Gene Therapy for Duchenne Muscular Dystrophy

(ENDEAVOR Trial)

Recruiting at 4 trial locations

Age: Any Age

Sex: Male

Trial Phase: Phase 1

Sponsor: Sarepta Therapeutics, Inc.

Must be taking: Glucocorticoids

Disqualifiers: Autoimmune disease, Cognitive impairment, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

55 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new gene therapy called delandistrogene moxeparvovec in people with Duchenne Muscular Dystrophy (DMD). The therapy aims to insert a healthy gene into the body to help improve muscle function. The study will last several years to evaluate safety and effectiveness.

Will I have to stop taking my current medications?

The trial requires that participants in Cohorts 1, 2, 3, 5, and 7 stay on a stable dose of oral glucocorticoids for at least 12 weeks before screening and throughout the first year of the study. For Cohorts 4 and 6, participants should not be receiving steroids at the time of screening.

What data supports the effectiveness of the treatment SRP-9001 for Duchenne Muscular Dystrophy?

The treatment SRP-9001 showed promising results in a study where it increased the expression of a key muscle protein called dystrophin in patients with Duchenne Muscular Dystrophy. Additionally, it helped stabilize motor function over two years, with significant improvements in younger children when compared to a control group. ^{1 2 3 4 5}

Is SRP-9001 gene therapy safe for humans?

The safety of SRP-9001, a gene therapy for Duchenne Muscular Dystrophy, has been evaluated in clinical trials. While specific safety data for SRP-9001 is not detailed in the provided research, similar gene therapies using adeno-associated virus (AAV) vectors have shown no serious adverse effects in animal studies and are considered safe for further clinical development. ^{6 7 8 9 10}

How is the treatment SRP-9001 for Duchenne Muscular Dystrophy different from other treatments?

SRP-9001 is a gene therapy that uses a virus to deliver a miniaturized version of the dystrophin gene directly to muscle cells, aiming to restore the production of dystrophin, a protein missing in Duchenne Muscular Dystrophy. This approach is unique because it targets the underlying genetic cause of the disease, unlike other treatments that may only address symptoms or use exon-skipping techniques. ^{4 8 11 12 13}

Research Team

Medical Director

Principal Investigator

Sarepta Therapeutics, Inc.

Eligibility Criteria

This trial is for boys with Duchenne Muscular Dystrophy (DMD). Different age groups can join: 4-8, ≥8 to <18 years old, and some who don't need steroids yet. They must be able to do motor tests and not have taken gene therapy or certain drugs recently. Those on stable steroid doses can also participate.

Inclusion Criteria

I have been officially diagnosed with Duchenne Muscular Dystrophy.

My genetic test results match the study's specific requirements.

I have been on a stable dose of oral corticosteroids for at least 12 weeks.

Exclusion Criteria

Has a concomitant illness, autoimmune disease, chronic drug treatment, and/or cognitive delay/impairment that in the opinion of the Investigator creates unnecessary risks for gene transfer

You have abnormal results in specific medical tests.

I have not had gene therapy or experimental treatments to boost dystrophin recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous (IV) infusion of delandistrogene moxeparvovec on Day 1

1 day

Follow-up

Participants are monitored for safety and expression of the gene therapy after treatment

156 weeks

Treatment Details

Interventions

• SRP-9001

Trial Overview The study is testing delandistrogene moxeparvovec, a gene transfer therapy for DMD. It's an open-label study where everyone gets the treatment to see if it's safe and how well it works over about three years.

Participant Groups

Group I: Delandistrogene Moxeparvovec Experimental Treatment 1 Intervention

Participants will receive a single intravenous (IV) infusion of delandistrogene moxeparvovec on Day 1.

Who Is Running the Clinical Trial?

Sarepta Therapeutics, Inc.

Lead Sponsor

Trials

54

Recruited

34,000+

Hoffmann-La Roche

Industry Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Findings from Research

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]

The micro-dystrophin gene transfer using rAAVrh74.MHCK7 was found to be well tolerated in a phase 1/2a trial with four young patients, showing only mild to moderate adverse events and no serious complications over one year.

