BB-301 for Muscular Dystrophy

Overseen By Sophie Mukadam

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Benitec Biopharma, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Pregnancy, Gene therapy, Neuromuscular diseases, others

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

Compensation: Varies

Number of Visits: 6

Duration: 1 day

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial involves injecting BB-301 into the throat muscles of patients with OPMD to help them swallow better. The study focuses on patients who have already been monitored for a period of time. The goal is to see if the treatment is safe and effective.

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

Is BB-301 safe for use in humans?

The research on similar treatments using adeno-associated virus (AAV) vectors, like AAV2.5 and AAV9, shows they were generally safe and well-tolerated in clinical trials for muscular dystrophy, with no significant immune responses or toxicity detected. ^{1 2 3 4 5}

What makes the treatment BB-301 unique for muscular dystrophy?

BB-301 is a gene therapy that uses an adeno-associated virus (AAV) to deliver genetic material directly to muscle cells, which is different from traditional treatments that may not target the genetic cause of muscular dystrophy. This approach aims to address the underlying genetic defect, potentially offering a more effective and long-lasting solution. ^{1 2 3 6 7}

What data supports the effectiveness of the treatment BB-301 for Muscular Dystrophy?

Research on similar AAV-based gene therapies shows promise in treating muscular dystrophies by effectively delivering genes to muscle cells, improving muscle function, and reducing symptoms in animal models. These studies suggest that AAV vectors can be engineered to enhance muscle targeting and gene delivery, which could be beneficial for treatments like BB-301. ^{3 5 8 9 10}

Who Is on the Research Team?

Milan R. Amin, M.D.

Principal Investigator

NYU Langone Health

Are You a Good Fit for This Trial?

This trial is for individuals with Oculopharyngeal Muscular Dystrophy (OPMD) who have trouble swallowing (dysphagia) and have been part of a previous OPMD study for at least 6 months. Participants will undergo surgery under general anesthesia to receive the treatment.

Inclusion Criteria

I am between 50 and 65 years old with a genetic diagnosis of OPMD.

I have moderate difficulty swallowing.

Subject was previously enrolled in the BNTC-OPMD-NH-001 natural history (NH) study and completed at least 6 months of follow-up in the NH study.

Exclusion Criteria

Subject with contraindication to the videofluoroscopy procedures.

I have had a throat stretching procedure in the last year.

I have undergone gene therapy in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intramuscular dose of BB-301 injected into the pharyngeal muscles through an open surgical procedure under general anesthesia

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at multiple time points

360 days

5 visits (in-person) at Day 90, Day 180, Day 270, Day 360

Long-term follow-up

Long-term monitoring of adverse events for up to 15 years following dosing

15 years

What Are the Treatments Tested in This Trial?

Interventions

• BB-301

Trial Overview The trial tests different doses of BB-301, an investigational drug, injected into throat muscles during surgery. The goal is to find the safest and most effective dose to improve swallowing in OPMD patients.

How Is the Trial Designed?

Group I: BB-301 Treatment Experimental Treatment 4 Interventions

The phase 1b component of the study is the dose escalation phase which will enroll up to 18 subjects in up to 3 dosing cohorts. The phase 2a component of the study is the dose expansion phase which will enroll up to 12 subjects.

Who Is Running the Clinical Trial?

Benitec Biopharma, Inc.

Lead Sponsor

Trials

2

Recruited

50+

Published Research Related to This Trial

The clinical trial demonstrated that the chimeric AAV2.5 vector is safe and well tolerated in boys with Duchenne muscular dystrophy (DMD), with no cellular immune response detected against the AAV2.5 capsid.

AAV2.5 showed effective gene transfer, with recombinant AAV genomes found in all patients, indicating its potential for efficient muscle transduction and paving the way for future gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Bowles, DE., McPhee, SW., Li, C., et al.[2022]

The study found that a pseudotyped adeno-associated virus (rAAV-2cap5) significantly enhances gene delivery to muscle cells, showing over 500-fold improvement in differentiated myocytes and over 200-fold in skeletal muscle compared to the standard rAAV-2 vector.

This improved transduction efficiency was also observed in a mouse model of Duchenne's muscular dystrophy, suggesting that using rAAV-2cap5 could enhance the effectiveness of gene therapy for muscle-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement of muscle gene delivery with pseudotyped adeno-associated virus type 5 correlates with myoblast differentiation. Duan, D., Yan, Z., Yue, Y., et al.[2018]

AAV1-U7 therapy shows promise for treating Duchenne muscular dystrophy (DMD) by successfully expressing dystrophin without causing immune rejection in preclinical models, such as mice and dogs.

