Investigational gene therapy shows benefits in two boys with DMD
Stable motor function sustained over long term during multiphase clinical trial
An investigational gene therapy called GNT0004Â has demonstrated sustained stabilization of motor function at up to two years of follow-up in two boys with Duchenne muscular dystrophy (DMD).
The boys received what was determined to be the effective dose of GNT0004, which was developed by Genethon, during the initial Phase 1/2 of a multiphase clinical trial named GNT-016-MDYF.
The new data were presented earlier this month at the annual meeting of the American Society of Gene and Cell Therapy (ASGCT), held in New Orleans. The oral presentation is titled “GNT0004, 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.
The first phase of the study was designed to assess the safety, tolerability, and early efficacy of two different dosing levels of GNT0004. Based on early clinical benefits and safety, the higher dose — 3×10¹³ vector genomes (vg)/kg — was selected for further evaluation in a pivotal Phase 3 trial that Genethon plans to launch by midyear in both Europe and the U.S.
Therapy delivers functional version of gene coding
DMD is caused by mutations in the DMD gene, which provides instructions to make dystrophin, a protein essential for maintaining the structural integrity of muscle fibers. Without functional dystrophin, muscle cells accumulate damage, ultimately leading to DMD symptoms like progressive muscle weakness and wasting.
Administered into the vein, or intravenously, GNT0004 uses a viral vector to deliver a shortened but functional version of the gene coding for dystrophin, called microdystrophin. The goal is to enable production of microdystrophin in muscle tissue and in the heart.
“The results of our gene therapy GNT0004 are very positive in patients treated at the dose of 3×10¹³ vg/kg, both in terms of microdystrophin expression and clinical efficacy criteria,” Frederic Revah, PhD, Genethon’s CEO, said in a company press release. “We are currently preparing the pivotal phase that we will conduct in Europe and the U.S.”
The ongoing Phase 1/2/3 clinical trial is evaluating GNT0004 in boys with DMD, ages 6 to 10, who can walk. In the Phase 1/2 portion of the study, two participants were treated with a lower dose, while three received the higher dose. The trial is ongoing in France and the U.K.
Previously reported results showed that eight weeks after infusion, the boys who received the higher dose showed microdystrophin protein expression in an average of 54% of muscle fibers. Levels of creatine phosphokinase (or creatine kinase), a blood marker of muscle damage, dropped by an average of 74% within 12 weeks and remained stably reduced through the 18-month follow-up in the first two patients who reached this timepoint. All three children treated at the effective dose showed improvements or stabilization in motor function.
Boys who received treatment showed improvement over untreated peers
Two-year data from the two patients treated at the effective dose who have reached this timepoint now show stabilization of motor function as assessed by the North Star Ambulatory Assessment (NSAA). The NSAA is a validated, 17-item functional scale specifically designed to evaluate motor abilities such as standing, running, climbing stairs, and rising from the floor in children with Duchenne.
One of these boys achieved the maximum NSAA score of 34 one year after treatment and maintained it through the two-year follow-up. This is in contrast with findings in untreated people with DMD, who typically experience a gradual worsening of motor abilities over time.
One year after receiving GNT0004, the boys had an average NSAA improvement of 4.7 points compared with 34 untreated, age-matched boys at the same clinical centers.
Levels of creatine phosphokinase remained stably reduced by more than 75% at 18 months, and this reduction was maintained through the two-year follow-up in the two patients with available data.
The therapy has also shown a favorable safety profile, with no serious adverse events reported at the selected dose.
“Besides these results, the advantage of our product lies in the selected dose for the pivotal phase, which is lower than those used in other gene therapy trials for Duchenne Muscular Dystrophy,” Revah said.
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