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

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

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Left to right, top to bottom: Carl Gordon, Adam Stone, Peter Moglia, David Schenkein, Robert Nelsen, Carol Gallagher; Srinivas Akkaraju, Ray Debbane, Jim Flynn, Peter Kolchinsky, Thilo Schroeder, Brad Bolzon

UP­DAT­ED: The top 100 bio­phar­ma ven­ture in­vestors at the mega­bil­lions deal ta­ble

The VC crowd took a step back last year, but nevertheless maintained a furious pace of new investments in therapeutic tech platforms and biotech startups. And the top 100 players completely dominated the megabillions game.

Just looking at the number of deals done by each of the top 100, OrbiMed came in at the top, with 20, followed by Alexandria (18), Perceptive (16) and the ubiquitous RA Capital at 16. It’s impossible to say exactly how much they invested in total — those numbers are only rarely provided — but it is clear from the numbers assembled by Chris Dokomajilar at DealForma who’s most likely to be found sitting at the table during the go-go days of biotech investing.

Dokomajilar tracked $14.06 billion in biotech venture investing last year, a dip from the frenzied pace of $16.02 billion in 2018 and more than $10 billion higher than he recorded for 2010, as the economy was recovering from a profound economic crisis.

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Rahul Ballal, Imara

As sick­le cell pa­tients find new op­tions, NEA-found­ed Imara pitch­es mid-stage al­ter­na­tive for $86M IPO

November 2019 proved to be a fruitful month for patients with blood disorders known as hemoglobinopathies. Within days, the FDA ushered two drugs for sickle cell disease and another for beta thalassemia to the market — livening up a barren field.

Imara, a relatively young plower, is riding on that enthusiasm as it shoots for an $86.25 million IPO.

Imara emerged from New Enterprise Associates’ orphan drug accelerator Cydan in 2016 as a single-product company. $77.3 million in private financing later IMR-687 remains the sole asset in its pipeline; the difference is the drug is now in Phase II for sickle cell disease, with topline data slated for later this year and two other mid-stage beta thalassemia studies lined up.

RA joins glob­al syn­di­cate to back a $98M round for CAN­bridge

A Beijing-based rare disease and oncology player has raised $98 million to help fund the expansion of its pipeline as well as a commercial portfolio.

CANbridge put out word Tuesday that the global private equity player General Atlantic joined forces with Chinese CRO Wuxi AppTec to lead the Series D, with both ready to chip in an extra $10 million each under the right conditions. The syndicate includes RA Capital Management, Hudson Bay Capital Management, YuanMing Prudence Fund and Tigermed.

Carol Robinson, Professor Dame Carol Robinson Research Group

UP­DAT­ED: Drug dis­cov­ery in HD: Ox­ford spin­of­f's mass spec­trom­e­try ap­proach scores fresh fund­ing

The technology used to detect explosives at airports — mass spectrometry — is being piloted as an engine for drug discovery.

Mass spectrometry is a tool designed to measure with profound accuracy the mass of a single molecule. Typically, mass spectrometers can be used to identify unknown compounds, to quantify known compounds, and to determine the structure and chemical properties of molecules.

UP­DAT­ED: Chi­na ap­proves flu drug be­ing tout­ed as a po­ten­tial coro­n­avirus treat­ment amid a rush of clin­i­cal stud­ies

One of the three drugs that China’s Ministry of Science and Technology has tapped as potential COVID-19 treatments to watch has notched its first Chinese OK — for the flu.

While there’s no proof yet that fapilavir, or favipiravir, is the cure that patients and physicians are yearning for, it stands out for a unique constellation of qualities. It’s been commercially available in Japan for several years (unlike Gilead’s experimental remdesivir) yet it’s new to China (unlike the malaria drug chloroquine phosphate). Perhaps more importantly, a domestic biotech — Zhejiang Hisun Pharma — owns the rights to manufacture and market the drug, preempting any concerns about patents.

FDA goes on high alert as coro­n­avirus rais­es threat to drug man­u­fac­tur­ing and clin­i­cal tri­als grind to a halt

The FDA isn’t quite sure just what the coronavirus outbreak in China will mean for the US pharma industry, but it has the potential to trigger a host of troublesome issues around the supply chain the country is directly plugged into.

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Warren Buffett, AP Images

War­ren Buf­fett gets a dou­ble take as the in­vest­ment pow­er­house set­tles on its first biotech in­vest­ment

Coke. American-Express. Apple. And Biogen?

Warren Buffet’s Berkshire Hathaway, which made itself into a symbol of rock-solid investment strategy, has revealed a stake in the big biotech as it takes on one of the biggest gambles in the industry.

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