AstraZeneca has presented top-line results of two pivotal Phase III trials investigating the potential of lesinurad, a selective uric acid re-absorption inhibitor (SURI), when used in combination with xanthine oxidase (XO) inhibitor allopurinol. The results show that approximately twice as many patients met the primary endpoint with a statistically significant higher proportion of patients reaching the target sUA goal of <6.0 mg/dL at month 6, compared to those treated with allopurinol alone. The data was presented as a late-breaking presentation at the American College of Rheumatology (ACR) 2014 Annual Meeting in Boston, Massachusetts. Lesinurad is an investigational agent that inhibits the uric acid transporter URAT1 in the kidney, increasing uric acid excretion and thereby lowering sUA.
The two replicate Phase III studies, CLEAR1 and CLEAR2, evaluated lesinurad (200mg or 400mg oral) in combination with allopurinol in symptomatic gout patients not achieving target sUA levels on their current allopurinol dose.
In both trials, 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 <6.0 mg/dL at month 6 compared to allopurinol alone (CLEAR1 - 28%, 54% and 59%; CLEAR2 - 23%, 55% and 67% for allopurinol alone, lesinurad 200mg + allopurinol and lesinurad 400mg + allopurinol respectively). Among the key secondary endpoints of mean gout flare rates and patients with complete tophus resolution, no significant differences were observed for mean gout flare rates (end of Month 6 to 12) or patients with complete tophus resolution.
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. The incidence of renal-related adverse events (including serious events) and incidence of kidney stones with lesinurad 200mg plus allopurinol was comparable to placebo plus allopurinol. The incidence of renal-related adverse events and kidney stones was higher with lesinurad 400mg plus allopurinol. Serum creatinine increases were observed, which resolved in most cases without interrupting study medication.
"There has not been much development over the last 30 years in treatment options for the millions of patients who fail to reach target serum uric acid levels on current standard of care therapy such as allopurinol alone," said Dr. Kenneth G. Saag, Professor of Medicine at the University of Alabama, Birmingham, Alabama and principal investigator of the study. "The results from this first of its kind large Phase III trial demonstrate the potential of combination therapy with lesinurad to provide a future treatment option for gout patients on allopurinol where additional therapy is needed."
The goal of all urate lowering treatments is to reduce sUA levels to the recommended targets. International treatment guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recommend achieving an sUA target at a minimum of <6.0 mg/dL in all gout patients and often to <5.0 mg/dL in gout patients with greater disease severity and urate burden, such as those with tophi.
"We are very encouraged by these data from CLEAR1 and CLEAR2 which demonstrates that combination therapy with lesinurad and allopurinol results in approximately twice as many patients achieving target serum uric levels compared to today's standard of care allopurinol alone," said James Mackay, Chief Operating Officer of Ardea Biosciences, a subsidiary of AstraZeneca that is responsible for the development of AstraZeneca's gout portfolio.
Additional results from the Phase III clinical trial program of lesinurad will be submitted to a scientific meeting in 2015. The company is proceeding with preparation of regulatory submissions for lesinurad combination therapy.
CLEAR1 and CLEAR2 were conducted by Ardea Biosciences, a wholly-owned subsidiary of AstraZeneca.
About the Design of the Studies
CLEAR1 and CLEAR2 (Combining Lesinurad with Allopurinol in Inadequate Responders) were 12-month (US and global, respectively) multicenter, randomized, placebo-controlled studies (n=603 and n=610, respectively) comparing the efficacy and safety of lesinurad (200mg and 400mg once daily) when added to the patient's current stable medically-appropriate dose of allopurinol (at least 300mg daily, and at least 200mg daily for those with moderate renal impairment) compared to placebo plus allopurinol. Patients entering CLEAR1 and CLEAR2 had multiple sUA levels above target and had also reported at least two gout flares in the 12 months prior to randomization.
Patients who completed the randomized pivotal Phase III clinical 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 200mg and 400mg with XO inhibitors.