Gene Therapy for Limb-Girdle Muscular Dystrophy

(EMERGENE Trial)

Recruiting at 4 trial locations

Overseen By Sarepta Therapeutics Inc. For Clinical Trial Information, Select Option 4

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Sarepta Therapeutics, Inc.

Must not be taking: Immunosuppressants

Disqualifiers: Cardiomyopathy, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

17 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are on active immunosuppressant treatment for an autoimmune disease, you may be excluded from the trial.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on active immunosuppressant treatment for an autoimmune disease, you may not be eligible to participate.

What data supports the idea that Gene Therapy for Limb-Girdle Muscular Dystrophy (also known as: Bidridistrogene Xeboparvovec (SRP-9003), SRP-9003) is an effective treatment?

The available research shows that gene therapy using AAV9.BVES significantly improved muscle mass, strength, and exercise performance in a mouse model of Limb-Girdle Muscular Dystrophy type R25. It also normalized heart rate under stress and showed no obvious toxicity. This suggests that gene therapy can effectively improve symptoms of muscular dystrophy. While the research primarily focuses on animal models, these results provide promising evidence for the potential effectiveness of gene therapy in treating this condition. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment Bidridistrogene Xeboparvovec (SRP-9003) for Limb-Girdle Muscular Dystrophy?

Research on similar gene therapies, like those using adeno-associated virus vectors for muscular dystrophies, shows promising results. For example, gene therapy in animal models has improved muscle strength and function, suggesting potential benefits for treatments like SRP-9003. ^{1 2 3 4 5}

What safety data exists for gene therapy in treating Limb-Girdle Muscular Dystrophy?

The safety data for delandistrogene moxeparvovec (SRP-9001) gene therapy, primarily studied for Duchenne muscular dystrophy, indicates that the most common treatment-related adverse events were vomiting, decreased appetite, and nausea, which mostly occurred within the first 90 days and resolved. Long-term safety and functional outcomes have been evaluated, showing robust expression of the therapeutic protein and stabilization of motor function up to 2 years post-treatment. No obvious toxicity was detected in related studies, suggesting a favorable safety profile. ^{1 2 3 6 7}

Is the gene therapy SRP-9003 safe for humans?

In studies involving patients with Duchenne muscular dystrophy, the gene therapy SRP-9003 (also known as delandistrogene moxeparvovec) was generally safe, with the most common side effects being vomiting, decreased appetite, and nausea, which resolved within the first 90 days. ^{1 2 3 6 7}

Is the treatment Bidridistrogene Xeboparvovec (SRP-9003) a promising treatment for Limb-Girdle Muscular Dystrophy?

The treatment Bidridistrogene Xeboparvovec (SRP-9003) shows promise for Limb-Girdle Muscular Dystrophy because similar gene therapies have been successful in improving muscle function and strength in other types of muscular dystrophy. These therapies use a virus to deliver a helpful gene to muscle cells, which can lead to better muscle performance and overall health. ^{1 2 4 6 7}

How is the treatment Bidridistrogene Xeboparvovec (SRP-9003) unique for limb-girdle muscular dystrophy?

Bidridistrogene Xeboparvovec (SRP-9003) is a gene therapy that uses an adeno-associated virus (AAV) vector to deliver a gene encoding a micro-dystrophin protein, which is a shortened version of the dystrophin protein. This approach is unique because it targets the underlying genetic cause of the disease, potentially offering a long-term solution by restoring the function of the dystrophin protein in muscle cells. ^{1 2 4 6 7}

What is the purpose of this trial?

This is a multicenter, global study of the effects of a single systemic dose of SRP-9003 on beta-sarcoglycan (β-SG) gene expression in participants with limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4). This study will consist of both ambulatory participants (Cohort 1) and non-ambulatory participants (Cohort 2).

Research Team

Medical Director

Principal Investigator

Sarepta Therapeutics, Inc.

Eligibility Criteria

This trial is for people with a muscle condition called Limb Girdle Muscular Dystrophy 2E/R4. It's open to those who can move around on their own (Cohort 1) and those who cannot (Cohort 2). Specific eligibility details are not provided, but typically participants must meet certain health criteria.

Inclusion Criteria

I can walk without help and do so quickly.

Cohort 2, only non-ambulatory participants: 10MWT ≥30 seconds or unable to perform, PUL 2.0 entry scale score ≥3, Participants must possess 1 homozygous or 2 heterozygous pathogenic and/or likely pathogenic β-SG DNA gene mutations, Able to cooperate with muscle testing, Participants must have adeno-associated virus serotype rh74 (AAVrh74) antibody titers <1:400 (that is, not elevated) as determined by AAVrh74 antibody enzyme-linked immunosorbent assay.

