Shisha, Tamas, Posch, Maximilian G, Jeanette, Lehmann, Feifel, Roland, Junt, Tobias, Hawtin, Stuart, Schuemann, Jens, Avrameas, Alexandre, Danekula, Rambabu, Misiolek, Patrycja, Siegel, Richard and Gergely, Peter (2023) First-in-human study of safety, pharmacokinetics, and pharmacodynamics of MHV370, a dual inhibitor of Toll-like receptors 7 and 8, in healthy adults. European Journal of Drug Metabolism and Pharmacokinetics, 1 (1). pp. 1-14. ISSN 21070180

Abstract

Background and Objective: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon stimulated genes in vitro and in vivo, and demonstrates efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of MHV370, in healthy adults, as well as the effects of food consumption on a single dose of MHV370.
Methods: This was a Phase 1, first-in-human, randomised, placebo-controlled study conducted in 3 parts. In study 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 study Part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200, and 400 mg MHV370 twice daily or placebo, for 14 days. In study Part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, PK, and PD parameters were evaluated.
Results: MHV370 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. The intake of food did not have an impact on the PK of MHV370. PD data indicated a time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells and TLR8-mediated TNF release, after ex-vivo stimulation.
Conclusion: The safety, PK and PD data support the further development of MHV370 in systemic autoimmune diseases driven by overactivation of TLR7 and TLR8.

Item Type:	Article
Keywords:	TLR7, TLR8, systemic autoimmune disease, Phase 1, first-in-human
Date Deposited:	29 Aug 2023 00:45
Last Modified:	29 Aug 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49986