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 of 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 currently in clinical trials (Apr 2018 conference news).
The production and characterization of this antibody have been 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. Endpoints are safety, pharmacokinetics and induction of anti-E2814 antibodies. The trial will run until November 2022.
In March 2021, E2814 was chosen to be evaluated in the DIAN-TU prevention trial in people with pathogenic APP and presenilin mutations. Dosing is expected to start in the fall (Mar 2021 news). The 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). Some participants will receive only E2814, and some will receive concurrent therapy. Eisai reported the first patient enrollment in January 2022 (press release).
For trial details, see clinicaltrials.gov.
Last Updated: 23 Jan 2022
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- Horie KW, Takahashi E, Aoyama M, Nakatani, Roberts M, Staddon J, de Silva R, Koyama A. 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
- Roberts M, Sevastou I, Imaizumi Y, Mistry K, Talma S, Dey M, Gartlon J, Ochiai H, Zhou Z, Akasofu S, Tokuhara N, Ogo M, Aoyama M, Aoyagi H, Strand K, Sajedi E, Agarwala KL, Spidel J, Albone E, Horie K, Staddon JM, de Silva R. 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.
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