Evaluation of EVT401, a P2X7 Receptor Antagonist, in Healthy Chinese Participants: a first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial.

PURPOSE: As a critical hub between extracellular danger signals and intracellular inflammation, the P2X7 receptor centrally drives synovitis and joint destruction in rheumatoid arthritis, making it an attractive therapeutic target. This study reported the first-in-human data for EVT401, an orally administered P2X7 receptor antagonist.

METHODS

A phase I trial was conducted in healthy Chinese participants aged 18 to 50 years, encompassing a single ascending dose study (40-1920 mg), a food-effect study (960 mg), and a multiple ascending dose study (480 mg-960 mg). This randomized, double-blind, placebo-controlled trial evaluated safety, tolerability, and pharmacokinetic characteristics as primary outcomes. Exploratory outcomes assessed the pharmacodynamic effects of EVT401 on cytokines and immune cells.

RESULTS

A total of 101 participants were enrolled in the trial. Only a few mild, transient adverse events were reported during the trial, and no serious adverse events were observed. The pharmacokinetic data obtained from each study were consistent, with Tmax ranging from 0.5 to 2.75 hours and mean half-lives from 12.7 to 28.3 hours. Dose-exposure analysis demonstrated that EVT401 had nonlinear pharmacokinetic characteristics. The food effect study showed that a high-fat meal increased the absorption and systemic exposure of EVT401. Exploratory pharmacodynamic results suggested that EVT401 exhibited an anti-inflammatory trend by upregulating regulatory T cells and suppressing helper T cells.

CONCLUSIONS

The first-in-human data for EVT401 have demonstrated a favorable safety profile and encouraging pharmacodynamic properties, providing strong support for its further clinical development.

CLINICAL TRIAL REGISTRATION: This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2600126139, ChiCTR2600125998).