Long-term follow-up of ambulatory boys treated with GNT0004, Genethon’s AAV-based gene therapy for Duchenne muscular dystrophy (DMD) in the phase 1/2

Topic:

Clinical Trials

Poster Number: 39 S

Author(s):

francesco Muntoni, MD, Hospital for Children Foundation Trust, London, UK, Vincent Laugel, MD, Hospital Hautepierre, Strasbourg, France, Jean Davion, MD, Pediatric neurology, Hospital of Lille, France, Silvana De Lucia, MD, Institut I-Motion, Hôpital Trousseau, 26 avenue du Dr Arnold Netter, Paris, France, Manon Sanz, PharmD, Genethon, 1bis rue de l'international, Evry France, Laurine Buscara, PhD, Genethon, Stephanie Blaie, PhD, Genethon, 1bis rue de l'international, Evry France, Marie-Astrid SAGOT, PhD, Genethon, 1bis rue de l'international, Evry France, Alexandra Barbier, Msc, Genethon, 1bis rue de l'international, Evry France, Estelle CREOFF, PhD, Genethon, 1bis rue de l'international, Evry France, Nathalie Daniele, PhD, Genethon, 1bis rue de l'international, Evry France, Eric Guemas, Msc, BIOSSEC, 9 rue Anatole de la Forge, 75017 Paris, France, Minh-Dan Barthelemy, PharmD, Genethon, 1bis rue de l'international, Evry France, Amanda Riviere, MSc, Genethon, 1bis rue de l'international, Evry France, Florence Masson, PhD, Genethon, 1bis rue de l'international, Evry France, Anne Gobert, Msc, Genethon, 1bis rue de l'international, Evry France, Marielle LELAIT, MSc, Genethon, 1bis rue de l'international, Evry France, Serge Braun, PharmD, Genethon, 1bis rue de l'international, Evry France, Arnaud Valent, MD, Genethon, 1bis rue de l'international, Evry France, fei cao, MD, Genethon, 1bis rue de l'international, Evry France, Gerald Perret, PhD, Généthon

GNT0004 is an AAV-8 based gene therapy for treating DMD, containing gene coding for a shortened functional dystrophin (hMD1) with a Spc5.12 promoter, targeting skeletal and cardiac muscles.
GNT0004 is being evaluated in the international all-in-one (phase 1/2/3) clinical trial GNT-016-MDYF, including a dose escalation (Part 1), a placebo-controlled pivotal Phase 3 (Part 2), and a long-term follow-up (Part 3).
Ambulatory DMD boys, aged 6 to 10 years on stable corticosteroid, with a stable or early decline in their North Star Ambulatory Assessment (NSAA) score and followed for at least 6 months in the natural history (NH) study GNT-014-MDYF were included.
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 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 remained persistently low for at least 18 months (mean CK: 19,175 IU/L at baseline; 4,037 IU/L at 18 months, representing a decrease of -79%). Clinically, functional outcomes were stable or improving, clearly differentiating from the mean NH progression across all efficacy parameters-for example, a delta of 4.7-point on NSAA scale (p <0.05) and of 0.1 m/s on the Stride velocity 95th centile at one year. These differences exceed their respective Minimal Clinically Important Difference. No serious adverse reactions were reported at Dose 2. GNT0004 at Dose 2 was well-tolerated, associated with persistent low levels of CK suggesting a long-term stabilization of the sarcolemma, and with better functional outcomes than NH patients. These effects need to be confirmed in the ongoing Phase 3 pivotal trial.