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Name: E2814
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Eisai Co., Ltd.


This humanized, monoclonal IgG1 antibody recognizes an HVPGG epitope in the microtubule-binding domain near the mid-domain of tau. This region is a predominant component of tau tangles and is involved in seeding and spreading pathological tau aggregates. The antibody is intended to bind extracellular tau, prevent cell-to-cell propagation of pathogenic species, and mediate clearance by microglia. Some data indicate that mid-region antibodies more potently interfere with the propagation of pathogenic, aggregated tau than do N-terminally targeted anti-tau antibodies, which have shown no efficacy in clinical trials (Apr 2018 conference news).

The production and characterization of this antibody were described in detail in a peer-reviewed publication (Roberts et al., 2020). Originally discovered in the lab of Rohan de Silva at University College London, E2814 recognized pathological tau structures in postmortem brain, including neurofibrillary tangles from AD and progressive supranuclear palsy and Pick bodies from Pick’s disease. The antibody also recognized normal tau. E2814 inhibited tau aggregation in vitro and in cell-based aggregation assays. It modestly reduced the propagation of aggregated tau in mice injected with K18 P301L tau fibrils, a model of tau transmission.


In December 2019, Eisai began a Phase 1 trial testing the safety and tolerability of a single intravenous infusion in healthy adults. Secondary outcomes included serum and CSF pharmacokinetics and immunogenicity. An exploratory outcome assessed target engagement by antibody binding to tau protein fragments in the CSF. The trial was completed in August 2020, and results were presented at the November 2020 CTAD conference. The study compared 3, 10, or 30 mg/kg antibody versus placebo in 24 volunteers of both sexes, including Japanese and non-Japanese, who were followed up for four months. Treatment resulted in no significant drug-related clinical changes or dose-limiting events. The most frequent side effects related to drug were headache, nausea, and vomiting. One participant in the highest-dose group had elevated C-reactive protein two to three days after dosing, which produced no symptoms and returned to baseline. Serum and CSF pharmacokinetics were dose-proportional, and comparable to other antibodies. Two participants developed anti-E2814 antibodies by four months. An LC/MS procedure was used to quantify antibody-bound and free-tau fragments containing the microtubule-binding region (Horie et al., 2019; Dec 2020 news). The results showed a dose-related increase in antibody-tau association, which persisted for at least a month. At the 30 mg/kg dose, 60 percent of tau mid-domain fragments were complexed with antibody. 

In 2021, the company added a multiple-ascending-dose phase to the study. Enrollment was boosted to 40, with two different dose cohorts receiving three infusions over four months. In 2022, Eisai added two single-dose and two multidose cohorts, increasing enrollment to 72. Endpoints are safety, pharmacokinetics, and induction of anti-E2814 antibodies. The trial was completed in March 2023.

In March 2021, E2814 was chosen to be evaluated in the DIAN-TU prevention trial in people with pathogenic APP and presenilin mutations (Mar 2021 news). In June 2021, a Phase 1/2 trial began to assess safety and target engagement in people with dominantly inherited Alzheimer’s disease. Eight participants with mild to moderate dementia were to receive antibody infusions for 12 weeks, with target engagement to be measured by change from baseline in CSF free, bound, and total tau microtubule-binding region fragments. A second phase will continue treatment for 96 weeks, against endpoints of adverse events, changes in laboratory values, vital signs, and electrocardiogram findings. An add-on cohort of five patients will receive treatment for one year. This trial also assesses pharmacokinetics, anti-E2814 antibodies, and change from baseline in CSF total tau and p-tau, and tau PET.

Eisai presented first trial data at the July 2023 Alzheimer’s Association International Conference (conference news). The drug was safe and well-tolerated up to the highest dose of 4,500 mg in both healthy and AD cohorts. Target engagement was verified by dose-dependent binding of E2814 to tau microtubule binding region epitopes in CSF. The MTBR-tau-243 fragment, an emerging CSF biomarker for tau tangles, declined between 30 and 70 percent after antibody treatment in the AD patients.

The DIAN-TU study design was amended in November 2021 to allow use of the anti-amyloid antibody lecanemab, in response to the FDA approval of Aduhelm (Nov 2021 news). According to the trial registry, the study will enroll 168 participants with normal cognition, mild cognitive impairment, or mild dementia. People with mild cognitive impairment or dementia will receive open-label intravenous lecanemab for 24 weeks, and then be randomized to intravenous E2814 or placebo plus lecanemab for the remainder of the four-year trial. Participants with normal cognition will start on E2814 or placebo for one year, and then add open-label lecanemab. The trial’s primary endpoint is tau spread during E2814 treatment, measured by tau PET in the symptomatic cohort. Secondary outcomes in this group include change in a cognitive composite, amyloid PET, and CSF neurofilament light chain. In the asymptomatic population, change in CSF ptau217/total tau ratio is the outcome. Eisai reported the first patient enrollment in January 2022 (press release). The study, at 39 locations around the world, will run through 2027.

For trial details, see

Last Updated: 23 Oct 2023


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News Citations

  1. MTBR-243 Tau: A Fluid Biomarker for Tangles Themselves?
  2. Aiming at the Tangle’s Heart? DIAN-TU Trial to Torpedo Tau’s Core
  3. CSF MTBR-tau-243 Tracks Tangles, Plummets in Response to Antibody
  4. Lecanemab Sweeps Up Toxic Aβ Protofibrils, Catches Eyes of Trialists
  5. To Block Tau’s Proteopathic Spread, Antibody Must Attack its Mid-Region

Therapeutics Citations

  1. Aduhelm

Paper Citations

  1. . P4‐696: Quantification of the Tau Microtubule Binding Region (Mtbr) in Cerebrospinal Fluid and Subsequent Validation of Target Engagement Assay for E2814, a Novel Anti‐Tau Therapeutic Antibody. Alzheimer's Association, July 2019
  2. . Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease. Acta Neuropathol Commun. 2020 Feb 4;8(1):13. PubMed.

Other Citations

  1. lecanemab

External Citations

  1. press release

Further Reading


  1. . Passive tau-based immunotherapy for tauopathies. Handb Clin Neurol. 2023;196:611-619. PubMed.