An Anti-tau Therapeutic Antibody Etalanetug (E2814)

Abstract

BACKGROUND: Etalanetug (E2814), an anti-tau monoclonal antibody (mAb), is intended to inhibit spreading of pathologic tau species by binding to the microtubule binding region (MTBR). It is being developed as a potential disease-modifying therapy for Alzheimer disease. METHODS: This randomized, placebo-controlled study comprised of 2 parts: single ascending doses evaluating 5 etalanetug doses and multiple ascending doses evaluating 4 fixed doses in each cohort, 8 healthy subjects were randomized (3:1) to single etalanetug dose or placebo. Safety, pharmacokinetics (PK), antidrug antibodies (ADA), and target engagement (TE) were assessed. RESULTS: Etalanetug was safe and well-tolerated following single and multiple infusions. After single-dose and multiple-dose administration, serum exposure of etalanetug increased in a dose-related manner. Serum-to-cerebrospinal fluid (CSF) concentration ratio at week 12 was ∼0.1% to 0.3% and ∼1% following single and multiple dosing, respectively. Mean t ½ was ∼19 to 25 days independent of dose and time. etalanetug immunogenicity was minimal, with low titers and no impact on PK. TE was demonstrated; CSF concentrations of etalanetug between 100 and 200 ng/mL saturated binding of MTBR-tau299 at 82.1% and binding of MTBR-tau354 at 64.9%. CONCLUSION: Etalanetug presented an adequate safety and immunogenicity profile in healthy adults. PK was comparable to other mAbs. Etalanetug demonstrated target engagement by binding to MTBR tau species.