OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT

Abstract

Background:D-0120 is a novel oral selective uric acid transporter (URAT1) inhibitor being developed for the treatment of hyperuricemia and gout by blocking the reabsorption of uric acid (UA) within the renal proximal tubule, thereby reducing serum uric acid concentrations. As a novel URAT1 inhibitor, D-0120 is anticipated to have more potent serum UA reducing effect than the approved URAT1 inhibitor lesinurad, but with less toxicity and wider therapeutic window. The pharmacological potential of D-0120 for the treatment of hyperuricemia and gout was demonstrated in preclinical studies. The results of the in vitro hURAT1 expressed CHO cell model showed that the inhibitory activity of D-0120 is 150-fold more potent than lesinurad and slightly more potent than verinurad.Objectives:The purpose of this dose escalation study is to evaluate the safety and tolerability of D-0120 in multiple ascending doses in healthy volunteer, to characterize the pharmacokinetics (PK) of D-0120 and to assess pharmacodynamic (PD) effects and determine the drug-drug interaction (DDI) effect of febuxostat and D-0120 in healthy volunteers.Methods:This is a randomized, double blind, multiple ascending doses Phase I study of D-0120 in healthy volunteers conducted at one site. Thirty-two healthy eligible volunteers with serum uric acid level ≥ 4.5 mg/dL but within normal range at screening were enrolled and dosed with D-0120 within 4 different single agent cohorts for a period of 7 days. Each cohort had 8 subjects randomized at 3:1 ratio for D-0120:placebo. A fifth cohort of 8 healthy eligible volunteers were enrolled and dosed with 5 mg of D-0120 in combination with 40 mg of febuxostat over a period of 9 days. Evaluation of safety, PK and PD was conducted at various timepoints while the patients were in confinement. Further safety evaluation took place on Day 14. A Safety Review Committee reviewed safety, PK and PD data for each cohort of D-0120 dose level (2.5 mg, 5 mg, 10 mg, 20 mg) as well as when D-0120 5 mg was combined with 40 mg febuxostat. PK evaluation for multiple dose parameters included AUC0-τ, Cmax, Cmin, Tmax and Fl.Results:Dose escalation of D-0120 from 2.5 mg/day to 20 mg/day was completed without any dose limiting toxicities. Most AEs occurred during the study were mild to moderate in severity and did not require any treatment before resolution. There was no SAE and no dose reduction during the treatment period. The pharmacokinetic (PK) evaluation of ascending dose levels of D-0120 suggested a dose proportional increase in drug exposure and there was no significant change of PK profile between Day 1 and Day 7 of dosing. For pharmacodynamic (PD) evaluation, the serum uric acid (UA) levels before and after D-0120 dosing was evaluated on multiple days. The UA reduction effect achieved maximum at about 4-8 hours after dosing and the effect lasted for at least 24 hours. After the 7-day dosing period, the mean percentage of UA reduction from baseline showed an increasing trend as the dose level increased.More detailed safety, PK and PD data from multiple D-0120 dose cohorts and D-0120/febuxostat combination cohort will be presented at the meeting.Conclusion:The oral daily administration of a novel URAT1 inhibitor, D-0120, in healthy volunteers for 7 days was well tolerated at dose levels from 2.5 mg/day to 20 mg/day. The PK profile demonstrated a dose proportional increase. D-0120 administration for 7 days resulted in significant reduction of serum UA levels. Further evaluation of this novel agent in longer treatment period and in patients with hyperuricemia and/or gout is warranted.