO two years ago. “We are the first gene edit­ing com­pa­ny in the world,” dat­ing back to 1999. “There was no gene edit­ing be­fore us; we are the lead­ers.”

To­day, Cel­lec­tis and Chouli­ka will be lead­ing a charge to re­solve their biggest chal­lenge to date. It won’t be easy.

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back -- this time flunk­ing fu­til­i­ty test -- as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

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Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

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Gilead dusts off a failed Ebo­la drug as coro­n­avirus spreads; Ex­elix­is boasts pos­i­tive Ph I/II da­ta

→ Less than a year ago Gilead’s antiviral remdesivir failed to make the cut as investigators considered a raft of potential drugs that could be used against an Ebola outbreak. But it may gain a new mission with the outbreak of the coronavirus in China, which is popping up now around the world.

Gilead put out a statement saying that they’re now in discussions with health officials in the US and China about testing their NUC against the virus. It’s the latest in a growing lineup of biopharma companies that are marshaling R&D forces to see if they can come up with a vaccine or therapy to blunt the spread of the virus, which has now sickened hundreds, killed at least 17 people and led the Chinese government to start quarantining cities.

UP­DAT­ED: Eli Lil­ly’s $1.6B can­cer drug failed to spark even the slight­est pos­i­tive gain for pa­tients in its 1st PhI­II

Eli Lilly had high hopes for its pegylated IL-10 drug pegilodecakin when it bought Armo last year for $1.6 billion in cash. But after reporting a few months ago that it had failed a Phase III in pancreatic cancer, without the data, its likely value has plunged. And now we’re getting some exact data that underscore just how little positive effect it had.

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UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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Alex Karnal (Deerfield)

Deer­field vaults to the top of cell and gene ther­a­py CD­MO game with $1.1B fa­cil­i­ty at Philadel­phi­a's newest bio­phar­ma hub

Back at the beginning of 2015, Deerfield Management co-led a $10 million Series C for a private gene therapy startup, reshaping the company and bringing in new leaders to pave way for an IPO just a year later.

Fast forward four more years and the startup, AveXis, is now a subsidiary of Novartis marketing the second-ever gene therapy to be approved in the US.

For its part, Deerfield has also grown more comfortable and ambitious about the nascent field. And the investment firm is now putting down its biggest bet yet: a $1.1 billion contract development and manufacturing facility to produce everything one needs for cell and gene therapy — faster and better than how it’s currently done.

Tri­fec­ta of sick­le cell dis­ease ther­a­pies ex­tend life ex­pectan­cy, but are not cost-ef­fec­tive — ICER

Different therapeutic traits brandished by the three approved therapies for sickle cell disease all extend life expectancy, but their impact on quality of life is uncertain and their long-term cost-effectiveness is not up to scratch according to the thresholds considered reasonable by ICER, the non-profit concluded in a draft guidance report on Thursday.

Sickle cell disease (SCD), which encompasses a group of inherited red blood cell disorders that typically afflict those of African ancestry, impacts hemoglobin — and is characterized by episodes of searing pain as well as organ damage.