SRP 9003 for the treatment of limb-girdle muscular dystrophy type 2E shows sustained expression and functional improvements 2 years after administration.- Sarepta

Sarepta Therapeutics, Inc. shared new results from the ongoing study of SRP 9003 (rAAVrh74.MHCK7.hSGCB), the Company’s investigational gene therapy for limb-girdle muscular dystrophy Type 2E (LGMD2E) . In the first look at expression data from biopsies taken two years after a single administration of SRP 9003, results 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 are being presented at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference. 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. Efficient transduction in skeletal muscle and robust beta-sarcoglycan protein expression were seen in both dose cohorts following infusion with SRP9003, and significant creatine kinase (CK) reductions were observed. Cohort 1 (Dosed at 1.85×1013 vg/kg), 24 months following treatment: i. As measured by western blot, mean beta-SG of 54% at 24 months of normal control, compared to 36% measured at Day 60. ii. Percent immunofluorescent (IF) positive fibers was 48% compared to normal control, compared to 51% at Day 60. iii. Participants showed a mean intensity of 35% of transduced beta-SG, properly localized to the muscle sarcolemma, as measured by IF, compared to 47% at Day 60. iv. The mean NSAD improvement from baseline of 5.7 points at 18 months was sustained through 24 months. v. All three participants demonstrated continued improvements from baseline across all functional measures, including time-to-rise, four-stair climb, 100-meter walk test and 10-meter walk test. Cohort 2 (Dosed at 7.41×1013 vg/kg), 12 months following treatment : i.At Day 60, the expression of beta-SG (72% mean positive fibers and 73% mean intensity) resulted in increased expression of delta-sarcoglycan, with 65% mean positive fibers and 103% intensity, and gamma-sarcoglycan, 60% mean positive fibers and 97% intensity. These results suggest treatment with SRP-9003 demonstrates reconstitution of the DAPC, which could lead to improved membrane integrity and thus improved clinical motor outcomes measures. ii. All three participants demonstrated improvements from baseline across all functional measures, including the NSAD, time-to-rise, four-stair climb, 100-meter walk test and 10-meter walk test. iii. The mean NSAD improvement from baseline was 4.0 points at one year, compared to 3.7 at 6 months. 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. Since the last update from this study in October 2020, there have been no new drug-related safety signals observed, and no decreases in platelet counts outside of the normal range and no evidence of clinical complement activation observed in either dose cohort. About SRP-9003 and the Study : SRP 9003 uses the AAVrh74 vector, which is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle, making it an ideal candidate 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 robustly express in the heart, which is critically important for patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), also known as beta-sarcoglycanopathy and LGMDR4, many of whom die from pulmonary or cardiac complications. This 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. 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 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 ambulation in the teen years and often leads to death before age 30. There is currently no treatment or cure for LGMD2E. Sarepta has five LGMD gene therapy programs in development, including subtypes for LGMD2E, LGMD2D, LGMD2C, LGMD2B and LGMD2L, and holds an option for a sixth program for LGMD2A.