Delandistrogene Moxeparvovec Gene Therapy in Individuals With Duchenne Muscular Dystrophy: Evidence in Focus: Report of the AAN Guidelines Subcommittee.

This Evidence in Focus reviews the current evidence on the efficacy and adverse effects of delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy (DMD) and presents clinical considerations regarding use. The author panel systematically reviewed available clinical trial data on delandistrogene moxeparvovec in patients with DMD. The risk of bias was evaluated using the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. Six clinical trials were identified, of which 4 had peer-reviewed data available. From the 4 studies with available data (2 Class I and 2 Class III), exposure data are available on 134 boys, of which 128 are ambulatory and aged ≥4 to <8 years. Both Class I studies failed to meet the primary functional motor outcome as assessed by change in the North Star Ambulatory Assessment score. Several secondary functional motor outcomes demonstrated improvement in the treatment group with small effect sizes, not meeting statistical significance from hierarchical analysis. Corticosteroid dose exposure was higher in the treatment group in the first 12 weeks after infusion, potentially contributing to measured differences between groups. Safety outcomes were similar across studies with multiple treatment-related adverse events, including peri-infusion effects, immune myositis and myocarditis, thrombocytopenia, and liver toxicity. One death has been reported in an individual who was treated with delandistrogene moxeparvovec outside of a trial. Despite not demonstrating efficacy in its primary outcome, delandistrogene moxeparvovec has been approved by the US Food and Drug Administration (FDA) for use in boys with DMD. This decision was supported by the relative safety of the product and secondary outcome measures data in the phase 3 clinical trial. As the drug may now be actively prescribed in the United States and other countries after FDA approval, providers should be aware of the limitations of the treatment and the need to monitor for immune-related side effects including myocarditis, liver injury, and thrombocytopenia, which may require expanded clinical infrastructure. Additional clinical trials and careful collection of real-world evidence from treated patients will be essential to establish short-term and long-term effectiveness and inform understanding of benefits and risks of delandistrogene moxeparvovec across the lifespan.