Background Lesinurad is a selective uric acid reabsorption inhibitor recently approved at 200 mg daily in combination with a xanthine oxidase inhibitor (XOI) for treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid on an XOI (allopurinol or febuxostat) alone.
Objectives To investigate the safety profile of lesinurad (LESU), we integrated safety data based on: (1) 3 large, pivotal, placebo-controlled, 12-month phase III (core) trials evaluating LESU 200 mg and LESU 400 mg in combination with an XOI; and (2) 2 extension studies, in which LESU-treated patients continued to receive LESU + XOI at the same dose and initially placebo-treated patients were randomized to receive LESU 200 mg or LESU 400 mg in addition to the XOI provided in the preceding core trial.
Methods Safety data were pooled from the 3 core studies and 2 12-month extension studies using descriptive statistics for patients receiving ≥1 dose of study medication. To adjust for varying treatment durations, treatment-emergent adverse events (TEAEs) are expressed as exposure-adjusted incidence rates (number of subjects with events per 100 person-years [PY]).
Results In the core studies, adverse event rates were comparable for XOI alone and LESU 200 mg + XOI groups for any TEAEs, serious TEAEs, and TEAEs leading to discontinuation (Table 1). Adverse event rates were higher with LESU 400 mg + XOI. Major adverse cardiovascular event (MACE) rates, which included cardiovascular death, myocardial infarction, or stroke, in the core studies were 0.71 (95% CI 0.15, 2.08), 0.96 (0.26, 2.47), and 1.94 (0.84, 3.82) per 100 PY for XOI alone, LESU 200 mg + XOI, and LESU 400 mg + XOI, respectively. Renal-related TEAE rates in the core studies were 5.6, 7.3, and 15.4 per 100 PY, respectively. Longer exposure in the core + extension studies did not result in increases in any TEAEs, serious TEAEs, or TEAEs leading to discontinuation (Table 2). MACE rates were low in the core + extension studies, at 1.05 (95% CI 0.50, 1.93) and 1.48 (0.81, 2.48) in the LESU 200 mg + XOI and LESU 400 mg + XOI groups, respectively. Renal events in the core + extension studies were lower in the LESU 200 mg + XOI than LESU 400 mg + XOI group at 8.6 and 14.6, respectively.
Conclusions Lesinurad at the approved dose of 200 mg once daily demonstrated a consistent, acceptable safety profile. There were no new safety concerns in the extension studies.
Acknowledgements This study was funded by Ardea Biosciences/AstraZeneca.
Disclosure of Interest M. Becker Grant/research support from: Takeda, Savient, Ardea/AstraZeneca, Consultant for: Takeda, Savient, Horizon, Ardea/AstraZeneca, CymaBay, Pfizer, R. Keenan Consultant for: AstraZeneca, Ironwood, Horizon, P. Khanna Grant/research support from: AstraZeneca, R. Malamet Employee of: AstraZeneca, K. Bos Employee of: AstraZeneca, J. Li Employee of: AstraZeneca, J. Hu Employee of: Ardea Biosciences, W. White Consultant for: AstraZeneca