Anti-Tau Agent Bepranemab Slows Tau Accumulation in Phase 2 TOGETHER Trial

In the phase 2 TOGETHER trial (NCT04867616), treatment with UCB’s bepranemab, an investigational monoclonal antibody targeting tau protein, led to slowing of tau accumulation in the tau mid-region in patients with prodromal to mild Alzheimer disease (AD). According to the study authors, this was the first clinical demonstration of such slowing, and marked the first time any tau-directed therapy has demonstrated a clinical benefit.¹

Presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada, the study included 466 patients who were randomly assigned 1:1:1 across 3 arms: 90 mg/kg bepranemab, 45 mg/kg bepranemab, and placebo. Across both arms, treatment with the tau-targeting therapy led to reduced tau accumulation by 33-58% relative to placebo after 80 weeks.

Study author William Byrnes, MD, global development lead at UCB, and colleagues used Genentech tau probe 1 (GTP1) and PET imaging tools at baseline, week 56, and week 80. The study comprised individuals aged 50-80 years with prodromal-mild AD, defined as National Institute on Aging and Alzheimer’s Association 2018 criteria Stage ¾. Coming into the study, patients had global Clinical Dementia Rating (CDR) score of 0.5, and CDR-Memory Box score of at least 0.5.

In the latest AAIC data, bepranemab-treated patients had slowed tau accumulation in whole cortical gray (n = scanned/total: 90 mg/kg bepranemab [113 of 152]; 45 mg/kg bepranemab [104 of 152]; and placebo [97 of 156]) and jack temporal meta regions (90 mg/kg bepranemab [114 of 152]; 45 mg/kg bepranemab [105 of 152]; and placebo [97 of 156]) at week 80.

READ MORE: Biogen Showcases Promising 4-Year Data for Alzheimer Therapy Lecanemab at AAIC 2025

At the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, data from TOGETHER showed that the investigational agent had no effect on the primary end point of change in CRD-Sum of Boxes total score, compared with placebo at 80 weeks. Despite these results, bepranemab-treated patients showed a significant improvement in change between baseline and week 80 in Alzheimer’s Disease Assessment Scale-Cognitive Subscale total score, a secondary end point of the study.²

Additional data from the previous readout highlighted a consistent treatment effect in a subgroup of patients with low tau burden who were non-carriers for apolipoprotein e4 (APOE4). In this post-hoc subgroup analysis, high-dose bepranemab (90 mg/kg) slowed the rate of tau accumulation vs placebo in key brain regions by 63%-67% at week 80, and slowed clinical progression by 29%, as measured by change in CDR-SB. In contrast, those with high tau at baseline who were APOE4 carriers had no benefit from high-dose bepranemab across clinical end points such as CDR-SB, A-iADL-Q, and ADSC-ADL scores.

In the previous update, Bepranemab had an acceptable safety profile, with an incidence of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and TEAEs leading to dropout that were similar to that observed with placebo. Most reported TEAEs were infections and infestations (placebo: 50.3%; bepranemab: 50.2%), nervous system disorders (placebo: 40.1%; bepranemab: 35.2%), and musculoskeletal disorders (placebo: 26.8%; bepranemab: 28.3%).

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REFERENCES
1. Maguire RP, Byrnes W, Barton ME, et al. Tau positron emission tomography results from TOGETHER, a double-blind, placebo-controlled Phase II study of bepranemab in prodromal–mild Alzheimer’s disease. Presented at: AAIC 2025; July 27-31; ABSTRACT 99279
2. UCB Presents Encouraging Data on Bepranemab in Early Alzheimer’s Disease in Phase 2a Study at CTAD 2024. News release. UCB. October 31, 2024. Accessed August 1, 2025. https://www.ucb.com/newsroom/press-releases/article/ucb-presents-encouraging-data-on-bepranemab-in-early-alzheimer-s-disease-in-phase-2a-study-at-ctad-2024