RGX-202 Gene Therapy for Duchenne Muscular Dystrophy

Recruiting at 7 trial locations

Overseen By Aravindhan Veerapandiyan, MD

Age: Any Age

Sex: Male

Trial Phase: Phase 2 & 3

Sponsor: REGENXBIO Inc.

Must be taking: Systemic glucocorticoids

Must not be taking: Ataluren, Exon-skipping therapy

Disqualifiers: Gene therapy, Cardiac dysfunction, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

65 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Participants must stop taking certain medications like ataluren or exon-skipping therapies for 5 years after receiving RGX-202. If taking vamorolone, it must be switched to prednisolone or prednisone before the study and can be resumed 12 weeks after RGX-202 dosing.

What data supports the effectiveness of the treatment RGX-202 for Duchenne Muscular Dystrophy?

Research shows that using gene therapy with adeno-associated virus (AAV) to deliver microdystrophin genes is a promising approach for treating Duchenne Muscular Dystrophy. This method has been developed over many years and aims to replace the defective gene responsible for the disease, potentially improving muscle function and slowing disease progression. ^{1 2 3 4 5}

Is RGX-202 gene therapy safe for humans?

Research on similar gene therapies for Duchenne muscular dystrophy in animals, like dogs, shows that the treatment was well tolerated with no acute or delayed adverse effects, including no systemic or immune toxicity. However, specific safety data for RGX-202 in humans is not provided in the available research. ^{1 6 7 8 9}

How is the RGX-202 treatment for Duchenne Muscular Dystrophy different from other treatments?

RGX-202 is unique because it uses gene therapy to deliver a modified version of the dystrophin gene, potentially reducing the need for high doses of viral vectors that can cause side effects. This approach aims to improve muscle function while minimizing immune responses and liver toxicity, which are common challenges in other gene therapies for Duchenne Muscular Dystrophy. ^{1 4 9 10 11}

What is the purpose of this trial?

RGX-202 is a gene therapy designed to deliver a transgene for a novel microdystrophin that includes functional elements of naturally-occurring dystrophin including the C-Terminal (CT) domain. This is a multicenter, open-label dose evaluation clinical study to assess the safety, tolerability, and clinical efficacy of a one-time intravenous (IV) dose of RGX-202 in participants with Duchenne.

Eligibility Criteria

This trial is for individuals with Duchenne Muscular Dystrophy (DMD) who have a specific gene mutation, can walk 100 meters without help, and have been on stable glucocorticoids for at least 12 weeks. They must not have had other gene therapies or certain DMD treatments recently and should not need to avoid immunosuppression.

Inclusion Criteria

I have been on a stable dose of steroids for at least 12 weeks before my recent tests.

I can walk 100 meters on my own without help.

My liver and kidney tests are normal or not concerning.

Exclusion Criteria

Participant is not a good candidate for the study, in the opinion of the investigator

Participant has received any investigational or commercial gene therapy product over his lifetime

Participant is currently taking any other investigational intervention or has taken any other investigational intervention within 3 months prior to the scheduled Day 1 intervention

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time intravenous dose of RGX-202 gene therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, tolerability, and efficacy of RGX-202

52 weeks

Multiple visits (in-person and virtual)

Long-term follow-up

Participants are assessed for long-term safety and efficacy of RGX-202

104 weeks

Open-label extension (optional)

Participants may opt into a separate long-term follow-up study

Treatment Details

Interventions

• RGX-202

Trial Overview The trial tests RGX-202, a one-time IV gene therapy aimed at delivering a microdystrophin transgene to treat DMD. It's an open-label study evaluating the safety, tolerability, and effectiveness of this new treatment in participants.

Participant Groups

Group I: Part 1: Cohort 2, 2c;, and Part 2; and Part 3: RGX-202 Dose 2 Experimental Treatment 1 Intervention

A single IV infusion of RGX-202 at a dose of 2x10\^14 GC/kg body weight

Group II: Part 1: Cohort 1 and 1b: RGX-202 Dose 1 Experimental Treatment 1 Intervention

A single IV infusion of RGX-202 at a dose of 1×10\^14 GC/kg body weight

Who Is Running the Clinical Trial?

