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 explores a new treatment called BB-301 (also known as AXO-AAV-OPMD) for individuals with oculopharyngeal muscular dystrophy (OPMD), a form of muscular dystrophy that affects swallowing. The main goals are to assess the treatment's safety, determine the optimal dose, and evaluate its impact on swallowing difficulties. Participants must have been part of a previous OPMD study and continue to experience swallowing issues. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative therapy.

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 there any evidence suggesting that BB-301 is likely to be safe for humans?

Research has shown that BB-301, a new treatment for oculopharyngeal muscular dystrophy (OPMD), is generally well-tolerated in early studies. The first three patients who received BB-301 did well over 3, 9, and 12 months, with no major safety issues reported.

The treatment involves a single injection into the throat muscles and aims to replace a faulty protein that causes muscle weakness. Although this might sound intense, data suggests the treatment is safe enough for continued testing. Prospective participants can find reassurance in the promising initial safety results. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for muscular dystrophy, which often focus on managing symptoms and improving quality of life, BB-301 takes a different approach by directly targeting the root cause of the disease at a genetic level. Researchers are excited about BB-301 because it uses gene therapy to deliver a modified version of a gene that can potentially restore muscle function. This innovative mechanism could provide a more effective and lasting solution, offering hope for improved outcomes in patients with muscular dystrophy.

What evidence suggests that BB-301 might be an effective treatment for muscular dystrophy?

Research has shown that BB-301, the investigational treatment in this trial, is a promising gene therapy for oculopharyngeal muscular dystrophy (OPMD). Early findings suggest that patients experience noticeable improvements in swallowing for up to 12 months post-treatment. This therapy targets the PABPN1 protein, linked to the disease, reducing its harmful effects and replacing it with a healthier version. Initial results from a few patients also demonstrated improved symptoms, supporting its potential effectiveness. Overall, BB-301 represents a new approach closely monitored for its ability to relieve OPMD symptoms. ^{1 2 3 4 6}

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

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

Citations

1. benitec.com benitec.com/for-investors/news-events/press-releases/detail/130/benitec-biopharma-reports-positive-interim-clinical-results-for-three-subjects-treated-with-bb-301-in-phase-1b2a-study-to-be-presented-at-the-2025-muscular-dystrophy-association-clinical-scientific-conference

News & Events Durable, clinically significant improvements in swallowing function achieved 12-months post-treatment with BB-301 for subject 1.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7940701/

BB-301: a silence and replace AAV-based vector for the ... A single intramuscular injection of BB-301 results in robust inhibition of mutant PABPN1 and concomitant replacement of the codon-optimized PABPN1 protein.

3. mdaconference.org mdaconference.org/abstract-library/interim-study-update-for-the-bb-301-gene-therapy-phase-1b-2a-first-in-human-trial-in-subjects-with-oculopharyngeal-muscular-dystrophy-with-dysphagia/

Interim Study Update for the BB-301 Gene Therapy Phase ... Interim study results for the first 3 subjects treated with BB-301 following 12-months, 9-months, and 3-months on treatment, respectively, demonstrate durable, ...

4. physicianfocus.nyulangone.org physicianfocus.nyulangone.org/gene-therapy-for-oculopharyngeal-muscular-dystrophy-shows-promising-results/

Gene Therapy Shows Promise for OPMD BB-301 is the first experimental gene therapy for OPMD to reach clinical trials. The first two patients treated exhibit improved symptoms.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06185673

NCT06185673 | A Study to Evaluate the Safety and Clinical ... A Study to Evaluate the Safety and Clinical Activity of Intramuscular Doses of BB-301 Administered to Subjects With Oculopharyngeal Muscular Dystrophy With ...

6. trialx.com trialx.com/clinical-trials/listings/254124/a-study-to-evaluate-the-safety-and-clinical-activity-of-intramuscular-doses-of-bb-301-administered-to-subjects-with-oculopharyngeal-muscular-dystrophy-with-dysphagia/?&geo_lat=40.7229&geo_lng=-73.8473&radius=10&place=Forest%20Hills&user_country=United%20States

A Study to Evaluate the Safety and Clinical Activity of ... A Study to Evaluate the Safety and Clinical Activity of Intramuscular Doses of BB-301 Administered to Subjects With Oculopharyngeal Muscular ...