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

Abstract

Objective. To assess the efficacy of pegloticase in achieving and maintaining plasma urate levels of <6 mg/dl in gout patients in whom other treatments have failed, and to assess the pharmacokinetics and safety of pegloticase.Methods. Forty-one patients were randomized to undergo 12-14 weeks of treatment with pegloticase at 1 of 4 dosage levels: 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks. Plasma uricase activity, plasma urate, and antipegloticase antibodies were measured, pharmacokinetic parameters were assessed, and adverse events were recorded.Results. The mean plasma urate level was reduced to <6 mg/dl within 6 hours in all dosage groups, and this was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups. The most effective dosage was 8 mg every 2 weeks. Twenty-six patients received all protocol doses. The percentage of the patients in whom the primary efficacy end point (plasma urate <6 mg/dl for 80% of the study period) was achieved ranged from 50% to 88%. Gout flares occurred in 88% of the patients. The majority of adverse events (excluding gout flare) were unrelated to treatment and were mild or moderate in severity. Infusion-day adverse events were the most common reason for study withdrawal (12 of 15 withdrawals). There were no anaphylactic reactions. Antipegloticase antibody, present in 31 of 41 patients, was associated with reduced circulating half-life of pegloticase in some patients.Conclusion. Pegloticase, administered in multiple doses, was effective in rapidly reducing and maintaining plasma urate levels at <6 mg/dl in most patients in whom conventional therapy had been unsuccessful due to lack of response, intolerability, or contraindication.ClinicalTrials.gov identifier: NCT00080210.

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

“…A similar rate is obtained using the mean maximum plasma uricase activity (Cmax), 26.0 ± 2.8 mU/mL, determined 2 h after this dose of pegloticase (20). After such an infusion, PUA declines rapidly to hypouricemic levels, indicating depletion of the soluble urate pool (19,20); thereafter (beyond 24-48 h after the first infusion), urate oxidation is limited to about the endogenous rate of urate production, ∼750 mg (4,500 μmol) per 24 h (9). The rate of dissolution of MSU deposits cannot be measured, but from the rate of tophus resolution it appears to be significantly less than the rate of urate biosynthesis.…”

“…The 26 patients studied had clinical features (Table 2) similar to those of refractory gout patients treated in other trials of pegloticase (19,20,31). Notably, 92% had tophaceous MSU deposits, indicating advanced disease, and the prevalence of hypertension, diabetes, and CVD was very high.…”

“…The relationship of uricase expression and PUA to oxidative stress is directly relevant to pegloticase, a PEGylated recombinant porcine uricase under investigation as an orphan drug for treating refractory gout when other therapies have failed to maintain PUA below 6 mg/dL (0.36 mM), the usual therapeutic target (19,20). In such patients, i.v.…”

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

“…Urate oxidase therapy is also being explored in tophaceous gout (23,26) and in patients with gout refractory to standard therapies (27,28). It has also been administered to a small number of patients after stroke (29) and in an individual with the Lesch-Nyhan syndrome (30).…”

“…It has also been administered to a small number of patients after stroke (29) and in an individual with the Lesch-Nyhan syndrome (30). In patients with gout, recombinant urate oxidase (26) and chemically modified preparations of recombinant urate oxidase with a prolonged half-life (27,31) have been used for up to 6 mo in clinical trials. These patients demonstrate prolonged biochemical evidence of uric acid breakdown, and some patients appeared to derive clinical benefit from this therapy (23).…”