Gene Therapy for Canavan Disease

(CANaspire Trial)

Recruiting at 2 trial locations

Overseen By Mary Rohrer, RN, BSN

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Aspa Therapeutics

Must not be taking: Immunosuppressants, Anti-epileptics

Disqualifiers: Anti-AAV9 antibodies, Prior gene therapy, others

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

Compensation: Varies

Number of Visits: 2

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy called BBP-812 to help children with Canavan disease, a rare brain condition. Researchers aim to assess the safety and mechanism of this treatment by testing different doses. Participants will receive a single infusion of BBP-812, either a low or high dose, to determine which is most effective. The trial seeks young children diagnosed with Canavan disease who have stable health. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes participants who are on high-dose immunosuppressants or have seizures that don't respond to three or more anti-epileptic medications.

Is there any evidence suggesting that BBP-812 is likely to be safe for humans?

Research has shown that BBP-812, a gene therapy being tested for Canavan disease, has generally been well-tolerated in studies so far. In previous studies, participants demonstrated a decrease in NAA levels, a substance usually elevated in children with Canavan disease. This suggests a positive effect from the treatment.

Safety checks revealed that the doses given to both animals and humans did not cause severe negative effects. The highest dose tested in animals proved safe, supporting further development of BBP-812. However, this treatment remains experimental and has not yet received full FDA approval for safety and efficacy. While early results are promising, more research is needed to fully understand the safety of BBP-812 in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Canavan Disease focus on managing symptoms and providing supportive care, as there currently isn't a cure. However, BBP-812 is unique because it aims to address the root cause of the disease through gene therapy. BBP-812 uses a viral vector to deliver a functional copy of the ASPA gene directly into patients' cells, potentially correcting the underlying genetic defect. Researchers are excited about this approach because it offers the possibility of long-term benefits from a single infusion, which is a significant advancement over existing therapies that do not modify the disease itself.

What evidence suggests that BBP-812 might be an effective treatment for Canavan disease?

Research has shown that BBP-812, a gene therapy, could be promising for treating Canavan disease. In this trial, participants will receive different doses of BBP-812. Previous studies demonstrated that patients who received BBP-812 experienced significant drops in N-acetylaspartate (NAA), a substance that accumulates in people with Canavan disease. Specifically, the low dose led to an average NAA reduction of 64.3%, while the high dose resulted in a 73.3% reduction. These decreases appeared in both urine and the fluid around the brain and spine. Such changes suggest that BBP-812 might help manage the condition, offering hope for a treatment option where none currently exists. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for children up to 30 months old with Canavan disease, a stable health condition, and no other serious diseases. They must have a genetic mutation in the ASPA gene and show signs of Canavan disease. Kids who've had previous gene therapy or certain immunosuppressants, or those with severe seizures uncontrolled by medication can't participate.

Inclusion Criteria

I have been diagnosed with Canavan disease through tests and symptoms.

I have a genetic mutation in the ASPA gene.

I'm sorry, but "Elevated urinary NAA" is not clear enough for me to simplify it for a fifth grader. Could you please provide more context or details about this criterion?

Exclusion Criteria

I exhibit involuntary, rigid body postures.

My Canavan disease has significantly worsened.

You have a positive result for antibodies against AAV9 when tested with a specific method called ELISA.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Finding Phase

Participants receive a single intravenous infusion of BBP-812 at either low or high dose on Day 0

1 day

1 visit (in-person)

Enrollment Expansion Phase

Participants receive a single IV infusion of BBP-812 at the selected dose from the dose-finding phase on Day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• BBP-812

Trial Overview The study tests BBP-812, an experimental gene therapy using AAV9 to treat Canavan disease in young children. It aims to assess how safe it is, how well patients tolerate it, and its effect on the body's functions related to the disease.

How Is the Trial Designed?

Group I: Enrollment Expansion Phase: BBP-812 Experimental Treatment 1 Intervention

Participants will receive a single IV infusion of BBP-812 at the selected dose from the dose-finding phase on Day 0 in expansion phase of the study.

Group II: Dose-Finding Phase: BBP-812 Dose Level 2 (Cohort 2) Experimental Treatment 1 Intervention

Participants will receive a single IV infusion of high-dose BBP-812 on Day 0 in the dose-finding phase of the study.

Group III: Dose-Finding Phase: BBP-812 Dose Level 1 (Cohort 1) Experimental Treatment 1 Intervention

Participants will receive a single intravenous (IV) infusion of low-dose BBP-812 on Day 0 in the dose-finding phase of the study.

Who Is Running the Clinical Trial?

Aspa Therapeutics

Lead Sponsor

Trials

2

Recruited

100+

Published Research Related to This Trial

A novel dual-function gene therapy approach combining ASPA gene replacement and suppression of the NAT8L enzyme showed promising results in reversing symptoms of Canavan disease in a mouse model, significantly reducing brain vacuoles and other pathological features.

