Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll-like receptors 7 and 8

Abstract

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll-like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double-blind, placebo-controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single-dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple-dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo-stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open-label, one-way crossover study in the 25 mg single-dose cohort. Single- and multiple-oral doses of enpatoran up to 200 mg were well tolerated and no significant dose-limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose-proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure-dependent inhibition of ex vivo-stimulated interleukin-6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID-19 pneumonia.

Keywords: autoimmune diseases; pharmacodynamics; pharmacokinetics; safety; toll-like receptors.

FIGURE 1

Study design and dose escalation scheme. Eight participants were randomized to each cohort; six to active treatment and two to placebo. Eight participants in Part A, Cohort 4, crossed over to Part C. ^aThe primary observation period was reduced to 17 days for Cohorts 3–5 of Part B, since available clinical data showed this timeframe provided sufficient safety and tolerability monitoring; ^bSingle‐dose cohort escalation (Part A): safety data from a single dose plus 1 week in‐house; ^cMultiple‐dose cohort escalation (Part B): safety data from 2 weeks of treatment until the end of the in‐house period. BID, twice daily; QD, once daily

FIGURE 2

Mean plasma concentration‐time profiles for enpatoran following (A) single and (B) multiple (Days 1–14) dosing on a log‐linear scale (PK analysis set). BID, twice daily; PK, pharmacokinetic; QD, once daily

FIGURE 3

Dose‐normalized enpatoran PK parameters (A) C _max and (B) AUC_0–∞ following a single dose, and (C) C _max and (D) AUC_{0– τ} on Day 14 of multiple‐dose administration (PK analysis set). Box plots show medians, with minimum and maximum values. Circles represent the arithmetic means and crosses represent outliers. AUC_{0– τ}, area under the curve during 24 h for QD and 12 h for BID; AUC_0–∞, area under the curve extrapolated to infinity; BID, twice daily; C _max, maximum plasma concentration; PK, pharmacokinetic; QD, once daily

FIGURE 4

Mean (SD) enpatoran plasma concentration‐time profiles following single administration in fasting (Study Part A) and fed (Study Part C) states (PK analysis set). PK, pharmacokinetic; SD, standard deviation

FIGURE 5

Mean (SD) percentage inhibition–time profile of (A) interleukin‐6 and (B) interferon α assessed using an ex vivo‐stimulated cytokine immunoassay on Day 1 of enpatoran multiple‐ascending‐dose administration (PD analysis set). BID, twice daily; PD, pharmacodynamic; QD, once daily; SD, standard deviation