Dosing Commenced for Phase 1a Study of Anti-Tau Antibody VY-TAU01 in Alzheimer Disease

Toby Ferguson, MD, PhD

According to a new announcement, the first participants in a phase 1a study assessing Voyager Therapeutics’ anti-tau antibody VY-TAU01, an investigational agent in development for Alzheimer disease (AD), have been dosed. VY-TAU01 us an intravenously-administered, recombinant, humanized IgG4 monoclonal antibody designed to inhibit the spread of pathological tau, which is closely correlated with disease progression and cognitive decline in AD.¹

The study, a single-ascending dose (SAD), double-blind, placebo-controlled trial, is conducted at a single center and is expected to enroll approximately 48 healthy volunteers in multiple cohorts. The belief is that results from this study will help inform the design of a phase 1b multiple ascending dose trial of patients with early AD, which Voyager expects to initiate in 2025. In addition, the company is expecting initial tau PET imaging data from the MAD to be released in the second half of 2026, which will help determine VY-TAU01’s true impact on pathological tau.

According to Voyager, VY-TAU01 is differentiated from other anti-tau antibodies based on the epitope it targets, which is located in the C-terminal rather than the N-terminal, mid-domain, or microtubule binding region of the tau protein. At the 2022 Alzheimer’s Association International Conference (AAIC), the company presented data demonstrating that an anti-tau antibody delivered intravenously inhibited the spread of pathological tau by more than 70% in a mouse seeding model.

"The initiation of clinical development of VY-TAU01 for the treatment of Alzheimer’s disease is an important milestone for Voyager; it demonstrates the executional abilities of our neurology drug development team, which will be central to our advancement of three wholly-owned and partnered neurology gene therapies towards IND filings next year," Toby Ferguson, MD, PhD, chief medical officer at Voyager, said in a statement.¹ "Alzheimer disease remains an area with tremendous unmet patient need, despite recent advances. We are encouraged by our preclinical data demonstrating the ability of VY-TAU01 to significantly slow tau spreading, and we look forward to evaluating the therapeutic potential of VY-TAU01 in the clinic."

In the analysis presented at AAIC 2022, voyager collected a diverse starting pool of 728 anti-tau antibodies/hybridomas targeting pathological tau from human AD brain. Of these, 4 antibodies (AB01, AB03, AB04, and Human AB5) were selected, each with novel sequences and epitopes that fit the target profile based on selectivity, functional inhibition in vitro and in vivo, and developability. Using a spaghetti plot, data demonstrated a robust reduction of tau pathology spreading from the hippocampus from the mice treated with AB01, AB03, AB04, and AB05, with AB01 demonstrating the best efficacy.²

Over the years, the limited success of amyloid-ß-targeting therapies for AD has led to a shift in focus towards the tau protein–the main component of the neurofibrillary tangles that comprise the other major pathological hallmark of AD. Most of the tau-targeting therapies in ongoing trials are immunotherapies, which can target tau intracellularly and/or extracellularly. The choice of epitope, the antibody subclass and its charge, the patient population, and mechanism of action have been noted as important aspects when selecting antibodies and vaccines for clinical trials.³

REFERENCES
1. Voyager Therapeutics announces first participants dosed in single ascending dose trial of VY-TAU101 for the treatment of Alzheimer’s disease. News release. Voyager Therapeutics. May 16, 2024. Accessed May 16, 2024. https://www.biospace.com/article/releases/voyager-therapeutics-announces-first-participants-dosed-in-single-ascending-dose-trial-of-vy-tau01-for-the-treatment-of-alzheimer-s-disease/
2. Liu W, Kurella V, Liu L, et al. Identification and characterization of novel anti-tau antibodies that inhibit tau-seed mediated pathology in a PS01S tauopathy mouse model of Alzheimer’s disease and tauopathies. Presented at: 2022 Alzheimer’s Association International Conference. ABSTRACT 62878
3. Congdon EE, Ji C, Tetlow AM, Jiang Y, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease: current status and future directions. Nature Reviews Neurol. 2023;19:715-736. doi:10.1038/s41582-023-00883-2