The 12-person Dephi panel reviewed data from 3 clinical trials of delandistrogene maxeparvovec (SRP-9001; Sarepta), and developed considerations for the management of vomiting, myocarditis, acute liver injury, and immune-mediated myositis.
A set of consensus considerations for the management of relevant adverse events (AEs) related to the use of the investigational gene therapy delandistrogene maxeparvovec (SRP-9001; Sarepta Therapeutics) in the treatment of Duchenne muscular dystrophy (DMD) has been established by the Delphi panel, which reviewed data from 3 clinical trials of the therapy.1
The considerations were for a set of occurring AEs: vomiting, myocarditis, acute liver injury, and immune-mediated myositis. They were presented in a late-breaking session at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas, by Natalie L. Goedeker, CPNP, a neurology nurse practitioner in the Neuromuscular Division at Washington University in St. Louis.
The trials included in developing these considerations were Study 101 (NCT03375164; n = 4), Study 102 (NCT03769116; n = 41), and Study 103, also known as ENDEAVOR (NCT24626674; n = 40). The trials included a range of patients, including children as young as 3 years old and as old as 19 years, and both ambulatory and nonambulatory individuals with DMD.
Goedeker said in her presentation that the considerations were based on the trial experience to date. “The Delphi panel discussed these considerations that we want people to start thinking about. Again, these are things we had to think through in caring for these boys the last couple of years,” she said.
She further explained to NeurologyLive® that, “There really isn't much in the literature about the particular events and how to manage what happens to [those who experience] them. Those main events include vomiting, which occurred in over half of the boys who were dosed; acute liver injury, which occurred in just over one-third of cases, but it was rarely severe. There were 3 serious adverse events that were liver-related and product-related in the clinical trials—that’s discussing the clinical trials with a total of 85 boys dosed.
“There was 1 trial with myocarditis and 1 trial with immune myositis. We did 2 telephone interviews to try to get consensus on managing some of those events, and then we did a live meeting to hammer out the details. There were 12 people who participated [on the panel],” she continued.
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For vomiting, which was the most commonly occurring AE (reported in 61.2% of patients), the Delphi panel offered those patients and caregivers should provide immediate follow-up if post-treatment vomiting occurs, while physicians should offer antiemetics as needed, with a recommended switch to intravenous (IV) steroids if oral administration is not able to be tolerated or retained. In the trials, vomiting was reported to have occurred as early as the day of treatment infusion with delandistrogene maxeparvovec, but was transient, often resolving within weeks.
Acute liver injury occurred in 36.5% of those in the utilized data, with most cases occurring within 4 to 8 weeks post infusion. The observed cases generally resolved within 2 months of onset. The Delphi panel offered considerations for patients and caregivers to provide immediate follow-up upon onset of symptoms such as jaundice or abdominal pain, and that close monitoring of liver function should be initiated, to be increased as clinically indicated.
“Further treatment considerations [for acute liver injury] depend on the timeline and severity of their symptoms, and the severity of the lab changes, but include optimizing the steroid regimen, whether that be increasing the oral steroids for certain situations—again, the boys have to be tolerating the oral steroid dosing—or the use of IV steroids depending on the circumstances,” Goedeker said. “Further workup and consultation with a hepatologist may also be considered.”
For the management of myocarditis, was reported by only a single patient (1.2%), though troponin I elevation was reported by other patients within the first week post infusion. Most of these cases resolved within 4 weeks. In this instance, the panel recommended informing patients and caregivers to follow-up immediately when symptoms such as chest pain or shortness of breath occurred, and monitoring of troponin levels by the clinician. The treatment considerations, Goedeker explained, should be based on the duration and severity of such elevations and symptoms, with steroid optimization to follow and suggestions for ECG, ECHO, and cMRI when necessary. Consultation with a cardiologist might also be considered, she said.
Finally, for immune-mediated myositis, which also occurred in 1 patient (1.2%), the panel recommended patient-caregiver follow-up when experiencing severe muscle weakness, hypophonia, dysphasia, and/or dyspnea. Physcial and laboratory monitoring of these symptoms should also be considered. Treatment for this AE may include targeted immunosuppressant therapy, steroid optimization, and other interventions when deemed clinically appropriate. In instances of immune-mediated myositis, a consultation with an immunologist was also recommended by the group.
Some of the limitations of the Delphi panel’s approach included a potential bias based on panelist selections, the exclusion of global perspectives in these considerations, and the absence of the patient/caregiver viewpoint, Goedeker explained. “But, overall, these do address some lack of available data and provide some insight on patient management of potential adverse events that could arise with treatment with gene therapies,” she said.
The Sarepta product is an investigational rAAV-based gene therapy designed to counterweigh missing dystrophin in DMD by delivery of a transgene encoding an engineered protein. Sarepta’s biologics license application (BLA) for the treatment is set for review by May 29, 2023, and just recently, the FDA determined that it would hold an advisory committee on the BLA,2 which was a change in plans based on what was communicated to Sarepta at the midcycle meeting.3
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