Exclusion Criteria

Left ventricular ejection fraction < 40% or clinical signs and/or symptoms of cardiomyopathy, Forced vital capacity ≤40% of predicted value and/or requirement for nocturnal ventilation, Diagnosis of (or ongoing treatment for) an autoimmune disease and on active immunosuppressant treatment, Presence of any other clinically significant illness or medical condition (other than LGMD2E/R4)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous (IV) infusion of SRP-9003

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Bidridistrogene Xeboparvovec (SRP-9003)

Trial Overview The study tests an experimental gene therapy named Bidridistrogene Xeboparvovec (SRP-9003), which aims to correct the genetic defect causing the disease. Participants will receive one dose of this therapy, and its effects on gene expression will be monitored.

Participant Groups

Group I: SRP-9003 Experimental Treatment 2 Interventions

Participants will receive a single intravenous (IV) infusion of SRP-9003.

Who Is Running the Clinical Trial?

Sarepta Therapeutics, Inc.

Lead Sponsor

Trials

54

Recruited

34,000+

Findings from Research

AAV9-mediated delivery of the human BVES gene significantly improved muscle function and cardiac health in BVES-knockout mice, demonstrating its potential as a gene therapy for limb-girdle muscular dystrophy type R25 (LGMDR25).

The treatment showed efficacy in both neonatal and adult mice, enhancing body weight, muscle mass, and exercise performance without any observed toxicity, suggesting a promising therapeutic approach for this currently untreatable condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. Li, H., Wang, P., Hsu, E., et al.[2023]

Delandistrogene moxeparvovec (SRP-9001) successfully induced dystrophin expression in all patients with Duchenne muscular dystrophy, achieving a mean change from baseline of 23.82% at Week 12 and 39.64% at Week 48, indicating its efficacy as a gene transfer therapy.

While the overall change in North Star Ambulatory Assessment (NSAA) scores was not statistically significant for the entire population, younger patients (4-5 years) with matched baseline motor function showed a significant improvement of +2.5 points, suggesting that age and baseline function may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy. Mendell, JR., Shieh, PB., McDonald, CM., et al.[2023]

Adeno-associated virus-mediated gene therapy using fordadistrogene movaparvovec showed promising results in a dystrophin-deficient rat model of Duchenne muscular dystrophy (DMD), with improvements in muscle strength, tissue architecture, and cardiac function directly linked to the dose administered.

The therapy was effective even in older rats with a more severe form of DMD, indicating its potential applicability for patients at various stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy. Le Guiner, C., Xiao, X., Larcher, T., et al.[2023]

A single injection of a recombinant adeno-associated virus (AAV) vector into the tibialis anterior muscle of dystrophic hamsters resulted in over 97% recovery of muscle strength and nearly complete restoration of physiological function, indicating high efficacy of this gene therapy approach for Limb Girdle Muscular Dystrophy (LGMD) 2F.

The treatment not only improved muscle strength but also prevented pathological changes, such as muscle hypertrophy, and led to normal muscle weight and size, showcasing the potential of AAV-mediated gene therapy for long-term benefits in LGMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. Xiao, X., Li, J., Tsao, YP., et al.[2019]

Gene therapy using a recombinant adeno-associated virus (rAAV) vector to deliver a canine microdystrophin gene has shown effectiveness in restoring dystrophin expression and improving symptoms in 12 golden retriever muscular dystrophy (GRMD) dogs.

Both locoregional and systemic delivery methods were safe, with no observed toxicity or adverse immune reactions, and systemic administration resulted in sustained microdystrophin levels and reduced dystrophic symptoms for over 2 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Le Guiner, C., Servais, L., Montus, M., et al.[2018]

Delandistrogene moxeparvovec is the first gene therapy approved for Duchenne muscular dystrophy (DMD) in the USA, specifically for ambulatory children aged 4 to 5 years with a confirmed mutation in the dystrophin gene.

This therapy uses an adeno-associated virus vector to deliver a micro-dystrophin gene to muscle cells, aiming to improve muscle function in DMD patients, and is administered as a single intravenous infusion at a dose of 1.33 × 10^14 vector genomes per kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delandistrogene Moxeparvovec: First Approval. Hoy, SM.[2023]

Delandistrogene moxeparvovec is a gene therapy that has shown a favorable safety profile in a small trial of 4 ambulatory boys aged 4 to 5 years with Duchenne muscular dystrophy, with all treatment-related adverse events resolving within 70 days.

The therapy resulted in significant functional improvements, with the North Star Ambulatory Assessment (NSAA) score increasing from 20.5 to 27.5 over 4 years, indicating that it may positively influence disease progression in DMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial. Mendell, JR., Sahenk, Z., Lehman, KJ., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. [2018]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Delandistrogene Moxeparvovec: First Approval. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial. [2023]