LTA4H inhibitor LYS006: Clinical PK/PD and safety in a randomized phase I clinical trial

• DOI: 10.1111/cts.13724
• Publication Date: 2024-02-03T05:24:43Z
• Authors: Christian Loesche; Damien Picard; Benjamin Van Hoorick; Imelda Schuhmann; Petra Jäger; Kai Klein; Carole Schuhler; Gebhard Thoma; Christian Markert; Birk Poller; Natasa Zamurovic; H. Markus Weiss; Heike Otto; Martin Fink; Till A. Röhn
• Keywords: Epoxide Hydrolases; Plasma; 0303 health sciences; 03 medical and health sciences; Neutrophils; Humans; Therapeutics. Pharmacology; RM1-950; Articles; Public aspects of medicine; RA1-1270; Skin

LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe complex pharmacokinetic to pharmacodynamic (PD) relationship blood, plasma, skin LYS006-treated nonclinical species healthy human participants. In randomized first study, participants were exposed single ascending doses up 100 mg multiple 80 b.i.d.. showed rapid absorption, overall dose proportional plasma exposure nonlinear blood distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production blister cells, leading greater than 90% predose inhibition from day 1 after initiation at 20 b.i.d. above. Slow re-distribution expressing cells resulted long terminal half-life long-lasting PD effect ex vivo stimulated despite low exposures. was well-tolerated demonstrated favorable safety profile highest tested, without any dose-limiting toxicity. This supported further phase II studies predominantly conditions, such as hidradenitis suppurativa, acne, ulcerative colitis.