First in human randomised trial of J2H‐1702: A novel 11β‐hydroxysteroid dehydrogenase type 1 inhibitor for non‐alcoholic steatohepatitis treatment

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which is an enzyme that converts cortisone to cortisol, plays a role in the regulation of glucose metabolism and inflammation. J2H-1702 is a novel 11β-HSD1 inhibitor, and the inhibition of 11β-HSD1 has been shown to improve insulin sensitivity, reduce inflammation, and prevent the development of nonalcoholic steatohepatitis (NASH) in preclinical models.We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of J2H-1702 after a single-dose oral administration.A randomised, double-blinded, placebo-controlled, single-dose, dose-escalation study was conducted on 50 healthy volunteers. Blood and urine samples were collected to assess the PK and PD of J2H-1702.The peak plasma concentration of J2H-1702 was observed at 2-2.9 h after a single-dose oral administration. J2H-1702 reduced 11β-HSD1 activity compared to the placebo at all dose levels. The drug reached its maximal inhibitory effect within 12-24 h post-dose administration, and the inhibitory effect was maintained till 1 day after administration of the study drug. The drug showed typical first-order elimination kinetics, with a mean elimination half-life of 9.8-14.7 h. Systemic exposure to J2H-1702 increased in a dose-dependent manner. J2H-1702 was well tolerated after a single oral administration of up to 300 mg. A total of 11 treatment-emergent adverse events (TEAEs) occurred in seven (14%) participants, all of which were mild and resolved spontaneously. The most common TEAE was diarrhoea (8%), followed by dizziness (4%).The results of this study suggest that J2H-1702 could be developed as an effective therapeutic option for NASH.