ADEL-Y01

None Alfred W. Sandrock, Jr., M.D., Ph.D.Chief Executive Officer of Voyager TherapeuticsAs the annual Clinical Trials on Alzheimer’s Disease (CTAD) conference approaches, new data on emerging targets such as tau and advanced delivery methods are converging.Researchers in the field of Alzheimer’s Disease (AD) are not known for optimism. We had decades with precious little to be optimistic about; decades in which one seemingly promising drug after another failed.Recently, the momentum in AD has begun to shift. We now have two FDA-approved drugs, lecanemab (Leqembi) and donanemab (Kisunla), shown to slow disease progression and cognitive and functional decline in some patients. Both drugs are anti-amyloid antibodies, and critics note that they are only about 30% effective. I would remind those critics that early drugs for multiple sclerosis were also only about 30% effective, while today’s MS drugs hit 60-70%; you have to start somewhere. In AD and neurodegenerative diseases in general, what has been particularly exciting is the speed at which human genetics and advances in brain imaging are helping us understand the molecular underpinnings of the disease – enabling us to know not only what to target, but how to reach it and how to measure the impact. Case in point is the explosion of interest around tau.The Emergence of Tau: the bullet causing neurodegeneration in ADWhile amyloid dominated AD research for decades, tau is emerging as the next critical target. Recent data have shown that the spread of pathological forms of tau protein in the brain is more closely correlated with the progression of dementia than amyloid. Increasing deposits of amyloid seem to cause tau to spread, and that spread of tau causes neurodegeneration. I often think of amyloid as the trigger, but tau as the bullet.Some of the most encouraging data on targeting tau to-date have come from Biogen’s BIIB080, an antisense oligonucleotide that, in an early clinical trial, robustly lowered tau burden as shown by tau PET imaging and resulted in favorable trends on cognition and function. Then at CTAD 2024, UCB made tau history by establishing with bepranemab that an antibody can inhibit the spread of pathological tau in the brain and slow cognitive decline – though the trial ultimately missed its primary endpoint on functional improvement.Large Phase II trials on Biogen’s BIIB080 and Johnson & Johnson’s anti-tau antibody posdinemab are expected next year. But in the interim, data on several other tau targeting programs are slated for presentation at CTAD this December, including Novartis’s NIO752, UCB’s bepranemab, Bristol Myers Squibb’s BMS-986446, Adel’s ADEL-Y01, and Voyager’s own VY7523. The Voyager team will continue to learn from the field as we complete our clinical trial of our anti-tau antibody VY7523, for which we expect tau PET imaging data next year, and prepare to move our tau silencing gene therapy VY1706 into the clinic next year.Brain-Targeted Delivery: The Key to Unlock AD Treatments?As exciting as the approved anti-amyloid and emerging anti-tau antibodies are, the hard truth remains that antibodies don’t get into the brain particularly well: on average only about 0.1% to 0.5% of the antibody gets into the brain. Fortunately, antibodies are so potent that this miniscule amount is enough to make a therapeutic difference – but no one can call it efficient.Delivery to the brain has long been the white whale of neurology drug development: the blood-brain barrier keeps out most large molecule drugs. Improving delivery could increase efficacy through improved brain targeting, enhance safety by reducing peripheral exposure, and potentially lower costs by reducing required doses.At Voyager we, and companies across the industry, are prioritizing delivery platforms to unlock the therapeutic potential of multiple modalities in neurological diseases. Voyager’s TRACER™ AAV capsids are designed to enable gene therapies for neurological diseases by providing high brain penetration following intravenous dosing. We are using this delivery approach for VY1706, our tau silencing gene therapy, as well as for an APOE gene therapy program for AD and multiple other neurology programs.Another emerging area of interest in brain-targeted delivery is “shuttles,” which leverage receptors on the blood-brain barrier to carry large molecules across it. At CTAD, Roche will share data on trontinemab, a shuttled anti-amyloid antibody. Unshuttled, the antibody (gantenerumab) worked in fewer than 30% of patients and had about a 30% rate of a dangerous side effect, ARIA-E. Trontinemab, which uses a transferrin receptor shuttle to target the antibody to the brain, has shown effectiveness in 91% of patients and reduced ARIA-E to below 5%. Recently Voyager unveiled initial data with our Voyager NeuroShuttle™, which builds on first-generation transferrin receptor shuttles by leveraging a different receptor, ALPL, which has been integral in our gene therapy work. Initial preclinical data showed a distinct pharmacokinetic profile, with brain uptake sustained for greater than 3 weeks post-dose, versus less than one week for transferrin shuttles.More Voyager NeuroShuttle data are on the way – though not in time for CTAD 2025. Even so, the data emerging across the industry on tau-targeted therapies, biomarkers, and next-generation delivery platforms give me optimism – a rare gift for an AD researcher.