Gene Therapy Continues to Show Promise in Canavan Disease


Participant 3 showed an 89% decrease in NAA in the CSF at 3 months post-treatment.

BridgeBio Pharma’s BBP-812, an investigational adeno-associated virus serotype 9 (AAV9) vector-based gene therapy intended to treat Canavan disease, has continued to demonstrate encouraging safety and efficacy in new data from the phase 1/2 CANaspire clinical trial (NCT04998396) which were presented in a poster at the 2022 Child Neurology Society conference held in San Francisco, CA, USA October 8-12, 2022.1,2

The new data included the study’s third participant (participant 3) and showed an 89% decrease in N-acetylaspartate (NAA) in the cerebrospinal fluid (CSF) and a 45% decrease in urine NAA at 3 months after administration of BBP-812. Additionally, participant 2 demonstrated continued reduction in urine NAA, reaching an 85% reduction at 6 months compared to pre-treatment levels. In terms of safety, it was noted that for all patients so far, the intravenous infusions of BBP-812 have been well-tolerated and no treatment-related serious adverse events (AEs) have been reported. This data was consistent with earlier data reported in June, which was previously covered by CGTLive.

"The most critical biomarker, in my mind, is NAA,” Guangping Gao, PhD, scientific founder, Aspa Therapeutics, a BridgeBio affiliate company which is developing BBP-812, said in a statement.1 “Reduction in NAA levels, whether in the brain, CSF fluids, or in the urine, may indicate a sign of improvement because the gene missing in Canavan disease directly leads to accumulation of NAA. So, showing that NAA is decreasing is very important.”

The study has dosed 3 patients so far, with patient 1 aged 27 months at the time of informed consent, patient 2 aged 18 months, and patient 3 aged 20 months.2 Patients 1 and 2 are male while patient 3 is female; patient 1 is Asian and patients 2 and 3 are white. All 3 patients have different mutations in the ASPA gene.

Although decreases ranging from 77% to 95% from baseline at 3 to 6 months after treatment in CSF NAA have been seen across the 3 patients, it was noted that NAA had not been reduced to non-Canavan levels. Despite this, NAA reduction was in general still greater than expected based on natural history data. The poster’s authors noted that the NAA decreases observed in the urine, CSF, and brain provide evidence for the successful restoration of aspartoacylase (ASPA), the enzyme encoded by ASPA. However, they pointed out that data from more participants and longer follow-up data are necessary to make clear the relationship between ASPA activity, decreased NAA, and clinical improvement. Functional data was measured with the Canavan Disease Rating Scale (CDRS). As of 292 days post-treatment, patient 1 showed a 2-point improvement from baseline on this scale, patient 2’s score had worsened by 2 points from baseline by 113 days post-treatment, and patient 3’s score had improved by 4 points from baseline at 56 days post-treatment. It was noted that patient 2’s score was stable overall except for feeding difficulties, which began worsening before dosing, and worsening epileptic seizures which were associated with systemic infection and reduced compliance with an oral anti-epileptic regimen.

So far, reported treatment-related AEs have been mild to moderate, and have included increased transaminases, lymphopenia, thrombocytopenia, vomiting, pyrexia, feeding disorder, irritability, and hypotension. A serious case of seizure occurred during treatment but was deemed unrelated to BBP-812. A data and safety monitoring committee (DSMC) endorsed continued enrollment and dosing based on a review of the safety data so far and provided a recommended immune prophylaxis regimen. All 3 participants received the trial’s lower dose, 1.32×1014 vg/kg.

CANaspire is currently active at Massachusetts General Brigham, Boston, MA, and activation of additional sites in the United States are pending. A separate study gathering additional natural history data, CANinform (NCT04126005), is also being carried out by Aspa Therapeutics.1 BridgeBio Pharma expects that additional efficacy, safety, and pharmacokinetic data from CANaspire will be announced in the first half of 2023.

“We are encouraged by the sustained reduction in key biomarkers for this condition, a novel observation in the treatment of Canavan disease, and by the early reports of improvement in function we are hearing from our investigator,” Genevieve Laforet, MD, PhD, vice president of Clinical Development, Aspa Therapeutics, added to the statement.1 “We are excited to continue advancing our development efforts for BBP-812 and look forward to our interactions with regulatory authorities to determine the optimal path for our program. Our deepest thanks go out to all the families in our natural history and gene therapy studies for their partnership as we work to deepen our understanding of Canavan disease and explore the potential of BBP-812 as a therapeutic option for Canavan patients.”

1. BridgeBio Pharma presents updated positive data from its BBP-812 Canavan disease gene therapy program at the 51st Annual Meeting of the Child Neurology Society. News release. BridgeBio Pharma, Inc. October 13, 2022. 
2. Eichler F, Laforet G, Andonian H, et al. CANaspire, a First-in-Human Phase 1/2 Controlled Open-Label Study of BBP-812, a Recombinant AAV9-hASPA Vector for the Treatment of Canavan Disease. Presented at: Child Neurology Society Annual Meeting San Francisco, CA, USA October 8-12, 2022.

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