#4328 CHK-336, A FIRST-IN-CLASS ORALLY ADMINISTERED LDH INHIBITOR: SAFETY, PK AND TARGET ENGAGEMENT IN A FIRST-IN-HUMAN PHASE 1 HEALTHY VOLUNTEER STUDY

Abstract

Abstract Background and Aims CHK-336 is a first-in-class, orally bioavailable, liver-targeted small molecule lactate dehydrogenase (LDH) inhibitor for the treatment of primary hyperoxalurias and other kidney stone disorders caused by oxalate overproduction. The primary objectives of this first-in-human (FIH) study were characterization of the safety and pharmacokinetics (PK) of CHK-336 following single and repeat doses in healthy volunteers (HVs). Exploratory objectives were demonstration of proof of mechanism in HVs based on inhibition of hepatic oxalate production using a stable-label 13C2-glycolate tracer for hepatic LDH target engagement and characterization of the exposure-response relationship. Method This Phase 1, placebo-controlled (6:2 randomization within a cohort), dose escalation study explored single ascending (SAD, 15-500 mg) and multiple ascending (MAD, 30 mg and planned up to 500 mg QD, 14 consecutive days) doses. A total of 104 subjects will be enrolled in this study. A stable-label 13C2-glycolate tracer was administered orally at baseline and following CHK-336 administration to evaluate the inhibition of LDH-mediated production of [13C2]-oxalate by CHK-336, as a measure of hepatic LDH target engagement in HVs. Food-effect was evaluated following a single dose after a standard high fat meal. CHK-336 concentrations were determined in plasma and urine by a validated LC-MS/MS assay. Total oxalate and 13C2-oxalate were determined in urine by validated GC/MS assays. Results CHK-336 was generally well tolerated following single doses from 15 – 500 mg, with no dose-related trends in total adverse events (AEs) or types of AEs. There were no serious AEs, or severe treatment-related AEs (TRAEs). Treatment-emergent AEs were observed in 10 of 56 (17.9%) subjects, 7 (12.5%) of whom experienced TRAEs; all TRAEs were mild or moderate in severity. CHK-336 PK profiles were characterized with a median tmax of 6 hrs following absorption in fasted-state followed by bi-exponential decline and a terminal half-life of 18 ± 8 hrs. Dose-proportional increases in exposure AUC were observed from 15 up to 500 mg. Cmax increase was greater than dose-proportional at ≥60 mg with a concomitant decrease in median tmax from 6hr to 2hr. A high fat meal decreased CHK-336 AUC0-72h by 32% (AUC0-72h) and Cmax by 55%. Renal elimination of unchanged CHK-336 was quantitatively minor (<1% of administered dose). A direct effect inhibitory Imax-IC50 model adequately described the relationship between CHK-336 plasma concentrations and urinary 13C2-oxalate (% of control). Robust target engagement was demonstrated with an exposure-related reduction in urinary 13C2-oxalate from 15 – 60 mg, with maximum inhibition achieved at CHK-336 doses ≥60 mg. Conclusion CHK-336 is a first-in-class, orally administered, liver-targeted LDH inhibitor that was generally well-tolerated following single doses from 15 – 500 mg, with dose proportional increases in AUC exposure. Hepatic oxalate production was robustly reduced by CHK-336, as measured by urinary 13C2-oxalate, thus achieving proof of mechanism in HVs.