A PHASE 2 STUDY OF MULTIPLE DOSES OF INTRAVENOUS POLYETHYLENE GLYCOL (PEG)-URICASE IN PATIENTS WITH HYPERURICEMIA AND TREATMENT-FAILURE GOUT

Background: A subset of gout patients are unresponsive to or intolerant of conventional therapy and have persistent manifestations of chronic disease. Treatment with PEG-uricase is being investigated in patients with treatment-failure gout.Objectives: This Phase 2, randomized, open label, multi-center, parallel group study assessed the urate response and the pharmacokinetic and safety profiles of PEG-uricase in patients with hyperuricemia and treatment-failure gout.Methods: Eligible patients were unresponsive to or intolerant of conventional therapy. 41 patients were randomly assigned to 12 weeks of treatment with intravenous PEG-uricase at one of four doses: 4 mg every 2 weeks (N=7); 8 mg every 2 weeks (N=8); 8 mg every 4 weeks (N=13); or 12 mg every 4 weeks (N=13). Antihyperuricemic medications were discontinued 7 days prior to initial dosing. Plasma uricase activity and urate levels were measured at defined intervals. Pharmacokinetic parameters, mean plasma urate, percentage of time that plasma urate was ≤ 6mg/dL and anti-PEG-uricase antibodies were determined. Adverse events (AEs) were recorded.Results: Mean age of patients was 58.1 years. 85% were male and 83% were white. Mean duration of disease was 14 years. One or more tophi were present in 71%. 27/41 patients received all intended doses of PEG-uricase. 38/41 subjects experienced an AE that was possibly treatment-related; the most common being gout flare (36 subjects). 21 adverse events that occurred within 24 hours of infusion in 18 subjects were considered possible infusion reactions (IR) and 9 of these subjects were withdrawn without rechallenge. 3 additional patients were rechallenged, experienced IRs and were withdrawn. There were no anaphylactic reactions. Of 13 serious AEs, 5 were described as possibly or probably treatment-related: gout flare (2), hypersensitivity reaction (1), anemia (1), and infected tophus (1). 33/41 patients had anti-PEG uricase antibody binding at some point in treatment. Rapid clearance of uricase activity occurred after one or more infusions in 11 of the 33 patients with anti-PEG-uricase antibody. However, persistent loss of uricase activity was observed in just 5 patients. Antibody binding was predominately IgM and was not associated with adverse events. Dose Group Mean (Std. Dev.) 4 mg/2 weeks 8 mg/2 weeks 8 mg/4 weeks 12 mg/4 weeks Pretreatment Plasma Urate (mg/dL) 7.33 (1.81) 9.09 (1.73) 9.01 (3.42) 8.86 (2.27) Mean Plasma Urate (mg/dL) over 12 Wks. 4.20 (2.47) 1.42 (2.06) 2.57 (1.67) 2.60 (3.08) % Time Plasma Urate < 6 mg/dL 73 (30) 92 (23) 86 (16) 84 (27) Conclusion: Multiple dose administration of PEG-uricase led to substantial and sustained lowering of plasma urate levels. The greatest reduction in plasma urate was observed in subjects who received 8 mg every 2 weeks. The most common AE was gout flare. 5/33 subjects with antibodies experienced persistent reduction in uricase activity. Future studies will determine the efficacy and safety of PEG-uricase as an antihyperuricemic treatment for gout patients who have failed conventional treatment.Citation: Ann Rheum Dis, volume 65, supplement II, year 2006, page 271Session: Miscellaneous rheumatic diseases