Sarepta Therapeutics Reports Positive Results for DMD, LGMD at World Muscle Society Conference

Rare Daily Staff

Sarepta Therapeutics reported positive two-year follow up results from four Duchenne muscular dystrophy clinical trial participants who received its experimental gene transfer therapy SRP-9001, as well as positive results from its experimental gene therapy for limb-girdle muscular dystrophy Type 2E.

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, 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.

SRP-9001 is an investigational gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of micro-dystrophin protein. In December 2019, the company announced a licensing agreement granting Roche the exclusive right to launch and commercialize SRP-9001 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.

Results presented at the 25th International Annual Congress of the World Muscle Society demonstrated that two years after a one-time infusion of SRP-9001, trial participants exhibited a mean 7.0-point improvement on the North Star Ambulatory Assessment compared to baseline.

“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,” said Doug Ingram, president and CEO, Sarepta. “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. We continue to work with urgency to bring this potentially transformative treatment to patients as quickly as possible.”

In the open-label trial, known as Study 101, four ambulatory participants between the ages of 4 and 7 were treated with an infusion of SRP-9001. The therapy was well-tolerated in all participants over the two-year period. All adverse events were considered mild or moderate, and occurred within 90 days of treatment. There were no serious adverse events or evidence of complement activation.

At day 90, all participants had confirmed vector transduction and showed functional improvement on the NSAA scale and reduced creatine kinase levels. Participants demonstrated a mean increase of 5.5 points from baseline one year after treatment and 7.0 points from baseline two years after treatment. The NSAA is a validated scale developed to measure functional motor abilities in ambulant children with Duchenne, with scores ranging from 0-34.

As previously disclosed, micro-dystrophin protein levels for participants in Study 101 were as follows: 12-weeks post-infusion, a mean of 81.2 percent muscle fibers expressing micro-dystrophin with a mean intensity at the sarcolemma by immunohistochemistry of 96 percent compared to normal biopsies. Adjusted for fat and fibrotic tissue, western blot showed a mean expression of 95.8 percent.

Sarepta also presented positive results from its ongoing study of SRP-9003, the company’s investigational gene therapy for limb-girdle muscular dystrophy Type 2E (LGMD2E). Results included 18-month functional data from three clinical trial participants in the low-dose cohort and 6-month functional data from three participants in the high-dose cohort.

SRP-9003 is a gene construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-sarcoglycan protein, the absence of which is the sole cause of the progressive degeneration and a shortened lifespan characterized by the disease.

Limb-girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begin in muscles around the hips and shoulders before progressing to muscles in the arms and legs. Patients with limb-girdle muscular dystrophy Type 2E (LGMD2E) begin showing neuromuscular symptoms such as difficulty running, jumping and climbing stairs before age 10. The disease, which is an autosomal recessive subtype of LGMD, progresses to loss of ability to walk in the teen years and often leads to early mortality. There is currently no treatment or cure for LGMD2E.

SRP-9003 is a gene construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-sarcoglycan protein, the absence of which is the sole cause of the progressive degeneration and a shortened lifespan characterized by the disease.

This first-in-human study is evaluating a single intravenous infusion of SRP-9003 among children with LGMD2E between the ages of 4 and 15 years with significant symptoms of disease. The SRP-9003 study has two cohorts, each studying a different dose-per-kilogram based on the weight of the patient.

“It’s very encouraging that we continue to see consistent, positive data from our investigational gene therapy SRP-9003 across several measures, as we know the community needs more options,” said Louise Rodino-Klapac, senior vice president of gene therapy, Sarepta Therapeutics. “The improvements in functional measures at 18 and six 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.”

Photo: Doug Ingram, president and CEO, Sarepta