Sarepta Therapeutics’ Limb-Girdle Muscular Dystrophy Gene Therapy SRP-9003 Produces “Robust Expression” of β-SG in Phase 3 Trial

Sarepta Therapeutics’ SRP-9003 (bidridistrogene xeboparvovec), an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat limb-girdle muscular dystrophy Type 2E (LGMD2E/R4, also known as beta sarcoglycanopathy), has demonstrated the ability to produce “robust expression” of β-sarcoglycan protein (β-SG) in the phase 3 EMERGENE clinical trial (NCT06246513).¹ The data were presented in a poster at the 30th annual International Congress of the World Muscle Society (WMS), held October 7 to 11 in Vienna, Austria.

The trial treated 11 ambulatory patients in its first cohort and 6 nonambulatory patients in its second cohort. Notably, the primary end point of the study, which was defined as the mean [SD] change from baseline (CFBL) to day 60 for ambulatory patients in β-SG expression, as measured by percent positive fibers using immunofluorescence staining (PPF), was met, with a mean 43.4% [29.9%] CFBL observed (P < .001). As for the nonambulatorycohort, which was analyzed as a secondary end point, a mean 23.9% [14.2%] (P < .02) CFBL was observed by PPF. Additional secondary and exploratory end points looked at the CFBL to day 60 as measured by percent fluorescent intensity (PFI) and Western blot. For ambulatory patients, a mean 18.23% [11.23%] CFBL was observed by PFI (P < .001) and a mean 33.58% [31.28%] CFBL was observed by Western blot (P < .01). For nonambulatory patients, a mean 21.81% [14.04%] CFBL was observed by PFI and a mean 12.99% [10.56%] CFBL was observed by Western blot.

The study also observed colocalization of the β-SG and δ-SG subunits, as assessed by PPF of biopsied muscle tissue, and found that the PPF for both β and δ increased in both the ambulatory and nonambulatory cohorts at day 60. Furthermore, the mean (SD; min, max) percent CFBL to day 60 for serum creatine kinase was −88.8% (10.9%; −99.6% to −66.8%) in the ambulatory cohort and −92.4% (4.5%; −97.1% to −86.7%) in the nonambulatory cohort.

As for safety, nausea (70.6%), decreased appetite (47.1%), vomiting (41.2%), upper abdominal pain (29.4%), and fatigue (29.4%) constituted the most common treatment-related treatment-emergent adverse events (TEAEs). Seven patients (41.2%) experienced TEAEs associated with acute liver injury as of the data cut, with 5 grade 2 to 3 cases occurring in the ambulatory cohort and 2 grade 1 cases occurring in the nonambulatory cohort. It was noted that 1 ambulatory patient’s nonserious case was ongoing as of the data cut. In addition, after the data cut, it was noted that 4 more patients experienced grade 1 TEAEs associated with acute liver injury. Although, no acute liver injuries were deemed treatment-related and the overall safety of the gene therapy product was characterized as “manageable with appropriate monitoring, with no notable differences between cohorts.”¹ No treatment-related deaths were reported.

“These findings demonstrate robust expression of β-SG at 60 days post treatment along with restoration of other component proteins of the sarcoglycan complex in both ambulatory and non-ambulatory patients,” first author Anne M. Connolly, MD, chief of the Division of Neurology at Nationwide Children’s Hospital, a professor of pediatrics at The Ohio State University College of Medicine, and a member of the Jerry R. Mendell Center for Gene Therapy in the Abigail Wexner Research Institute, and colleagues wrote in the poster’s conclusion.¹ “The safety and tolerability results were consistent with previous results and were observed up to 90 days post treatment. These findings indicate that bidridistrogene xeboparvovec treatment induces a biological cascade likely to predict clinical benefit.”

Notably, Sarepta was the first company to receive the FDA’s new platform technology designation for the rAAVrh74 viral vector used in SRP-9003.² rAAVrh74 is also used in Sarepta’s delandistrogene moxeparvovec-rokl (marketed as Elevidys), an FDA-approved gene therapy intended to treat Duchenne muscular dystrophy and Sarepta’s investigational gene therapy SRP-9004, which is in development for nonambulant LGMD type 2D/R3.³ Shortly after the FDA granted the platform technology designation in June 2025, however, it revoked the same designation just about a month later in July 2025, following the death of a 51-year-old patient who was treated with SRP-9004 in a phase 1 clinical trial (DISCOVERY; NCT01976091).^4,5 In its announcement of the revocation, the FDA also made reference to 2 previous deaths that occurred among patients who received Elevidys, which also uses the AAVrh74 vector.⁶

REFERENCES
1. Connolly AM, Laverty CG, Proud CM, et al. Expression of SGCB and safety following bidridistrogenexeboparvovec treatment in patients with LGMD2E/R4: results from the EMERGENE phase 3 study. Presented at WMS, October 7-11, Vienna, Austria. #734LBP
2. U.S. FDA grants platform technology designation to the viral vector used in SRP-9003, Sarepta’s investigational gene therapy for the treatment of limb girdle muscular dystrophy type 2E/R4. News release. Sarepta Therapeutics Inc. June 4, 2025. Accessed October 20, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/us-fda-grants-platform-technology-designation-viral-vector-used
3. Fidler B. FDA to use new review tool on Sarepta’s gene therapy work. Biopharma Dive. June 4, 2025. Accessed October 20, 2025. https://www.biopharmadive.com/news/sarepta-platform-technology-designation-gene-therapy-rare-disease/749845/
4. Sarepta Therapeutics provides statement on Elevidys. News release. Sarepta Therapeutics Inc. July 18, 2025. Accessed October 20, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-statement-elevidys
5. Philippidis A. StockWatch: Sarepta shares nosedive after LGMD gene therapy patient dies. Genetic Engineering & Biotechnology News. July 20, 2025. Accessed October 20, 2025. https://www.genengnews.com/topics/genome-editing/stockwatch-sarepta-shares-nosedive-after-lgmd-gene-therapy-patient-dies/
6. FDA requests Sarepta Therapeutics suspend distribution of Elevidys and places clinical trials on hold for multiple gene therapy products following 3 deaths. News release. FDA. July 18, 2025. Accessed October 20, 2025. https://www.fda.gov/news-events/press-announcements/fda-requests-sarepta-therapeutics-suspend-distribution-elevidys-and-places-clinical-trials-hold