Gene Therapy for Duchenne Muscular Dystrophy

(HORIZON Trial)

No longer recruiting at 3 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, delandistrogene moxeparvovec, for boys with Duchenne Muscular Dystrophy (DMD), a condition that causes muscle weakness. The goal is to determine if this treatment is safe and can help the body produce dystrophin, a protein missing in people with DMD. Participants must be able to walk, have a specific genetic change causing DMD, and have undergone stable treatment with certain steroids for at least 12 weeks. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that delandistrogene moxeparvovec is likely to be safe for humans?

Research has shown that delandistrogene moxeparvovec, a gene therapy for Duchenne muscular dystrophy (DMD), generally has a manageable safety profile. In earlier studies, participants experienced some side effects, but these were usually mild or manageable. Common side effects included mild immune reactions, which doctors often control with medication. As this treatment remains under study, more information is needed to fully understand its safety. However, current research suggests it is generally well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Duchenne Muscular Dystrophy, which primarily focus on managing symptoms and slowing disease progression through corticosteroids and physical therapy, delandistrogene moxeparvovec offers a novel approach by using gene therapy. This treatment works by delivering a functional version of the dystrophin gene using a viral vector, potentially addressing the root cause of the disease. Researchers are excited because this could lead to significant improvements in muscle function and quality of life for patients, something current treatments can't achieve.

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

In previous studies, delandistrogene moxeparvovec has shown promise in treating Duchenne muscular dystrophy (DMD). Research indicates that this gene therapy can lead to strong production of micro-dystrophin, a protein crucial for muscle strength and function. Some studies have demonstrated that this treatment can slow the progression of DMD by improving muscle health. Specifically, patients in earlier studies had micro-dystrophin present in their muscle cells up to 60 weeks after treatment. These findings suggest that delandistrogene moxeparvovec could help maintain muscle function in those with DMD. Participants in this trial will receive a single intravenous infusion of delandistrogene moxeparvovec after undergoing a plasmapheresis procedure, provided that AAVrh74 antibodies are sufficiently low. ^{1 3 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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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. 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).

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10228300/

Assessing the value of delandistrogene moxeparvovec ... Delandistrogene moxeparvovec (SRP-9001) is an investigational gene therapy that may delay progression of Duchenne muscular dystrophy (DMD).

3. nature.com nature.com/articles/s41591-024-03304-z

AAV gene therapy for Duchenne muscular dystrophy In these studies, delandistrogene moxeparvovec micro-dystrophin expression was robust with sarcolemmal localization up to 60 weeks after ...

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. anthem.com anthem.com/medpolicies/abcbs/active/mp_pw_e002509.html

MED.00144 Gene Therapy for Duchenne Muscular ... Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: a phase 1/2a ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10366687/

Expression of SRP-9001 dystrophin and stabilization ... Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of ...

7. elevidyshcp.com elevidyshcp.com/about-elevidys/mechanism-of-action

Mechanism of action | ELEVIDYS (delandistrogene ... Indication. ELEVIDYS is indicated for the treatment of Duchenne muscular dystrophy (DMD) in individuals at least 4 years of age: ... Limited data are available ...