Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 10¹⁴ vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (−0.64 (−1.06, −0.23)), 10-meter Walk/Run (−0.42 (−0.71, −0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (−3.29 (−8.28, 1.70)), time to ascend 4 steps (–0.36 (−0.71, −0.01)), PROMIS Mobility and Upper Extremity (0.05 (−0.08, 0.19); −0.04 (−0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (−0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by biallelic variants of the Survival Motor Neuron 1 gene (SMN1) that affects approximately 1 in 15,000 live births. Availability of 3 SMN-enhancing treatments for SMA has led to urgency to review how clinicians and patients use these treatments for SMA, while additional research and real-world data and experience are being collected. This work describes important factors to assist with decision-making for SMN-enhancing treatments. A systematic literature review was conducted on SMN-enhancing treatments for SMA and related studies. A working group of American and European health care providers with expertise in SMA care identified barriers and developed recommendations through a modified Delphi technique with serial surveys and feedback through virtual meetings to fill gaps for information where evidence is limited. A community working group of an individual living with SMA and caregivers provided insight and perspective on SMA treatments and support through a virtual meeting to guide recommendations. The health care provider working group and the community working group agreed that when determining whether to start, change, add, or discontinue a treatment, essential considerations include patient and family/caregiver perspective, and treatment safety and side effects. When initiating treatment for patients newly diagnosed with SMA, important patient characteristics are age and Survival Motor Neuron 2 gene (SMN2) copy number. Furthermore, when initiating, changing, or adding treatment, current clinical status and comorbidities drive decision-making. When considering a medication or treatment plan change, unless there is an urgent indication, a treatment and associated patient outcomes should be monitored for a minimum of 6–12 months. When determining a treatment plan with an adolescent or adult with SMA, consider factors such as quality of life, burden vs benefit of treatment, and reproductive issues. Access to care coordination and interdisciplinary/multidisciplinary care are essential to treatment success. Sharing information about current knowledge of treatments and shared decision-making between health care providers and patients living with SMA and caregivers are essential to overcoming barriers to providing SMN-enhancing treatments.