AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial

Abstract

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.

Fig. 1. Patient disposition.

^aOne patient was enrolled in Japan as part of a regional extension and was too late for inclusion in the primary analysis.

Fig. 2. Primary endpoint and key functional secondary endpoints.

a, Forest plot showing the primary endpoint (change from baseline to week 52 in NSAA total score, points) and key functional secondary endpoints (change from baseline to week 52 in TTR, seconds, and change from baseline to week 52 in 10MWR, seconds) for delandistrogene moxeparvovec and placebo groups in the modified intent-to-treat population. LSMs (of change from baseline) and CIs were standardized by dividing by the s.e. LSM differences are on original scale (without s.e. adjustment). TTR and 10MWR signs were reversed in the forest plot to align favorable directions among endpoints. Numerical results of LSM difference kept the original signs. One patient in the placebo group had missing data at week 52; functional tests were marked as invalid by the clinical evaluator due to back pain from compression fractures. b, Line graph showing LSM change from baseline to week 52 in NSAA total score, points, for delandistrogene moxeparvovec (n = 63) and placebo (n = 61) groups in the modified intent-to-treat population. Data are presented as LSM values ± 95% CI. c, Line graph showing LSM change from baseline to week 52 in TTR, seconds, for delandistrogene moxeparvovec (n = 63) and placebo (n = 61) groups in the modified intent-to-treat population. Data are presented as LSM values ± 95% CI. d, Line graph showing LSM change from baseline to week 52 in 10MWR, seconds, for delandistrogene moxeparvovec (n = 63) and placebo (n = 61) groups in the modified intent-to-treat population. Data are presented as LSM values ± 95% CI. a–d, The widths of the CIs have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. Negative values for TFTs (TTR and 10MWR) show an improvement in the time taken to achieve these endpoints.

Fig. 3. Other functional endpoints—SV95C, 100MWR and time to ascend 4 steps.

a, Forest plot showing other functional endpoints (change from baseline to week 52 in SV95C, meters per second; 100MWR, seconds; and time to ascend 4 steps, seconds) for delandistrogene moxeparvovec and placebo groups in the modified intent-to-treat population. LSMs (of change from baseline) and CIs were standardized by dividing by the s.e. Numerical results of the LSMs are on original scale (without s.e. adjustment). Signs of TFTs (100MWR and time to ascend 4 steps) were reversed in the forest plot to align favorable directions among endpoints. Numerical results of LSM difference kept the original signs. SV95C: a small number of patients did not have sufficient recorded hours at week 52 for analysis; 100MWR and time to ascend 4 steps: a small number of tests at either baseline or week 52 were marked as invalid by the clinical investigator; the most common reason was due to behavior. b, Line graph showing LSM change from baseline to week 52 in SV95C, meters per second, for delandistrogene moxeparvovec (n = 57) and placebo (n = 61) groups in the modified intent-to-treat population. Data are presented as LSM values ± 95% CI. c, Line graph showing LSM change from baseline to week 52 in 100MWR, seconds, for delandistrogene moxeparvovec (n = 59) and placebo (n = 57) groups in the modified intent-to-treat population. Data are presented as LSM values ± 95% CI. d, Line graph showing LSM change from baseline to week 52 in time to ascend 4 steps, seconds, for delandistrogene moxeparvovec (n = 62) and placebo (n = 60) groups in the modified intent-to-treat population. Data are presented as LSM values ± 95% CI. a–d, The widths of the CIs have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. Negative values for TFTs (100MWR and time to ascend 4 steps) show an improvement in the time taken to achieve these endpoints.

Fig. 4. Delandistrogene moxeparvovec micro-dystrophin expression at 12 weeks after infusion in a subset of patients.

a, Delandistrogene moxeparvovec micro-dystrophin expression at week 12 as measured by western blot, percent normal (n = 17) and placebo (n = 14) groups in patients who had a muscle biopsy. Baseline data were not available as muscle biopsies were performed only at week 12. Each patient had two samples of biopsies taken, and all samples were analyzed. b, Representative western blots for delandistrogene moxeparvovec micro-dystrophin (left) and loading controls (right) from week 12 biopsies. Lane 1: DMD pool (negative control); Lanes 2–3: samples from placebo-treated patients; Lanes 4–5: samples from delandistrogene moxeparvovec–treated patients; Lanes 6–10: recombinant micro-dystrophin protein standard curve (21.85, 43.70, 87.39, 174.79 and 349.58 fmol mg⁻¹). The faint upper lower molecular weight bands are non-specific. The 137-kDa band denotes the presence of delandistrogene moxeparvovec micro-dystrophin and was quantified. Each patient had two samples of biopsies taken, and all samples were analyzed.

Fig. 5. Timeline of TR-SAEs in delandistrogene moxeparvovec–treated patients.

a, The timeline of events for the 10 TR-SAEs experienced by seven patients treated with delandistrogene moxeparvovec, detailing SAE symptom onset, hospital admission, hospital discharge and SAE resolution. See Extended Data Table 3 for a complete TR-SAE safety narrative. b, ^aGLDH increases were based on investigator assessment and their institution’s normal range. Shown are summaries of AEs, SAEs, TEAEs, TR-TEAEs, TR-SAEs, AEs leading to study discontinuation, deaths and TR-TEAEs occurring in more than 10% of patients. The safety population included all patients who received study treatment (excluding one patient enrolled under a regional addendum). Events are listed in descending order of frequency in the delandistrogene moxeparvovec group. AEs were classified according to the Medical Dictionary for Regulatory Activities.