Sustained gains for Duchenne Boys evident in gene therapy trials


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

The company, in presenting this data, also provided more details on 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, long-term data set for gene therapy for Duchenne muscular dystrophy,” said Doug Ingram, president and chief executive officer of Sarepta, in a press release. Press release.

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

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SRP-9001 uses a harmless virus to deliver the gene encoding micro-dystrophin directly to muscle cells for the targeted production of a micro-dystrophin protein. In Duchenne, changes in the DMD The gene results in little or no production of the muscle-affecting dystrophin protein, but the large size of the gene required 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 phase 1/2 proof-of-concept study, called Study 101 (NCT03375164), follows four DMD boys, aged 4 to 7 years at the time of enrollment, for five years to assess safety and efficacy of therapy over time. All were treated with a single infusion dose of SRP-9001, and the trial is expected to end in April 2023.

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

New data showed that patients’ NSAA scores improved by 8.6 points in the three years since administration of SRP-9001, compared to a matched group of natural history patients. The natural history study follows the course of a disease in the absence of investigative treatment.

“Compared to a matched natural history cohort, people with Duchenne who received SRP-9001 either perform better on the NSAA or show stabilization in NSAA scores where we would expect to see a decrease,” said Louise Rodino-Klapac, PhD, executive. vice-president and scientific director of Sarepta.

In the double-blind, two-part phase 2 trial, called Study 102 (NCT03769116), 41 boys with DMD, ages 4 to 7, were randomized to receive a single infusion of SRP-9001 or a placebo . The main objectives of Part 1 were expression of the micro-dystrophin gene at 12 weeks and changes from baseline (study start) in total NSAA scores at 48 weeks (approximately one year).

Previously reported results showed greater improvement in the total NSAA score in treated boys aged 4 to 5 years, compared to the placebo group for that age.

The new data presented covered changes in NSAA scores for the 12 boys treated at 6 and 7 years old. Those scores showed a difference of 2.9 points from baseline at 48 weeks compared to a matched natural history cohort, Sarepta said.

In the second part of study 102, which is currently ongoing, patients initially assigned to placebo receive SRP-9001 and similar evaluations. All continue to be evaluated for the safety and effectiveness of the treatment, with the trial due to end in April 2026.

The open-label phase 1 ENDEAVOR study (NCT04626674), conducted with Roche, enrolled 32 DMD patients: 20 boys, aged 4 to 7 years, and 12 older patients, both ambulatory (able to walk) and not ambulatory. All receive a single infusion of a commercial version of SRP-9001 and are evaluated for five years for changes from baseline in microdystrophin protein levels and safety of treatment. Changes in motor skills are exploratory parameters (objectives).

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

“The functional results of the study 103 [ENDEAVOR] … Provide additional confidence in our ability to confirm a treatment effect with SRP-9001 as we progress through our pivotal Phase 3 trial, ”said Rodino-Klapac.

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

EMBARK, the global, double-blind, placebo-controlled phase 3 trial, also conducted in collaboration with Roche, plans to recruit 120 Duchenne patients, aged 4 to 7 years, at sites mainly in the United States, Europe and in Asia. At least half of all participants will be between 4 and 5 years old, and patients will be stratified based on their age and NSAA scores at the start of the study.

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

A two-part trial, like Study 102, the first part of EMBARK will be a comparison of the treatment and placebo groups for 52 weeks. His second part will remain blind, 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 body of evidence shows that SRP-9001 is a significantly differentiated gene therapy product candidate with a single dosage and a stable tolerability profile, results in robust expression and evidence of sustained functional benefit. in our various studies, ”Ingram said. .

“Sarepta, along with our partner Roche, will continue to work tenaciously and urgently to bring this potentially transformative treatment to people with Duchenne around the world,” Ingram added.

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