Sarepta Reports DMD Gene Therapy Shows Statistically Significant Functional Improvements

Sarepta Therapeutics said topline results from Part 2 of its study SRP-9001-102, an ongoing, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, efficacy and tolerability of a single dose of its gene therapy for the progressive neuromuscular condition Duchenne muscular dystrophy, showed statistically significant functional improvements in patients.

Duchenne muscular dystrophy (DMD) is a rare, fatal neuromuscular genetic disease that occurs in approximately one in every 3,500-5,000 males worldwide. DMD is caused by a change or mutation in the gene that encodes instructions for dystrophin. Symptoms of DMD usually appear in infants and toddlers. Affected children may experience developmental delays such as difficulty in walking, climbing stairs or standing from a sitting position. As the disease progresses, muscle weakness in the lower limbs spreads to the arms and other areas. Most patients require full-time use of a wheelchair in their early teens, and then progressively lose the ability to independently perform activities of daily living such as using the restroom, bathing and feeding. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and patients usually succumb to the disease in their twenties.

SRP-9001 (delandistrogene moxeparvovec) is an investigational gene transfer therapy intended to deliver the micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein. Sarepta is responsible for global development and manufacturing of SRP-9001 and plans to commercialize SRP-9001 in the United States upon receiving FDA approval.

In December 2019, Roche partnered with Sarepta to combine Roche’s global reach, commercial presence and regulatory expertise with Sarepta’s gene therapy candidate for Duchenne to accelerate access to SRP-9001 for patients outside the United States. Sarepta has exclusive rights to the micro-dystrophin gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital.

Study SRP-9001-102 (Study 102) is a double-blind, 1:1 randomized, placebo-controlled clinical trial of SRP-9001 in 41 participants with Duchenne muscular dystrophy between the ages of 4 to 7. Study 102 uses clinical process SRP-9001 material and has two primary endpoints: micro-dystrophin expression at 12 weeks and change in NSAA total score at 48 weeks compared to placebo.

Secondary endpoints include certain timed functional tests; micro-dystrophin expression measured by immuno-fluorescence fiber intensity; and micro-dystrophin expression measured by immuno-fluorescence percent dystrophin positive fibers. In Part 1, results from the treatment and placebo groups were compared through 48 weeks following treatment. In Part 2, the study remained blinded to the participants and investigators, while all participants in the placebo group crossed over to active treatment and all participants were followed for another 48 weeks while safety and efficacy were evaluated. Participants will be evaluated for five years total after treatment.

SRP-9001-treated participants from the placebo crossover group scored a statistically significant 2.0 points higher on the mean North Star Ambulatory Assessment at 48 weeks compared to propensity-score weighted external controls. Mean NSAA scores from these Part 2 participants improved 1.3 points from baseline for the SRP-9001 treated group and the NSAA scores in the external control group declined 0.7 points from baseline. Additional results will be shared at a future medical congress. The NSAA is a 17-item rating scale that is used to measure functional motor abilities in ambulant individuals with Duchenne. It is used to monitor the progression of the disease and treatment effects which makes it suitable as an endpoint in clinical trials for Duchenne.

The external control used a prospectively defined consolidated comparison group of Duchenne patients, matched for variables including age, steroid usage, baseline NSAA and timed function tests with the participants in Study 102. The prospectively defined propensity score analysis allows for a robust balancing of the multiple variables.

The safety profile of patients treated in Part 2 of Study 102 is consistent with that seen in Part 1. There were no treatment-related serious adverse events, no deaths and no study discontinuations due to an adverse event. The most common treatment-related adverse event in patients treated in Part 2 was vomiting, similar to Part 1. For patients treated in Part 1, no new safety signals emerged after two years of follow up.

Study 102 remains ongoing, and all participants continue to be monitored for safety in addition to longer-term assessments of functional outcomes.

“Study 102, Part 2 results add to the totality of evidence for SRP-9001 generated thus far ‒ with promising results across multiple clinical trials and more than 80 patients dosed, encompassing a wide range of phenotypes as well as the oldest and heaviest Duchenne patients to be dosed with a full body AAV gene therapy infusion to date,” said Doug Ingram, president and CEO of Sarepta. “The totality of results that we have seen across our multiple trials bolsters our confidence in the potential disease-modifying benefits of this therapy and reinforces our conviction in the probability of success of EMBARK, our large, phase 3 placebo-controlled global study presently underway and dosing.” 

Photo: Doug Ingram, president and CEO of Sarepta

Author: Rare Daily Staff