AAV mini-dystrophin gene therapy for Duchenne muscular dystrophy: a phase 1b trial.

Gene therapy represents a promising approach for Duchenne muscular dystrophy (DMD), a rare X-linked genetic muscle disease. Fordadistrogene movaparvovec (PF-06939926) is an adeno-associated virus serotype 9 gene therapy containing a miniaturized dystrophin being developed for DMD, which aims to restore functional protein to muscle. We present 1-year data from ambulatory and nonambulatory participants in a phase 1b, multicenter, single-arm, open-label trial. Pediatric ambulatory male participants with a genetic DMD diagnosis and receiving stable glucocorticoids received a single intravenous low-dose (n = 3) or high-dose (n = 16) fordadistrogene movaparvovec. The primary endpoint was safety and tolerability at 1 year after dosing. In the ambulatory group, mean ± s.d. age at dosing was 8.6 ± 1.6 years. The most common treatment-emergent adverse events in the ambulatory group were vomiting (n = 15), nausea (n = 10), thrombocytopenia (n = 9), pyrexia (n = 9), decreased appetite (n = 8), fatigue (n = 7) and headache (n = 7). Three treatment-related serious adverse events occurred after dosing (dehydration, acute kidney injury, thrombocytopenia; all resolved within 15 days). In a small nonambulatory group (n = 3), mean ± s.d. age at dosing was 15.1 ± 1.0 years. The most common treatment-emergent adverse events were nausea (n = 3), vomiting (n = 3) and headache (n = 3); two severe treatment-related adverse events (hemolytic uremic syndrome and fatal cardiogenic shock) were observed. In the high-dose ambulatory group, the secondary endpoint of mini-dystrophin quantification showed robust expression. Mean (95% confidence interval) percent of mini-dystrophin-positive fibers for baseline, 2 months and 1 year were 0.1% (0.1-0.2), 20.3% (12.2-29.3) and 34.8% (21.1-49.8), respectively. At the 1-year time point of primary completion, fordadistrogene movaparvovec demonstrated an acceptable safety profile in the ambulatory population. Larger trials are needed to assess the efficacy of the gene therapy in DMD. ClinicalTrials.gov registration no. NCT03362502 .