DMD Boys Experience Biological, Functional Gains in SRP-9001 Study

The investigational gene therapy SRP-9001 safely leads to the production of a functional form of dystrophin in boys with Duchenne muscular dystrophy (DMD) — and to improvements in their motor abilities, according to top-line results of a Phase 2 trial.

However, following almost one year of the Sarepta Therapeutics treatment, functional improvements relative to a placebo were only statistically significant in younger boys ages 4 to 5, as reported in a press release.

Study 102 (NCT03769116) included 41 boys, ages 4 to 7, and assessed the efficacy and tolerability of a single dose of SRP-9001, given directly into the bloodstream, in comparison with a placebo.

SRP-9001 uses a harmless adeno-associated virus to deliver a shorter version of the DMD gene to muscle cells. Once inside the cell, the cell’s own molecular machinery “reads” the inserted gene and produces micro-dystrophin, a trimmed-down version of dystrophin, the protein missing in those with DMD.

One of the trial’s two main endpoints, or goals, were changes in the amount of micro-dystrophin produced — known as its expression — over 12 weeks, or about three months. The other goal was a change in North Star Ambulatory Assessment (NSAA) scores over 48 weeks, or nearly one year. The NSAA is a 17-item rating scale assessing motor abilities in DMD children who can walk independently.

Following 12 weeks of treatment, the group receiving SRP-9001 achieved a mean micro-dystrophin expression of 28.1%, thereby achieving the trial’s main biological goal.

In terms of the functional goal, NSAA scores were significantly higher, when comparing data at 48 weeks with the study’s start, in boys receiving SRP-9001. However, no difference was seen relative to the placebo group.

Notably, a pre-specified analysis among boys ages 4 to 5 (16 participants), also at 48 weeks, showed a statistically significant increase in the total NSAA score in boys receiving SRP-9001 relative to a placebo. The boys receiving the experimental therapy had an increase in that total NSAA score of 4.3 points, compared with 1.9 points among those taking the placebo.

According to Sarepta, differences in baseline characteristics — those measured at the study’s start — between the treatment and the placebo groups might account for the lack of a significant improvement in boys ages 6 to 7.

In fact, initial NSAA scores were not balanced when comparing boys randomly assigned to receive either a placebo or SRP-9001. That resulting in children with milder disease in the placebo group, Sarepta said. In contrast, the functional status of younger boys — those ages 4 and 5 — was similar between the two groups.

“We are very disappointed that the randomization process resulted in a significant imbalance in baseline NSAA scores … making the 6-7 age groups non-comparable and likely substantially contributing to the inability to achieve statistical significance,” said Doug Ingram, Sarepta’s president and CEO.

The trial met several secondary biological goals, including the percent of micro-dystrophin-positive muscle fibers, the number of viral copies per cell, and a reduction in creatine kinase, which is a measure of muscle damage.

No new safety concerns arose during the trial. Most (85%) of the boys receiving SRP-9001 experienced at least one side effect related to treatment, compared with 43% in the placebo group.

SRP-9001-related side effects were largely mild to moderate in severity (82%). Three participants in the treatment group experienced serious side effects. These consisted of rhabdomyolysis — a serious breakdown of muscle tissue — and elevation of a liver enzyme, suggesting liver damage. One boy in the placebo group experienced rhabdomyolysis, a serious syndrome due to a muscle injury.

Study 102 is expected to run through 2026 and remains blinded for now, meaning that neither the patients nor the researchers know which participant is receiving the treatment and which the placebo.

All 41 participants have entered what is called a crossover phase, in which boys switch from SRP-9001 treatment to a placebo and vice-versa. The investigators will continue to monitor all of the boys for safety during this phase. As before, the boys will have their micro-dystrophin production and other biological markers measured at 12 weeks, followed by analyses of longer-term functional assessments.

An extension period where all boys will receive SRP-9001 will then be conducted, for a total follow-up duration of five years.

“Study 102 reinforces our confidence in the potentially transformative benefits of SRP-9001,” Ingram said.

Sarepta also is planning or conducting several other clinical trials involving SRP-9001. Ingram said the company already has dosed the first 11 participants in the Phase 1 Study 103, called ENDEAVOR (NCT04626674, still recruiting at four sites in the U.S.), which evaluates the safety and expression of SRP-9001 over five years. The company expects to report biomarker and safety results from those patients later this year.

“We intend to continue to move forward with diligence and urgency to generate the evidence necessary to bring SRP-9001 to waiting Duchenne patients around the world,” Ingram added.