All patients demonstrated significant expression of micro-dystrophin in muscle fibers and improvements in functional measures, such as North Star Ambulatory Assessment scores and reduced creatine kinase levels, indicating potential benefits beyond standard care for Duchenne muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. Mendell, JR., Sahenk, Z., Lehman, K., et al.[2021]

In a phase 1 clinical trial involving 10 patients with Duchenne muscular dystrophy (DMD), the morpholino antisense oligonucleotide NS-065/NCNP-01 was found to have a favorable safety profile, with no severe adverse reactions reported during the 12-week treatment period.

NS-065/NCNP-01 successfully induced exon 53 skipping in dystrophin mRNA in a dose-dependent manner, leading to increased dystrophin expression in 7 out of 10 patients, suggesting its potential efficacy and warranting further investigation in phase 2 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Komaki, H., Nagata, T., Saito, T., et al.[2019]

The study developed shorter 25-mer phosphorodiamidate morpholino oligonucleotides (PMOs) that can effectively induce dystrophin restoration in Duchenne muscular dystrophy (DMD), showing comparable efficacy to the longer 30-mer PMO eteplirsen.

Using shorter PMOs could allow for higher dosing, which enhances drug uptake into muscle fibers, potentially leading to greater dystrophin restoration and improved clinical outcomes for patients with DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD. Akpulat, U., Wang, H., Becker, K., et al.[2021]

The study developed a human codon-optimized version of microutrophin (µUtrn) that showed robust muscle expression and functional improvement in mdx mice, indicating its potential as a safer alternative to traditional dystrophin gene therapy for Duchenne muscular dystrophy (DMD).

Long-term administration of rAAV9-µUtrn resulted in lower immunogenicity and no adverse effects in toxicity studies, supporting its safety for clinical development as a gene therapy for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. Starikova, AV., Skopenkova, VV., Polikarpova, AV., et al.[2022]

The study demonstrated that a recombinant adeno-associated virus vector (rAAV8) carrying a modified U7snRNA sequence is safe for use in treating Duchenne muscular dystrophy (DMD) in 18 Golden Retriever Muscular Dystrophy (GRMD) dogs, with no adverse effects observed.

A dose-dependent response was noted, with up to 80% of myofibers expressing dystrophin at the highest dose, indicating that a minimum threshold of dystrophin expression is necessary for therapeutic effects, supporting future trials in nonambulatory DMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. Le Guiner, C., Montus, M., Servais, L., et al.[2022]

Gene therapy using adeno-associated virus (rAAV) to deliver mini/micro-dystrophin shows promise for treating Duchenne Muscular Dystrophy (DMD), but high doses of rAAV can lead to immune responses and liver toxicity, especially in older patients.

Research suggests that using utrophin, a protein similar to dystrophin, along with a novel MyoAAV delivery system, could enhance therapeutic effects while reducing the required rAAV dose, potentially making gene therapy safer and more effective for a broader range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. Li, N., Song, Y.[2022]

Gene therapy using dystrophin cDNAs in dystrophin-deficient mice shows promise for treating Duchenne muscular dystrophy (DMD), with regional restoration of muscle morphology observed in transgenic models.

Direct injection methods yielded low expression rates of dystrophin in adult muscle fibers, but recombinant adenovirus vectors showed greater efficiency in young mice, highlighting the need for improved delivery systems for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy in Duchenne muscular dystrophy. Inui, K., Okada, S., Dickson, G.[2019]

References

1. 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]

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

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Gene therapy progress and prospects: Duchenne muscular dystrophy. [2012]

4. China pubmed.ncbi.nlm.nih.gov

[Study on the recombinant adeno-associated virus vector carrying LacZ gene expression in the skeletal muscle]. [2007]

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

Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. [2019]

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

Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update. [2022]

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

Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping. [2021]

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

Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. [2022]

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

Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy. [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Gene therapy in Duchenne muscular dystrophy. [2019]