Gene Therapy for Canavan Disease Shows Early Promise in Safety and Pharmacodynamics

BridgeBio Pharma’s BBP-812, an investigational gene therapy for the treatment of Canavan disease, has a promising pharmacodynamic and safety profile, according to early data from the first 2 patients treated in the phase 1/2 clinical trial CANaspire (NCT04998396).

At 6 months post-treatment, the first participant showed a 77% reduction in N-acetylaspartate (NAA), considered a marker for disease severity, in the cerebrospinal fluid (CSF). The second participant showed an 89% reduction at 3 months. Additionally, magnetic resonance spectroscopy (MRS) imaging detected a 15% reduction in NAA in brain white matter in the first participant, and a more than 50% reduction in the second participant. Decreases in urine NAA levels of approximately 50% and 81% were observed in the first and second participants, respectively. However, it remains to be seen whether these reductions in NAA levels will relate to actual changes in motor assessments and other measures of clinical outcome.

BBP-812 has been well-tolerated, with no serious treatment-related adverse events reported for any patient involved in the study so far.

“To see this biochemical change suggests that we are reaching cells critical to the disease process, a milestone in this disease. The ongoing myelination seen on MRI and the new interactions witnessed between children and their parents are both encouraging," Florian Eichler, MD, director of the Leukodystrophy Service and principal investigator at Massachusetts General Hospital, and lead investigator of the CANaspire trial, said in a statement.¹

The open-label study is enrolling children up to 30 months of age who have a diagnosis of Canavan disease, including elevated urinary NAA, biallelic mutation of the ASPA gene determined at screening or documented in the participant's medical history, and active clinical signs. Children who have significantly progressed Canavan disease, characterized by presence of continuous/constant decerebrate or decorticate posturing, recurrent status epilepticus, or recalcitrant seizures that do not have a response to 3 or more antiepileptic medications, will be excluded from the study. Additional exclusion criteria are having received prior gene therapy or other therapy involving AAV and being treated with high-dose immunosuppressants.

A total of 18 participants are expected to enroll in the study, which includes a dose-finding phase and an expansion phase. In the dose-finding portion, participants will receive a single intravenous (IV) infusion of either low-dose (Cohort 1) or high-dose (Cohort 2) BBP-812. In the expansion phase, participants will receive a single IV infusion of BBP-812 at a selected dose from the dose-finding phase. The primary end point for safety will be the number of participants who experience adverse events. The primary efficacy end points will measure change from baseline to 12-months post-infusion in urine NAA and in central nervous system NAA. Secondary end points include change from baseline to 12-months in gross and fine motor assessments, cognitive assessments, communication assessments, and adaptive function assessments.

“Taken together, these robust decreases in urine, cerebrospinal fluid (CSF) and brain N-acetylaspartate (NAA), along with MRI signs of new myelination reported by the principal investigator are exciting and suggest we are on the right track when it comes to potentially making a difference for patients with this disease, and we look forward to gathering more data as the trial progresses,” said Genevieve Laforet, MD, PhD, vice president of clinical development at Aspa Therapeutics, the BridgeBio Gene Therapy affiliate company developing the gene therapy for Canavan disease. “We are continuing to recruit and dose new participants for CANaspire and we are grateful to be able to collaborate with the advocacy organizations in the Canavan community in the pursuit of potential meaningful therapeutic advances for children with this cruel and fatal disorder.”

Data from the first 2 patients will be presented at the National Tay Sachs & Allied Diseases Association Annual Family Conference in Denver, Colorado on July 8, 2022. Further data from the study is expected to be announced later this year.