Late Friday, the U.S. FDA revealed that it is looking into the death last month of another patient who received Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) gene therapy Elevidys, which was quickly confirmed by Sarepta and its ex-U.S. partner Roche to have occurred in a young boy in Brazil.
Although the latest death—the third reported in an Elevidys patient this year and the fourth for a person on a Sarepta gene therapy in general—has been deemed unlikely to be related to Sarepta’s treatment, the fatality adds another wrinkle to concerns about the safety burden of AAV-based gene therapies overall.
The situation could further erode confidence in Sarepta’s management, too, given that they did not disclose the death when pressed about additional unreported safety events on a conference call earlier in the month.
The FDA is investigating the death of an 8-year-old boy, treated with Elevidys, who passed away on June 7. The regulator did not disclose further details about the case in Friday’s announcement.
In its own communique issued shortly after the FDA’s, Sarepta elaborated on the situation and confirmed a Roche statement to Bloomberg News that linked the probe to a fatality in Brazil and held that the death of the patient was unrelated to Elevidys itself.
The boy wasn’t a clinical trial participant, according to the Roche statement paraphrased by Sarepta. Sarepta stressed that it reported the event to the FDA on June 18 through the agency’s voluntary adverse event reporting system FAERS.
Elevidys was approved in Brazil in December to treat ambulatory DMD patients between the ages of 4 and 7 years. Some 10 boys in Brazil have been treated with the gene therapy, the country’s health regulator, Anvisa, said in a July 24 statement, citing information provided by Roche.
To date, Anvisa says it has received three adverse event reports from Roche tied to patients who received Elevidys. The first two were determined to have likely been caused by the gene therapy but were classified as having “a favorable outcome, consistent with the effects already described in the package insert and observed in clinical studies.”
The third reported case that led to the latest patient death had an “unlikely causal link with the use of Elevidys,” Anvisa clarified, noting that the fatality may have been caused by a severe flu infection that was intensified by the immunosuppression regimen gene therapy patients receive to counter the body’s response to the treatment.
While it’s a given that suppressing the immune system makes one more vulnerable to infections, the death “suggests additional research and education is needed regarding the risks associated with immunosuppression in the context of gene therapies,” analysts at William Blair wrote to clients Monday.
The analysts flagged that the boy was a year older than the cutoff for Elevidys treatment under its approval in Brazil, which suggests that the patient “may have been treated expeditiously before aging out of eligibility, and therefore treatment could not be delayed until after Brazil’s flu season.”
In light of the situation, Roche has elected to pause shipments of Elevidys in Brazil, Anvisa said. The Brazilian hold “is in effect until the recent safety uncertainties related to reports of fatal cases of acute liver failure in patients treated with the product in the United States are fully clarified,” the regulator added.
The move comes after Roche last week halted distribution of the commercial gene therapy in countries where Elevidys approvals were based on the U.S. FDA’s decisions, following a similar move by Sarepta in the U.S. At that time, the Roche list of affected countries included several states in the Gulf Region, but notably excluded Brazil and Japan.
While available information is limited, the patient's death does appear “unrelated to Elevidys itself and is distinctly different from the other patient deaths reported this year,” the William Blair team said Monday.
Sarepta was forced to reckon with disgruntled analysts on a conference call earlier this month after a third patient death was unveiled by reporters a day after Sarepta shelved much of its gene therapy pipeline in a major restructuring. Sarepta had not disclosed the death prior to it coming out in news reports.
During the call, analysts repeatedly asked Sarepta’s executives whether there were any other deaths or safety events the company was aware of that had not been reported publicly. Sarepta’s management repeatedly said there were not.
Unlike the two that came before it this year, the third death that prompted the analyst call was not recorded in an Elevidys patient. Instead, the patient had received an investigational Sarepta gene therapy dubbed SRP-9004 in a clinical trial for a different form of muscular dystrophy. Crucially, however, both Elevidys and SRP-9004—which had its development put on hold a little less than two weeks ago—use the same adeno-associated virus (AAV) platform.
All three patients whose deaths were linked to a Sarepta gene therapy died from acute liver failure. Liver toxicity is a known side effect of AAV-based gene therapies.
Both Sarepta and Roche have continued to stand behind Elevidys despite the constant stream of safety controversies in recent months.
Late last week, Roche said it would continue to seek a path forward for Elevidys in the European Union after the bloc’s Committee for Medicinal Products for Human Use knocked back the company’s bid for approval.
Back in the U.S., the FDA is reportedly considering whether to require new analyses of Elevidys to confirm the gene therapy’s safety. The FDA is “looking at all the tools we have” when it comes to evaluating the commercial treatment’s market position, a Department of Health and Human Services spokesperson told Fierce Pharma on Friday.
The William Blair team found the FDA’s new investigation into the patient death in Brazil puzzling given that it doesn’t appear to be linked to Elevidys itself. Nevertheless, the probe’s launch “suggests the FDA’s hawkish stance on Elevidys could create more headwinds for its return to market,” the analysts warned.