When the FDA reworked the prescribing information for Sarepta Therapeutics' Duchenne muscular dystrophy (DMD) gene therapy Elevidys earlier this month, the company touted a plan to study a regimen designed to reduce liver-associated risks and potentially reach patients left off of the drug's new label. Now, with the FDA's go-ahead, the company is commencing with that effort.
The FDA gave Sarepta the green light to use an “enhanced immunosuppressive regimen” in the planned Cohort 8 of its Endeavor study, the company announced in a Tuesday press release. The regimen, which features the administration of sirolimus prior to and after the Elevidys infusion, will be studied in non-ambulatory individuals with DMD or those who can no longer walk independently.
Under a label change this month, non-ambulatory patients are no longer included in the FDA label for commercial Elevidys use. The FDA removed the patient group from the label after two non-ambulatory patients developed acute liver failure and died after receiving Elevidys earlier this year.
With the Cohort 8 effort, Sarepta aims to see whether the sirolimus regimen can cut risks associated with acute liver injury and acute liver failure associated with AAV-based gene therapies.
Once Sarepta has the data in hand, the company plans to hold discussions with the FDA about "resuming commercial dosing" for non-ambulatory patients, the company said.
Sarepta will enroll approximately 25 non-ambulatory patients who will receive sirolimus infusions for the 14 days prior to their Elevidys administration and continue 12 weeks after the Elevidys dose. At the end of the 12 weeks, the company will assess the incidence of acute liver injury and Elevidys-dystrophin expression as the cohort's primary endpoints. Previously, the two deaths happened within two months of the Elevidys infusion.
“We remain deeply committed to serving all individuals living with Duchenne, including those who have lost the ability to walk,” Sarepta’s president of R&D and technical operations, Louise Rodino-Klapac, Ph.D., explained in the company’s release. “Guided by real-world experience, external clinician expertise, and FDA input, Cohort 8 of the Endeavor study will evaluate integrating sirolimus into our immunosuppression approach, with the goals of mitigating the risk of acute liver injury and restoring access for non-ambulant individuals living with Duchenne.”
The company plans to initiate the effort by the end of this year and collect data on the cohort's primary endpoints in the second half of 2026, Rodino-Klapac added. Cohort 8 is the newest addition to the phase 1b study, which has so far enrolled 55 participants across seven cohorts.
The news comes a week after the FDA limited Elevidys’ indication to ambulatory patients aged four and up, removing its previous non-ambulatory endorsement. The therapy had no longer been sold in that population since June, when a second non-ambulatory patient died of acute liver failure after receiving the gene therapy.
In a note to clients, William Blair analysts wrote that the FDA’s green light for the Endeavor study update is a “constructive step” toward addressing the safety concerns that have limited Elevidys’ reach as of late. The approach offers a “viable pathway” to restoring a broader label, the analysts added.
If the effort is successful, positive results could allow Sarepta to pursue another label change as early as 2027, the analysts wrote in a Tuesday note to clients.
The analysts pointed to a poster presented at last month’s World Muscle Society Congress, in which Vanderbilt University Medical Center researchers ran an independent retroactive analysis of sirolimus as a prophylaxis among a small group of DMD patients who received Elevidys. None of the six patients who received sirolimus prior to infusion developed acute liver failure, a result that the team at William Blair sees as supportive to the Endeavor update, the analysts noted.
Elevidys’ liver safety flags have loomed over the gene therapy since the spring, when Sarepta reported that a non-ambulatory patient died from liver failure after using the product. After a second patient death in June, the company paused dosing in its ongoing Elevidys studies and was looking to amend its trial protocol to include the use of sirolimus, CEO Doug Ingram said on a conference call at the time. According to Ingram, the FDA had already proactively asked the company if it had considered using additional immunosuppression, including sirolimus, alongside the gene therapy.
The new Elevidys label also came with updated safety information, including a boxed warning. A new limitation of use further clarifies that the therapy is "not recommended in patients with preexisting liver impairment, recent vaccinations, or recent/active infections,” a change from the previous label that suggested treatment be “carefully considered” in those with preexisting liver impairment or chronic hepatic viral infection. Patients are also now recommended to stay near an “an appropriate medical facility” for at least two months post-dosing.
The gene therapy brought in third-quarter sales of $131.5 million, down sharply from $282 million in the second quarter. Sarepta had briefly paused all shipments of the drug in July, following a request from the FDA, before the agency quickly changed course to allow shipments to ambulatory patients.