Sarepta Therapeutics' Limb-Girdle Muscular Dystrophy Gene Therapy SRP-9003 Shows Safety in 5-Year Data
Adverse events related to the gene therapy itself were mild or moderate, with most occurring in the first 90 days posttreatment.
This article originally appeared on our sister site, NeurologyLive®.
Sarepta Therapeutics' bidridistrogene xeboparvovec (also known as SRP-9003), an investigational gene therapy being evaluated for the treatment of limb-girdle muscular dystrophy 2E/R4 (LGMD2E/R4), demonstrated safety in over a 4-to-5-year follow-up in newly updated data from a phase 1/2 clinical trial (NCT03652259).1 The results were presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas.
Most treatment-related treatment-emergent adverse events (TR-TEAEs) occurred within the first 90 days post infusion; although, it was noted that this was a small scale study. The findings comprised 6 patients across 2 cohorts who were treated with a one-time intravenous dose of either 1.85x1013 vg/kg (cohort 1; n = 3) or 7.41x1013 vg/kg (cohort 2; n = 3) of the gene therapy. There were 25 TR-TEAEs over the year year timespan, most of which were deemed mild (n = 13) or moderate (n = 10) with regard to severity. TR-TEAEs seen within the first 90 days posttreatment included vomiting and increased gamma-glutamyltransferase.
The study included patients aged 4 to 15 years who have mutations at both alleles and who tested negative for antibodies against adeno-associated virus serotype rh74 (rAAVrh74). In the study, which was led by Jerry Mendell, MD, a neuromuscular expert and advisor to the Jerry R. Mendell Center for Gene Therapy, the 2 remaining TR-TEAEs that were considered severe both resolved with clinical care. These TR-TEAEs constituted a case of acute liver injury in a patient in cohort 1, which was resolved with hospitalization, and a case of dehydration in a patient in cohort 2, which was resolved via appropriate care and medication.
SRP-9003 uses a AAVrh74 vector, which is designed to be delivered to skeletal, diaphragm, and cardiac muscles in a systemic and robust manner. The gene therapy is intended to provide a full-length beta-sarcoglycan (SGCB) transgene using the MHCK7 promoter, which was selected for its strong expression in cardiac tissue. For people with limb-girdle muscular dystrophy Type 2E (LGMD2E), also referred to as beta-sarcoglycanopathy or LGMDR4, this is of particular importance, as many of these patients succumb to pulmonary or cardiac complications.
SRP-9003 is also currently being evaluated in a phase 3 study, referred to as EMERGENE (NCT0624613), that the company hopes to use for a future biologics license application (BLA) submission for accelerated approval. This multinational, open-label study comprises ambulatory and non-ambulatory patients with LGMD2E/R4, aged 4 and older, using change in the expression of SGCB at 60 days as the primary end point. The trial, which completed enrollment in December 2024, includes several other functional measures and safety objectives through 60 months of dosing.2
To be included in the study, ambulatory participants must walk unaided, complete a 10-meter walk test in under 30 seconds, and have an NSAD score of at least 25. Non-ambulatory participants must complete the walk test in 30 seconds or more (or be unable to perform it) and have a PUL 2.0 score of at least 3. All participants must have pathogenic beta-sarcoglycan gene mutations, low AAVrh74 antibody titers (<1:400), and be able to cooperate with muscle testing. Exclusions include severe cardiac or respiratory issues, active autoimmune disease, or other significant medical conditions.
Interim data from the phase 1/2 trial was previously published in Nature Medicine in early 2024, with results that showed robust SGCB expression of 36.2% in cohort 1 and 62.1% in cohort 2 at 60 days. Post-hoc exploratory analyses revealed preliminary improvements in motor function, as assessed through the North Star Ambulatory Assessment for Limb-girdle Type Muscular Dystrophies, through year 2. In addition, at 60 days post-treatment serum creatine kinase (CK) levels were reduced in all patients (cohort 1: –92.4%; cohort 2: –94.9%). At 2 years post-treatment, all patients in cohorts 1 and 2 maintained reductions in serum CK levels.3
Over 2 years of follow-up, patients treated with SRP-9003 showed greater improvements in NSAD scores compared to the natural history cohort. The least-squares mean difference in NSAD score change at Year 2 was 7.3 (95% CI, 0.7–13.9), with an unadjusted mean difference of 8.9 (95% CI, 3.5–14.4). Timed function tests also improved, with least-squares mean differences of −6.2 s (95% CI, −19.6 to 7.1) for the 100-m test and −0.8 s (95% CI, −2.2 to 0.6) for the 10-m test. Unadjusted differences were −8.1 s (95% CI, −22.3 to 6.2) for the 100-m test and −0.1 s (95% CI, −1.2 to 1.0) for the 10-m test.
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