Gatlik, Ewa, Mehes, Beata, Voltz, Emilie Francoise, Sommer, Ulrike, Tritto, Elaine, Lestini, Giulia, Pal, Parasar, Fu, Yunlin, Opipari, Anthony, Dennis, Dean and Junge, Guido (2024) First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor. Clinical and translational science, 17 (5). e13789. ISSN 1752-8062

Abstract

This first-in-human study evaluated the safety, tolerability, single- and multiple-dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three-part trial including single and 2-week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3-600 mg] and MAD [fasted: 10-200 mg, once-daily or fed: 25 and 50 mg, twice-daily]). DFV890 was generally well-tolerated. Neither deaths nor serious adverse events were reported. A less than dose-proportional increase in exposure was observed with the initially used crystalline suspension (3-300 mg); however, an adjusted suspension formulation using spray-dried dispersion (SDD; 100-600 mg) confirmed dose-proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, Cmax of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05- and 1.49-fold increase in Cmax and AUC0-last compared with the fasting condition. The median IC50 and IC90 for ex-vivo lipopolysaccharide-stimulated interleukin IL-1β release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once-daily or 25 mg twice-daily were sufficient to maintain ~90% of the IL-1β release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology.

Item Type:	Article
Keywords:	Humans Male NLR Family, Pyrin Domain-Containing 3 Protein Adult Female Administration, Oral Middle Aged Young Adult Interleukin-1beta Dose-Response Relationship, Drug Healthy Volunteers Food-Drug Interactions Double-Blind Method Biological Availability Adolescent Drug Administration Schedule
Date Deposited:	09 Jul 2024 00:46
Last Modified:	09 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/53146