Anti-Tau Agent E2814 Shows Impact on Early and Late Tau Biomarkers, Further Supporting Development

Kristin Wildsmith, PhD

Data from E2814-G000-103, an open-label, phase 1b/2 study (NCT04971733) of patients with dominantly inherited Alzheimer disease (DIAD), showed that treatment with E2814 (Eisai), an investigational anti-tau therapeutic antibody, resulted in significant effect on both early and late tau biomarkers in treated patients. Notably, E2814 did not affect phosphorylated tau (p-tau)217 or MTBR-tau243 levels in healthy volunteers, suggesting its effects are specific to those with tau pathology and thus further supporting its clinical development.¹

Presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1 in Madrid, Spain, the study featured 8 participants who each received E2814 intravenously (IV) every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg (min of 3 doses/dose level). Following the 4500 mg dosage, patients stayed on 4500 mg for up to 108 weeks. To be included, patients had a confirmed mutation for presenilin 1 (PSEN1), amyloid precursor positive, or presenilin 2 (PSEN2) gene that is also associated with DIAD. Patients also had to have a Clinical Dementia Rating-Sum of Boxes score between 5 to 12 at screening, as well as undergo MRI, lumbar puncture, and PET.

Led by Kristin Wildsmith, PhD, a senior director of translational medicine at Eisai, patients showed a 30.4% reduction in p-tau217 after 12 weeks of treatment (n = 7), and an even greater reduction at 36 weeks (48.6%; n = 5) and 108 weeks (57.9%; n = 2). E2814, a drug designed to bind to the microtubule biding region (MTBR) of tau, resulted in a 50.6% reduction in concentrations of MTBR-tau243 in early-stage patients (n = 7) after 12 weeks of treatment. Notably, the greatest reduction in MTBR-tau243 levels (-71.6%) occurred at week 36 (n=4) and was maintained up to 108 weeks (n=2).

The study, which was designed for initial safety, pharmacokinetic, target engagement, and proof-of-mechanism of E2814, also analyzed and compared cerebrospinal fluid (CSF) of healthy volunteers from the previously completed phase 1 E2814-G000-001 trial, to compare pharmacodynamic effects on early and late tau biomarkers in a population without tau pathology. In this group of individuals, treatment with E2814 resulted in no effect on MTBR-tau243 or p-tau217 after 12 weeks of treatment.

In the analysis, 3 patients with DIAD had tau PET acquired at week 60 and week 108. After 60 weeks of treatment 1 of these patients showed an overall 20% slowing of tau accumulation. At 108 weeks, there was no tau accumulation observed via tau PET in any of the 3 patients.

READ MORE: Risk of ARIA-E in Donanemab Attenuated Through New Enhanced Titration Method of Delivery

E2814 is a humanized, monoclonal immunoglobulin antibody that recognizes an HVPGG epitope in the MTBR domain near the mid-domain of tau and is developed as a disease-modifying agent for tauopathies including sporadic AD. It is intended to bind extracellular tau, prevent cell-to-cell propagation of pathogenic species, and mediate clearance by microglia. It is currently being investigated in a phase 2/3 trial of DIAD, dubbed Tau NexGen, which had its first patient enrolled in January 2022.

Announced in March 2021, E2814 became the first investigational antitau drug selected by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to be in its next-generation program, which will evaluate 3 antitau drugs in clinical studies. Led by investigators at Washington University School of Medicine in St. Louis, the study aims to determine whether such drugs affect tau phosphorylation, tau tangles, and their damage caused, thereby slowing or stopping the progress of AD.²

In the study, patients with symptomatic DIAD will receive lecanemab (Leqembi; Eisai) for 6 months before being randomly assigned to also receive E2814 or placebo. By randomly assigning presymptomatic patients to either E2814 or placebo for 1 year prior to lecanemab, investigators will be able to tell the true effect of the anti-tau drug. If at 2 years into treatment, both primary and secondary end points are positive, the study will be extended for an additional 2 years to evaluate its effects on cognitive decline and tau pathology.

E2814 was also assessed in a phase 1 study of healthy volunteers, the same cohort used in the new analysis presented at CTAD 2024. In the trial, study investigators evaluated 3-mg/kg, 10-mg/kg, and 30-mg/kg doses of the drug, with secondary outcomes that included serum and cerebrospinal fluid pharmacokinetics (PK) and immunogenicity. After the 4-month follow-up, treatment resulted in no significant drug-related clinical changes or dose-limiting events. Headache, nausea, and vomiting were the most reported side effects related to the drug, and 1 participant in the 30-mg/kg group had elevated C-reactive protein 2-3 days after receiving study drug, which produced no symptoms and returned to baseline.³

Click here for more CTAD 2024 coverage.

REFERENCES
1. Horie K, Charil A, Barthelemy N, et al. Anti-tau therapeutic antibody, E2814, reduces early and late tau pathology biomarkers in patients with DIAD. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 29-November 1, 2024; Madrid, Spain. ABSTRACT OC04.
2. First subject enrolled in phase 2/3 study of Eisai’s anti-MTBR tau antibody E2814 for dominantly inherited Alzheimer disease (DIAD), conducted by DIAN-TU. News release. Eisai. January 18, 2022. Accessed October 29, 2024. https://www.prnewswire.com/news-releases/first-subject-enrolled-in-phase-iiiii-study-of-eisais-anti-mtbr-tau-antibody-e2814-for-dominantly-inherited-alzheimers-disease-diad-conducted-by-dian-tu-301463234.html
3. Aceves P, Giroux M, Boyd P, et al. A phase 1, first-in-human, single ascending dose study of the novel anti-tau therapeutic antibody E2814 in healthy volunteers. Presented at 2020 Clinical Trials in Alzheimer Disease annual meeting. Poster LB23.