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Positive Phase III Results Reported for Gout Drug Lesinurad
Positive results have been reported from three pivotal phase III trials investigating the potential of lesinurad (AstraZeneca), a selective uric acid re-absorption inhibitor (SURI), as a part of combination therapy for the treatment of patients with symptomatic gout.
Lesinurad is an investigational agent that inhibits uric acid transporter-1 (URAT1), thereby increasing uric acid excretion and lowering serum uric acid (sUA) levels.
The 12-month, randomized, placebo-controlled CLEAR1 and CLEAR2 (Combining Lesinurad With Allopurinol in Inadequate Responders) trials studied lesinurad (200 mg and 400 mg once daily) in combination with the xanthine oxidase (XO) inhibitor allopurinol in 603 and 610 patients, respectively, with symptomatic gout who did not achieve target sUA levels on their current allopurinol dose.
The 12-month, randomized, placebo-controlled CRYSTAL (Combination Treatment Study in Subjects With Tophaceous Gout With Lesinurad and Febuxostat) trial studied lesinurad (200 mg and 400 mg once daily) in combination with the XO inhibitor febuxostat (80 mg once daily) in 324 gout patients with tophi (visible nodules of uric acid crystals deposited in joints and skin).
In the CLEAR1 and CLEAR2 trials, lesinurad 200 mg and 400 mg in combination with allopurinol met the primary endpoint, with a significantly greater proportion of patients reaching the target sUA goal of less than 6.0 mg/dL at month 6 compared with allopurinol alone (P < 0.0001).
In the CRYSTAL trial, lesinurad 400 mg in combination with febuxostat met the primary endpoint, with a significantly greater proportion of patients reaching the target sUA goal of less than 5.0 mg/dL at month 6 compared with febuxostat alone (P < 0.0001). Although lesinurad 200 mg did not achieve statistical significance at month 6 (P = 0.13), this dose in combination with febuxostat was superior to placebo plus febuxostat at all other time points (i.e., months 1 to 5, 8, 10, and 12; nominal P < 0.05).
The three most common adverse events in the CLEAR1 and CLEAR2 trials for patients receiving lesinurad in combination with allopurinol were upper respiratory tract infection, nasopharyngitis, and back pain. In the CRYSTAL trial, the three most common adverse events for patients receiving lesinurad in combination with febuxostat were nasopharyngitis, arthralgia, and upper respiratory tract infection.
The incidence of renal-related adverse events (including serious events) and kidney stones associated with lesinurad 200 mg plus an XO inhibitor was comparable with that of placebo plus an XO inhibitor. The incidence of renal-related adverse events and kidney stones was higher with lesinurad 400 mg plus an XO inhibitor.
Patients who completed the pivotal phase III studies had the option to enroll in two on-going open-label, uncontrolled extension studies to continue to evaluate the safety and efficacy of combination therapy with lesinurad (200 and 400 mg) and XO inhibitors.
Source: AstraZeneca; August 13, 2014.