#MDA2021 – Gene Therapy SGT-001 Shows Continued Benefit in DMD Boys

Editor’s note: The Muscular Dystrophy News Today team is providing in-depth coverage of the 2021 MDA Virtual Clinical and Scientific Conference, March 15–18. Go here to read the latest stories from the conference.

The investigational gene therapy SGT-001 continues to lead to improvements in physical functioning, disease-related biomarkers, and patient-reported outcomes in boys with Duchenne muscular dystrophy (DMD), according to interim data from the IGNITE DMD trial. 

No new therapy-related safety concerns were reported in six boys now up to 37 months (over three years) post-dosing.

These findings were presented at the 2021 MDA Virtual Clinical & Scientific Conference in an oral presentation, “Phase 1/2 ascending dose study of single IV infusion of SGT-100 microdystrophin gene therapy for DMD: One-year efficacy and safety results.”

“The totality of the functional and biomarker data, as well as the patient-reported outcome measures, reported today suggest that SGT-001 may provide benefit to patients with Duchenne, a serious disease for which there is no cure,” Barry Byrne, MD, PhD, the principal investigator of IGNITE DMD who gave the presentation, said in a press release.

“I am particularly encouraged by these early data when compared with the natural history of this disease,” Byrne, director of the Powell Gene Therapy Center at the University of Florida, added. “I look forward to the continued enrollment in IGNITE DMD and evaluating the data as the study progresses.”

SGT-001 is designed to deliver a gene that carries the instructions for the protein microdystrophin — a shorter but functional version of dystrophin which missing in Duchenne patients. The delivery carrier is a modified and harmless adeno-associated virus (AAV) that specifically targets muscle cells. 

IGNITE DMD (NCT03368742) is a Phase 1/2 trial evaluating the safety and preliminary effectiveness of SGT-100, by Solid Biosciences, in boys with DMD, ages 4 to 17. All are being given a single infusion of the therapy directly into the bloodstream, and then are followed for about five years.

Participants, currently being recruited at four sites in the U.S., include children who can walk as well as adolescents who are unable to walk 10 meters without assistance. 

Primary outcomes include safety evaluations, and changes in microdystrophin protein production (expression) measured by muscle biopsies. Functional tests are also being conducted, and include lung function assessments, the 6-minute walking test — 6MWT, which refers to the distance walked in six minutes — and the North Star Ambulatory Assessment (NSAA) of motor abilities.

Data presented at MDA 2021 were collected between one and two years after three boys received a one-time dose of 5e13 vector genomes (vg)/kg, and three more received a higher dose of 2e14 vg/kg. Results in these six children were compared with three patients in a delayed treatment group, included as untreated controls, and data representing the disorder’s natural history (progression in the absence of treatment).

NSAA scores at one year in both high- and low-dose groups suggest treatment benefits compared with natural history data. Patients in the untreated control group showed a mean decline of 4.0 points from study start (baseline) to one year, while those in the low-dose group showed a mean improvement of 1.0 point. Boys in the high-dose group had a mean improvement of 0.3 points as compared to baseline.

Control group patients demonstrated a decline of 8.5 meters in the 6MWT from baseline to one year. In contrast, low-dose patients improved by 37 meters and those at high dose improved by 49.7 meters over that same year, both groups being above the accepted minimally clinically important difference of 30 meters. 

Untreated controls also exhibited a mean decline in lung function of 10.7% at one year (as assessed by a measure called forced vital capacity), compared to a 3.9% improvement in low-dose participants and 16.7% in the high-dose group.

Biopsies of skeletal muscle taken three months after SGT-001 infusion at a high dose showed the widespread distribution of microdystrophin-positive muscle fibers at about 10% of normal levels. 

In this same group, there was an average sustained decline of about 50% in creatine kinase levels  — a marker of muscle injury — which “suggests improved integrity of the muscle fibers and a potential protective effect of the treatment,” said Byrne. 

Benefits were also evident in patient-reported outcomes that assessed how caregivers and boys evaluated patients’ ability to walk, stand, and perform daily living and recreational activities. Interviews with patients and caregivers favored an overall improvement in functional and school-related activities, with a subjective decrease in fatigue seen in all treated boys.

“Boys with Duchenne rarely run, so it’s been very rewarding to hear from families when these newfound abilities to run and other skills have led to the ability to participate in sports or even ride a bike,” Byrne said. 

The most common treatment-related adverse events were reported early after dosing, and included nausea and vomiting. Two serious adverse events occurred due to the activation of the complement system, part of the immune system that enhances the ability to clear microbes. 

Two additional serious events included a case of immune attack against the liver, resolved rapidly with corticosteroids, and another unrelated to SGT-001. Others included low platelets and red blood cells, as well as kidney injury in two participants. All serious events were resolved, and the researchers saw no new treatment-related safety findings 17 to 37 months post-dosing.

Based on these serious side effects, the U.S. Food and Drug Administration (FDA) had placed a second clinical hold on IGNITE DMD until Solid amended the trial’s protocol, the therapy’s manufacturing processes, and provided more data. Based on a satisfactory response, the FDA lifted the hold, and now a seventh patient has been dosed with manageable adverse events, none of which were serious. 

“We are encouraged with the successful resumption of dosing in the IGNITE DMD trial under our amended clinical protocol and using SGT-001 manufactured with a second-generation process,” said Ilan Ganot, Solid’s CEO. “The safe dosing of the seventh patient gives us increased confidence in our dosing strategy as we move forward with clinical development in the IGNITE DMD clinical trial.” 

“We are grateful to this patient and his family, and to all those who choose to participate in clinical trials,” he added. “We look forward to continuing to dose patients and reporting clinical outcomes from additional patients in the second half of 2021.”