DMD Gene Therapy, SRP-9001, Showing ‘Robust’ Micro-dystrophin in Trial

Sarepta Therapeutics‘ investigational gene therapy SRP-9001 showed early signs of biologic efficacy in muscle biopsies from 11 boys with Duchenne muscular dystrophy (DMD) treated in a Phase 1 clinical trial, the company announced in a press release.

“Robust” expression of micro-dystrophin was evident in cells at 12 weeks post-treatment, and no new safety signals were reported.

“We are delighted by these seminal results … our first trial results with SRP-9001 made by our commercial-scale manufacturing process,” said Doug Ingram, Sarepta’s president and CEO.

Duchenne is caused by mutations in the DMD gene, which encodes a protein called dystrophin that is important for muscle function. SRP-9001 (rAAVrh74.MHCK7.micro-dystrophin) is designed to use an engineered viral vector to deliver a gene encoding micro-dystrophin — a shortened, but working version of the dystrophin protein — to muscle cells.

These new data come from the Phase 1 ENDEAVOR (NCT04626674) study, which Sarepta is sponsoring in collaboration with Roche. This open-label (no placebo group) trial aims to evaluate the safety and production of SRP-9001 in about 20 boys with DMD, ages 4 to 7, over the course of five years.

The trial is actively recruiting patients at four locations in the U.S.: University of California, Davis, California; Washington University in Saint Louis, Missouri; Nationwide Children’s Hospital in Columbus, Ohio; and Children’s Hospital of The King’s Daughters in Norfolk, Virginia.

Reported results are from the first 11 boys treated with SRP-9001, at a dose of 1.33e14 vector genomes (vg)/kg. Muscle biopsies from these patients were taken 12 weeks (about three months) after treatment.

The biopsies showed that the gene therapy led to “robust” expression of micro-dystrophin protein, according to Sarepta: mean levels were 55.4% of what is normal, as assessed by a technique called Western blot.

In addition, a mean of 70.5% of muscle fibers were expressing the protein, compared with a mean of 12.8% at pre-treatment (a baseline measure), and mean intensity at the sarcolemma (the membrane of muscle cells) was 116.9%, compared with 41% at baseline.  These findings suggest that SRP-9001 led to micro-dystrophin expression in the parts of muscle cells where the protein normally is found, and at levels more comparable to what is found in people without DMD.

The mean gene therapy vg copies per nucleus reached 3.87 in the biopsies, indicating the gene therapy is effectively getting into muscle cells.

Safety data to date from the trial have been consistent with earlier studies of the investigational therapy. Two patients experienced serious adverse events — nausea and vomiting in one, and abnormal levels of the liver enzyme transaminase in the other — that were fully resolved.

“These data show strong transduction [delivery to cells] of the micro-dystrophin gene, resulting in robust expression of the properly localized micro-dystrophin protein … Armed with these data, we will seek a meeting with the FDA [U.S. Food and Drug Administration] with the goal of rapidly starting our registrational study,” Ingram added.

Data from a previous Phase 2 clinical trial, called Study 102 (NCT03769116), suggested that the gene therapy could effectively induce micro-dystrophin expression in muscle cells and improve motor abilities. Significant gains in functional abilities, however, were only observed in younger participants (those 4 to 5 years old).

Sarepta reported at the time that the treatment and placebo groups for older boys, those 6 and 7 years old, lacked balance, and this might have been a reason post-treatment distinctions did not reach significance. Older children randomly assigned to placebo, it said, had milder disease than did those assigned to treatment.