DURHAM, North Carolina—A new, experimental urate-lowering drug, pegloticase, may help rheumatologists better care for their patients with treatment-resistant gout, Duke researchers report in the September issue of Arthritis & Rheumatism.¹ The new drug is being developed by Savient Pharmaceuticals, Inc in East Brunswick, NJ.

Unlike the gold standard gout drug allopurinol, pegloticase works by degrading uric-acid stores. By contrast, allopurinol inhibits xanthine oxidase and prevents the formation of new uric acid.

“For many patients with treatment-failure gout who are intolerant to currently available urate-lowering treatments or whose disease is nonresponsive to treatment, pegloticase can substantially reduce urate levels, which may in turn  potentially alleviate clinical manifestations of gout in patients without other treatment options,” conclude researchers led by John S. Sundy, MD, PhD of Duke University Medical Center in Durham, NC. The results from the phase II trial of pegloticase will be presented at the annual meeting of the American College of Rheumatology in October 2008.

In the 12-to-14 week open-label trial, 41 patients with treatment-failure gout were randomized to one of four injectable doses of pegloticase (4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks). Patients were either intolerant to conventional urate-lowering therapy or had inadequate responses to allopurinol, had mean disease duration of 14.4 years, and had a mean eight gout attacks in the year prior to study enrollment. There was a mean serum uric acid level of 10.3 mg/dL and visible tophi in 71% of study patients.

Urate level drops dramatically within 6 hours

Overall, the mean plasma urate level was reduced to ≤6 mg/dL within 6 hours in all dosage groups. This effect was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups, the study found. The most effective dosage was 8 mg every 2 weeks.

A total of 26 patients received all protocol doses. The percentage of the patients in whom the primary efficacy endpoint (plasma urate <6 mg/dl for 80% of the study period) was achieved ranged from 50% to 88%; the percentage of patients who experienced gout flares was 88%. Moreover, the majority of adverse events (excluding gout flare) was unrelated to treatment and mild or moderate in severity; they included nephrolithiasis and arthralgia. Infusion-day adverse events were the most common reason for study withdrawal, accounting for 12 of 15 withdrawals. Importantly, there were no anaphylactic reactions. Antipegloticase antibody was present in 31 of 41 patients and was associated with reduced circulating half life of the new drug, suggesting that this factor may have an important influence on how this drug fits into the current armamentarium.

Translating research into practice

In an editorial accompanying the new study,² N. Lawrence Edwards, MD, of the University of Florida in Gainesville, writes that “despite this relatively clear understanding of the etiopathogenesis of hyperuricemia and gout and decades of experience with urate-lowering therapies, gout remains a form of arthritis that is very poorly managed by both primary care physicians and rheumatologists.”

Novel therapies are needed for treatment-resistant gout, he writes. “All rheumatologists from time to time see patients who would be classified into this subgroup, using even the strictest of definitions and we should all be pleased by the prospect of an expansion of pharmacological approaches to this challenging and frustrating condition.”

References

1.  Sundy JS, Becker MA, Baraf HSB, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout. Results of a phase II randomized study. Arthritis Rheum. 2008;58:2882-2891.
2.  Edwards NE. Treatment-failure gout: A moving target. Arthritis Rheum. 2008;58:2587-2590.