Sustained Gains for DMD Boys Evident in SRP-9001 Trials: Sarepta

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

A pair of hands, a stethoscope and a handful of pills surround a graph showing measured improvements in a clinical trial.

New data across clinical trials of SRP-9001 show the investigative gene therapy induces sustained functional improvements in people with Duchenne muscular dystrophy (DMD), and does so with good tolerability, Sarepta Therapeutics, its developer, announced.

The company, in presenting these data, also offered more details about the recently launched and pivotal Phase 3 EMBARK trial.

“With 77 patients treated to date, the multi-study development program for SRP-9001 represents the most comprehensive and long-term dataset for a Duchenne muscular dystrophy gene therapy in existence,” Doug Ingram, president and CEO of Sarepta, said in a press release.

“We commence our EMBARK pivotal trial — currently the only truly global Phase 3 trial with a Duchenne gene therapy — with great conviction in the transformative potential of SRP-9001,” Ingram added.

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Pivotal Trial of DMD Gene Therapy SRP-9001 Launches Globally

SRP-9001 uses a harmless virus to deliver the gene encoding micro-dystrophin directly to muscle cells for targeted production of a micro-dystrophin protein. In Duchenne, mutations in the DMD gene results in little or no dystrophin protein production, affecting muscles, but the gene’s large size necessitated a “micro” version.

The gene therapy candidate is being evaluated in three separate trials, and will be further tested in the Phase 3 study.

The proof-of-concept Phase 1/2 study, called Study 101 (NCT03375164), is following four DMD boys, ages 4–7 at enrollment, for five years to assess the therapy’s safety and efficacy over time. All were treated with a single infusion dose of SRP-9001, and the trial is due to conclude in April 2023.

These children are also being evaluated for changes with treatment in micro-dystrophin levels, in the North Star Ambulatory Assessment (NSAA) total scores (a 17-item test of motor abilities in Duchenne patients), as well as in the 100-meter timed test.

New data showed that patients’ NSAA scores had improved by 8.6 points over the three years since being given SRP-9001, when compared with a matched natural history patient group. The natural history study follows a disease’s course in the absence of investigative treatment.

“When compared to a matched natural history cohort, individuals with Duchenne who received SRP-9001 are performing better on the NSAA or showing stabilization of NSAA scores where we would expect to see a decline,” said Louise Rodino-Klapac, PhD, an executive vice president and chief scientific officer at Sarepta.

In the double-blind and two-part Phase 2 trial, called Study 102 (NCT03769116), 41 boys with DMD, ages 4 to 7, were randomized to a single infusion of SRP-9001 or a placebo. Part one’s main goals were micro-dystrophin gene expression at 12 weeks, and changes from baseline (study start) in NSAA total scores at 48 weeks (about one year).

Results reported earlier showed a greater improvement in the total NSAA score among treated boys ages 4 to 5, relative to the placebo group for this age.

New data presented covered changes in NSAA scores for the 12 boys treated at ages 6 and 7. These scores showed a  a 2.9-point difference from baseline at 48 weeks compared with a matched natural history cohort, Sarepta said.

In part two of Study 102, now underway, patients originally assigned to a placebo are given SRP-9001 and similar assessments. All are continuing to be evaluated for treatment safety as well as efficacy, with this trial due to end in April 2026.

The open-label Phase 1 ENDEAVOR (NCT04626674), being conducted with Roche, enrolled 32 DMD patients: 20 boys, ages 4–7, and 12 older patients, both ambulatory (able to walk) and non-ambulatory. All are being given a single infusion of a commercially manufactured version of SRP-9001, and evaluated for five years for changes from baseline in micro-dystrophin protein levels, and treatment safety. Changes in motor skills are exploratory endpoints (goals).

The first 11 boys treated showed a significant 3.0-point improvement in NSAA scores at six months, compared with their baseline scores, new data showed.

“The functional results from Study 103 [ENDEAVOR] … provide additional confidence in our ability to confirm a treatment effect with SRP-9001 as we advance our pivotal Phase 3 trial,” Rodino-Klapac said.

SRP-9001’s safety and tolerability profile across these studies continues to be similar to past reports, Sarepta reported. Treatment-related adverse events observed generally occurred within 90 days of treatment and resolved; the most common was vomiting, usually within the first week post-infusion.

EMBARK, the global, double-blind and placebo-controlled Phase 3 trial, also being run in collaboration with Roche, plans to enroll 120 Duchenne patients, ages  4–7, at sites largely in the U.S., Europe, and Asia. At least half of all enrolled will be ages 4 to 5, and patients will be stratified according to their age and NSAA scores at the study’s start.

Its primary endpoint will be changes from baseline in NSAA total scores at one year (week 52) in treated patients compared with those given a placebo. Secondary trial goals include the number of skills gained or improved with treatment, as measured by NSAA, at week 52; micro-dystrophin levels at week 12; timed function tests; and safety assessments of  SRP-9001, again in a commercially manufactured version.

A two-part trial, like Study 102, EMBARK’s first part will be a comparison of treatment and placebo groups for 52 weeks. Its second part will remained blinded, but all those previously in the placebo arm will be treated with SRP-9001 as a single infusion; safety and efficacy evaluations will continue for an additional 52 weeks.

So far, “the totality of evidence shows that SRP-9001 is a significantly differentiated gene therapy product candidate with one-time dosing and a stable tolerability profile, results in robust expression and evidence of sustained functional benefits across our various studies,” Ingram said.

“Sarepta, along with our partner Roche, will continue working with tenacity and urgency to bring this potentially transformative treatment to individuals with Duchenne around the world,” Ingram added.

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