RARE Daily

Sarepta DMD Gene Therapy Meets Primary Endpoint but Fails to Show Functional Benefit, Shares Fall

January 8, 2021

Rare Daily Staff

Sarepta Therapeutics said that initial results from its study evaluating the safety, efficacy and tolerability of a single dose of SRP-9001, its gene therapy for the treatment of Duchenne muscular dystrophy, met the primary endpoint of micro-dystrophin protein expression at 12 weeks post treatment, but failed to show a significant increase on the primary functional endpoint of improvement in NSAA total score compared to placebo at 48 weeks post-treatment.

Shares of the company sank 53 percent on the news, wiping out $7 billion of its valuation.

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. Disease progression leads to muscle weakness in the lower limbs that spreads to the arms, neck 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.

Study SRP-9001-102 is an ongoing, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, efficacy and tolerability of a single dose of SRP-9001 in 41 patients with Duchenne muscular dystrophy. SRP-9001 is an experimental gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein.

At 12 weeks post-treatment compared to baseline, the study met its primary biological endpoint of micro-dystrophin protein expression. Participants who received SRP-9001 (n=20) had mean micro-dystrophin expression of 28.1 percent, as measured by western blot. Accompanying secondary biological endpoints including vector genome copies per nucleus, percent positive fibers, intensity, and reduction in creatine kinase (exploratory) were also met.

In the primary functional endpoint, SRP-9001-treated participants showed an increase in NSAA total score compared to placebo at 48 weeks; however, the difference was not statistically significant. The NSAA is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne.

At every time point measured, the cohort of SRP-9001 treated participants outperformed the placebo group, and, at 48 weeks, participants in the treatment group demonstrated a statistically significant increase of 1.7 points in NSAA total score compared to baseline, while participants in the placebo group saw an increase of 0.9 points on the NSAA total score compared to baseline, which was not statistically significant.

Study randomization was stratified by age group, and patients in the 4- to 5-year-old group at the time of treatment demonstrated a statistically significant 4.3-point improvement on NSAA total score at 48 weeks post treatment compared to a 1.9-point improvement in the age-matched placebo group.

Results from Study 102 reinforced the favorable safety and tolerability profile of SRP-9001 with no new safety signals identified.

President and CEO Doug Ingram said in a statement that the randomization process of the trial my have been a reason for the disappointing functional results in DMD patients in the 6 to 7 year age group, linking it to “a significant imbalance in baseline NSAA scores between the active and placebo cohorts of the participants ages 6-7, making the 6-7 age groups non-comparable and likely substantially contributing to the inability to achieve statistical significance.”


Study 102 remains blinded and the company will analyze the functional results for all patients, including cross-over participants, once they have achieved the 48-week time point in Part 2. Sarepta has already enrolled and dosed 11 participants in Study 103, using commercial process material, and plans to have biomarker and safety results from that cohort in the second quarter of 2021.


“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,” said Ingram.


Sarepta licensed rights to SRP-9001 from the Abigail Wexner Research Institute at Nationwide Children’s Hospital, where it was initially developed. 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. In December 2019, the company granted Roche the exclusive right to launch and commercialize SRP-9001 outside the United States.


Photo: Doug Ingram, president and CEO of Sarepta

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