Gene Therapy for Duchenne Muscular Dystrophy

(ENVISION Trial)

Not currently recruiting at 65 trial locations

Overseen By Aravindhan Veerapandiyan, MD

Age: Any Age

Sex: Male

Trial Phase: Phase 3

Sponsor: Sarepta Therapeutics, Inc.

Must be taking: Corticosteroids

Disqualifiers: Gene therapy, Investigational medication, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy treatment called delandistrogene moxeparvovec for Duchenne Muscular Dystrophy (DMD), a genetic disorder that causes muscle weakness. The study will assess the safety and effectiveness of this treatment for both non-ambulatory (unable to walk) and ambulatory (able to walk) males with DMD. Participants will receive either the gene therapy or a placebo, with an opportunity to switch treatments during the trial. Ideal candidates are males with a confirmed DMD diagnosis who are stable on their current medication and can participate in physical assessments. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for DMD.

Will I have to stop taking my current medications?

The trial requires participants to stay on a stable daily dose of oral corticosteroids for at least 12 weeks before the study and throughout its duration, except for dose changes due to weight. The protocol does not specify if other medications need to be stopped.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that delandistrogene moxeparvovec is generally safe for people with Duchenne muscular dystrophy (DMD). One study found that patients maintained or improved their mobility a year after receiving the treatment, suggesting potential benefits. Over two years, safety results aligned with earlier findings, revealing no major new safety issues.

Another study examined results over five years and also supported its safety for DMD patients. While side effects can occur with any treatment, these studies indicate that this gene therapy could be a safe option for many people with DMD. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Duchenne Muscular Dystrophy?

Most treatments for Duchenne Muscular Dystrophy (DMD) focus on managing symptoms and slowing progression with corticosteroids or other supportive care. Unlike these options, Delandistrogene Moxeparvovec is a gene therapy that targets the root cause by delivering a micro-dystrophin gene directly to muscle cells. This approach aims to produce a functional version of the dystrophin protein, which is missing or defective in DMD patients. Researchers are excited because this could lead to more meaningful and long-lasting improvements in muscle function, potentially transforming DMD from a progressive disease to a manageable condition.

What evidence suggests that SRP-9001 (Delandistrogene Moxeparvovec) might be an effective treatment for Duchenne Muscular Dystrophy?

Research has shown that delandistrogene moxeparvovec, a treatment in this trial, may help treat Duchenne muscular dystrophy (DMD). This gene therapy adds a smaller version of the dystrophin protein, called micro-dystrophin, into muscles, strengthening them. One study found that after one year, patients who received this therapy had better muscle function than those who did not. Additionally, long-term data suggest that the treatment is generally well tolerated. These findings offer hope for better outcomes in DMD patients. Participants in this trial may receive delandistrogene moxeparvovec either initially or after a placebo phase. ^{1 2 4 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 non-ambulatory and ambulatory males with Duchenne Muscular Dystrophy (DMD), aged ≥8 to <18, who can perform motor assessment tests. They must be on a stable dose of corticosteroids and have specific genetic mutations in DMD. Those with high antibodies against the therapy vector or prior gene therapy are excluded.

Inclusion Criteria

I cannot walk by myself according to the study's specific rules.

My genetic test shows a specific mutation in my DNA.

My body does not have high levels of antibodies against rAAVrh74.

Exclusion Criteria

I haven't had gene therapy or experimental drugs to boost dystrophin recently.

Abnormality in protocol-specified diagnostic evaluations or laboratory tests

Presence of any other clinically significant illness, medical condition, or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risk for gene transfer

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive either a placebo or delandistrogene moxeparvovec IV infusion

72 weeks

Treatment Part 2

Participants receive the alternate treatment: those who received placebo in Part 1 receive delandistrogene moxeparvovec, and vice versa

56 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• SRP-9001 (Delandistrogene Moxeparvovec)

Trial Overview The study tests delandistrogene moxeparvovec, a gene transfer therapy for DMD. Participants will either receive this treatment or a placebo via IV over approximately 128 weeks in a randomized, double-blind setup where neither they nor the researchers know who gets what until after the study.

How Is the Trial Designed?

Group I: Delandistrogene Moxeparvovec followed by Placebo Experimental Treatment 2 Interventions

Participants will receive single IV infusion of delandistrogene moxeparvovec on Day 1. Then, participants will receive a single IV infusion of matching placebo at approximately 72 weeks.

Group II: Placebo followed by Delandistrogene Moxeparvovec Placebo Group 2 Interventions

Participants will receive matching placebo IV infusion on Day 1. Then, participants will have the opportunity to receive a single IV infusion of delandistrogene moxeparvovec at approximately 72 weeks.

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

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]

A new adenoviral vector, which is modified to delete all viral open reading frames, successfully delivers a full-length dystrophin minigene, showing promise for treating Duchenne muscular dystrophy (DMD).

This modified vector demonstrated efficient gene transfer in both mdx mice and muscle fibers in vivo, indicating its potential for developing effective gene therapies for DMD and possibly other diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo expression of full-length human dystrophin from adenoviral vectors deleted of all viral genes. Haecker, SE., Stedman, HH., Balice-Gordon, RJ., et al.[2012]

The study developed an engineered plasmid DNA that reduces immune responses against both the wild-type dystrophin protein and the AAV6 vector used for gene therapy in Duchenne muscular dystrophy, showing promise in overcoming immunological challenges.

In experiments with mdx/mTRG2 mice, treatment with this engineered DNA significantly decreased antibody responses and improved muscle force, suggesting enhanced efficacy of gene therapy for muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy. Ho, PP., Lahey, LJ., Mourkioti, F., et al.[2022]

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]

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]

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]

Duchenne muscular dystrophy (DMD) is a severe genetic disorder primarily affecting boys, leading to muscle degeneration and early death, highlighting the urgent need for effective treatments.

AAV-based gene therapy using shortened microdystrophin genes shows promise as a treatment for DMD, and the article advocates for using microdystrophin expression as a surrogate endpoint to facilitate accelerated approval in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials. Chamberlain, JS., Robb, M., Braun, S., 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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37539981/

1-Year Interim Results from Study SRP-9001-103 ... Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, ...

2. investorrelations.sarepta.com investorrelations.sarepta.com/static-files/676e4e3c-654c-4d38-8b89-de1d9a1579ab

Delandistrogene Moxeparvovec in Duchenne Muscular ... Delandistrogene Moxeparvovec in Duchenne Muscular Dystrophy: Long-Term EMBARK 2-Year Functional Outcomes, Safety, and. Micro-Dystrophin ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06270719

NCT06270719 | An Observational Study Comparing ... The study is designed to collect both medical history and prospective data on Duchenne muscular dystrophy (DMD) treatment outcomes in participants receiving ...

4. 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 ...

5. investorrelations.sarepta.com investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-present-new-data-its-neuromuscular-0

Press Release - Investor Relations | Sarepta Therapeutics, Inc. 176P: 3-year functional outcomes of patients with Duchenne muscular dystrophy: Pooled delandistrogene moxeparvovec clinical trial data vs ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03375164

Study Details | NCT03375164 | A Gene Transfer Therapy ... A Gene Transfer Therapy Study to Evaluate the Safety of Delandistrogene Moxeparvovec (SRP-9001) in Participants With Duchenne Muscular Dystrophy (DMD).

7. 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 ...