Genethon’s Gene Therapy GNT0004 Stabilizes or Improves Motor Functions in Patients With Duchenne Muscular Dystrophy
All 3 patients who received the high dose showed stabilization of motor function, as assessed by the 34-point North Star Ambulatory Assessment.
Genethon’s GNT0004, an investigational recombinant adeno-associated virus (AAV) vector-based gene therapy intended to treated Duchenne muscular dystrophy (DMD), has demonstrated the ability to stabilize or improve motor function in patients treated in the phase 1/2 portion of a phase 1/2/3 clinical trial.1
The phase 1/2 portion of the study treated 2 patients a lower dose level (1x1013 vg/kg) and 3 patients at a higher dose level (3x1013 vg/kg). The patients were aged between 6 and 10 years old.
All 3 patients who received the high dose showed stabilization of motor function, as assessed by the 34-point North Star Ambulatory Assessment, at 1 to 2 years posttreatment. Notably, 1 of these patients showed improvement with a maximum score of 34 recorded 12 months after dosing. This improvement was later confirmed at the 18 month time point. By contrast, untreated patients followed in a natural history studied being carried out by Genethon showed a rapid decline in motor function over the same course of time.
Furthermore, in the patients treated at the high dose in the trial, 15% to 85% (mean, 54%) of muscle fibers showed expression of microdystrophin as measured via immunohistochemistry at 8 weeks posttreatment. In addition, 0.4 to 2.4 (mean, 1.2) vector genome copies per muscle fiber nuclei were reported at the same time point. At 12 weeks posttreatment, levels of the biomarker creatine phosphokinase had dropped by 50% to 87% (mean, 74%). This drop was sustained at up to 18 months posttreatment for the first 2 patients treated in the higher dose group.
With regard to safety, GNT0004, which was administered in conjunction with transient immunological prophylaxis, was deemed to be tolerated well. In light of the promising safety and efficacy results, Genethon plans to enroll patients in the trial’s pivotal portion in the United States and Europe in the middle of next year.
“The results of treatment with our GNT0004 gene therapy are very positive in patients treated at the higher of 2 doses, both in terms of microdystrophin expression and clinical improvement,” Frederic Revah, PhD, the chief executive officer of Genethon, said in a statement.1 “In addition, the strength of our product lies in this selected dose, which is lower than those used in other gene therapy trials for DMD. GNT0004 has the potential to be the best-in-class curative gene therapy for DMD. These clinical resultsdemonstrate that gene therapy can provide solutions to one of the most complex genetic diseases. Our aim is to start the confirmatory (pivotal) phase in more than 60 children in Europe in the second quarter of 2025, followed by the US.”
Four of the 5 patients treated in the study thus far were treated in France, and 1 patient was treated in the United Kingdom.2 The study, which originally launched in 2021, resumed in 2022 after having been paused in relation to a serious adverse event (SAE) that occurred in the first patient dosed. The resumption of the trial commenced after the SAE resolved.
Besides GNT0004, Genethon is also developing GNT-003 (GNT0003), an investigational AAV vector-based gene therapy for the treatment of Crigler-Najjar syndrome.3 Results from a phase 1/2 clinical trial (NCT03466463) reported in The New England Journal of Medicine in August 2023 showed that patients with the rare liver disease who received the trial’s higher dose (n = 3; 5×1012 vg/kg) experienced a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration.
“Although our study is small, among the patients who received the dose of 5×1012 vg/kg, GNT0003 restored UGT1A1 activity to levels that permitted suspension of phototherapy, and the efficacy persisted at 18 months after the treatment,” study author Lorenzo D’Antiga, MD, of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, in Bergamo, Italy, and colleagues wrote.4 “A test of replication in a larger, well-characterized cohort of patients will be important.”
