192PGNT0004, Genethon's AAV-based gene therapy for Duchenne muscular dystrophy: long-term follow-up of ambulatory boys enrolled in the dose-escalation phase of GNT-016-MDYF

GNT0004 is an AAV-8 based gene therapy, containing a shortened functional dystrophin gene (hMD1) with a Spc5.12 promoter, targeting skeletal and cardiac muscles for treating Duchenne muscular dystrophy (DMD). GNT0004 is being evaluated in the international all-in-one (phase 1/2/3) clinical trial GNT-016-MDYF, including a first-in-human dose escalation (Part 1), a placebo-controlled pivotal Phase 3 (Part 2), and a long-term follow-up (Part 3). Ambulatory boys with DMD, aged 6 to 10 years, with a stable or early decline in their North Star Ambulatory Assessment (NSAA) score are included. Participants are on stable corticosteroid treatment and have been followed for at least 6 months in the natural history (NH) study GNT-014-MDYF. Long-term data from Part 1 patients receiving Dose 2 (3 × 10¹³ vg/kg, selected for Part 2) are presented. A comparison with an external control group from the NH study was conducted to explore clinical efficacy. Five patients were enrolled in Part 1, three of whom received Dose 2. At week 8, biopsy results showed a mean of 53% hMD1-positive fibers at Dose 2. A significant decrease in serum creatine kinase (CK) levels was observed post-dose that remains persistently low from week 8 and up to 2 years. At one year, the mean CK level was 5,306 IU/L, representing a mean decrease of -68% compared to baseline (mean: 19,175 IU/L). Clinically, functional outcomes were stable or improving, clearly differentiating from the NH progression across all efficacy parameters (e.g., a delta of 4.7-point on NSAA scale and of 0.1 m/s on the Stride velocity 95th centile (SV95C) at one year). No serious adverse events reported at Dose 2. GNT0004 at Dose 2 was well-tolerated and provided long-term stabilization of the sarcolemma, as evidenced by persistent low levels of CK, with a clear clinical benefit. These effects will need to be confirmed in Part 2 with 64 DMD patients to be enrolled.