Gene Therapy Shows Promise for Limb-Girdle Muscular Dystrophy Type 2E
Table of Contents
- 1. Gene Therapy Shows Promise for Limb-Girdle Muscular Dystrophy Type 2E
- 2. Long-Term Safety and Tolerability
- 3. Mechanism of action and Clinical Importance
- 4. Phase 3 EMERGENE Study and Future Outlook
- 5. Previous Phase 1/2 Trial Results
- 6. The Future of LGMD2E Treatment
- 7. How can this gene therapy potentially address the underlying cause of LGMD2E?
- 8. Gene Therapy Shows Promise for Limb-Girdle Muscular Dystrophy Type 2E
- 9. Understanding Bidridistrogene Xeboparvovec: An Interview
Dallas, TX (2025-03-16) – New findings presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference indicate positive long-term safety results for the gene therapy bidridistrogene xeboparvovec in patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), also known as beta-sarcoglycanopathy or LGMDR4. The five-year follow-up data from a phase 1/2 trial showcases the potential of this innovative therapy.
Long-Term Safety and Tolerability
The study, led by neuromuscular expert Jerry Mendell, MD, assessed the safety of bidridistrogene xeboparvovec over a five-year period. The findings, presented at the MDA conference, involved six patients across two cohorts who received a one-time intravenous dose of either 1.85×1013 vg/kg (cohort 1; n = 3) or 7.41×1013 vg/kg (cohort 2; n = 3).
- Over the five-year period, there were 25 treatment-related, treatment-emergent adverse events (TR-TEAEs).
- The majority of these events were either mild (n = 13) or moderate (n = 10) in severity.
- TR-TEAEs observed within the first 90 days included vomiting and increased gamma-glutamyltransferase.
While some severe TR-TEAEs were observed, such as acute liver injury and dehydration, these were resolved with appropriate clinical care.
Mechanism of action and Clinical Importance
Bidridistrogene xeboparvovec, also known as SRP-9003, utilizes an AAVrh74 vector designed for systemic delivery to skeletal, diaphragm, and cardiac muscles. The gene therapy delivers a full-length beta-sarcoglycan (SGCB) transgene using the MHCK7 promoter, which is selected for it’s strong expression in cardiac tissue. This is crucial because many patients with LGMD2E/R4 often succumb to pulmonary or cardiac complications.
Phase 3 EMERGENE Study and Future Outlook
Currently, bidridistrogene xeboparvovec is being evaluated in a phase 3 study called EMERGENE (NCT0624613). The goal is to use the data from this study for a future biologics license application (BLA) submission, seeking accelerated approval. The EMERGENE trial, a multinational, open-label study, includes both ambulatory and non-ambulatory patients with LGMD2E/R4, aged 4 and older. The primary endpoint is the change in the expression of SGCB at 60 days.The trial completed enrollment in December 2024 and includes additional functional measures and safety objectives followed thru 60 months post-dosing. [2]
to be included in the EMERGENE study, specific criteria apply:
- Ambulatory participants must walk unaided, complete a 10-meter walk test in under 30 seconds, and have a North Star Ambulatory Assessment for Limb-girdle type Muscular Dystrophies (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 Performance of the Upper Limb (PUL) 2.0 score of at least 3.
- All participants must have pathogenic beta-sarcoglycan gene mutations and low AAVrh74 antibody titers.
Previous Phase 1/2 Trial Results
Interim data from the phase 1/2 trial, published in Nature Medicine in early 2024, demonstrated promising results. [3] the data showed robust SGCB expression of 36.2% in cohort 1 and 62.1% in cohort 2 at 60 days. Exploratory analyses revealed preliminary improvements in motor function, assessed through the North Star Ambulatory Assessment for Limb-girdle Type Muscular Dystrophies, through year 2.Serum creatine kinase (CK) levels were reduced in all patients at 60 days post-treatment (cohort 1: –92.4%; cohort 2: –94.9%). These reductions were maintained at 2 years post-treatment.
The Future of LGMD2E Treatment
The results from both the completed phase 1/2 trial and the ongoing phase 3 EMERGENE study provide hope that bidridistrogene xeboparvovec may offer a importent advancement in the treatment of LGMD2E, addressing critical unmet needs for patients facing this challenging condition.