However, the immune response to AAV1 can hinder the effectiveness of multiple injections, as antibodies against AAV1 develop quickly. Immunomodulation strategies can prevent this immune response, allowing for effective treatment across multiple muscles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transient immunomodulation allows repeated injections of AAV1 and correction of muscular dystrophy in multiple muscles. Lorain, S., Gross, DA., Goyenvalle, A., et al.[2022]

Engineered adeno-associated viral (AAV) vectors showed increased specificity for skeletal muscle and reduced targeting to the liver, enhancing their potential for safe and effective gene delivery in muscle disorders.

In mouse models of X-linked myotubular myopathy and Duchenne muscular dystrophy, the best-performing vectors (AAVMYO2 and AAVMYO3) significantly improved survival, muscle strength, and function, indicating their therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. El Andari, J., Renaud-Gabardos, E., Tulalamba, W., et al.[2022]

Adeno-associated viral vector (AAV)-based gene therapy is being explored as a promising treatment for various types of muscular dystrophy (MD), which currently lacks effective therapies for most patients.

Recent studies and ongoing clinical trials are focusing on different strategies using AAV, including gene replacement, gene knockdown, and gene editing, showing potential for treating conditions like Duchenne MD and myotonic dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV-based gene therapies for the muscular dystrophies. Crudele, JM., Chamberlain, JS.[2022]

In a study of 100 male patients with Duchenne muscular dystrophy (DMD), 42% tested positive for anti-AAV9 neutralizing antibodies, which could hinder the effectiveness of AAV gene therapy.

The prevalence of these antibodies varied significantly by age, with no positive cases in children under 4 years old, and also showed regional differences, indicating that younger patients and those from urban areas may be more suitable candidates for AAV gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence of Adeno-Associated Virus-9 Neutralizing Antibody in Chinese Patients with Duchenne Muscular Dystrophy. Wei, C., Li, D., Zhang, M., et al.[2023]

AAV9-mediated delivery of the human BVES gene significantly improved muscle function and cardiac health in BVES-knockout mice, demonstrating its potential as a gene therapy for limb-girdle muscular dystrophy type R25 (LGMDR25).

The treatment showed efficacy in both neonatal and adult mice, enhancing body weight, muscle mass, and exercise performance without any observed toxicity, suggesting a promising therapeutic approach for this currently untreatable condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. Li, H., Wang, P., Hsu, E., et al.[2023]

The Muscular Dystrophy Association (MDA) has invested over $125 million in gene therapy for neuromuscular disorders over the past 20 years, highlighting its commitment to advancing treatments in this field.

In January 2022, MDA organized a summit with experts to discuss safety challenges and adverse events related to adeno-associated virus (AAV) gene therapies, emphasizing the need for collaboration to overcome obstacles in translating these therapies from research to clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'. Lek, A., Atas, E., Hesterlee, SE., et al.[2023]

AAV9-mediated gene therapy successfully rescued the disease phenotype in a mouse model of spinal muscular atrophy with respiratory distress type 1 (SMARD1) by delivering the wild-type IGHMBP2 gene, leading to a 450% increase in lifespan and improvements in motor function and neuromuscular physiology.

In human-derived motor neurons from SMARD1 patients, the introduction of the wild-type IGHMBP2 gene resulted in increased cell survival and longer axons, indicating strong potential for this gene therapy approach in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Nizzardo, M., Simone, C., Rizzo, F., et al.[2018]

The study demonstrated that the recombinant adeno-associated virus vector (rAAV) carrying the dystrophin minigene SMCKA3999 effectively restored dystrophin expression in the skeletal muscle of mdx mice, a model for Duchenne muscular dystrophy (DMD).

rAAVSMCKA3999 not only improved the integrity of myofiber membranes but also corrected ultrastructural changes associated with DMD, indicating its potential as a promising gene therapy approach for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adeno-associated virus vector carrying human minidystrophin gene SMCKA3999 effectively ameliorates dystrophic pathology in mdx model mice]. Li, HH., Zhang, SM., Fang, SY., et al.[2012]

Citations

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

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. [2022]

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

Enhancement of muscle gene delivery with pseudotyped adeno-associated virus type 5 correlates with myoblast differentiation. [2018]

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

Transient immunomodulation allows repeated injections of AAV1 and correction of muscular dystrophy in multiple muscles. [2022]

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

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. [2022]

5. England pubmed.ncbi.nlm.nih.gov

AAV-based gene therapies for the muscular dystrophies. [2022]

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

Prevalence of Adeno-Associated Virus-9 Neutralizing Antibody in Chinese Patients with Duchenne Muscular Dystrophy. [2023]

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

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'. [2023]

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

Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. [2018]

10. China pubmed.ncbi.nlm.nih.gov

[Adeno-associated virus vector carrying human minidystrophin gene SMCKA3999 effectively ameliorates dystrophic pathology in mdx model mice]. [2012]