REGENXBIO Inc.

Lead Sponsor

Trials

25

Recruited

3,100+

Findings from Research

The study successfully demonstrated that regional vascular delivery of rAAV8 and rAAV6 carrying micro-dystrophin significantly improved muscle transduction efficiency in mdx mice, achieving over 89% transduction after three months, which is crucial for potential gene therapy in Duchenne muscular dystrophy (DMD).

The promising results in mice were translated to non-human primates, showing effective gene expression in multiple muscles, indicating that this delivery method could be adapted for clinical trials in children with DMD, enhancing the safety and efficacy of gene therapy approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. Rodino-Klapac, LR., Janssen, PM., Montgomery, CL., et al.[2018]

Duchenne muscular dystrophy (DMD) is a significant genetic disease targeted for gene therapy, with the defective dystrophin gene identified as a key focus for treatment development over the past 30 years.

Despite challenges like the gene's large size and the extensive muscle tissue involved, advancements in gene replacement therapy for DMD have been promising, with several groups preparing for imminent human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward Gene Therapy for Duchenne Muscular Dystrophy. Chamberlain, JR., Chamberlain, JS.[2022]

Current therapies for Duchenne muscular dystrophy (DMD) include gene therapy, cell therapy, and pharmacological therapy, each targeting different aspects of the disease's progression.

Despite advancements, there is still no cure for DMD due to challenges in gene replacement and the complex nature of the symptoms, highlighting the need for more effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of therapy for Duchenne muscular dystrophy. Zhang, S., Xie, H., Zhou, G., et al.[2012]

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]

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 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]

High-capacity adenoviral vectors (HC-AdVs) are less cytotoxic than traditional adenoviral vectors and can effectively deliver RNA-guided CRISPR-Cas9 nucleases for gene editing in Duchenne muscular dystrophy (DMD).

Using HC-AdVs, researchers achieved up to 42% correction of defective DMD alleles in muscle cells, leading to the production of Becker-like dystrophins, which are crucial for muscle function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Capacity Adenoviral Vectors Permit Robust and Versatile Testing of DMD Gene Repair Tools and Strategies in Human Cells. Brescia, M., Janssen, JM., Liu, J., et al.[2021]

In adult mdx mice with existing muscle weakness, adenovirus-mediated dystrophin gene transfer showed a narrow therapeutic margin, where both toxicity and gene transfer efficiency were dependent on the dose of the vector used.

With optimal dosing and immunosuppressive therapy, the treatment successfully improved muscle strength and reduced disease progression over two months, highlighting its potential for treating Duchenne muscular dystrophy in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice. Yang, L., Lochmuller, H., Luo, J., et al.[2021]

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]

The study demonstrated that human dystrophin expressing chimeric (DEC) cell therapy is safe for long-term use, showing no complications or DNA damage in a mouse model of Duchenne muscular dystrophy (DMD) after 180 days post-administration.

Biodistribution analysis confirmed that DEC cells effectively targeted the heart, diaphragm, and gastrocnemius muscle while showing minimal presence in non-target organs, indicating a promising therapeutic approach for DMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Biodistribution and Safety of Human Dystrophin Expressing Chimeric Cell Therapy After Systemic-Intraosseous Administration to Duchenne Muscular Dystrophy Model. Siemionow, M., Brodowska, S., Langa, P., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. [2018]

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

Progress toward Gene Therapy for Duchenne Muscular Dystrophy. [2022]

3. China pubmed.ncbi.nlm.nih.gov

Development of therapy for Duchenne muscular dystrophy. [2012]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. [2022]

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

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

6. United States 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. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

High-Capacity Adenoviral Vectors Permit Robust and Versatile Testing of DMD Gene Repair Tools and Strategies in Human Cells. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice. [2021]

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

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

10. 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]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Long-Term Biodistribution and Safety of Human Dystrophin Expressing Chimeric Cell Therapy After Systemic-Intraosseous Administration to Duchenne Muscular Dystrophy Model. [2022]