Pegloticase for chronic gout

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Pegloticase for chronic gout.
Anderson A, Singh JA.
Cochrane Database Syst Rev. 2010 Mar 17;3:CD008335.
(http://www.ncbi.nlm.nih.gov/pubmed/20238366?dopt=Abstract)
BACKGROUND: Pegloticase is a potential new treatment option for patients with chronic gout intolerant to other urate-lowering therapies. OBJECTIVES: To assess safety (adverse events, death) and efficacy (pain, function, frequency of flares, quality of life, uric acid level, radiographic damage) of pegloticase in various doses or as compared to placebo or other interventions for treatment of hyperuricemia in patients with chronic gout.

SEARCH STRATEGY: We searched six databases: The Cochrane Central Register of Controlled Trials (CENTRAL), via The Cochrane Library, OVID MEDLINE, CINAHL (via EBSCOHost), OVID SPORTdiscus, EMBASE and the Science Citation Index (Web of Science). SELECTION CRITERIA: All published randomized controlled trials (RCTs) or controlled clinical trials that compared various doses of pegloticase alone or pegloticase alone or in combination with other urate-lowering or anti-inflammatory medications to placebo alone or placebo in combination with these medications, in patients with gout.

DATA COLLECTION AND ANALYSIS: Two review authors (AA, JS) independently extracted data from the included trials, including trial and population characteristics, primary and secondary outcomes. For dichotomous and continuous outcomes, we calculated the risk ratio and mean difference, respectively with 95% confidence interval. Major outcomes were: (a) Efficacy: frequency of gout flares and change in serum uric acid; and (b) safety: adverse events, serious adverse events, withdrawals and death. Minor/secondary outcomes were pain, patient/physician global assessment, tophus burden, health related quality of life, function and radiographic progression.

MAIN RESULTS: Only one open-label, phase-II RCT (n=41) met the selection criteria that compared various doses of pegloticase without comparison to placebo or another treatment. Patients were randomized to one of the four doses of pegloticase for 12 to 14 weeks - 4mg every 2 weeks, 8mg every 2 weeks, 8mg every 4 weeks and 12mg every 4 weeks. Percent responders (uric acid below 6 mg/dl 80% or more time) in the four dose groups were 56%, 88%, 52% and 62%. Percent time without hyperuricemia (uric acid below 6 mg/dl) was 78%, 92%, 76% and 76% respectively. No between dose differences were noted. Most common adverse events (10% or more patients) included nephrolithiasis, arthralgia, anemia, dyspnea, headache, muscle spasms, nausea and pyrexia. 89% reported one or more gout flares during the study. Pain, patient/physician global, function, quality of life, tophus size/regression and radiographic progression were not reported in this study.

AUTHORS' CONCLUSIONS: There are no published double-blind, placebo-controlled RCTs of pegloticase. More evidence is needed to assess risks/benefits of pegloticase in patients with chronic gout.

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Press Release:
Medication For Severe, Chronic Gout Associated With Improvement in Symptoms
As an alternative to a conventional treatment for gout that some patients may not respond to, patients with severe, chronic gout who received the medication pegloticase for 6 months had greater improvement in measures of uric acid levels as well as physical function and quality of life, according to a study in the August 17 issue of JAMA.

Long-term urate (a salt derived from uric acid) lowering therapy in gout aims to maintain concentrations of uric acid (UA) below a certain level. However, it is common for UA levels to exceed a recommended goal urate range during oral urate-lowering therapy among the 5 to 6 million U.S. patients with gout, according to background information in the article. Although available oral urate-lowering agents can achieve target UA in most patients, urate-lowering therapy fails for perhaps 3 percent of patients because of refractoriness (resistant to treatment), contraindication, or intolerance. Without effective urate lowering, many such patients may progress to severe chronic gout characterized by symptoms including frequent arthritic flares and chronic arthropathy (a joint disease), often accompanied by deformity, chronic pain, functional disability, and impaired health-related quality of life (QOL). Pegloticase, a recently approved drug, was developed for patients in whom conventional urate-lowering agents are not effective. The drug is intravenously administered and remains in the circulation where it degrades urate.

John S. Sundy, M.D., Ph.D., of Duke University Medical Center, Durham, N.C., and colleagues report results of two randomized, placebo-controlled, 6-month trials of the urate-lowering and clinical efficacy and tolerability of pegloticase in patients with refractory gout. The trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol (a drug to treat gout) intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. Patients received 12 biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo. The primary measured outcome was plasma uric acid levels of less than 6.0 mg/dL measured at months 3 and 6.

The researchers found that when analyzed separately by dose, patients treated with biweekly pegloticase experienced response rates (of meeting the primary outcome) of 47 percent (20/43) and 38 percent (16/42) in the 2 trials. Patients treated with monthly pegloticase reported response rates of 20 percent (8/41) and 49 percent (21/43), and response rates were 0 percent in both placebo groups. "When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42 percent), 29 of 84 patients in the monthly group (35 percent), and 0 of 43 patients in the placebo group," the authors write. Average plasma UA for responders was substantially below 6.0 mg/dL for the entire 6-month treatment period.

The researchers also found that both pegloticase dosing groups reported significant improvements in physical function and QOL compared with placebo. Patient-reported pain was significantly reduced with biweekly pegloticase vs. placebo.

One or more adverse events (AE) occurred in more than 90 percent of participants in each treatment group. Serious AEs occurred more frequently in patients treated with biweekly (24 percent) and monthly pegloticase (23 percent) than in patients receiving placebo (12 percent). Gout flare was the most common AE and was reported in approximately 80 percent of patients across the 3 pooled study groups. Seven deaths (4 among patients assigned pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008).

"These parallel, 6-month, placebo-controlled trials of pegloticase treatment have documented sustained UA reductions and significant clinical improvements in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy. The significant disease-modifying benefits of pegloticase given every 2 weeks were demonstrable within 6 months, a time frame unique in randomized controlled trials of urate-lowering agents," the authors write.