Gene Therapy for Duchenne Muscular Dystrophy

(ENDEAVOR Trial)

Not currently recruiting at 5 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy called SRP-9001 for individuals with Duchenne Muscular Dystrophy (DMD), a condition that gradually weakens muscles. The main goal is to assess the treatment's safety and its ability to help the body produce dystrophin, a protein missing in those with DMD. Participants will receive a one-time IV infusion of the treatment and will be monitored for about three years. Individuals diagnosed with DMD, regardless of their ability to walk, and who meet specific genetic criteria, may qualify for this study. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that SRP-9001, also known as delandistrogene moxeparvovec, is generally safe for patients. In earlier studies, patients who received this gene therapy for Duchenne Muscular Dystrophy (DMD) mostly did not experience serious side effects.

One study found that the treatment led to lasting improvements in patient function without major safety issues. Other findings support this, showing that individuals who received the gene therapy responded well. Overall, the treatment appears safe based on past experiences, but ongoing studies continue to monitor safety for all participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Duchenne Muscular Dystrophy, which often focus on managing symptoms and slowing disease progression, SRP-9001 offers a groundbreaking approach by using gene therapy. This treatment employs a unique mechanism of action, utilizing a viral vector called delandistrogene moxeparvovec to deliver a micro-dystrophin gene directly into muscle cells. This innovative method aims to address the root cause of the disease by enabling the production of functional dystrophin, a protein missing in individuals with Duchenne Muscular Dystrophy. Researchers are excited about this potential because it could significantly alter the disease's progression and improve muscle function more effectively than existing therapies.

What evidence suggests that this treatment might be an effective treatment for Duchenne Muscular Dystrophy?

Studies have shown promising results for delandistrogene moxeparvovec, the treatment being tested in this trial for Duchenne muscular dystrophy (DMD). In one study, a year after treatment, patients showed stable or improved movement abilities, suggesting a positive effect. Another study found that these improvements lasted for over five years. This gene therapy helps the body produce a protein that DMD patients lack, essential for healthy muscles. Early research indicates that this treatment could help slow the disease's progression. ^{1 3 5 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Sarepta Therapeutics, Inc.

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. investorrelations.sarepta.com investorrelations.sarepta.com/static-files/a9bf712a-d35f-465c-a86f-466b15f1b314

Five-Year Outcomes With Delandistrogene Moxeparvovec in ... The authors thank the patients and their families for their participation in Study 101. (SRP-9001-101), as well as the investigators and ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37539981/

1-Year Interim Results from Study SRP-9001-103 ... One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit ...

3. neurology.org neurology.org/doi/10.1212/WNL.0000000000213604

Delandistrogene Moxeparvovec Gene Therapy in ... This Evidence in Focus reviews the current evidence on the efficacy and adverse effects of delandistrogene moxeparvovec in patients with Duchenne muscular ...

4. investorrelations.sarepta.com investorrelations.sarepta.com/static-files/a479a06b-7f40-495b-b540-96fde84f6725

Five-year outcomes with delandistrogene moxeparvovec in ... Five-year outcomes with delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy (DMD):. A Phase 1/2a study. JR Mendell,1,2 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05096221

Study Details | NCT05096221 | A Gene Transfer Therapy ... The study will evaluate the safety and efficacy of gene transfer therapy in boys with DMD. It is a randomized, double-blind, placebo-controlled study.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37577753/

A phase 1/2a nonrandomized trial Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained ...

7. neurology.org neurology.org/doi/10.1212/WNL.0000000000202973

A Phase 2 Clinical Trial Evaluating the Safety and Efficacy ... Objective: To evaluate safety and efficacy of delandistrogene moxeparvovec (SRP-9001), compared with placebo, in patients with Duchenne muscular dystrophy (DMD) ...