Juno scram­bles to avoid be­ing crushed by a hold, but ex­perts ques­tion its best case sce­nario

“Flu­dara­bine in some ways acts like a dose am­pli­fi­er,” says Juno CEO Hans Bish­op, ex­plain­ing the com­pa­ny’s the­o­ry of what went wrong.

John Car­roll, Ed­i­tor

About the last thing a biotech wants to see in the lead­up to a wide­ly her­ald­ed reg­u­la­to­ry fil­ing is a clin­i­cal hold from the FDA af­ter pa­tients in a piv­otal tri­al are killed by your treat­ment. The in­stinc­tive re­sponse is to get out in front of the dis­as­ter, see if you can iden­ti­fy a fac­tor oth­er than your drug that could have caused the deaths, and re­as­sure in­vestors that you have a plan – or soon will have one – that will get you back on track AS­AP.

Then, with­out burn­ing through too many hours be­tween the hold and the news, you host a press con­fer­ence and put out a re­lease and hope your stock doesn’t get evis­cer­at­ed in the re­ac­tion.

By that mea­sure, the past 24 hours at Juno Ther­a­peu­tics must have been a blur of non­stop ac­tion. They not on­ly im­me­di­ate­ly iden­ti­fied the cause of death in their lead CAR-T study, cere­bral ede­ma, they al­so ID’d a prime sus­pect, new­ly added flu­dara­bine, which in­ves­ti­ga­tors were us­ing to help prep pa­tients for a bet­ter re­sponse to the treat­ment.

So­lu­tion: Drop the flu­dara­bine, get the doc­u­men­ta­tion back to the FDA and wait for the green light. All while as­sur­ing in­vestors that this could all be over soon.

But it may not be any­thing near­ly as easy as that at Juno. And there are ma­jor im­pli­ca­tions here for the whole field.

Sal­ly Church, a No­var­tis vet with a doc­tor­ate from King’s Col­lege, writes the high­ly re­gard­ed Biotech Strat­e­gy Blog, where she spe­cial­izes in cov­er­ing can­cer treat­ments. She’s been fol­low­ing the CAR-T field close­ly for 4 years, and she was im­me­di­ate­ly puz­zled by Juno’s po­si­tion.

Sal­ly Church, Biotech Strat­e­gy Blog

The chemo flu­dara­bine was used in the study to com­plete a round of lym­phode­ple­tion, elim­i­nat­ing dis­eased B cells to as­sist the new­ly in­sert­ed CAR-T cells to re­pop­u­late and do their work. It’s the same type of con­di­tion­ing pa­tients re­ceive for hematopoeitic stem cell trans­plants. It’s al­so a pro­ce­dure used in oth­er CAR-T tri­als, with no his­to­ry of cere­bral ede­mas. And there’s no record of flu­dara­bine be­ing linked to cere­bral ede­mas, she writes in her blog. Church gave me ac­cess to the ar­ti­cle, which you can find here. (Note: There is a pay wall. If you’ve got the bud­get, we high­ly rec­om­mend you sign up.)

Then she asked a group of hema­tol­o­gists what they knew of a con­nec­tion. Re­sponse: Noth­ing. And she queried Dr. Stephan Grupp (CHOP), who “prob­a­bly treat­ed more pe­di­atric ALL pa­tients with CAR T cell ther­a­py than any­one”:

“We have not seen sig­nif­i­cant cere­bral ede­ma in any of our pe­di­atric ALL pa­tients on the CHOP/Penn study treat­ed with CTL019, many of whom re­ceived flu­dara­bine. CNS-re­lat­ed side ef­fects have been seen, in­clud­ing con­fu­sion, apha­sia and seizures in a small num­ber of pa­tients, but these ef­fects have all re­solved. Ob­vi­ous­ly, it is al­ways hard to at­tribute tox­i­c­i­ty to the chemo vs. the CAR T cells when both are giv­en around the same time, but we be­lieve the self-lim­it­ed CNS side ef­fects we have re­port­ed are more like­ly to be due to the T cells.”

Both Juno as well as ri­val Kite Phar­ma use CD-28 as a co-stim­u­la­tion do­main, she adds. Penn/CHOP/No­var­tis use 4–1BB. There are dif­fer­ences in pa­tient re­spons­es, but no cas­es of cere­bral ede­ma have been re­port­ed by Kite so far, though Kite has had the same lim­it­ed CNS is­sues that Juno has re­port­ed.

It’s not un­usu­al to see a dif­fer­ence of opin­ion among sci­en­tists and com­pa­nies en­gaged in ri­val stud­ies. The point here is that there’s thought­ful con­sid­er­a­tion of a much big­ger mys­tery about what went wrong for Juno. And a mys­tery is ex­act­ly what Juno doesn’t want to ex­plore – es­pe­cial­ly when your com­pe­ti­tion at Kite an­nounced that it had ful­ly en­rolled its ri­val study on the same day Juno stunned in­vestors with news of the clin­i­cal hold.

