Gene ther­a­py deaths push back Astel­las-Au­den­tes' ap­proval by at least two years

The three deaths in an Astel­las gene ther­a­py tri­al last year will push back the ex­per­i­men­tal ther­a­py’s ap­proval by “more than two years” as Astel­las plans a sec­ond study, the com­pa­ny told End­points News in an email Tues­day. That means a reg­u­la­to­ry ap­pli­ca­tion would not come un­til at least mid-2022.

When Astel­las bought out the gene ther­a­py biotech Au­dentes for $3 bil­lion in De­cem­ber 2019, the Japan­ese phar­ma be­lieved they could file for ap­proval for their lead can­di­date in the US in mid-2020 and in Eu­rope in the lat­ter half of 2020. The ther­a­py was a one-time treat­ment for a rare and dead­ly mus­cle-wast­ing dis­or­der X-linked my­otubu­lar my­opa­thy, or XLMTM, and ex­ec­u­tives be­lieved the 26-per­son study would be enough to se­cure ap­proval.

But in May, the first of what would ul­ti­mate­ly be three pa­tient deaths oc­curred af­ter suf­fer­ing a se­vere re­ac­tion to a high dose of the vec­tor. The study was halt­ed while in­ves­ti­ga­tors tried to de­ter­mine what hap­pened.

Al­though the FDA agreed to al­low Astel­las to re­sume the study at a low­er dose last De­cem­ber, they have yet to en­roll new pa­tients. The com­pa­ny said in the Tues­day email that they planned to do so by June. The path to ap­proval, how­ev­er, re­mains un­cer­tain.

“We can’t pro­vide an ac­cu­rate time­line at this stage,” a spokesper­son said. “But fil­ing with the FDA and EMA is ex­pect­ed to be de­layed more than two years.”

The plan for sub­mis­sion, they said, had changed. Orig­i­nal­ly, Astel­las planned on sub­mit­ting the ther­a­py for ap­proval for pa­tients of all ages af­ter com­plet­ing the first tri­al, known as AS­PIRO, even though AS­PIRO on­ly en­rolled pa­tients up to the age of five.

Now, how­ev­er, they be­lieve they need to fin­ish the AS­PIRO tri­al and then run a sec­ond study for pa­tients over the age of 5. The three boys who died — al­most all XLMTM pa­tients are male — were among the old­est and largest pa­tients in the ini­tial tri­al, mean­ing they re­ceived among the high­est dos­es and raised con­cerns about how to bring the ther­a­py to old­er pa­tients.

Astel­las is wait­ing to com­plete dos­ing in AS­PIRO be­fore plan­ning the sec­ond tri­al, the spokesper­son said, “so that ad­di­tion­al clin­i­cal da­ta can best in­form the ap­proach.” The com­pa­ny plans to meet with the FDA this spring and the EMA this sum­mer to pre­pare for a fil­ing.

Ear­li­er this week, Astel­las an­nounced that it had writ­ten off $540 mil­lion of the $3 bil­lion buy­out, cit­ing their be­lief that the drug would be ap­proved lat­er and for a small­er pa­tient pop­u­la­tion than orig­i­nal­ly thought.

De­spite the trag­ic set­backs, in­ves­ti­ga­tors say the ther­a­py re­mains a promis­ing treat­ment for a ge­net­ic dis­ease that kills most pa­tients be­fore they reach adult­hood. Kids who re­ceived a low dose of the ther­a­py hit key mo­tor mile­stones for the first time: Six out of six were able to breathe with­out a ven­ti­la­tor and five out of six were able to walk for the first time.

Still, Astel­las has drawn crit­i­cism from out­side ex­perts and ex­ec­u­tives for fail­ing to dis­close or pub­lish de­tailed in­for­ma­tion around the pa­tients’ deaths, leav­ing open the ques­tion of pre­cise­ly what went wrong and how to pre­vent it in the fu­ture.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; 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.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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Crit­ics push back on Alzheimer’s As­so­ci­a­tion ad blitz to get Medicare to change its Aduhelm rul­ing: 'Dead wrong'

The latest Alzheimer’s Association advertising campaign encourages people to fight.

Not against the disease or for more research or treatments, but against the Centers for Medicare and Medicaid Services. More specifically, CMS’ recent reimbursement decision to only pay for Biogen and Eisai’s controversial Alzheimer’s drug Aduhelm for patients in clinical trials.

With CMS’ preliminary decision now in a 30-day comment period, patient advocates’ goal is to convince CMS to reverse its decision with a marketing blitz and public pressure.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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