Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today 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 today 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.

“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, Ph.D., 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. LGMD2E is one of the most severe forms of LGMD and causes significant disability in children while frequently leading to early mortality and the data continue to suggest this treatment could bring much needed hope to these patients.”

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.

Cohort 1 (Dosed at 1.85×1013 vg/kg), 24 months following treatment:

• As measured by western blot, mean beta-SG of 54% at 24 months of normal control, compared to 36% measured at Day 60.
• Percent immunofluorescent (IF) positive fibers was 48% compared to normal control, compared to 51% at Day 60.
• 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.
• The mean NSAD improvement from baseline of 5.7 points at 18 months was sustained through 24 months.
• 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:

• 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.
• 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.
• 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.