FDA lets blue­bird re­sume tri­als for sick­le cell gene ther­a­py af­ter can­cer scare, but big ques­tions linger over field

Blue­bird bio an­nounced that the FDA has lift­ed its holds on clin­i­cal tri­als for their gene ther­a­pies for sick­le dis­ease and be­ta-tha­lassemia, end­ing a 4-month saga that be­gan af­ter the biotech re­port­ed that two pa­tients had come down with can­cer and a can­cer-like con­di­tion.

Reg­u­la­tors were con­cerned that the cas­es may have been trig­gered by the virus blue­bird us­es to de­liv­er a healthy gene for he­mo­glo­bin in­to pa­tients with rare blood dis­or­ders, as had hap­pened in a 2004 gene ther­a­py tri­al that re­lied on a sim­i­lar virus. Blue­bird large­ly al­layed those con­cerns in March, when they re­leased a ge­net­ic analy­sis show­ing that the virus didn’t in­ter­fere with the pa­tient’s DNA in a way like­ly to trig­ger can­cer, but ex­perts say the cas­es have broad­ly raised con­cerns about the risks any of the more than half dozen of sick­le dis­ease gene ther­a­pies now in clin­i­cal de­vel­op­ment may pose.

Ak­shay Shar­ma, a pe­di­atric bone mar­row spe­cial­ist at St. Jude, said doc­tors al­ready knew peo­ple with sick­le cell dis­ease are at greater risk of de­vel­op­ing leukemia. But the cas­es high­light­ed how any form of ge­net­ic ma­nip­u­la­tion — in­clud­ing the CRISPR-based ap­proach­es Ver­tex, No­var­tis, Beam and oth­ers are pur­su­ing — could ex­ac­er­bate that pre­dis­po­si­tion.

Ak­shay Shar­ma

“We def­i­nite­ly need more re­search to un­der­stand ex­act­ly what is this pre­dis­po­si­tion, and once we know it, on­ly then will we sat­is­fac­to­ri­ly an­swer this ques­tion: Is it safe or not?” Shar­ma, who has served as an in­ves­ti­ga­tor on gene ther­a­py tri­als, told End­points News. “And I think the an­swer may be in the mid­dle. Per­haps these ge­net­ic ther­a­pies are safe for most pa­tients, but some pa­tients are at greater risk.”

For blue­bird, the hold was an­oth­er in a se­ries of set­backs the Cam­bridge biotech has faced in the years since they first showed da­ta from a hand­ful of pa­tients sug­gest­ing that their gene ther­a­py can be a func­tion­al cure for sick­le cell dis­ease. Un­able to prove to the FDA they could man­u­fac­ture their prod­uct safe­ly at scale, they’ve re­peat­ed­ly pushed back the date for fil­ing for ap­proval.

Most re­cent­ly, they pushed their time­line in­to late 2022, al­though that was be­fore the FDA hold came down. The de­lays have al­lowed Ver­tex and CRISPR Ther­a­peu­tics to catch up with a gene edit­ing ap­proach that en­tered the clin­ic five years lat­er. The two now be­lieve they will be first-to-mar­ket with a sick­le cell cure, which could pro­vide a ma­jor com­mer­cial ad­van­tage.

Nev­er­the­less, the FDA de­ci­sion re­newed in­vestor faith in blue­bird’s path ahead. The stock $Blue rose 6% in pre-mar­ket trad­ing, from $30.92 to $33.00.

In Feb­ru­ary, blue­bird an­nounced that a sick­le cell pa­tient who re­ceived their gene ther­a­py five years pri­or was di­ag­nosed with acute myeloid leukemia. A sec­ond, they said, had been di­ag­nosed with a sus­pect­ed case of myelodys­plas­tic syn­drome, a can­cer-like dis­ease that oc­curs in the bone mar­row. They lat­er said the lat­ter case was in fact a mis­di­ag­nosed case of trans­fu­sion-de­pen­dent ane­mia.

