Background/Purpose: Pegloticase was approved in the US in late 2010 for patients with chronic gout refractory to xanthine oxidase inhibitors (XOIs). The clinical development program for pegloticase used a primary endpoint based on uric acid (UA) response <6 mg/dL and 42% of treated patients were classified as “responders” (vs 0% with placebo; P<0.001).^1,2 Post hoc analyses revealed that UA nonresponse was associated with high titer antibodies against pegloticase resulting in increased drug clearance and risk for infusion reactions (IRs). Pegloticase treatment recommendations thus included that UA be monitored preinfusion and discontinuation considered if serum UA was >6 mg/dL (particularly with 2 consecutive levels >6 mg/dL). Postapproval safety data has provided valuable insights into UA monitoring, concomitant medication use, and risk mitigation. Here we present pharmacovigilance data with a focus on infusion-related reactions and educational efforts to prevent the use of concomitant XOIs. Concomitant XOI use can mask the loss of UA response to pegloticase and confound the use of UA as a biomarker of efficacy and IR risk. Guidance cautioning against the use of pegloticase and XOIs was distributed via a Dear Healthcare Provider (DHCP) letter and a label update.

Methods: For safety surveillance, IRs were defined as adverse events (AEs) that occurred during or within 2 hours following the end of study drug infusion and could not be reasonably attributed to another cause. The incidence of IRs was drawn from voluntary AE reporting via MedWatch from September 2010 to March 2013 (to be updated through September 2013). All cases of IRs were evaluated for concomitant XOI use. An estimate of the total number of infusions given was based on the number of vials sold.

Results: During the postapproval period of 2.5 years, there were an estimated 12,736 vials sold and the sponsor received 91 spontaneous reports of patients with IRs (70 reports of IRs and 21 reports of possible anaphylaxis). When compared with IR rates from the clinical trials, postapproval data represents a significant reduction in IR risk of 72%. Among the 91 IRs, 78 events occurred during the infusion and 4 occurred in the 2 hours postinfusion (9 did not provide timing). The incidence of concomitant XOI use with pegloticase among patients with IRs was reduced (P=0.0028) after the DHCP letter and label change (table).

Conclusion: Given known limitations of estimating based on unsolicited AE reporting during pharmacovigilance, increasing utilization of pegloticase has been associated with a decline in the number of IRs. Educational efforts have led to significant reductions in the proportion of IRs with concomitant XOI use. Continued educational efforts regarding the need for UA monitoring with pegloticase and avoidance of concomitant XOI use should further reduce IR risk.

References:

1. Sundy et al. JAMA. 2011.

2. Becker et al. Ann Rheum Dis. 2012.