First‐in‐Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP1617, a Cathepsin‐S Inhibitor, in Healthy Adult Subjects

ASP1617 is a novel, highly selective inhibitor of cathepsin-S, an important protease for antigen peptide loading onto major histocompatibility complex class II molecules. Preclinically, ASP1617 prevented progression of lupus-like glomerulonephritis in an NZB/W F1 mouse model of systemic lupus erythematosus. In this double-blind, randomized, placebo-controlled, first-in-human study in healthy subjects, ASP1617 was generally well tolerated. Treatment-emergent adverse events of rash and throat tightness were reported in two subjects receiving the highest doses of 110 mg BID in multiple ascending dose (MAD) cohorts, leading to withdrawal of ASP1617 in both subjects. Mean elimination half-life was 10.4-15.9 h in single ascending dose (SAD) cohorts and 13.7-20.5 h in MAD cohorts. ASP1617 exposure increased slightly greater than dose proportionally between SAD cohorts and dose proportionally between MAD cohorts and was similar between Japanese and non-Asian subjects. A high-fat, high-calorie meal slightly decreased peak and total exposure and delayed absorption. Both single and multiple dosing of ASP1617 led to rapid and maximal inhibition (> 80% at 3 h post-dose) of cathepsin-S activity as well as the downstream increase of invariant chain p10 (Lip10) in B cells, indicating target engagement. However, in all MAD cohorts, cathepsin-S activity gradually rebounded during treatment, surpassing baseline levels after the last dose, and cathepsin-S mass increased significantly, fivefold above baseline, and prolonged after treatment. Due to the observed safety events, induction of the cathepsin-S target, and gradual loss of pharmacodynamic effects during repeated dosing, appropriate mitigation strategies are necessary for the further clinical development of ASP1617. Trial Registration: ClinicalTrials.gov Identifier: NCT04077879.