Long-Term Safety Data Raise No New Concerns for Approved Lesinurad Dose in Gout

The approved dose of lesinurad 200 mg once daily in combination with a xanthine oxidase inhibitor (XOI) did not increase renal, cardiovascular, or other adverse events compared with XOI alone, except for serum creatinine elevations, in patients with gout, according to the results of a study published in Rheumatology.

Researchers pooled safety data from three 12-month phase 3 trials that evaluated lesinurad, 200 mg/d and 400 mg/d, combined with XOI, and two 12-month extension studies. The investigators expressed treatment-emergent adverse events as exposure-adjusted incidence rates to adjust for treatment duration.

A total of 1332 patients with gout received lesinurad during the core and extension studies; 95% of the patients were men. In the three 12-month phase 3 core studies, the exposure-related incidence rates were comparable for lesinurad, 200 mg, with XOI and for XOI alone, but were higher for the 400-mg dose of lesinurad with XOI for any treatment-emergent adverse event (TEAE), any TEAE with Rheumatology Common Toxicity Criteria grade 3 or 4, serious TEAEs, fatal TEAEs, and TEAEs leading to discontinuation of lesinurad. In both the core and extension studies, the incidence of TEAEs increased with increasing exposure to lesinurad, 200 mg with XOI, or lesinurad, 400 mg with XOI, but exposure-related incidence rates were lower than in the core studies.

The most common TEAEs were upper respiratory tract infections and nasopharyngitis, and the most common serious TEAEs were acute myocardial infarction, coronary artery disease, and acute renal failure. However, exposure-related incidence rates were low in the core studies and did not increase in the core and extension studies. Likewise, exposure-related incidence rates for renal-related TEAEs in the core studies were similar in both the lesinurad, 200 mg with XOI, and XOI monotherapy groups, but higher in the lesinurad, 400 mg with XOI group.

The most common renal TEAE was increased blood creatinine, which was dose related. The most common serious renal-related TEAEs were acute renal failure, renal failure, chronic renal failure, and renal impairment. However, in the core studies these events only occurred in the XOI monotherapy and lesinurad, 400 mg plus XOI, groups; exposure-related incidence rates were 0 to 0.5 events per 100 person-years, whereas in the core and extension studies, the rates for these events were ≤0.2 per 100 person-years, except for acute renal failure in the lesinurad, 400 mg with XOI group, in which the rate was 1.0 per 100 person-years.

Study limitations included the failure to follow all dropouts and patients who had serum creatinine elevations after the study. The researchers noted that the extension studies provided no evidence of new safety concerns.

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Reference

Terkeltaub R, Saag KG, Goldfarb DS, et al. Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout [published online August 14, 2018]. Rheumatology. doi:10.1093/rheumatology/key245