This late-stage gene therapy not only improved neurological function but also suggests the potential for a permanent treatment option for Canavan disease, expanding the possibilities for future therapies in adult patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual-function AAV gene therapy reverses late-stage Canavan disease pathology in mice. Fröhlich, D., Kalotay, E., von Jonquieres, G., et al.[2023]

Canavan disease is a rare genetic disorder caused by mutations in the ASPA gene, leading to severe neurological symptoms that typically appear between 3 to 5 months of age.

Cranial ultrasound findings in a patient with Canavan disease suggest a characteristic pattern that may help in early diagnosis, as observed through comparisons with other documented cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain ultrasound in Canavan disease. Drera, B., Poggiani, C.[2021]

This clinical protocol outlines a groundbreaking approach using virus-based gene transfer to treat Canavan disease, a severe childhood disorder caused by a defective gene for the enzyme aspartoacylase, affecting brain myelination.

The study involves administering approximately 900 billion genomic particles of a recombinant adeno-associated virus (AAV) containing the functional ASPA gene directly into the brains of 21 patients, marking the first use of AAV for gene therapy in humans and potentially offering a new treatment avenue for neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Janson, C., McPhee, S., Bilaniuk, L., et al.[2012]

In a trial for Canavan disease involving a single patient, dual administration of gene therapy (intravenous and intracerebroventricular) led to significant improvements in white matter myelination and motor function over two years, while preventing severe epilepsy.

Prophylactic immunomodulation was effective in preventing immune responses to the therapy, allowing for repeat dosing and indicating that this approach may enhance the safety and efficacy of gene replacement therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation. Corti, M., Byrne, BJ., Gessler, DJ., et al.[2023]

The study involved ten subjects receiving a gene therapy for Canavan disease using a viral vector (rAAV2) delivered directly to the brain, which showed promising safety with minimal immune response and inflammation.

Most subjects (7 out of 10) did not develop neutralizing antibodies against the AAV2 vector, indicating that the treatment is well tolerated and suggesting a relatively safe profile for further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune responses to AAV in a phase I study for Canavan disease. McPhee, SW., Janson, CG., Li, C., et al.[2012]

Gene therapy using recombinant adeno-associated viruses (rAAVs) significantly improved survival and alleviated symptoms in a mouse model of Canavan's disease, extending the lifespan of treated mice to up to 2 years when administered as late as postnatal day 20.

The study successfully employed microRNA-mediated detargeting to limit the expression of therapeutic genes to the central nervous system, reducing the risk of harmful effects from overexpression in other tissues, while still enhancing CNS myelination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. Ahmed, SS., Li, H., Cao, C., et al.[2022]

A new knock-out mouse model for Canavan disease has been successfully created, which displays neurological impairments and elevated N-acetylaspartic acid (NAA) levels, mimicking the human condition.

This model will aid in the development of gene therapy vectors for Canavan disease and enhance understanding of its pathophysiology, potentially benefiting research on other neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. Matalon, R., Rady, PL., Platt, KA., et al.[2012]

Citations

1. bridgebio.com bridgebio.com/news/bridgebio-receives-fdas-regenerative-medicine-advanced-therapy-rmat-designation-for-bbp-812-canavan-disease-gene-therapy-program/

BridgeBio Receives FDA's Regenerative Medicine ... All patients dosed with BBP-812 with at least one follow-up assessment have shown reductions in N-acetylaspartate (NAA), both in urine and in ...

2. ulf.org ulf.org/2024/10/bridgebio-shares-positive-data-from-canavan-disease-study/

BridgeBio Shares Positive Data from Canavan Disease Study To date, the average reduction in urine NAA at the low dose was 64.3% and 73.3% at the high dose. An average reduction of 70% in cerebrospinal ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04998396

NCT04998396 | A Study of AAV9 Gene Therapy in ... The main objective of this trial is to evaluate the safety, tolerability, and pharmacodynamic activity of BBP-812, an investigational AAV9-based gene therapy, ...

4. bridgebio.com bridgebio.com/news/bridgebio-shares-positive-data-from-high-dose-cohort-of-phase-1-2-canaspire-study-of-gene-therapy-bbp-812-for-canavan-disease-at-esgct-2024/

BridgeBio Shares Positive Data from High Dose Cohort of ... BridgeBio's gene therapy for Canavan disease could be the first therapeutic option for children born with this fatal neurodevelopmental disorder.

5. treatcanavan.com treatcanavan.com/wp-content/uploads/2024/04/2023-NTSAD-Family-Conference-Aspa-Presentation-20230523.pdf

Aspa Therapeutics' BBP-812 Gene Therapy Program for ... The following slides show early data from Aspa's investigational gene therapy BBP-812 which has not been evaluated as safe and effective by the FDA or other ...

6. bridgebio.com bridgebio.com/wp-content/uploads/2021/09/BBIO-Canavan-GTx-BBP-812-ASGCT-2021-NHP.pdf

Safety Evaluation of IV-administered BBP-812, an AAV9- ... NOAELs were determined to be 3.18x1014vg/kg in NHP and 3.0x1014 vg/kg in mice. • Results support the continued clinical development of BBP-812 for the treatment ...