BridgeBio Pharma’s Gene Therapy BBP-812 Demonstrates Biomarker Reductions in Patients With Canavan Disease

Florian Eichler, MD

The latest findings from CANaspire were presented orally in a session entitled “Gene and Cell Therapy Trials in Progress” at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, by Florian Eichler, MD, a neurologist at Massachusetts General Hospital. During the presentation, Eichler discussed the findings from the study’s evaluations of NAA levels in the urine, cerebrospinal fluid (CSF), and brain, along with some additional preliminary efficacy and safety results.

Shortly before the presentation, CGTLive™ spoke with Eichler about the results and their implications for the healthcare community. He emphasized the importance of early diagnosis and newborn screening for rare inherited diseases like Canavan disease, particularly as gene therapy clinical trials for these indications become more prevalent.

CGTLive: Can you give some background about Canavan disease?

Florian Eichler, MD: I'm presenting on a systemic AAV9-mediated gene therapy for Canavan disease. Canavan disease is a devastating monogenic disorder of early childhood leading to spongiform encephalopathy. There's high unmet need and there's currently no treatment options for these children.

Can you give an overview of the key results that you are presenting at ASGCT’s 2023 conference?

Canavan disease leads to accumulation of NAA, as the enzyme that degrades it is deficient. There's accumulation of NAA in multiple body parts including the brain and kidney. These children develop white matter lesions in the brain that are confluent and destructive. None of these children normally reach any developmental milestones. We've treated 6 children so far under the age of 30 months with systemic AAV9 delivering a healthy copy of the ASPA gene at a low dose of 1.3x10¹⁴ genome copies per kilo.

The 6 children, to date, have all shown dramatic reductions in urine NAA, as well as NAA in the brain as evidenced by CSF and magnetic resonance spectroscopy. We've seen new myelination occur in the brainstem and cerebellar peduncles that has made us very hopeful about future outcomes. So far, we have follow-up periods from 1 month to 17 months and some of these children are starting to raise their head and establish more eye control, and 1 patient in particular is sitting independently and taking steps and walking—and that is certainly something I've never seen with Canavan disease, and it is a true delight as a child neurologist to have such a success on hand. So, it's still early days, but the data are very encouraging and we're excited about the future for Canavan disease.

What would you say are the main implications that the healthcare community should take away from these findings?

I think for the general practitioner, or the neurologist, who might be seeing these kinds of patients: early identification is key. There are now trials that are available that are delivering safely a healthy copy of the gene. This has the potential to really allow for some of these children to attain milestones that have never been seen before. But it all requires a timely diagnosis and referral to trial sites. And we're hoping that in the future this [trial] will lead to an eventual approval, but we're still years away from that.

Have there been any challenges or limitations in the study that you have encountered so far or areas of interest for future research that you can discuss?

As with most systemic AAV gene therapy trials, there have been immune responses. We see transient drops in platelets, as well as some elevation in liver function enzymes, but all of these we've been able to manage with both preventive high dose steroids, as well as rescue steroids, to date. There certainly is a need to develop future research around understanding how to modulate immune responses. In addition, we are still awaiting results on the higher dose cohort. Knowing that we can [treat patients at the high dose] safely and effectively will be key.

Is there anything else you'd like to share with the audience?

I think, for the most part, there's always been a question in the community at large as to why you should diagnose conditions that you cannot treat or that you don't have good options for. I think with the progress in gene therapy, this is a rapidly changing landscape. I would encourage the practitioner in the field to take this opportunity to sort of say, “Maybe early diagnosis and, eventually, newborn screening could alter the plight of these families and that is a worthy goal that as a community we can strive for.”

Transcript edited for clarity.

Click here for more coverage of ASGCT 2023.

REFERENCE
1. Eichler F, Nagy A, Laforet G, et al. Initialvbiomarker and clinical findings from the CANaspire Canavan disease gene therapy trial: Exploration of connections between NAA and disease severity. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Abstract #358.