LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults

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INTRODUCTION: This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of the ketohexokinase inhibitor LY3522348 in healthy participants. METHODS: This first-in-human phase 1 study evaluated LY3522348, a highly selective, oral dual inhibitor of human ketohexokinase (KHK) isoforms C and A. The study was conducted in two parts: a single-ascending dose (SAD) study and a multiple-ascending dose (MAD) study, including a drug-drug interaction analysis with midazolam. Participants in the SAD study received single oral doses of LY3522348 ranging from 5 to 380 mg, while participants in the MAD study received once-daily doses of 50 mg, 120 mg, and 290 mg for 14 days. RESULTS: A total of 65 healthy participants were included; of these 40 were in the SAD study (placebo = 10; LY3522348: 5 mg = 6; 15 mg = 6; 50 mg = 6; 150 mg = 6; 380 mg = 6) and 25 in the MAD study (placebo = 6; LY3522348: 50 mg = 6; 120 mg = 6; 290 mg = 7). LY3522348 was well tolerated, with the majority of the reported adverse events being mild. PK analysis showed an approximately dose-proportional increase in LY3522348 exposure, and the half-life ranged from 23.7 to 33.8 h. PD analysis indicated a dose-dependent increase in plasma fructose concentrations following the administration of a fructose beverage, supporting the inhibition of fructose metabolism by LY3522348. CONCLUSIONS: LY3522348 demonstrated a favorable safety profile and well-behaved pharmacokinetics following once-daily oral dosing, and effective inhibition of fructose metabolism. The study was registered on ClinicalTrials.gov (NCT04559568).

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