Background A subset of patients develops refractory gout (RG) characterized by ongoing disease manifestations and inability to control serum urate (SUA) with conventional therapy. Pegloticase (PL) reduces SUA and improves signs and symptoms of RG, and was recently approved in the US1. Subjects with solid organ transplants or with prior use of PL were not eligible for enrollment in pivotal clinical trials.
Objectives To assess the urate lowering response, improvement in clinical outcomes and safety of short term administration of PL in patients with RG; including patients with solid organ transplant or prior PL treatment.
Methods 30 patients with RG were enrolled in an open label trial of PL 8 mg administered IV every 3 weeks for 5 doses. The trial was conducted under a sponsor investigator IND (11274) from the USFDA. Outcome measures included: reduction in plasma urate (PUA), plasma uricase activity, assessment of adverse events (AE), improvement in clinical outcomes of swollen and tender joint counts, tophus burden, and patient reported outcomes.
Results 30 subjects received at least one dose of PL (22M/8F, mean age 57Y, mean BMI 31.5, tophi in 28/30). 7 subjects had a solid organ transplant (5 renal, 2 renal/pancreas). 3 subjects received PL in prior Phase 1 or 2 trials. 21 subjects completed the trial, and 7 withdrew due to adverse events. Sustained PUA response (mean <0.36 mM) was observed in 16/21 completers. Transient PUA response was observed in 13 subjects of whom 8 withdrew before study completion. All transient responders produced high titer antibody to PL. Among transplant patients, 6/7 had no detectable antibody to PL at the time of the last infusion. Two transplant patients withdrew before the final treatment – one died of apparent myocardial infarction before the 4th infusion (antibody pos), one withdrew due to bowel perforation before the 3rd infusion (antibody neg). All 3 subjects with previous exposure to PL also previously expressed PL antibody. All were transient responders upon re-exposre and withdrew early because of rapid clearance or infusion related reactions. One subject experienced syncope at the initial infusion, and pre-existing PL antibody was subsequently detected. The most common AE was gout flare with 119 flares in 27 subjects. Other common AEs occurring in >3 subjects: exacerbation of chronic gouty arthritis (5), nausea (5), and hypertension (4). Serious AEs occurred in 5 patients: infusion reactions (2), death (1), GI bleed (1) and bowel perforation (1). Improvement in clinical outcome measures of tophus burden, swollen joint counts, and patient reported outcomes were observed in some patients after 5 doses of PL.
Conclusions PL 8 mg every 3 weeks led to rapid and sustained reduction in PUA levels in 16/30 patients with RG; similar to response rates observed in Phase 3 clinical trials. PL effectively controlled PUA in 5/7 organ transplant patients, a difficult to treat gout population. Patients with a remote history of transient response to PL remained transient responders upon re-exposure to PL. Clinical responses to PL treatment were observed in some patients after just 15 weeks of treatment. The safety of PL was comparable to that observed in larger Phase 3 studies.
Sundy JS, et al. JAMA. 2011 Aug 17;306(7):711-20.
Disclosure of Interest J. Sundy Shareholder of: Academic Partners for Medical Education, General Electric, Grant/Research support from: Ardea Biosciences, Pharmos, Metabolex, Consultant for: Ardea Biosciences, Pharmos, Novartis, BioCryst, Savient Pharmaceuticals, N. Gansen: None Declared, S. Kelly: None Declared, E. Scarlett: None Declared, D. Jaggers: None Declared, M. Hershfield Consultant for: Savient Pharmaceuticals