OP0129 A 12-WEEK, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY OF RUZINURAD (SHR4640) IN COMBINATION WITH FEBUXOSTAT FOR PRIMARY GOUT AND HYPERURICEMIA WITH AN INADEQUATE RESPONSE TO FEBUXOSTAT ALONE

Background:

Despite the use of xanthine oxidase inhibitors (XOIs), a large proportion of gout patients fail to achieve or maintain the target serum uric acid (sUA) level. Adding a uricosuric agent to a XOI represents an attractive therapeutic strategy for XOI inadequate responders. Ruzinurad (SHR4640) is a highly selective and potent inhibitor against uric acid transporter 1 (URAT1, a major urate reabsorption transporter in kidney). In previous clinical studies, ruzinurad was well-tolerated and showed robust sUA lowering effect in patients with hyperuricemia [1, 2]. Moreover, the combination of ruzinurad and the XOI febuxostat exhibited a synergistic effect in reducing sUA [3].

Objectives:

This 12-week, multicenter, randomized, double-blind, placebo-controlled, phase 2 study aimed to assess the efficacy and safety of ruzinurad plus febuxostat in patients with primary gout and hyperuricemia with an inadequate response to febuxostat alone (NCT05513976).

Methods:

Gout adults with fasting sUA ≥390 µmol/L despite on stable dose of febuxostat (40, 60, or 80 mg/day) for ≥6 weeks were randomly assigned (1:1:1) to ruzinurad 10 mg, ruzinurad 5 mg, or placebo groups, stratified by the febuxostat dose at screening (40 vs. 60 vs. 80 mg). Administration of ruzinurad started with a low dose of 1 mg/day and was gradually up-titrated to the tested dose, whereas febuxostat was continued at the same dose at screening (Figure 1). All study medications were taken orally once daily for 12 weeks. The primary endpoint was proportion of patients achieving sUA level of ≤360 μmol/L at Week 12.

Results:

A total of 151 patients were randomized, and all received study treatment. Baseline characteristics were generally balanced among ruzinurad 10 mg, ruzinurad 5 mg, and placebo groups (male, 96.1%/95.9%/98.0%; mean age, 34.6/37.5/38.5 years; mean sUA, 514.1/514.0/504.8 μmol/L; eGFR <90 mL/min, 37.3%/36.7%/35.3%; tophi, 74.5%/67.3%/72.5%). At Week 12, significantly greater proportions of patients in the ruzinurad groups achieved the target sUA level of ≤360 μmol/L (56.9% in the 10 mg group and 53.1% in the 5 mg group) compared to the placebo group (13.7%; OR, 8.7 [95% CI, 3.3–23.2] and 7.1 [95% CI, 2.7–18.9], respectively; P < 0.0001 for both comparisons; Figure 2). Consistently, subgroup analyses based on baseline eGFR, sUA, and tophus demonstrated superior effects of ruzinurad over placebo. Proportions of patients achieving sUA level of ≤300 μmol/L at Week 12 were also greater in the ruzinurad groups (43.1% in the 10 mg group and 38.8% in the 5 mg group) versus placebo group (9.8%; OR, 7.2 [95% CI, 2.4–21.2] and 5.8 [95% CI, 1.9–17.2], respectively; nominal P=0.0001 and 0.0009, respectively; Figure 2). Treatment-emergent adverse events (TEAEs) occurred in 74.5%, 87.8%, and 80.4% of the patients in the ruzinurad 10 mg, ruzinurad 5 mg, and placebo group, respectively, with the most common being gout flares (39.2%, 49.0%, and 45.1%). The majority of TEAEs were mild or moderate. No TEAEs led to treatment discontinuation or death.

Conclusion:

Addition of the URAT1 inhibitor ruzinurad (both 10 and 5 mg) to febuxostat demonstrated superior sUA lowering effect versus placebo plus febuxostat and was generally well-tolerated in patients with primary gout and hyperuricemia uncontrolled on febuxostat alone.

REFERENCES:

[1] Lin Y, Chen X, Ding H, Ye P, Gu J, Wang X et al. Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricaemia: a randomized controlled phase II study. Rheumatology. 2021; 60:5089-5097. [2] Tang H, Cui B, Chen Y, Chen L, Wang Z, Zhang N et al. Safety and efficacy of SHR4640 combined with febuxostat for primary hyperuricemia: a multicenter, randomized, double-blind, phase II study. Therapeutic Advances in Musculoskeletal Disease. 2022; 14:1759720X211067304. [3] Wang C, Yu Q, Jiang X, Deng Y, Sun F, Li X et al. A Drug–Drug Interaction Study of a Novel Selective Urate Reabsorption Inhibitor, SHR4640, and Xanthine Oxidase Inhibitor, Febuxostat, in Patients With Primary Hyperuricemia. The Journal of Clinical Pharmacology. 2023; 63:239-249.

Acknowledgements:

NIL.

Disclosure of Interests:

Chunde Bao: None declared, Huihua Ding: None declared, Qing Dai: None declared, Jiankang Hu: None declared, Lei Yang: None declared, Zhenyu Jiang: None declared, Xiaoyan Xu: None declared, Changsong Lin: None declared, Hua Wei: None declared, Qibing Xie: None declared, Yu Zhuang: None declared, Xiaofei Shi: None declared, Jing Wen: None declared, Lin Tang: None declared, Guixiu Shi: None declared, Xiaohong He: None declared, Long Qian: None declared, Wen Hu: None declared, Yanlin Ma Jiangsu Hengrui Pharmaceuticals Co., Ltd., Guangchao Dong Jiangsu Hengrui Pharmaceuticals Co., Ltd.