Durable Safety and Motor Gains Evident in Trial of SRP-9001, DMD Gene Therapy

A single dose of SRP-9001, Sarepta Therapeutics’ investigational gene therapy for  Duchenne muscular dystrophy (DMD), continues to be safe and to improve motor function in four boys treated two years ago, according to data from an ongoing Phase 1/2 trial.

Updated results from Study-101 (NCT03375164), as the trial is called, were presented by the company at the ongoing, virtual 25th International Annual Congress of the World Muscle Society.

“We continue to be encouraged by the safety profile and enduring treatment response that we have seen to date with SRP-9001 gene transfer therapy,” Doug Ingram, president and CEO of Sarepta, said in an accompanying press release.

SRP-9001 uses a harmless adeno-associated virus (AAV) vector called AAVrh74 to deliver a shorter version of the DMD gene. It allows muscle cells to produce a smaller but working form of dystrophin (called micro-dystrophin), the protein missing in DMD patients.

Two ongoing clinical trials — Study-101 and the Phase 2 Study-102 (NCT03769116) — are assessing the safety and effectiveness of a single dose of SRP-9001 in young boys with DMD.

Study-101 enrolled four boys, ages 4–7, who were able to walk by themselves but had high levels of creatine kinase, a marker of muscle damage. All were given a single infusion of SRP-9001 at a dose of 2×10¹⁴ vector genomes per kilogram (vg/kg).

One-year data from the trial found that one-time treatment to be safe, well-tolerated, and able to both induce the activity of the micro-dystrophin gene and increase levels of the resulting dystrophin protein in the boys’ muscle tissues. SRP-9001’s use also lowered the levels of creatine kinase and improved boys’ motor and muscle function, as assessed by a variety of tests.

New two-year data from Study-101 continue to show favorable safety and tolerability. All reported side effects were mild or moderate in severity, and occurred within the first three months of treatment. No activation of the complement system (part of the immune system) was evident in any of these patients.

An average 7-point increase in the boys’ North Star Ambulatory Assessment (NSAA) score from baseline (study’s start) was reported at two years post-treatment, an improvement on the 5.5-point gain seen at one year. The NSAA is a 17-item rating scale that assesses motor abilities in DMD children who are able to walk independently.

“The consistent results and functional improvements sustained over two years give us added confidence as we prepare for the results from Study 102, our randomized, double-blind, placebo-controlled study of SRP-9001,” Ingram said. “We continue to work with urgency to bring this potentially transformative treatment to patients as quickly as possible.”

Study-102 is assessing the safety and effectiveness of a single dose of SRP-9001 in 41 DMD children, ages 4 to 7. The trial includes an initial 48-week period in which SRP-9001 will be compared to a placebo, and a 96-week extension study. It is expected to conclude in October 2022.

The company recently completed a meeting with the Office of Tissues and Advanced Therapies, an arm of the U.S. Food and Drug Administration, in preparation for its next clinical trial of SRP-9001.

Sarepta also announced new data from Phase 1/2 trial (NCT03652259) assessing the safety and effectiveness of a single dose of SRP-9003, its experimental gene therapy for limb girdle muscular dystrophy (LGMD) type 2E, in six children ages 4–13.

SRP-9003 uses the same AAV vector as SRP-9001 to deliver a functional copy of the SGCB gene to muscle cells with the goal of increasing the levels of beta-sarcoglycan. This protein plays a key role in muscle integrity, and is found at low levels in people with LGMD2E.

During the study, children were divided into two groups of three. Those in the first group received a low dose of SRP-9003 (5×10¹³ vg/kg), and those in the second group were given a higher dose (2×10¹⁴ vg/kg).

One-year data from the three low-dose group children showed that SRP-9003 led to significant improvements in motor abilities. Treatment was also safe and well-tolerated.

In updated 18-month data, SRP-9003’s use continues to be safe and well-tolerated, with no new safety concerns identified. As previously reported, none of the low-dose children saw drops in their platelet counts or showed any signs of complement system activation.

All three also continued to show improvements in several functional outcomes measures, including the North Star Assessment for Dysferlinopathies (a 54-itemscale used to evaluate motor abilities), time-to-rise, four-stair climb, 100-meter walk test, and 10-meter walk test.

Sarepta also announced gains across functional measure at six months for the three children treated with SRP-9003 at the higher dose.  

This was the first report of functional outcomes for this treatment group. In a previous update in June, the company announced two-month data showing these children had a higher number of muscle fibers with beta-sarcoglycan than those from the low-dose group.

No new safety concerns have been identified in these three boys, including no cases of low platelet counts or complement system activation.

“The improvements in functional measures at 18- and 6-months in participants from both cohorts who received SRP-9003 are distinctly different from what an age-matched, natural history group would predict with LGMD2E. This sustained durability of the response in functional outcomes reinforces that SRP-9003 is getting to the muscle and suggestive of improvement against disease-mediated muscle damage,” Louise Rodino-Klapac, PhD, senior vice president of Gene Therapy at Sarepta, said in a press release.

“When coupled with the strong expression results and encouraging safety profile seen to date, today’s results increase our confidence in the construct and provide additional evidence as we advance the higher dose of SRP-9003 into the next stage of clinical testing,” Rodino-Klapac added.