Commercial-Scale SRP-9001 Shows Robust Results in DMD

Doug Ingram

SRP-9001 manufactured with commercial materials demonstrated robust transduction efficiency and high gene expression levels in the first 11 patients with Duchenne muscular dystrophy (DMD) treated in the phase 1 ENDEAVOR trial, according to 12-week topline findings announced by Sarepta, the developer of the microdystrophin-encoding gene therapy.

In the study, SRP-9001 transduced a mean 3.87 vector genome copies per nucleus. At the 12-week analysis, the mean microdystrophin expression was 55.4% of normal levels as measured by western blot. The therapy also demonstrated similar safety with the commercial materials as in previous studies using prior materials.

“We are delighted by these seminal results from the ENDEAVOR study, our first trial results with SRP-9001 made by our commercial-scale manufacturing process," Doug Ingram, president and chief executive officer, Sarepta, said in a statement. "These data show strong transduction of the microdystrophin gene, resulting in robust expression of the properly localized microdystrophin protein, and did so with no new or unexpected safety signals."

SRP-9001 utilizes an rAAVrh74 vector with a MHCK7 promoter, which targets the therapy to the skeletal muscles where it encodes a micro version of the dystrophin gene that is lacking in patients with DMD. Prior studies exploring the agent have utilized standard laboratory processes whereas the ENDEAVOR study looked at commercial processes and manufacturing, to simulate a real-world setting.

“In addition to characterizing and differentiating SRP-9001, these results confirm the extraordinary work done over the last 2 and a half years to build an at-scale gene therapy manufacturing process and corresponding analytics sufficient to meet the needs of the Duchenne population with what we believe will be a potentially life-changing therapy," said Ingram. "Armed with these data, we will seek a meeting with the FDA with the goal of rapidly starting our registrational study.”

The open-label phase 1 study enrolled 20 patients between the ages of 4 and 7 with DMD. SRP-9001 was administered as a single IV infusion at 1.33x10^14 vg/kg. For the topline analysis, muscle biopsies with 12 weeks of follow-up were available for 11 patients. The remainder of patients continue to be followed until the 12-week mark.

At baseline compared with normal biopsies, dystrophin was expressed on a mean 12.8% of muscle fibers with sarcolemma intensity of 41%. On the muscle biopsies at 12-weeks, dystrophin expression improved to a mean of 70.5% in muscle fibers (P = .001), with an intensity of 116.9% at the sarcolemma (P = .002).

There were no cases of complementary activation noted across the 11 patients. Two patients experienced serious adverse events, which included transaminase elevation in one and nausea and vomiting in the other. Both events fully resolved.

Earlier in the year Sarepta released findings for 41 patients with DMD from part 1 of study 102. In this study, SRP-9001 manufactured with prior methods was compared with placebo. In those who received SRP-9001, the mean micro-dystrophin expression was 28.1%, as measured by western blot, which met 1 of the co-primary end points of the study. For the second co-primary end point, there was an increase in North Star Ambulatory Assessment with SRP-9001; however, it did not meet statistical significance.