Al­though blue­bird’s analy­sis showed that the virus blue­bird us­es — a re-en­gi­neered form of HIV, called a lentivirus — didn’t in­ter­fere with genes known to cause can­cer, Shar­ma said the ther­a­py could have el­e­vat­ed the pa­tients’ risks in oth­er ways. It could have made more sub­tle ge­net­ic al­ter­ations, or the chemother­a­py “con­di­tion­ing” reg­i­ment pa­tients pri­or to the ther­a­py could have made them more sus­cep­ti­ble.

Af­ter a pa­tient who re­ceived blue­bird’s ther­a­py was di­ag­nosed with myelodys­plas­tic syn­drome in 2018, the com­pa­ny at­trib­uted it to the chemother­a­py.

Re­cent stud­ies, Shar­ma not­ed, have linked the risk of leukemia af­ter a trans­plant to spe­cif­ic ge­net­ic mu­ta­tions. Re­searchers need to de­vel­op meth­ods of screen­ing for pa­tients who have that mu­ta­tion and po­ten­tial­ly oth­er mu­ta­tions that could put them at greater risk and quan­ti­fy pre­cise­ly how high that risk is. They will al­so need ways of min­i­miz­ing those risks, such as by de­vel­op­ing safer al­ter­na­tives to chemother­a­py — a task com­pa­nies such as Ma­gen­ta and Jasper Ther­a­peu­tics are now work­ing on.

He em­pha­sized that it would not be a prob­lem just for blue­bird but to any of the near­ly dozen at­tempts to cure sick­le cell dis­ease now at or near the clin­ic.

“If some­body has a pre­dis­po­si­tion,” he said, “any type of ge­net­ic al­ter­ation or ex­po­sure to chemother­a­py could ac­cel­er­ate that and lead to leukemia.”

In­side Track: Be­hind the Scenes of a Ma­jor Biotech SPAC

Dr. David Hung and Michelle Doig are no strangers to the SPAC phenomenon. As Founder and CEO of Nuvation Bio, a biotech company tackling some of the greatest unmet needs in oncology, Dr. Hung recently took the company public in one of this year’s biggest SPAC related deals. And as Partner at Omega Funds, Doig not only led and syndicated Nuvation Bio’s Series A, but is now also President of the newly formed, Omega-sponsored, Omega Alpha SPAC (Nasdaq: OMEG; oversubscribed $138m IPO priced January 6, 2021).

Barry Greene, Sage CEO

UP­DAT­ED: Sage's sec­ond chance at de­pres­sion hits the PhI­II pri­ma­ry, but ques­tions re­main over dura­bil­i­ty, side ef­fects

Looking to make a comeback after a big Phase III flop, Sage Therapeutics revealed data they believe could change the entire depression treatment landscape, given the vast array of failures in the field. But some results are spooking investors, sending Sage $SAGE shares down early Tuesday.

First, the primary: Sage and Biogen reported Phase III data for once-daily zuranolone Tuesday morning, saying the experimental drug hit its primary endpoint by spurring a statistically significant change from baseline in the 17-item Hamilton Rating Scale for Depression total score. After 15 days, patients in the drug arm saw an average change of -14.1 points, compared to -12.3 on placebo.

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Bio­gen sig­nals a big PhI­II fail­ure as the lead gene ther­a­py in their $800M Night­star buy­out goes down in flames

That $800 million buyout of Nightstar has turned into a bust for Biogen as the lead therapy in the deal failed a pivotal study, signaling a severe setback for the biotech’s ambitions in gene therapies.

The big biotech put out the word after the market closed on Monday that the gene therapy they picked up in the deal for a degenerative blindness called choroideremia failed the Phase III study, just a month after their #2 drug in the deal also flopped in a mid-stage study.

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Harith Rajagopalan (Fractyl)

Af­ter a decade in the Type 2 di­a­betes game, Fractyl Lab­o­ra­to­ries recharges with a fresh $100M and a new name

Harith Rajagopalan compared the way Type 2 diabetes is managed to sticking your fingers in a dam that’s leaking from a number of places.

