Rare Daily Staff

Sarepta Therapeutics reported new analyses and functional data from its SRP-9001 gene therapy development program for the treatment of Duchenne muscular dystrophy.

In new analyses presented at “SRP-9001 Micro-dystrophin Day,” results from four participants age 4 to 7 treated with SRP-9001 in Study SRP-9001-101 found that participants improved 8.6 points on the North Star Ambulatory Assessment (NSAA), a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne, compared to a matched natural history cohort three years following a single administration of SRP-9001.

In Study SRP-9001-102, SRP-9001-treated 12 participants ages 6 to 7 had a positive 2.9-point difference on NSAA change from baseline compared to a matched natural history control.

In addition, the first functional results were presented from Study SRP-9001-103 (ENDEAVOR), which uses commercially representative SRP-9001 material. Results from the first 11 participants in Cohort 1, ages 4 to 7, demonstrated a 3.0-point improvement from baseline on NSAA six months after treatment.

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.

“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. 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,” said Doug Ingram, president and CEO of Sarepta.

SRP-9001 is an experimental gene transfer therapy intended to deliver the micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein. It is being developed in partnership with Roche to accelerate regulatory approval and commercialization outside the United States. Sarepta is responsible for global development and manufacturing for SRP-9001 and plans to commercialize SRP-9001 in the United States upon receiving FDA approval. Sarepta has exclusive rights to the micro-dystrophin gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital.

“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. The functional results from Study 103, as early as 6 months following treatment, provide additional confidence in our ability to confirm a treatment effect with SRP-9001 as we advance our pivotal phase 3 trial,” said Louise Rodino-Klapac, executive vice president and chief scientific officer of Sarepta. “Given our experience with the AAVrh74 vector in more than 80 individuals with Duchenne and limb-girdle muscular dystrophy, we are very encouraged by the sustained and meaningful clinical results and consistency of the safety profile of SRP-9001.”

The safety and tolerability profile of SRP-9001 is like past reports. Across all three studies, treatment-related adverse events (TRAEs) generally occurred within 90 days of treatment and subsequently resolved. No clinically relevant complement activation was observed​ in any of the studies. The most common treatment-related adverse event was vomiting, generally within the first week post-infusion. Increases in liver enzymes were transient and responsive to steroids​. In Study 9001-103, safety data were consistent with data from previous studies of SRP-9001 (101 and 102). There was one immune-mediated myositis serious adverse event in Cohort 2​ specific to the participant’s mutation; participant received treatment including plasmapheresis and has since returned to pre-event function.

Sarepta and Roche are beginning enrollment in the EMBARK study, the first global phase 3 pivotal double-blind gene therapy trial in Duchenne to enroll 120 patients in the United States, Europe and Asia. The primary endpoint will assess the change in NSAA total score from baseline to week 52 compared to placebo. Key features of EMBARK include stratification of participants by age and baseline NSAA, with a minimum of 50 percent of patients ages 4 to 5 enrolled. Inclusion criteria include a stable daily dose of oral corticosteroids for at least 12 weeks before screening and rAAVrh74 antibody titers of less than 1:400. Participants with mutations between or including exons 1-17 or mutations fully contained within exon 45 (inclusive) are not eligible.

Secondary endpoints of the trial include the number of skills gained or improved at week 52 as measured by NSAA, the quantity of micro-dystrophin protein expression at week 12 (Part 1) as measured by western blot, timed function tests and safety. In Part 1, results from the treatment and placebo groups are compared through 52 weeks following treatment. In Part 2, the study remains blinded to investigators and participants while all participants in the placebo group cross over to active treatment and all participants are followed for another 52 weeks while safety and efficacy continue to be evaluated.

Photo: Louise Rodino-Klapac, executive vice president and chief scientific officer of Sarepta

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