Sarepta Therapeutics announced a restructuring plan Wednesday that will eliminate 36% of its workforce — approximately 500 employees — as the gene therapy company grapples with fatal safety events tied to its $3.2-million Duchenne muscular dystrophy (DMD) gene therapy Elevidys (delandistrogene moxeparvovec-rokl).
The company, whose stock surged over 35% in after-hours trading, expects the restructuring to deliver $400 million in annual cost savings while refocusing its pipeline on siRNA-based therapies.
“Faced with environmental changes, we have decided to act decisively, implementing a focused strategy to ensure Sarepta remains a vibrant, financially enduring, patient-centric organisation dedicated to improving the lives of those with rare genetic diseases,” said CEO Doug Ingram, who added that the layoffs were a “very painful” decision.
The workforce reduction comes as Sarepta faces scrutiny over two fatal liver failure cases linked to Elevidys. Both deaths involved non-ambulatory patients who developed severe liver complications after receiving the one-time treatment, prompting the company to pause shipments for this patient population in June (see – KOL Views Q&A: Second death on Elevidys will weigh on enthusiasm for DMD gene therapies).
Elevidys first entered the market under an accelerated FDA approval in 2023 — restricted to use in ambulatory boys aged four to five — even though the Phase III EMBARK trial had missed its primary goal. Sarepta later won a label expansion allowing use in non-ambulatory boys and those aged four years and older. Earlier this year, the company touted encouraging two-year data showing lasting motor improvements in ambulatory children.
Boxed warning
Sarepta says the FDA has now requested that it include a boxed warning for acute liver injury and acute liver failure in the Elevidys label, mirroring warnings required for other AAV-delivered gene therapies. The change appears to resolve any material issues with the ambulant portion of the Elevidys label, but “more dialogue is required” when it comes to the non-ambulatory patient population, Ingram said on an analyst call Wednesday afternoon.
The company has brought together an expert panel to address cases of acute liver failure linked to Elevidys in non-ambulant patients. The group recommended an enhanced immunosuppressive protocol using sirolimus, which Sarepta plans to present to the FDA and potentially evaluate further in a new cohort of the Phase I ENDEAVOR study, dubbed Cohort 8, while also exploring real-world data collection for ambulant patients.
“What we’re looking for in all of this is to look for signals of reductions in elevated liver enzymes and other biomarkers. We obviously can’t look for [acute liver failure] because that is an unbelievably rare signal that would take years and years. But if you can significantly reduce even liver stress and liver injury through things like liver enzymes, bilirubin and the like, one would obviously posit you’ve…reduced that risk very, very significantly,” Ingram said.
Sarepta also shared preliminary second-quarter financial results, including revenue of $513 million, with Elevidys contributing $282 million and the company’s RNA-based phosphorodiamidate morpholino oligomer (PMO) therapies generating $231 million.
Emphasis on siRNA assets
As part of its pivot, Sarepta is refocusing its pipeline on siRNA platform assets, which the company believes offer potentially best-in-class chronically administered therapies for neurodegenerative and pulmonary diseases. The experimental siRNA programmes include SRP-1001 for facioscapulohumeral muscular dystrophy, SRP-1003 for myotonic dystrophy type 1, and SRP-1004 for spinocerebellar ataxia type 2 (SCA2), as well as preclinical programmes for Huntington’s disease, SCA1 and SCA3. Preliminary data from single ascending dose studies of SRP-1001 and SRP-1003 are due this half.
Ingram had highlighted the biotech’s siRNA portfolio as a “strategic part of the future of Sarepta” at the JP Morgan Healthcare Conference in January (see – JPM25: siRNA sliding into CNS).
However, several programmes, including most gene therapies in development for limb-girdle muscular dystrophy (LGMD) will be paused, with the exception of SRP-9003 for LGMD-2E, where a biologics license application will be filed in the second half. “Our hope is that we can find partners for these programmes…Unfortunately, we aren’t going to be able to pursue them ourselves,” Ingram said.