You can take drugs to lower your blood sugar, cholesterol, or blood pressure, but you’re not addressing what he says is the core issue — the metabolic abnormality that causes the disease.

“We’re so busy plugging the holes in the dam, we don’t have time to see that the whole infrastructure is at risk,” he said. “That infrastructure is a full-body systemic metabolic abnormality called metabolic syndrome, that we’re ignoring while we’re so busy trying to treat all of the individual symptoms of the condition.”

Hal Barron, GSK R&D chief (Endpoints News)

Hal Bar­ron gam­bles $625M cash on high-wire TIG­IT act, throw­ing Glax­o­SmithK­line in­to heat­ed race and com­plet­ing next-gen I/O trin­i­ty

Count Hal Barron and GlaxoSmithKline in for the TIGIT fight.

The stakes are as high as the risks: While a growing pack of Big Pharma rivals is lending credence to the hypothesis that TIGIT will be the next big immune checkpoint and cancer drug target, the first clinical trials have shown response rates that can be described as modest at best. But Barron’s bet is on the whole “axis” that the receptor sits on, with an eye on testing its new anti-TIGIT antibody not just in combo with PD-1 but also in triplets.

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Michel Sade­lain puts his name and new cell en­gi­neer­ing tech be­hind 'ag­nos­tic' CAR-T start­up chas­ing epi­ge­net­ic anti­gens

It felt natural for Alain Maiore and Sebastian Amigorena to bring in Michel Sadelain as a co-founder of Mnemo Therapeutics. A CAR-T pioneer, Sadelain had been involved as an advisor since the early days — enthusiastic about Amigorena’s work in a genetic knockout that could enhance T cell memory and a new class of potential targets he’s discovered — and could introduce some well-known technologies to the toolbox. So they got the initial cash from Sofinnova Partners to plant roots in Paris and New York in early 2019; within a few months, they began to see more clearly just what the antigen discovery platform might unlock.

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Geoffrey Porges, SVB Leerink

Top an­a­lyst maps a rocky road for Ver­tex — un­less they adopt a $10B M&A cam­paign to save the pipeline

After repeatedly poking Vertex $VRTX execs with pointed criticism of their R&D strategy, top SVB Leerink analyst Geoffrey Porges is now turning up the heat to a full-scale roasting.

In a note out early Monday morning, Porges spotlights the impact of Vertex’s recent follow-up failure on AATD — their treatment hit the endpoint but missed on commercial prospects — rewriting his recommended scenario for CEO Reshma Kewalramani as she grapples with the setback.

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Lynn Fitch, Mississippi Attorney General (Rogelio V. Solis/AP Images)

Mis­sis­sip­pi sues Eli Lil­ly, Sanofi and No­vo over in­sulin prices as in­ter­change­able biosim­i­lars may ar­rive soon

Mississippi Attorney General Lynn Fitch last week sued the top three insulin manufacturers, which collectively cover almost the entire US insulin market, alleging that they’ve colluded to raise their prices in lockstep, and in some cases by more than 1,000% for drugs that are decades old.

“Because of Manufacturer Defendants’ collusive price increases, nearly a century after the discovery of insulin, diabetes medications have become unaffordable for many diabetics,” the lawsuit says.

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Andrew Hopkins, Exscientia CEO

Ex­sci­en­tia spends Soft­Bank's cash in bid to edge out AI ri­vals

Exscientia is sprinting to win the great AI biotech race.

The UK company, having long labored on small discovery deals with large pharmas, raised up to $525 million in a Series D led by the infamous Japanese conglomerate SoftBank in April and followed it up less than a month later with a Bristol Myers Squibb deal that paid $50 million cash and $1.2 billion in milestones.

Now, the Oxford spinout is splurging on a shiny new tool. On Monday they announced they purchased the three-year-old molecule-screening biotech Allcyte, a longtime collaborator, for $60.6 million in cash and stock.

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