The Delphi panel considerations were informed by safety data from 3 clinical trials of the therapy, and included vomiting, myocarditis, acute liver injury, and immune-mediated myositis.
This content is coutesy of NeurologyLive, a sister publication. Click here to access the original article.
At the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas, a set of consensus considerations for the management of relevant adverse events (AEs) in Duchenne muscular dystrophy (DMD) related to the use of the investigational gene therapy delandistrogene maxeparvovec (SRP-9001; Sarepta Therapeutics) were presented.1
The Delphi panel considerations were informed by safety data from 3 clinical trials of the therapy. The considerations including the most commonly occurring AEs: vomiting, myocarditis, acute liver injury, and immune-mediated myositis. Natalie L. Goedeker, CPNP, a neurology nurse practitioner in the Neuromuscular Division at Washington University in St. Louis, presented the panel's assessment in a late-breaking session at MDA.
The trials included were Study 101 (NCT03375164; n = 4), Study 102 (NCT03769116; n = 41), and Study 103, also known as ENDEAVOR (NCT24626674; n = 40). These included children as young as 3 years old and as old as 19 years, and both ambulatory and nonambulatory individuals with DMD.
“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,” Goedeker said in her presentation. She told CGTLive™'s sister publication, 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."
“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.
WATCH NOW: Courtney Young, PhD, on Gene Editing Approaches to Treating Neuromuscular Disease
Vomiting was the most commonly occurring AE (reported in 61.2% of patients). The Delphi panel concluded that those patients and caregivers should provide immediate follow-up if posttreatment vomiting occurs, with antiemetics be used as needed. Additionally, they recommended switching to intravenous (IV) steroids if oral administration is untolerated or unable to be retained. 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, the second most common AE, occurred in 36.5% of patients, with most cases occurring within 4 to 8 weeks post infusion, generally resolving within 2 months of onset. The Delphi panel provided considerations that patients and caregivers should provide immediate follow-up when experiencing jaundice or abdominal pain, with close monitoring of liver function to be initiated and 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 in the presentation. “Further workup and consultation with a hepatologist may also be considered.”
The final 2 AEs were myocarditis—reported by only a single patient (1.2%)—and immune-mediated myositis—which also occurred in 1 patient (1.2%).
Although myocarditis was rare, troponin level elevation occured in others within the first week post infusion, though 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 for myocarditis 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, Goedeker explained. Consultation with a cardiologist might also be considered, she said.
For immune-mediated myositis, the panel recommended patient and caregiver follow-up upon the onset of severe muscle weakness, hypophonia, dysphasia, and/or dyspnea. Physcial and laboratory monitoring of these symptoms should also be considered, Goedeker said. Treatment can include targeted immunosuppressant therapy, steroid optimization, and other interventions, if deemed clinically appropriate. Similar to the other AEs, consultation with specialist—in this case, 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.
Additional data presented at MDA on the therapy included a comparison of functional data from patients with DMD and an external control cohort of patients that were propensity-score-weighted, whic suggests that the treatment results in a beneficial modification of disease trajectory.2
Those treated with the gene therapy experienced benefits on North Star Ambulatory Assessment (NSAA) total scores, 10-meter walk/run scores, and time to rise scores relative to the external control cohort. Treated patients received 1.33 x1014 vg/kg of delandistrogene moxeparvovec. All told, 1-year postbaseline, the functional analysis cohort (n = 52) showed a change of 2.3 points on the NSAA compared with a change of –0.1 points in the propensity-score-weighted cohort (n = 105) (least-squares mean ∆, 2.4; P <.0001).
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. The FDA recently determined that it would hold an advisory committee on the BLA.3
Click here for more coverage of MDA 2023.