Background/Purpose: Pegloticase is a recombinant modified mammalian uricase conjugated to mPEG and approved for treatment of refractory chronic gout. Pegloticase safety was evaluated during 2 replicate, 6-month randomized, placebo-controlled trials (RCTs).¹ An open-label extension (OLE) of these trials for up to 2.5 additional years of therapy evaluated long-term safety.

Methods: Patients completing one of the RCTs (n=157) could enroll in the OLE study conducted at 46 sites in the US, Canada, and Mexico. Patients (n=149) received pegloticase 8 mg infusions Q2 weeks or Q4 weeks. Patients received prophylaxis for infusion-related reactions (IRs) and gout flares (flare prophylaxis could be discontinued after 3 months in the OLE). Safety was evaluated with special interest in gout flares and IRs (defined as any adverse event occurring during or within 2 hours after infusion and not reasonably attributable to another cause).

Results: Of 157 RCT completers, 151 (96%) entered the OLE study and 149 received pegloticase (2 patients chose observation only). Patients received a mean of 28 ± 18 (SD) pegloticase infusions (range= 1-59) and were followed for a mean of 25 ± 11 months in the OLE study. The most common reasons for study withdrawal were AEs in 18% (27/149) of patients and loss of urate-lowering response in 11% (16/149). Nearly all patients (98%) had at least one AE during the OLE study. Gout flares and IRs were the most frequently reported adverse events (see table below); these were less common in patients sustaining urate-lowering response to treatment and those receiving the q2wk dosing regimen. Most AEs were investigator-rated (worst category per patient) as moderate (53%) in intensity. Overall, 54 patients (36%) had AEs rated as severe; these were deemed treatment-related in 25 (17%) patients. The most common treatment-related severe AEs were IRs and flares in 11 (7.4%) and 10 (6.7%) subjects, respectively. No patients with sustained urate-lowering response to treatment had a severe treatment-related IR or a severe gout flare.

Among the 13 serious AEs considered possibly related to pegloticase, there were 11 IRs, 1 skin necrosis, and 1 nephrolithiasis. Among the 11 serious IRs, all but one (91%) occurred when serum UA exceeded 6 mg/dL. A total of 4 deaths occurred during the OLE study; all were judged as unlikely related to study drug by the investigator. Laboratory assessments (CBC, CMP and U/A) identified no significant treatment-related change from baseline (except in UA).

Conclusion: The safety profile of long-term pegloticase treatment was consistent with that observed during the 6-month RCTs with no new safety signals identified. As all but one of the 11 serious IRs reported during this study occurred when the UA level was >6 mg/dL, UA should be measured prior to infusions and pegloticase should be discontinued when UA levels rise >6 mg/dL after an initial response.

1. Sundy et al. JAMA. 2011;306:711-20