Children diagnosed with Canavan disease, who have always faced a grim prognosis—the inability to speak, walk, or maintain head control for their short lifespans with this fatal rare neurodegenerative disorder—may soon be treatable, even “curable.”
At the 31st annual European Society for Cell and Gene Therapy (ESCGT) meeting, BridgeBio presented positive data on gene therapy BBP-812 for Canavan Disease, currently being evaluated in an open-label phase I/II clinical study called CANaspire. For the first time, BridgeBio is showing that BBP-812 can deliver a gene therapy to correct the aspartoacylase gene (ASPA), which can reduce levels of its substrate, the causative toxic substrate N-acetyl-aspartate (NAA).
Eric David, MD, CEO of Gene Therapy and U.K. R&D at BridgeBio, told Inside Precision Medicine, “We have a participant who’s walking unassisted, and others are walking with minimal support. We’re seeing things that we’ve never seen children with Canavan have been able to do. That’s a pretty good sign when you can say it’s the first-in-human case.”
A thirty-year journey
To fully appreciate BridgeBio’s Canavan disease drug program, one must go back to the mid-1990s. Guangping Gao, known for discovering AAV9 in 2004 while at Jim Wilson’s lab, cloned the gene for Canavan disease and has been working on a gene therapy for this specific leukodystrophy ever since.
The first two clinical trials of gene transfer therapy for Canavan disease were conducted in 1996 and 1998. They demonstrated that intraventricular administration of a nonviral vector containing the ASPA gene was safe, but clinical improvements were limited and variable between individuals.
Over the last decade, Gao’s lab at the University of Massachusetts has brought his work in AAV and Canavan disease together, developing a gene therapy that has shown promise in animal models, with intravenous and intracerebroventricular delivery of a recombinant AAV gene therapy that prevents Canavan disease and extends survival in a mouse model. Further optimization of this gene therapy not only completely prevented Canavan disease in mice but also rescued mice after the onset of symptoms. These preclinical studies led to BridgeBio’s BBP-812 and the CANaspire trial.
In early September, BridgeBio announced receiving Regenerative Medicine Advanced Therapy (RMAT) Designation for its BBP-812 Canavan Disease Gene Therapy Program. This designation will enable early and more frequent interactions with the FDA to establish an Accelerated Approval pathway for BBP-812.
According to David, what’s remarkable is the durability of the treatment. “The ability to very quickly reduce the NAA levels and keep them down as far as three years out and the patients who are the longest out in the study down to levels associated with much milder disease and then see that correlate with improvements in these different metrics of clinical function, whether they be the gross motor scales or eye tracking, head control, reaching and grasping, sitting up.”
The rare disease financial model
BridgeBio remains very committed to tackling rare diseases that most companies will not tackle. Running a successful business focused on treating rare diseases requires a unique financial design, which, according to David, is why Andrew Lo, an MIT economist, is one of BridgeBio’s co-founders.
“Andrew believed that with a balanced portfolio of larger rare diseases and smaller rare diseases, you can get to the rare diseases that most pharma companies would regard as too small to treat,” said David. “Canavan is one of those programs that all the major pharma companies pass on.”
David said that even after Novartis acquired AveXis for $8.7 billion in 2018 to target spinal muscular atrophy (SMA), rare diseases like Canavan were still considered too small for pharmaceutical companies to tackle.
“After the AveXis acquisition, when everyone was acquiring programs like crazy, it was still on the very small side, and that’s 1,000 patients—there are smaller patient [populations],” said David. “We go after the targets and diseases where we feel there is a true unmet need and have a good probability of success based on our technical criteria. We will take on diseases on the smaller and larger sides within rare diseases.”
The smallest program that Bridge had is a drug for Molybdenum cofactor deficiency (MoCD) type A, a rare genetic disorder that causes brain dysfunction and other health problems with about a hundred patients a year in the world. In 2021, they got approval for that drug, Nulibry.
“No company can have a portfolio of only n of 10 or 20 diseases; it’s just that’s not financially viable,” said David. “All of us, including our board and our investment committee, are committed to the model of going after rare diseases in a way that does allow us to tackle some of these diseases that everyone else looks at and says, ‘We just can’t do that because it’s too small.’”
An evergrowing toolkit
The financial aspect gets tricky because focusing on rare diseases requires being therapeutic modality agnostic, according to David. After all, each requires bespoke treatment and works with different patient populations.
“We reserve gene therapy for those cases where we just cannot drug a disease any other way,” said David. “Small molecules and conventional biologic approaches will probably not be amenable. However, it is still a disease where we feel a true unmet need and a good scientific hypothesis. I feel that’s the way to use gene therapy. You have to be selective since it’s a more expensive and time-consuming modality. It’s hard to be a rare disease company focused on genetic diseases if you don’t have gene therapy in your toolkit.”
David said he will always look for the best treatment option, including gene editing. To him, CRISPR is another potential tool, and if there are disorders where BridgeBio feels like gene editing would be a better approach than gene replacement, they will find a way to do that.
Working with different modalities, BridgeBio has adopted a model of outsourcing clinical trial-scale and GMP manufacturing, though smaller-scale manufacturing, such as that for preclinical studies, is done in-house. To keep manufacturing costs down, BridgeBio designs and optimizes its vectors in-house, which is cheaper and faster, and then hands over a fully optimized process to a contract manufacturer.
“The nice thing is you can scale that to any size,” said David. “For ultra-rare diseases, one could work on a 200-liter scale and have as much as you may need for the entire population of that community, but you can also scale up from there. We’ve worked in 200 liters, we’ve worked in 500 liters, we’ve worked in 1000 liters—it really depends on the program. You can scale it, and it’s cheaper and easier to scale than the kind of manufacturing you’d have to do for CAR T’s, where cell therapy manufacturing introduces a whole other set of challenges at scale.”
It takes a village
Core to BridgeBio is the belief that success for any rare disease program requires talking to members of the rare disease communities because, as David put it, they are experts in the diseases.
“What I think is so interesting about these rare neurological disease communities is that they know more about these diseases than most clinicians in the world do, even more than most pediatric neurologists know,” said David.
BridgeBio routinely invites members of the community into their labs to learn from them what success would look like. For example, with Canavan disease, David said connecting with the patient community to answer their questions about gene therapy, such as the cost and when to intervene, is vital to rolling out a successful clinical trial. To facilitate these interactions, BridgeBio routinely hosts patients for a day, typically at least once a quarter.
“They are incredibly realistic about what can and cannot be achieved,” said David. “They have no expectation that all of a sudden children will be normal for every aspect of cognitive or motor function. But they will come in, and they’re very thoughtful about saying, ‘Here’s what success looks like for me. If my child could look me in the eyes and track things with their eyes, if they could hold a toy and play with a toy, if it didn’t look to me as if they were constantly uncomfortable and in pain, if they could sit up, that would change my life because the level of care that I have to provide for them when they can’t sit up is very different from the level of care if they’re able to sit up on their own.’”
If approved, BridgeBio’s gene therapy for Canavan disease could be the first therapeutic option for children born with this devastating and fatal neurodevelopmental disorder.
