First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of MHV370, a Dual Inhibitor of Toll-Like Receptors 7 and 8, in Healthy Adults.

BACKGROUND AND

objectiveMHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.

methodsThis was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.

resultsMHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).

conclusionThe safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.