Sarepta Reports Positive Results from Gene Therapy Trial for form of LGMD

Rare Daily Staff

Photo: Doug Ingram, President and CEO, Sarepta

Sarepta Therapeutics reported positive results from a study of its experimental gene therapy for the rare neuromuscular condition limb-girdle muscular dystrophy Type 2E that showed the therapy is driving robust expression in the muscles where it is needed.

The results included safety and expression data from three clinical trial participants in the high-dose cohort measured at 60 days, and one-year functional data from three clinical trial participants in the low-dose cohort.

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 before age 10. The disease progresses to loss of ambulation in the teen years and often leads to early mortality. There is currently no treatment or cure for limb-girdle muscular dystrophy type 2E.

SRP-9003 uses the AAVrh74 vector, which is designed to be delivered to skeletal, diaphragm, and cardiac muscle to treat peripheral neuromuscular diseases. AAVrh74 has lower immunogenicity rates than reported with other human AAV vectors. The MHCK7 promoter has been chosen for its ability to express in the heart, which is critically important for patients with limb-girdle muscular dystrophy Type 2E, many of whom die from pulmonary or cardiac complications. Sarepta has five limb-girdle muscular gene therapy programs in development and holds an option for a sixth program.

SRP-9003 is in development for the treatment of LGMD2E, which is caused by a lack of beta-sarcoglycan (beta-SG) proteins. 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 progressive degeneration and a shortened lifespan characterized by the 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 5×1013 vg/kg and an additional three participants in the high-dose cohort (Cohort 2) received a one-time infusion dosed at 2×1014 vg/kg. The six participants were between the ages of 4 and 13. Post-treatment biopsies were taken at 60 days. Sarepta previously shared data from Cohort 1 in 2019, including positive and robust expression and biomarker data and positive 9-month functional results.

Preliminary results from the higher-dose Cohort 2 of three patients showed a strong dose-dependent increase transduction and expression when compared with the low-dose cohort. The three participants showed a robust mean expression of 72.3 percent of transduced beta-SG, properly localized to the muscle sarcolemma, as measured by immunohistochemistry. These results exceeded the pre-defined measure of success for the study of 50 percent positive fibers, which was previously achieved in Cohort 1.

All participants showed robust quantification of beta-SG, as measured by Western blot, with mean beta-SG of 62.1 percent of normal control. All participants showed a reduction in serum creatine kinase (CK) levels from pre-treatment baseline measure to last measure at 90 days, with a mean CK reduction of 89.1% from baseline. CK is an enzyme biomarker strongly associated with muscle damage.

Adverse events in Cohort 2 were generally mild to moderate in severity. There was one serious adverse event – dehydration resulting from vomiting three days after infusion, which resolved in two days. No other clinically significant laboratory findings were observed, including no finding of decreases in platelet counts outside of the normal range or signs of complement activation.

“We were very encouraged by the previously reported results from our first cohort of patients treated with a lower dose of SRP-9003, including impressive expression, good tolerability, and positive functional signals, which continue impressively at one year.  We are excited to have been able to achieve even more impressive expression and other biomarkers in our higher-dose cohort for SRP-9003, along with good tolerability,” said Doug Ingram, president and CEO, Sarepta. “These data support the conclusion that the therapy is achieving its intended purpose, driving robust expression in the muscles where it is needed.”