Fur­ther con­found­ing all of this, Bish­op re­port­ed a few days ago that he had sold $4.5 mil­lion in stock; a small part of his hold­ings, but not the kind of thing in­vestors like to see when bad news fol­lows soon af­ter.

Juno has al­ready ac­knowl­edged that its pre­dic­tion of a 2017 mar­ket launch will have to be de­layed a year. And for now, de­spite its con­fi­dent as­ser­tion that this can all be re­solved in short or­der, there’s rea­son to be­lieve that this could go on for much longer than Juno wants.

— John Car­roll@John­Cendpts

A fa­vorite in Alex­ion’s C-suite is leav­ing, and some mighty sur­prised an­a­lysts aren’t the least bit hap­py about it

Analysts hate to lose a biotech CFO they’ve come to trust and admire — especially if they’re being blindsided by a surprise exit.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

David Grainger [file photo]

'Dis­con­nect the bas­tard­s' — one biotech's plan to break can­cer cell­s' uni­fied de­fens­es

Chemotherapy and radiotherapy are the current gladiators of cancer treatment, but they come with well-known limitations and side-effects. The emergence of immunotherapy — a ferocious new titan in oncologist’s toolbox — takes the brakes off the immune system to kill cancer cells with remarkable success in some cases, but the approach is not always effective. What makes certain forms of cancer so resilient? Scientists may have finally pieced together a tantalizing piece of the puzzle, and a new biotech is banking on a new approach to fill the gap.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

While No­var­tis ban­ish­es Zol­gens­ma scan­dal scars — Bio­gen goes on a Spin­raza 'of­fen­sive'

While Novartis painstakingly works to mop up the stench of the data manipulation scandal associated with its expensive gene therapy for spinal muscular atrophy (SMA) Zolgensma— rival Biogen is attempting to expand the use of its SMA therapy, Spinraza. 

The US drugmaker $BIIB secured US approval for Spinraza for use in the often fatal genetic disease in 2016. The approval covered a broad range of patients with infantile-onset (most likely to develop Type 1) SMA. 

Jason Kelly. Mike Blake/Reuters via Adobe

Eye­ing big ther­a­peu­tic push, Gink­go bags $290M to build a cell pro­gram­ming em­pire

Ginkgo Bioworks is on a roll. Days after publicizing a plan to nurture new startups via partnerships with accelerators Y Combinator and Petri, the Boston biotech says it has raised another $290 million for its cell programming platform to reach further and wider.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: Speak­er Nan­cy Pelosi to un­veil bill for fed­er­al­ly ne­go­ti­at­ed drug prices

After months of buzz from both sides of the aisle, Speaker Nancy Pelosi will today introduce her plan to allow the federal government to negotiate prices for 250 prescription drugs, setting up a showdown with a pharmaceutical industry working overtime to prevent it.

The need to limit drug prices is a rare point of agreement between President Trump and Democrats, although the president has yet to comment on the proposal and will likely face pressure to back a more conservative option or no bill at all. Republican Senator Chuck Grassley is reportedly lobbying his fellow party members on a more modest proposal he negotiated with Democratic Senator Ron Wyden in July.

Jeff Kindler's Cen­trex­ion re­news bid to make pub­lic de­but

Jeffrey Kindler’s plan to take his biotech — which is developing a slate of non-opioid painkillers — public, is back on.

The Boston based company, led by former Pfizer $PFE chief Kindler, originally contemplated a $70 million to $80 million IPO last year— but eventually postponed that strategy. On Wednesday, the company revived its bid to make a public debut in a filing with the SEC — although no pricing details were disclosed.

Zachary Hornby. Boundless

'A fourth rev­o­lu­tion in can­cer ther­a­pies': ARCH-backed Bound­less Bio flash­es big check, makes big­ger promis­es in de­but

It was the cellular equivalent of opening your car door and finding an active, roaring engine in the driver seat.

Scientists learned strands of DNA could occasionally appear outside of its traditional home in the nucleus in the 1970s, when they appeared as little, innocuous circles on microscopes; inexplicable but apparently innate. But not until UC San Diego’s Paul Mischel published his first study in Science in 2014 did researchers realize these circles were not only active but potentially overactive and driving some cancer tumors’ superhuman growth.

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

Mer­ck helps bankroll new part­ner Themis' game plan to fin­ish the chikun­gun­ya race and be­gin on­colyt­ic virus quest

As Themis gears up for a Phase III trial of its chikungunya vaccine, the Vienna-based biotech has closed out €40 million ($44 million) to foot the clinical and manufacturing bills.

Its heavyweight partners at Merck — which signed a pact around a mysterious “blockbuster indication” last month — jumped into the Series D, led by new investors Farallon Capital and Hadean Ventures. Adjuvant Capital also joined, as did current investors Global Health Investment Fund, aws Gruenderfonds, Omnes Capital, Ventech and Wellington Partners Life Sciences.