Gene Therapy for Duchenne Muscular Dystrophy

(ENVISION Trial)

Recruiting at 49 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

148 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment SRP-9001 (Delandistrogene Moxeparvovec) for Duchenne Muscular Dystrophy?

Research shows that SRP-9001 leads to the expression of a shortened dystrophin protein, which helps stabilize motor function in children with Duchenne Muscular Dystrophy. In a study, children aged 4 to 5 showed significant improvement in motor function scores compared to those who received a placebo. ^{1 2 3 4 5}

What safety data exists for delandistrogene moxeparvovec (SRP-9001) gene therapy in humans?

In clinical trials for Duchenne muscular dystrophy, the most common side effects of delandistrogene moxeparvovec were vomiting, decreased appetite, and nausea, which mostly occurred within the first 90 days and resolved over time. ^{1 2 3 4 6}

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

SRP-9001 is a unique gene therapy that uses a virus to deliver a shortened version of the dystrophin gene directly to muscle cells, helping them produce a functional protein that is missing in Duchenne Muscular Dystrophy. This approach is novel because it targets the root genetic cause of the disease, unlike other treatments that may only address symptoms. ^{2 3 4 7 8}

What is the purpose of this trial?

The study will evaluate the safety and efficacy of delandistrogene moxeparvovec gene transfer therapy in non-ambulatory and ambulatory males with DMD. This is a randomized, double-blind, placebo-controlled 2-part study. Participants will be in the study for approximately 128 weeks. All participants will have the opportunity to receive intravenous (IV) delandistrogene moxeparvovec in either Part 1 or Part 2.

Research Team

Medical Director

Principal Investigator

Sarepta Therapeutics, Inc.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

References

1. 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]

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

Delandistrogene Moxeparvovec: First Approval. [2023]

4. 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]

5. 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]

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

Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials. [2023]

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

In vivo expression of full-length human dystrophin from adenoviral vectors deleted of all viral genes. [2012]

8. United States 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. [2022]