Sarepta’s shares crashed 41% in premarket trading Monday morning to $21.01 after the biotech reported a second death from acute liver failure, a known side effect of adeno-associated virus-based gene therapies.
Another patient has died after being treated with Sarepta Therapeutics’ approved Duchenne musculur dystrophy (DMD) gene therapy Elevidys.
The death was linked to acute liver failure, a known side effect of adeno-associated virus (AAV)-based gene therapies—and of Elevidys itself, the biotech announced Sunday. Sarepta first announced in March that a patient on the gene therapy had died from this cause, noting at the time that the fatality “represents a severity of acute liver injury not previously reported for Elevidys.” Both deaths were in non-ambulatory patients.
In a press call Monday morning, Sarepta’s CSO Louise Rodino-Klapac said that the patient who died was 15 years and a patient in Sarepta’s Phase III ENVISION trial.
“There were some similarities with the first [patient death], and some differences as well,” she added without elaborating.
“Liver injury is a known risk of AAV therapies, historically,” CEO Doug Ingram said on the call, while noting that there are no clinical-stage gene therapies that do not use AAVs as a delivery system.
Sarepta is suspending its 2025 revenue guidance and will provide an updated guidance at its second quarter revenue call, Ingram said.
Writing to investors on Sunday evening, analysts at BMO Capital Markets called the death “unsurprising,” arguing that these deaths are likely “part of AAV risk”—a broader trend in the industry where the use of this delivery technology has been associated with safety concerns. Still, Sunday’s news raises concerns of additional deaths and the potential of Elevidys’ “withdrawal from the market,” though the analysts believe that the therapy’s ambulatory approval is unlikely to be pulled.
Sarepta’s shares were down 41% in pre-market trading Monday morning to $21.01.
For Jefferies, this latest patient death “may raise serious questions on Elevidys’ sales outlook,” noting that “sales may no longer accelerate” in the second half of the year. Still, the analysts expect Sarepta’s market in ambulatory patients to be “mostly intact,” with the biotech seeing some $1 billion to $1.5 billion in annual sales out to 2029.
Following the second Elevidys death, Sarepta on Sunday put in place a slew of safety initiatives for the gene therapy, including assembling an “independent group” of experts who will consider an “enhanced immunosuppression regimen” for Elevidys. The biotech is also temporarily halting Elevidys shipments for non-ambulatory patients until it has settled on a new immunosuppressive approach for these patients.
On the press call, Ingram and Rodino-Klapac discussed adding the immunosuppressant Sirolimus to the regimen, sharing data indicating that using Sirolimus did not affect Elevidys’ function. Ingram said that the company will have discussions with the FDA about updating Elevidys’ protocol to add Sirolimus.
Rodino-Klapac noted that Sirolimus is not itself without risks, and that it can increase the risk of infections.
“The attitude of the FDA on the mitigation strategy will be known when we have discussions with the FDA,” Ingram said. He emphasized the company is moving quickly to make changes, and will discuss the death with the DMD patient community at the upcoming Parent Project Muscular Dystrophy conference, starting on June 19 in Las Vegas.
“For Duchenne patients, time is muscle, we always say.”
Simultaneously, Sarepta has suspended dosing in its Phase III ENVISION study, which is testing Elevidys in both ambulatory and non-ambulatory patients with DMD. The freeze, which has been communicated to the FDA, will let Sarepta assess potential amendments to its protocol and to implement any improvements to the immunosuppressive regimen.
ENVISION is the designated confirmatory study that Sarepta will use to convert Elevidys’ accelerated approval into a full one.
While the suspended dosing can provide clarity on any potential future death risks, “it increases the uncertainty around regulatory implications for Elevidys,” according to BMO analysts, who also argued that it could have broader negative implications on the gene therapy space. “The second Elevidys death could increase the regulatory bar/scrutiny of investigational DMD gene therapies.”
Jefferies concurred, noting that this latest fatality “will strengthen the notion [that] a safety event is simply unpredictable with gene therapies, making it challenging to invest in this space.”
Gene therapies have been enduring a “cold winter” as of late, BlueRock Therapeutics CEO Seth Ettenberg told BioSpace earlier this month. Safety issues are a big part of the problem as deaths have been linked to several investigational therapies, including Rocket’s Danon disease asset, Neurogene’s Rett Syndrome treatment and Beam’s sickle cell disease gene editor.
