UCB Pharma's bepranemab has shown the first signal that a monoclonal antibody might slow the progression of tau pathology in the brain, specifically in a subset of Alzheimer's patients. The Phase 2 TOGETHER trial, involving 466 participants with prodromal to mild Alzheimer's disease, revealed that while the drug did not meet its primary endpoint of improving cognition and function in the overall population, it did demonstrate a significant reduction in tau accumulation in a specific subgroup.
The findings, presented at the 16th Clinical Trials on Alzheimer’s Disease conference (CTAD), suggest that bepranemab may offer clinical benefits to individuals with low baseline tau levels and who are not carriers of the ApoE4 mutation. In this subgroup, bepranemab appeared to halve cognitive decline compared to placebo, as measured by the ADAS-Cog, a secondary outcome. Conversely, participants with high tau levels at baseline seemed to fare worse on the treatment than on placebo.
Implications for Tau-Targeting Therapies
"It’s an important milestone for the field," said Adam Boxer, University of California San Francisco, highlighting the potential of tau antibodies not only as treatments but also as tools to understand the role of tau seeding and propagation in driving Alzheimer's symptoms. Rakez Kayed, University of Texas Medical Branch, Galveston, echoed this sentiment, stating, "I think it’s really promising finally to see an antibody against tau moving the needle."
This development is particularly noteworthy considering that four earlier antibodies targeting the N-terminal region of tau failed to show any effect on tau clearance or symptoms in clinical trials. Martin Citron of UCB, Brussels, explained that these earlier antibodies might have been ineffective because the N-terminal region of tau is cleaved off before aggregation, rendering it irrelevant to the disease process. Bepranemab, along with most current investigational tau antibodies, targets the microtubule binding region (MTBR), which is crucial for tau aggregation and potentially the source of tau seeding in the brain.
Trial Details and Future Directions
The Phase 2 TOGETHER trial assessed bepranemab's impact over 80 weeks, revealing a reduction in tau accumulation measured by PET by up to 58 percent compared to placebo. However, the lack of measurable effect in people with the ApoE4 genotype remains a point of discussion among scientists, as the role of ApoE4 in tau propagation and its contribution to clinical symptoms are still debated.
Randall Bateman, Washington University, St. Louis, noted the parallels with anti-amyloid antibodies, which also tend to be most effective in the early stages of the disease. He suggested that identifying the right population and timing for treatment with tau antibodies is crucial to prevent the growth and spread of tau pathology.
UCB is currently considering whether to conduct another Phase 2 trial specifically targeting an early tau population before proceeding to a pivotal Phase 3 study. Michelle Farrell, Massachusetts General Hospital, Boston, emphasized the importance of using PET or fluid biomarkers to identify individuals most likely to benefit from immunotherapy, as low tau pathology burden does not always correlate with mild symptoms.
Other Tau-Targeting Approaches
Other companies are also actively pursuing tau-targeting therapies. Janssen is conducting the Autonomy Phase 2 trial for posdinemab, an antibody targeting phosphorylated tau near the p217 site in tau’s proline-rich mid-domain region. This trial is monitoring tau spread using tau PET to assess whether the antibody can reduce the propagation of tangles in the brain.
Eisai presented results for an open-label, ascending-dose trial of E2814, an antibody with two separate binding sites in the MTBR. Data from this study suggest that E2814 can reduce CSF pTau217 concentration over two years of treatment, with trends toward a reduction in tau PET scans. The Phase 2/3 NexGen trial, run by the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU), is also testing E2814 concurrently with lecanemab.
BMS-986446, another antibody binding to tau’s MTBR, is being evaluated in the Phase 2 TargetTau-1 trial, which is enrolling individuals with mild cognitive impairment or mild Alzheimer's pathology.
Combination Therapies and Future Trials
Given the limitations of amyloid-targeting therapies, which slow disease progression by approximately 30 percent, there is growing interest in combining tau antibodies with amyloid antibodies. Several trials, including DIAN-TU’s NextGen trial and the new E2814 trial, are already exploring this approach.
Adam Boxer is planning to launch the Alzheimer’s Clinical Trial Consortium tau platform trial (ATP) in 2025 to test two tau therapies alone or in combination with amyloid drugs. The trial will initially enroll 750 people with late preclinical to prodromal Alzheimer's, with a primary endpoint of slowing tau accumulation as per PET over two years.
Despite the progress, Rakez Kayed emphasized the need to examine postmortem brains to determine whether tau antibodies are targeting all forms of aggregated tau or only those visible on PET imaging.
