New Gout Treatment Effective, Safe in Short Term
Lesinurad plus allopurinol significantly increased uric acid clearance.
By Nancy Walsh, MedPage Today
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The recently approved uric acid reabsorption inhibitor lesinurad (Zurampic) was effective in lowering serum urate when given with allopurinol in patients with gout, a phase II study found.
After 4 weeks of treatment, the mean reduction in serum urate among patients receiving 200 mg, 400 mg, or 600 mg/day of lesinurad was 16 percent, 22 percent, and 30percent, respectively, compared with an increase of 3 perrcent in those given placebo, according to Fernando Perez-Ruiz, MD, of Hospital Universitario Cruces in Barakaldo, Spain, and colleagues.
And in the three dose groups, the percentages achieving serum urate levels below 6 mg/dL were 63 percent, 73.8 percent, and 79.2 percent, compared with 25 percent of the placebo group, the researchers reported online inAnnals of the Rheumatic Diseases.
Last month the FDA approved lesinurad, 200 mg/day, for use in combination with a xanthine oxidase inhibitor such as allopurinol or febuxostat (Uloric) for patients whose serum urate level cannot be controlled by the xanthine oxidase inhibitor alone.
The agency's advisory panel had previously voted to approve the drug, but cited safety concerns with the higher doses, including potential renal and cardiac toxicities.
Lesinurad "inhibits the URAT1 transporter responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen," which results in greater excretion of uric acid.
Current guidelines recommend target serum urate levels of 6 mg/dL or lower, with first-line therapy usually consisting of titrated xanthine oxidase inhibitors. However, in clinical trials of allopurinol, fewer than half of patients were able to lower their serum urate levels below 6 mg/dL.
Moreover, although allopurinal is approved in dosages up to 800 mg/day, titration to more than 300 mg/day is uncommon.
Therefore, to evaluate the safety and efficacy of combination therapy, the investigators enrolled 208 adults whose serum urate level was 6 mg/dL or higher despite allopurinol treatment for at least 6 weeks. Individuals with cardiac, hepatic, or liver disease were excluded.
In addition to lesinurad or placebo plus allopurinol, all patients were given colchicine for 3 weeks to help prevent flares.
Participants' mean age was 50, and the majority were white men. Baseline serum urate levels averaged 6.8 mg/dL.
At week 4, the percent change from baseline in renal uric acid clearance was 43.7 percent, 84.9 percent, and 118.8 percent in the 200-mg, 400-mg, and 600-mg groups compared with 8 percent in the placebo group.
In subgroup analyses, the serum urate decrease with all lesinurad doses was greater than with placebo regardless of allopurinol dose or baseline serum urate level, with the exception of urate levels of 10 mg/dL or higher. There were too few patients in that subgroup for analysis, the investigators noted.
In a pharmacokinetics substudy, trough plasma concentrations were dose related among patients with normal renal function but showed increases among patients with chronic kidney disease. The use of lesinurad did not alter the urinary excretion of allopurinol and had no apparent impact on colchicine pharmacokinetics.
The incidence of adverse events was similar in the four treatment groups, at 45.7 percent in the 200-mg group, 47.6 percent in the 400-mg group, 54.2 percent in the 600-mg group, and 45.8 percent in the placebo group. The most common events were gout flares, nasopharyngitis, headache, and arthralgias, and most were mild or moderate.
At week 4, the mean change from baseline in serum creatinine was 0.031 mg/dL, 0.101 mg/dL, 0.072 mg/dL, and -0.003 mg/dL for the 200-mg, 400-mg, 600-mg, and placebo groups, respectively, while the mean change in estimated creatinine clearance was -5 mL/min, -0.7 mL/min, -2.6 mL/min, and 0.7 mL/min.
In the four groups, the proportion of patients whose serum creatinine had been normal at baseline but was above the reference range after a month of treatment was 2.5 percent, 10 percent, 7.5 percent, and 1.6 percent, respectively.
"No clinically relevant changes in vital signs or ECG findings suggesting short-term cardiac safety risk were observed," the investigators reported.
Limitations of the study included its short duration and relatively small number of patients.
"Larger studies are needed to evaluate the long-term efficacy and safety of lesinurad in a wider range of patients and to more fully evaluate efficacy and safety in patients with renal function impairment," the investigators concluded.
The study was funded by Ardea Biosciences. Some co-authors are company employees.
Perez-Ruiz disclosed relevant relationships with AstraZeneca, Menarini, Novartis, Pfizer, SOBI, and the Asociación de Reumatólogos del Hospital de Cruces. Some co-authors disclosed relevant relationships with Ardea, AstraZeneca, Novartis, Menarini, Pfizer, SOBI, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Jazz Pharmaceuticals, Merck, and Par Pharma.
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