Background/Purpose: AR882 is a potent and selective uric acid transporter 1 (URAT1) inhibitor under development for the treatment of hyperuricemia or gout. A Phase 1 single ascending dose clinical study in healthy adult male subjects was conducted to evaluate pharmacokinetics and dose-dependent serum uric acid (sUA) lowering effect.

Methods: Analysis of sUA reduction was conducted in a randomized, double-blind, placebo-controlled single dose study with 31 healthy male volunteers. Eight subjects per group (6 active and 2 placebo) were planned to be dosed AR882 under fasted conditions at 15, 50, or 100 mg with an immediate release formulation, or at 50 mg following a high-fat, high- calorie meal. Correlation of increased uric acid excretion in urine with sUA lowering was assessed to further evaluate the effect of URAT1 inhibition in the tubule. Laboratory safety tests, vital signs, and electrocardiograms were collected throughout the study

Results: Following administration of AR882, exposure of AR882 exhibited dose proportional increase and was significantly lower than the no-observed-adverse-effect level (NOAEL) in rats and monkeys.  The rate of absorption was moderate (Tmax 3-5 hours) with a half-life of AR882 of approximately 10-13 hours. When administrated with a high-fat, high-calorie meal, AR882 absorption was slower (Tmax 8 hours), with Cmax lowered by approximately 33% but AUC was similar to that in the fasting conditions. The mean changes in sUA at the 24 hours postdose from baseline were 2.0% in the pooled placebo group, -5.8%, -42.4% and -58.4% in the 15 mg, 50 mg (P< 0.001 vs placebo) and 100 mg (P< 0.001 vs placebo) fasted groups, respectively.  Time to reach highest sUA reduction range between 12 – 36 hr post-dose with median TEmax at 24 hr post-dose.  sUA returned to baseline after 4 to 5 days post-dose following 50 mg and 100 mg dosing. Food did not alter sUA lowering effect of AR882.  sUA lowering effect was similar among subjects irrespective of differing sUA baseline values which ranged between 3 to 9 mg/dL.  Urinary excretion of AR882 and uric acid were evaluated on Day 1 at 6 to 12 hours intervals. Significantly higher amounts of uric acid were eliminated through urine on Day 1 at all collection intervals, indicating sustained inhibition of URAT1 over 24 hours following dosing.  AR882 was well tolerated at all doses tested. All adverse events (AEs) were mild in severity and no serious adverse events (SAEs) were reported. There were no clinically significant laboratory or ECG abnormalities noted.

Conclusion: AR882 exhibited outstanding ability to reduce sUA level at ≥ 50 mg ( > 40% reduction following a single dose). It is anticipated the sUA lowering will accumulate following multiple doses.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/ar882-a-potent-and-selective-uric-acid-lowering-agent-acting-through-inhibition-of-uric-acid-reuptake-shows-excellent-pharmacokinetics-and-pharmacodynamics-in-a-phase-1-clinical-trial/