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

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'


Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

Rahul Singhvi, Resilience CEO

A Bob Nelsen start­up turns to Har­vard to help sharp­en its tech, in­spir­ing first spin­out

One of Bob Nelsen’s latest projects is headed to Harvard.

Resilience, a company started with the goal of establishing itself as a “one-stop-shop” for companies looking to scale manufacturing, including for hard-to-develop cell and gene therapies, is less than a year old. Friday, it announced a five-year R&D deal with Harvard University that includes $30 million to develop biologics, including vaccines, nucleic acids and cell and gene therapies.

Susan Galbraith speaking at Endpoints News' virtual EUBIO21 summit

Imfinzi/treme­li­mum­ab com­bo scores As­traZeneca an­oth­er OS win — this time in liv­er can­cer

Is the tide turning on AstraZeneca’s battered PD-L1/CTLA4 combo?

A single priming dose of the experimental tremelimumab, followed by Imfinzi every four weeks, beat Nexavar (sorafenib) in helping a group of liver cancer patients live longer in a Phase III study, the company reported, meeting the primary endpoint.

Specifically, the two drugs extended overall survival for patients with unresectable hepatocellular carcinoma who had not received prior systemic therapy and were not eligible for localized treatment.

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FDA+ roundup: Marks on Wood­cock­'s tenure as act­ing com­mis­sion­er; FDA lead­ers of­fer per­spec­tive on bar­ri­ers to di­ver­si­ty in re­search

CBER director Peter Marks praised Janet Woodcock’s work as acting FDA commissioner, and while noting that Biden needs to nominate someone to fill the role permanently by Nov. 16, he said he has “no idea” when that actually might occur.

“Dr. Woodcock has been at the agency for over three decades and she, during that time, has proven herself to be a remarkably capable manager,” Marks said at the Alliance for Regenerative Medicine’s meeting Tuesday. “And she’s been managing as if she’s commissioner, unlike some previous acting [commissioners] who are afraid to actually do things. She doesn’t appear to be afraid to do things. I have not felt any different now from when we had a commissioner in place,” he added.

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