AstraZeneca today announced positive top-line results from CLEAR1, CLEAR2 and CRYSTAL, the pivotal Phase III clinical trials investigating the potential of lesinurad, a selective uric acid re-absorption inhibitor (SURI), as a combination therapy for the treatment of patients with symptomatic gout. Lesinurad is an investigational agent that inhibits the URAT1 transporter, increasing uric acid excretion and thereby lowering serum uric acid (sUA).
CLEAR1 and CLEAR2 studied lesinurad (200mg and 400mg once daily) in combination with the xanthine oxidase (XO) inhibitor allopurinol, in symptomatic gout patients not achieving target sUA levels on their current allopurinol dose. CRYSTAL studied lesinurad (200mg and 400mg once daily) in combination with the XO inhibitor febuxostat (80mg once daily) in gout patients with tophi (visible nodules of uric acid crystals that are deposited in joints and skin).
In the CLEAR1 and CLEAR2 trials, both lesinurad 200mg and 400mg in combination with allopurinol met the primary endpoint, with a statistically significant higher proportion of patients reaching the target sUA goal of <6.0mg/dL at month 6 compared to allopurinol alone (p<0.0001).
In the CRYSTAL trial, lesinurad 400mg in combination with febuxostat met the primary endpoint, with a statistically significant higher proportion of patients reaching the target sUA goal of <5.0mg/dL at month 6 compared to febuxostat alone (p<0.0001). Although lesinurad 200mg 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 (measured at months 1 to 5, 8, 10 and 12; nominal p<0.05).
The three most commonly reported adverse events across the CLEAR1 and CLEAR2 trials for patients receiving lesinurad in combination with allopurinol were upper respiratory tract infection, nasopharyngitis and back pain. In CRYSTAL, the three most commonly reported 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 incidence of kidney stones with lesinurad 200mg plus XO inhibitor was comparable to placebo plus XO inhibitor. The incidence of renal-related adverse events and kidney stones was higher with lesinurad 400mg plus XO inhibitor. A full assessment of the safety and tolerability findings of all three studies is ongoing.
“Gout is a serious, chronic and debilitating inflammatory disease. There is a significant unmet need, with 40 to 70 percent of gout patients not reaching target levels of serum uric acid with the current standard of care,” said Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer. “We are encouraged by our initial review of the top-line results from the CLEAR1, CLEAR2 and CRYSTAL studies which provide important new information on the efficacy and safety of lesinurad in combination with febuxostat and allopurinol. These data indicate that combination therapy with lesinurad may be a potential treatment option for gout patients.”
CLEAR1, CLEAR2 and CRYSTAL were conducted by Ardea Biosciences, a wholly-owned subsidiary of AstraZeneca. Results from these Phase III clinical trials will be submitted to a scientific meeting later in 2014. The company is proceeding with preparation of regulatory submissions for lesinurad (200mg) combination therapy.