References:
- Mendell J, Connolly AM, Sahenk Z, et al. Long-Term Safety of Bidridistrogene Xeboparvovec After 5-Year Follow-up From a Phase 1/2 Trial. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. ABSTRACT P223
- Sarepta Therapeutics Completes Enrollment in EMERGENE, a Phase 3 Clinical Study of SRP-9003 for the Treatment of Limb-Girdle Muscular Dystrophy Type 2E/R4. News release. sarepta Therapeutics. December 18, 2024. Accessed March 13, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-completes-enrollment-emergene-phase-3
- Mendell JR, Pozsgai ER, Lewis S, et al.Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results. Nature Medicine. 2024;30:199-206. doi:10.1038/s41591-023-02730-9
How can this gene therapy potentially address the underlying cause of LGMD2E?
Gene Therapy Shows Promise for Limb-Girdle Muscular Dystrophy Type 2E
Understanding Bidridistrogene Xeboparvovec: An Interview
We’re here today with Dr. Aris Thorne, a leading researcher in neuromuscular diseases, to discuss the promising new gene therapy, bidridistrogene xeboparvovec, for Limb-Girdle Muscular Dystrophy Type 2E (LGMD2E). Dr. Thorne, thank you for joining us.
It’s my pleasure to be here.
Dr. Thorne, coudl you briefly explain what LGMD2E is and why this new gene therapy is so significant?
LGMD2E, also known as beta-sarcoglycanopathy, is a genetic muscle-wasting disease caused by mutations in the beta-sarcoglycan (SGCB) gene. this leads to muscle weakness and loss, frequently enough affecting the limbs, and can regrettably lead to pulmonary or cardiac complications. bidridistrogene xeboparvovec is significant because it’s a gene therapy designed to deliver a working copy of the SGCB gene directly to the muscles,potentially addressing the underlying cause of the disease.
The five-year follow-up data from the phase 1/2 trial was recently presented. What where the key takeaways regarding the long-term safety of this therapy for LGMD2E patients?
The data showed that bidridistrogene xeboparvovec demonstrated an acceptable safety profile over the five-year period. While there were some treatment-related adverse events,the majority were mild or moderate,and any severe events were resolved with clinical care. This is encouraging as we consider the long-term implications of gene therapy.
Let’s delve into the mechanism. How exactly does bidridistrogene xeboparvovec work?
Bidridistrogene xeboparvovec,also known as SRP-9003,uses an AAVrh74 vector to deliver a full-length beta-sarcoglycan (SGCB) transgene to skeletal,diaphragm,and cardiac muscles. The MHCK7 promoter drives strong expression in cardiac tissue and aims to restore SGCB protein production in the muscles, compensating for the missing or faulty protein caused by the patient’s genetic condition.
the therapy is currently being evaluated in the Phase 3 EMERGENE study. What are the goals of that study, and what are the eligibility criteria for patients to participate?
The EMERGENE study aims to confirm the efficacy and safety of bidridistrogene xeboparvovec in a larger patient population. The goal is to gather sufficient data to support a future biologics license request (BLA) and seek accelerated approval. The trial includes both ambulatory and non-ambulatory patients with LGMD2E/R4, aged 4 and older.
Eligibility includes specific criteria related to walking ability, as assessed by the 10-meter walk test and North Star Ambulatory Assessment (NSAD) score for ambulatory patients, and the Performance of the Upper limb (PUL) 2.0 score for non-ambulatory patients. Additionally, participants must have confirmed pathogenic beta-sarcoglycan gene mutations and low AAVrh74 antibody titers.
The Phase 1/2 trial showed promising initial results. Could you elaborate on the improvements observed in patients who received the gene therapy?
The Phase 1/2 trial data showed robust SGCB expression in the treated patients. Exploratory analyses revealed encouraging preliminary improvements in motor function, as assessed by the North Star Ambulatory Assessment. We also observed reductions in serum creatine kinase (CK) levels, which indicated reduced muscle damage. These effects were maintained for at least two years post-treatment.
What is the future outlook for LGMD2E treatment, and how does bidridistrogene xeboparvovec fit into that future?
The future of treatment for LGMD2E is very shining. Bidridistrogene xeboparvovec represents a significant advancement, potentially addressing the root cause of the disease. Positive results from the EMERGENE study could pave the way for regulatory approval and provide a much-needed treatment option for patients facing this challenging condition. Further research and growth in gene therapy are crucial to continue improving outcomes for individuals with LGMD2E.
dr. Thorne, what is one question you wish more people would ask about LGMD2E and it’s treatment?
That’s a great question. I wish more people would ask: “How can we ensure equitable access to these potentially life-changing gene therapies for all LGMD2E patients, nonetheless of their location or socioeconomic status?” I think it’s a critical conversation we must have as we move forward.
Dr. Thorne,thank you so much for your insights today. It’s been incredibly informative.
My pleasure. Thank you for having me.
