Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single- and Multiple-Dose Administration of LLX-424, a Glycolate Oxydase Inhibitor, in Healthy Participants

Background: Idiopathic calcium oxalate kidney stones are highly prevalent. There is need for evidence-based treatments that effectively reduce stone recurrence. LLX-424 is a prodrug of LLX-152, an inhibitor of glycolate oxidase (GO) in development for prevention of recurrent calcium oxalate stones. Oxalate is highly insoluble in the urine and can lead to formation of calcium oxalate stones. The majority of urinary oxalate is synthesized via GO in the liver. Inhibition of GO is expected to decrease urinary oxalate levels and recurrence of oxalate kidney stones. This Phase 1 study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of LLX-424 in healthy volunteers (HV). Methods: This randomized, double-blind, placebo-controlled study evaluated 5 single ascending dose (SAD) cohorts (50, 100, 200, 400, and 800 mg LLX-424) and 3 multiple ascending dose (MAD) cohorts (100, 200, and 300 mg LLX-424 once-daily for 14 days) during in-unit confinement. LLX-424 was administered fasted except for the 200 mg SAD cohort, in which a second dose was administered, after a washout, with a high-fat high-calorie meal, and the 300 mg MAD cohort which was administered under fed conditions. Plasma and urine concentrations of LLX-424, LLX-152, glycolate (the substrate of GO and a marker of target enzyme engagement) were determined by validated LC/MS/MS methods. Urine oxalate was assessed in MAD cohorts. Results: 72 subjects were randomized in the study. There were no serious or severe adverse events or adverse events requiring dose adjustment or discontinuation. LLX-424 and LLX-152 exhibited linear and time independent PK. A high-fat high-calorie meal modestly increased exposure of LLX-424 and LLX-152 (~55% Cmax and ~50-75% AUCinf). LLX-424 exhibited dose dependent increases in plasma glycolate PD parameters and reduced urinary oxalate. Conclusion: In this first-in-human study, LLX-424, an orally administered glycolate oxidase inhibitor, safely and effectively inhibited glycolate oxidase in a dose dependent manner; inhibition was maintained over an up to 2-week dosing period. The safety, tolerability, PK, and PD of LLX-424 supports further clinical evaluation in patients with recurrent kidney stones. Funding: Commercial Support - Lilac Therapeutics Inc.