In response to a request from the European Medicines Agency (EMA) following the death of a 16-year-old patient in the U.S., Sarepta and Roche have temporarily halted three clinical trials in Europe of their Duchenne muscular dystrophy (DMD) gene therapy Elevidys.
In a March 31 letter (PDF) from Roche to the World Duchenne Organization, the Swiss drugmaker said that the companies are pausing enrollment and dosing in the studies while continuing to monitor already-enrolled participants and collect data.
The paused trials include the Sarepta-sponsored phase 3 Envision study, which is evaluating Elevidys in boys aged 8 to 17; Roche’s phase 2 Envol study, which is investigating Elevidys in babies and newborns; and Sarepta’s Study 104, a phase 1 look at Elevidys in boys ages 4 to 9 with pre-existing antibodies to a particular serotype.
The trials have been halted in all EU countries, and the Envol study has been paused in the U.K. The trials are on hold until “analysis into the cause of death is complete,” Roche wrote. Meanwhile, four other U.S.-based Elevidys studies remain ongoing.
“While any clinical hold is concerning, we believe the EMA's request to pause the 3 Elevidys studies will likely be temporary and unlikely materially delay their completion timelines or the EMA review of Elevidys' marketing authorization application (MAA),” analysts from Mizuho Securities wrote in a note to investors.
In an update on Friday, April 4, Sarepta said that an independent data monitoring committee (DMC) met and concluded that "based on the totality of evidence, the overall benefit-risk profile remains favorable to continue dosing in the paused clinical trials without changes to the study protocols."
Sarepta and Roche plan to submit the DMC's findings to EU regulators "within a week" for review.
Two weeks ago, Sarepta disclosed the patient’s death, which was attributed to acute liver failure. Serious liver injury is a known safety risk of Elevidys.
“We cannot rule out the possibility that Elevidys was a contributing factor,” a Sarepta spokesperson told Fierce Pharma last month.
The incident brought increased attention to the safety of gene therapies that use adeno-associated viruses (AAVs) as vectors to deliver therapeutic genes. In Elevidys’ case, the administered gene produces microdystrophin, a shortened version of the normal dystrophin protein that’s missing in Duchenne patients.
In 2022, Novartis recorded two deaths for its AAV-based, spinal muscular atrophy gene therapy Zolgensma.
Although it is not a new safety signal, acute liver failure leading to death is a severity of the disorder not previously reported for Elevidys, which has been provided to more than 800 patients, Sarepta said. The company also reported that testing revealed the deceased patient had a recent cytomegalovirus infection that was identified by his treating physician as a possible contributing factor.
Since the report of the patient death, Sarepta’s share price has dropped by 42%.
“This is yet another unfortunate development for a story that cannot seem to catch a break,” Leerink wrote on Wednesday, adding that the weight of a 16-year-old patient likely means that he was provided a higher dose than the average Elevidys recipient.
“We acknowledge that such severe side effects associated with mortality can certainly be alarming and cause the community to question the risk/benefit of treating older patients. However, we believe that the very low overall incidence is encouraging,” Leerink wrote, adding that its projection of the likelihood of an EU approval remains unchanged at 60%.
Elevidys was approved on an accelerated basis in the U.S. in June of 2023 for boys ages 4 and 5. In June of last year, the FDA expanded its label to include all DMD patients aged 4 and up.
Both FDA nods stirred controversy, as neither was based on a trial that met its primary endpoint. During development of the treatment, trials were halted in 2018 and 2021 because of safety concerns. Also drawing ire was the $3.2 million price tag for the one-time treatment.
Still, sales have scaled up quickly, indicating the unmet need in the indication. In the fourth quarter, Sarepta reported revenue of $383 million from Elevidys, which was a 110% increase from the previous quarter. Leerink Partners projects Elevidys sales to reach $2 billion this year.
Editor's note: This story was updated at 9 a.m. EDT on Friday, April 4, to include the latest information from Sarepta.