Presenter of 1 Presentation
SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF SINGLE AND MULTIPLE ASCENDING DOSES OF THE NOVEL ANTI-TAU THERAPEUTIC ANTIBODY E2814: A PHASE 1, FIRST-IN-HUMAN STUDY IN HEALTHY VOLUNTEERS
Abstract
Aims
E2814 is a novel anti-tau therapeutic monoclonal antibody (mAb) that inhibits the propagation of pathological tau species by binding to the microtubule binding region (MTBR). This study evaluated safety, pharmacokinetics (PK), immunogenicity and target engagement (TE) of single and multiple doses of E2814.
Methods
This randomized, placebo-controlled, Phase 1 study evaluated 3 single ascending doses (SAD) and 2 multiple ascending doses (MAD) in healthy adults. Subjects (n=8/cohort) received single or multiple (every 4 weeks) 1-hour IV infusions of E2814 (or placebo). PK was characterized in blood and CSF samples. TE was evaluated in CSF by measuring E2814-bound and free MTBR-tau proxy peptide concentrations (MTBR-tau354 and MTBR-tau299 containing epitopes in R4 and R2, respectively).
Results
E2814 has an adequate single and multiple dose safety profile. No dose limiting events were observed. E2814 exposures (Cmax, AUC) increased in a dose-related manner. E2814 acumulation index on multiple dosing (Rac=1.5) was consistent with its elimination half-life (22 days). The serum-to-CSF ratio was 0.2%. TE was dose related and sustained over time with maximum TE levels of 45% and 76% in the SAD and 47% and 62% in the MAD for MTBR-tau354 and MTBR-tau299, respectively. In the SAD, 2 out of 24 subjects had transient low level anti-drug antibody (ADA) titers by the last study day; no post dose ADA were detected in the MAD.
Conclusions
E2814 presented an adequate safety, PK and immunogenicity profile in healthy adults. Increase in TE was dose-related and sustained. These results support further development of E2814 as a disease-modifying therapy for AD.