RARE Daily

Sarepta Reports Positive 2-Year Results from LGMD2E Gene Therapy Trial

March 18, 2021

Rare Daily Staff

Sarepta Therapeutics shared new results from its ongoing study of SRP-9003, an experimental gene therapy for limb-girdle muscular dystrophy Type 2E that found sustained protein expression in muscle tissue.

In functional outcomes assessments taken two years following treatment in Cohort 1 (low-dose cohort) and one year after treatment in Cohort 2 (high-dose cohort), patients continued to demonstrate stability in their NSAD (North Star Assessment for Dysferlinopathies) total score and improvements on timed function tests. Results were presented at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference.

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), one of the most severe forms of LGMD, 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 ambulation in the teen years and often leads to early mortality. There is currently no treatment or cure for LGMD2E.

SRP-9003 is in development for the treatment of LGMD2E (also known as beta-sarcoglycanopathy and LGMDR4), a devastating monogenic neuromuscular disease caused by a lack of beta-sarcoglycan (beta-SG) proteins. SRP-9003 is a gene therapy construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-SG protein, the absence of which is the sole cause of the progressive degeneration and a shortened lifespan characterized by the disease.

“This data is the first look at longer-term expression data with any gene therapy for muscular dystrophy. The meaningful and sustained levels of beta-sarcoglycan protein expression at two years and continued strength of the functional outcomes measured are tremendously positive and support continued advancement of this investigational treatment for patients,” said Louise Rodino-Klapac, executive vice president and chief scientific officer, Sarepta Therapeutics. “In Cohort 2, we also saw strong expression of delta-sarcoglycan and gamma-sarcoglycan proteins in addition to beta-sarcoglycan, which suggests that SRP-9003 is working to restore the dystrophin associated protein complex, or DAPC, which provides biological support for the sustained functional benefits observed in both cohorts.”

Efficient transduction in skeletal muscle and robust beta-sarcoglycan protein expression were seen in both dose cohorts following infusion with SRP-9003, and significant creatine kinase (CK) reductions were observed.

The open label, 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. Three participants in the low-dose cohort (Cohort 1) were treated with a one-time infusion of SRP-9003 dosed at 1.85×1013 vg/kg and an additional three participants in the high-dose cohort (Cohort 2) received a one-time infusion dosed at 7.41×1013 vg/kg based on linear standard qPCR titer method. The six participants were between the ages of 4 and 13. Post-treatment biopsies were taken at 60 days.

Results show that protein expression in muscle was sustained for two years following treatment in the low dose cohort, with mean beta-sarcoglycan expression of 54 percent at 24 months, compared to 36 percent at Day 60, as measured by western blot.

In an exploratory evaluation of all SRP-9003 treated patients compared to a natural history cohort; patients treated with SRP-9003 demonstrated significant improvements in functional outcomes after 24 months. The mean decline in total NSAD score for patients in the natural history cohort was 4.6 points while SRP-9003 treated patients demonstrated a mean improvement of 4.6 points for a clinically meaningful difference of 9.2 points.

Results in both cohorts continued to reinforce the safety and tolerability profile of SRP-9003.

Sarepta, which has five LGMD gene therapy programs in development, has exclusive rights to the LGMD2E gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital.

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


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