CTAD Poster Shows Etalanetug Reduced Tau Pathology Biomarkers in Dominantly Inherited Alzheimer Disease

New data from an open-label phase 1b/2 study (E2814-G000-103, NCT04971733) showed that etalanetug (Eisai), an investigational antitau antibody, reduced several measures of MTBR-tau243 in both cerebrospinal fluid (CSF) and plasma among patients with mild-to-moderate dominantly inherited Alzheimer disease (DIAD). These findings, presented at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-4, 2025, in San Diego, California, offer evidence that etalanetug decreases the propagation of tau pathology.¹

In the trial, researchers observed that the eMTBR-tau243 assay performance was not affected by etalanetug in CSF or plasma in the drug interference testing. In CSF from participants with DIAD (n = 5), findings showed that the mean reductions in eMTBR-tau243 were greater than those observed for tryptic MTBR-tau243 (nondeamidated, −87%; deamidated, −89% vs −69%). Notably, results revealed that the nondeamidated and deamidated forms of eMTBR-tau243 were highly correlated (Pearson r = 0.99; Spearman r = 0.97; n = 33).

“Results support that eMTBR-tau243 in CSF is a more sensitive biomarker than tryptic MTBR-tau243 at detecting the effects of etalanetug on tau pathology. The results observed for eMTBR-tau243 in CSF translate to plasma,” lead author Kristin Wildsmith, PhD, senior director of translational medicine at Eisai, and colleagues wrote.² “This is the first report demonstrating plasma eMTBR-tau243, which is highly correlated with tau PET, can serve as a pharmacodynamic biomarker reflecting mechanism of action of anti-tau therapy.”

eMTBR-tau243 emerged out of the earlier MTBR-tau243 work in CSF, where a truncated fragment from tau’s microtubule-binding region was shown to track neurofibrillary tangle burden and AD clinical stage much more specifically than classic p-tau measures.³ Building on that, Horie and colleagues recently characterized an endogenously cleaved, plasma-detectable form (eMTBR-tau243) that retains this tangle specificity and shows tight correlations with tau PET signal and cognition across the AD spectrum, outperforming plasma p-tau217 and p-tau205.⁴

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The phase 1/2 study of etalanetug enrolled participants with mild-to-moderate cognitive impairment because of DIAD to assess safety, pharmacokinetics, target engagement, and proof-of-mechanism using tau pathology biomarkers. Participants received intravenous etalanetug every 4 weeks with escalating doses of 750-mg, 1500-mg, 3000-mg, and 4500-mg, followed by 4500-mg for up to 108 weeks. Plasma and CSF samples were collected every 3 months during the first year and 108 weeks, with additional plasma sampling on days 15, 29, and 57 during the 750-mg dosing period.¹

Researchers specifically evaluated eMTBR-tau243 as a biomarker of tau pathology progression and assessed changes in CSF and plasma. MTBR-tau243 and eMTBR-tau243 were measured using immunoprecipitation followed by mass spectrometry. Drug interference testing was conducted at etalanetug concentrations spanning those observed in clinical samples and exceeding twofold these levels. Plasma from healthy participants in the phase 1 study was also analyzed to compare pharmacodynamic effects in individuals without tau pathology.

Although multiple forms of MTBR-tau243 are detectable in CSF, authors noted that only the deamidated form of eMTBR-tau243 was measurable in plasma. In participants receiving etalanetug (n = 4) at the lowest dose tested (750-mg), plasma eMTBR-tau243 decreased by 25% after 2 doses and 78% after 3 doses, with maximal reductions exceeding 90% maintained throughout treatment. Researchers also observed that plasma eMTBR-tau243 was undetectable in healthy participants treated with placebo or up to 3 doses of etalanetug at 4500-mg.

Etalanetug, granted fast track designation by the FDA, is designed to bind to the microtubule-binding region of tau protein and prevent the seeding and propagation of tau pathology. The agent is currently being investigated in 2 ongoing clinical trials. These trials include the Tau NexGen phase 2/3 trial (NCT05269394) for DIAD, led by the Dominantly Inherited Alzheimer Network Trials Unit at Washington University School of Medicine in St. Louis, and a global randomized phase 2 trial (Study 202, NCT06602258) in individuals with early sporadic AD, assessing etalanetug with lecanemab (Leqembi; Eisai), an antiamyloid β protofibril antibody, as a standard of care treatment.

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REFERENCES
1. Eisai Presents New Data on Anti-Tau Antibody Etalanetug (E2814) at CTAD 2025. News release. Eisai. December 1, 2025. Accessed December 1, 2025. https://www.eisai.com/news/2025/news202583.html
2. Wildsmith K, Horie K, Boyd P, et al. Anti-tau therapeutic antibody, etalanetug, reduces the novel biomarker plasma eMTBR-tau243 in patients with DIAD. Presented at: 2025 Clinical Trials on Alzheimer Disease conference. December 1-5; San Diego, CA. Abstract LB2.
3. Toombs J, Zetterberg H. Untangling the tau microtubule-binding region. Brain. 2021;144(2):359-362. doi:10.1093/brain/awaa468
4. Horie K, Salvado G, Koppisetti RK, et al. Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease. Nat Med. 2025;31(6):2044-2053. doi:10.1038/s41591-025-03617-7