#MDA2022 – DMD Gene Therapy PF-06939926 Safe at High Dose: Trial
Treatment with PF-06939926, an experimental gene therapy for Duchenne muscular dystrophy (DMD), was generally well-tolerated among ambulatory patients — boys able to walk — in a Phase 1B clinical trial.
Data also hint at the efficacy of the gene therapy, being developed by Pfizer, with researchers noting that PF-06939926 slowed the decline of motor function among trial participants.
The findings were shared at the Muscular Dystrophy Association (MDA) 2022 Annual Meeting, in a presentation titled “One Year Data From Ambulatory Boys in a Phase 1B, Open-label Study of Fordadistrogene Movaparvovec (PF-06939926) for Duchenne Muscular Dystrophy (DMD).” The study was sponsored by Pfizer.
Russell Butterfield, MD, PhD, an associate professor in the departments of neurology and pediatrics at the University of Utah, who presented the data, said the findings support further clinical development of PF-06939926.
The Phase 1B clinical trial (NCT03362502) is being conducted by Pfizer to test the gene therapy’s safety in boys with DMD.
DMD is caused by mutations in the gene that provides instructions for making dystrophin, a protein that is critical for muscle health. PF-06939926, also known as fordadistrogene movaparvovec, is designed to deliver a gene encoding mini-dystrophin — a shortened, but functional version of the dystrophin protein — to muscle cells in the body using a specially engineered viral vector.
The study enrolled 19 boys, ages 4 to 12, who were ambulatory (able to walk) and were on a stable regimen of corticosteroids. All but three participants were white. The first three boys were treated with the experimental therapy at a low dose, and the remaining 16 got a high dose (1E14 or 2E14 vector genomes per kilogram).
Based on muscle biopsy data, all of the boys in the study had virtually no dystrophin expression (activity) at the beginning of the trial — which is typical in DMD. At two months after receiving PF-06939926, the mean levels of dystrophin were about 22% of normal in the high-dose group. At one year after treatment, dystrophin levels were approximately 40% of normal in these patients’ muscles. The percentage of dystrophin-positive muscle fibers similarly increased.
“We saw robust expression [of dystrophin] in the muscle biopsies for these ambulatory participants,” Butterfield said.
Motor function in the study was measured with the North Star Ambulatory Assessment (NSAA), in which higher scores represent better function.
One year after treatment with the gene therapy, the median change in the NSAA score for trial participants was a one-point increase, indicating stable or slightly improved symptoms. As a comparison, a group of 66 clinically and demographically similar participants who were given a placebo in prior clinical trials showed a four-point decrease in their median NSAA score over the same time period.
Put another way, 74% of PF-06939926-treated patients had stable or improving NSAA scores over the course of one year in the trial. In the comparison untreated patients, 3o% had stable or improved NSAA scores after one year.
Other measures of physical function have generally shown similarly beneficial trends.
“The functional assessments at the one-year follow-up are consistently trending toward benefit,” Butterfield said.
Butterfield noted that boys ages 8 and younger tended to see a more pronounced benefit from the gene therapy, in terms of NSAA scores, compared with older participants.
Safety data for the experimental gene therapy were generally positive. Over a median follow-up period of 18 months, three participants experienced three serious adverse events (side effects) related to treatment: dehydration, acute kidney injury, and low levels of platelets in the blood, called thrombocytopenia. All of these adverse events occurred within the first few weeks after dosing with PF-06939926, and all of them resolved within about two weeks.
“These preliminary results indicate that [PF-06939926] has an acceptable safety profile, and potential to benefit ambulatory patients with Duchenne muscular dystrophy by slowing or preventing loss of function,” Butterfield concluded.
The trial is currently scheduled to run through May 2028.
Note: The Muscular Dystrophy News Today team is providing coverage of the 2022 MDA Clinical and Scientific Conference March 13–16. Go here to see the latest stories from the conference.