Gene Therapy for Duchenne Muscular Dystrophy

(HORIZON Trial)

Recruiting at 1 trial location

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

Age: < 18

Sex: Male

Trial Phase: Phase 1

Sponsor: Sarepta Therapeutics, Inc.

Must be taking: Corticosteroids

Disqualifiers: Cardiomyopathy, Significant illness, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

16 Participants Needed

Trial Summary

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

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. The protocol does not specify if other medications need to be stopped, but it mentions that any chronic drug treatment that poses unnecessary risks may exclude participation.

What data supports the effectiveness of the treatment delandistrogene moxeparvovec for Duchenne Muscular Dystrophy?

Research shows that delandistrogene moxeparvovec leads to the expression of a shortened dystrophin protein, which helps stabilize motor function in children with Duchenne Muscular Dystrophy. In a study, children treated with this therapy showed improved scores in motor function tests compared to those who did not receive the treatment. ^{1 2 3 4 5}

Is delandistrogene moxeparvovec gene therapy safe for humans?

Delandistrogene moxeparvovec, a gene therapy for Duchenne muscular dystrophy, has been tested in clinical trials and is generally considered safe, with common side effects including vomiting, decreased appetite, and nausea, which usually resolve within 90 days. ^{1 2 3 4 6}

How is the treatment delandistrogene moxeparvovec unique for Duchenne muscular dystrophy?

Delandistrogene moxeparvovec is a unique gene therapy for Duchenne muscular dystrophy because it uses a virus to deliver a shortened version of the dystrophin gene directly to muscle cells, helping them produce a protein that is crucial for muscle function. This is the first gene therapy approved for this condition, offering a novel approach compared to traditional treatments that do not address the genetic cause of the disease. ^{1 2 4 7 8}

What is the purpose of this trial?

This is a gene transfer therapy study evaluating the safety of and delandistrogene moxeparvovec dystrophin protein expression from delandistrogene moxeparvovec following therapeutic plasma exchange (plasmapheresis) in ambulatory male participants with DMD and pre-existing antibodies to AAVrh74 over a period of 58 weeks.

Research Team

Medical Director

Principal Investigator

Sarepta Therapeutics, Inc.

Eligibility Criteria

This trial is for ambulatory male participants with Duchenne Muscular Dystrophy (DMD) who already have antibodies to AAVrh74. The study spans 58 weeks and involves a gene transfer therapy followed by plasmapheresis, a process that filters the blood.

Inclusion Criteria

My genetic test shows a specific mutation in the DMD gene, not including exon 8 or 9.

I can walk and move around on my own.

I can participate in tests that assess my muscle movements.

Exclusion Criteria

My heart's pumping ability is lower than normal.

Exposure to gene therapy, investigational medication, or other protocol-specified treatment within the protocol specified time limits

Presence of any other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy or concomitant illness or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risks for gene transfer or a medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the participant's ability to comply with the protocol required testing or procedures or compromise the participant's wellbeing, safety, or clinical interpretability

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Plasmapheresis and Treatment

Participants undergo plasmapheresis followed by a single intravenous infusion of delandistrogene moxeparvovec

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and dystrophin protein expression over a period of 58 weeks

58 weeks

Treatment Details

Interventions

• delandistrogene moxeparvovec
• Plasmapheresis

Trial Overview The trial tests delandistrogene moxeparvovec's safety and its ability to express dystrophin protein in patients with DMD after they undergo therapeutic plasma exchange (plasmapheresis).

Participant Groups

Group I: Delandistrogene Moxeparvovec After Plasmapheresis Procedure Experimental Treatment 2 Interventions

Participants will receive a single intravenous (IV) infusion of delandistrogene moxeparvovec on Day 1 after plasmapheresis procedure if AAVrh74 antibodies are sufficiently low.

delandistrogene moxeparvovec is already approved in United States for the following indications:

Approved in United States as Elevidys for:

• Duchenne muscular dystrophy (DMD) in ambulatory and non-ambulatory patients aged 4 years and older with a confirmed mutation in the DMD gene

Who Is Running the Clinical Trial?

Sarepta Therapeutics, Inc.

Lead Sponsor

Trials

54

Recruited

34,000+

Findings from Research

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]

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]

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]

The study compared four different AAV-based constructs for delivering shortened dystrophin in mdx mice, finding that rAAVrh74.MHCK7.micro-dystrophin resulted in the highest expression and improved muscle function after 4 weeks.

This construct not only enhanced muscle force output but also normalized the muscle environment, highlighting the importance of both promoter choice and transgene design for effective treatment of muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression and function of four AAV-based constructs for dystrophin restoration in the mdx mouse model of Duchenne muscular dystrophy. Potter, RA., Griffin, DA., Heller, KN., 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]

AAV2-MCKDeltaCS1, a recombinant adeno-associated virus vector expressing microdystrophin, showed extensive and long-term expression in 5-week-old mdx mice, leading to significant improvements in muscle force generation.

In 10-day-old mdx mice, while microdystrophin expression was limited, the treatment still resulted in hypertrophy of muscle fibers and notable recovery of contractile force, suggesting that early intervention may still provide benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype. Yoshimura, M., Sakamoto, M., Ikemoto, M., et al.[2012]

References

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

Delandistrogene Moxeparvovec: First Approval. [2023]

2. 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]

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. 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]

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. England pubmed.ncbi.nlm.nih.gov

Expression and function of four AAV-based constructs for dystrophin restoration in the mdx mouse model of Duchenne muscular dystrophy. [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

AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype. [2012]