POS1128 COMBINATION TREATMENT OF AR882, A NEW URAT1 INHIBITOR, AND XANTHINE OXIDASE INHIBITORS ALLOPURINOL OR FEBUXOSTAT: EFFECT ON URIC ACID, HYPOXANTHINE AND XANTHINE IN PLASMA OR SERUM AND URINE

Background: Xanthine oxidase inhibitors (XOI) are commonly used as urate lowering therapy (ULT) for the treatment of gout. Allopurinol, the first-line treatment, demonstrates low response rate ( Objectives: To evaluate the effect of AR882 alone or in combination with allopurinol or febuxostat on circulating levels and urinary excretion of hypoxanthine, xanthine and uric acid. Furthermore, to elucidate the contribution of each drug towards the combination effect in sUA lowering. Methods: Plasma, serum, and urine samples were collected from 17 patients with gout who received a once-daily dosing of AR882 50 mg, allopurinol 300 mg or febuxostat 40 mg, or in combination for one week in a phase 2a study. Samples were collected to measure hypoxanthine, xanthine and uric acid levels in plasma or serum and the amount of each excreted in the urine. Plasma Cmax and AUC and 24-hour urine excretion amount (mg) of hypoxanthine and xanthine were calculated by non-compartmental analysis method. Results: In monotherapy, AR882 demonstrated better sUA lowering effect (↓53%) compared to allopurinol (↓35%) or febuxostat (↓39%). Combination of AR882 and allopurinol lowered sUA by 66% while combination of AR882 and febuxostat lowered sUA by 71%. Based on the change of xanthine in plasma following combination treatments, it can be calculated that allopurinol contributed 28% of the urate lowering effect, whereas AR882 contributed 38% of the effect. Similarly, febuxostat contributed 33% of the urate lowering effect and AR882 contributed to about 36-38% of the effect when used in combination. The combination treatments significantly increased the response ratio for patients achieving sUA levels Conclusion: AR882 dose alone had no effect on plasma or urine hypoxanthine and xanthine levels. AR882 contributed to a greater portion of the serum urate lowering effects when used in combination with XO inhibitors, and with 100% of patients achieving levels below 4 mg/dL when combined with allopurinol. The use of AR882 in combination with XO inhibitors may provide an option for preventing flares as well as tophi reduction in advanced patients. Disclosure of Interests: Zancong Shen Employee of: arthrosi therapeutics, Chris Colton Employee of: Arthrosi therapeutics Inc, Rongzi Yan Employee of: Arthrosi therapeutics Inc, Elizabeth Polvent Employee of: Arthrosi therapeutics Inc, Vijay Hingorani Consultant of: Arthrosi therapeutics Inc, Shunqi Yan Employee of: Arthrosi therapeutics Inc, Li-Tain Yeh Employee of: Arthrosi therapeutics Inc.