Two linked controlled trials indicate that pegloticase, a long-acting mammalian uricase, lowered serum uric acid levels in patients with chronic, treatment-resistant gout.

Treatment of gout relies on lowering serum uric acid levels long-term, most commonly using allopurinol. A small proportion of patients do not achieve sufficiently low levels with oral therapy: for these patients, treatment with recombinant mammalian uricase offers an option. Uricase degrades uric acid to the much more soluble allantoin, a process that occurs naturally in most mammals, however the currently available version (rasburicase) is not licensed in gout and must be given daily. Pegloticase is recombinant mammalian uricase conjugated to polyethylene glycol, which increases its duration of action. These two linked trials included patients with severe chronic gout intolerant of or refractory to maximum doses of allopurinol. They were randomised to three groups: pegloticase every two weeks, pegloticase and placebo alternately every two weeks (i.e. pegloticase monthly), or placebo every two weeks, all by 2-hour IV infusion. Trial duration was 6 months, and the primary outcome was plasma uric acid levels of less than 6.0 mg/dL (= 356.9 micromol/l) in months 3 and 6.

Of 262 patients screened over the two trials, 225 were eligible and randomised; 13 did not receive any study drug and were excluded, leaving 212 who received at least one infusion for analysis (85 in the biweekly group, 84 in the monthly group, and 43 in the placebo group). The results showed pegloticase to be significantly superior to placebo: overall, the primary outcome was reached in 36 of 85 patients in the biweekly group (42%; 95% CI, 32% to 54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24% to 46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0% to 8%; P < 0.001 for each comparison). Secondary outcome measures of clinical response also favoured pegloticase, although there was a higher incidence of gouty flares in these groups over the first three months.

Serious adverse effects occurred more often in the pegloticase groups than in the placebo group (24% and 23% vs.12%), and gouty flares were the most frequent adverse effect. Infusion reactions were the second most frequent adverse event (26%, 24%, vs. 5%) and serious infusion reactions occurred in 5% and 8% of biweekly and monthly pegloticase patients, respectively. Pegloticase antibodies appeared in 89% of patients receiving it, but only neutralised the enzyme in 1 patient.

The authors conclude that in this patient population, pegloticase reduced serum uric acid levels compared to placebo. It also gave improvements in clinical outcomes and quality of life scores. Infusion reactions, in some cases serious, were the most common adverse effect causing withdrawal from trials, and the authors note the need for prophylaxis against these to be given to all patients. A number of patients had serious cardiovascular events during the trials, however all had cardiovascular risk factors and the authors suggest that attention to these is necessary before considering treatment.

[Editor’s note: pegloticase was licensed and launched in the US last year, with strong warnings over the risk of serious adverse effects. It is not currently available in the EU, however a licence application has been submitted to the European licensing authority: usual timescales would suggest that if it is approved, it would be licensed late 2012 to early 2013. There are no comparisons with febuxostat.]