The wins in brain conditions like Alzheimer’s, Huntington’s and Parkinson’s disease are beginning to stack up. But one major challenge still stands in the way of many promising treatments: the blood-brain barrier.
Drug development for brain diseases is surging. In 2024, clinical trials rose by nearly 15%, making the central nervous system one of the fastest-growing R&D therapeutic areas, according to Citeline.
But the BBB, which protects the brain from viral and bacterial invaders, also repels an estimated 98% of drugs. Even drugs approved to treat neurodegenerative diseases have trouble getting through. Some studies suggest that less than 0.1% of a dose of the Alzheimer’s drug Leqembi makes it into the brain after intravenous administration.
To overcome this problem, medications destined for the brain often require multiple high doses. As a result, researchers have had to shelve promising candidates because the doses needed are too high to be used safely.
Biotechs like Denali Therapeutics are looking to change that. Denali has filed an approval application for a drug that uses new technology to transport drugs directly into the brain, potentially ushering in a new era of brain drug development.
The company received FDA fast track status for the drug tividenofusp alfa to treat Hunter syndrome, a rare disease that causes progressive brain and organ damage. Despite an earlier delay, the candidate has a regulatory decision deadline of April 5.
If approved, tividenofusp alfa would be the first to use the company’s modular transferrin receptor-enabled TransportVehicle platform designed to carry enzymes, oligonucleotides and antibodies across the BBB.
Denali’s candidate delivers the missing enzyme that drives Hunter syndrome, which is difficult to shuttle past the BBB. But patients in a mid-stage trial showed a 91% reduction in heparan sulfate, a biomarker for the disease. They also showed early signs of improvement in hearing and on key measures of adaptive behavior and cognition at 24 weeks.
The shuttle technology could also become a platform for other treatments, Denali CEO Ryan Watts said in a statement.
“In addition to evaluating our TransportVehicle to enable enzyme replacement across lysosomal storage disorders and neurodegenerative diseases, we are pursuing the potential of the platform to deliver antibodies and oligonucleotides for diseases that impact the brain,” Watts said.
The BBB pipeline
Pharma giant Roche has also taken a similar BBB-bypassing technology into clinical trials with trontinemab to treat amyloid plaques that often accompany Alzheimer’s disease. According to a Roche spokesperson, the Brainshuttle technology works by binding the extracellular domain of transferrin receptors expressed at the BBB.
“This protein is highly expressed on endothelial cells of the blood-brain barrier and involved in the supply of the brain with iron,” the spokesperson said in an email.
Because the technology can carry large-molecule drug types, including enzymes, oligonucleotides and gene therapies, it could have broad applications that include other neurodegenerative diseases, movement disorders, multiple sclerosis and neurodevelopmental disorders, the spokesperson said.
The company recently announced a partnership with Manifold Bio, which will help it further expand work in this space. The deal allows Roche access to Manifold’s AI technology, which helps ferret out new biological pathways to get medications into specific tissues, allowing Roche to build on the shuttle technology.
Other earlier-stage companies working on BBB transport technology include Vect-Horus, which has partnered with Novo Nordisk and Ionis Pharmaceuticals. The Korean biotech ABL-Bio also recently announced a licensing agreement to allow GSK use of its BBB shuttle platform.
Beyond the barrier
In addition to companies using shuttle technology, researchers are trying other novel ways to bypass the BBB, one of which uses focused ultrasound to breach the cellular wall.
A study led by Dr. Ali Rezai, a neurosurgeon at the Rockefeller Neuroscience Institute in Morgantown, West Virginia, showed that using ultrasound to activate tiny expanding and contracting bubbles could create temporary openings. The MRI-guided procedure allowed an Alzheimer’s drug to penetrate the brain more effectively and reduce beta amyloid plaque.
Other research is exploring strategies like electromagnetic fields or intranasal delivery.
