Background/Purpose: Using data pooled from the randomized, placebo-controlled trials (RCTs) of pegloticase, post-hoc analyses of urate-lowering, antibody titers and the patterns of infusion-related reactions (IRs) were carried out to evaluate predictors of risk for IRs. These analyses eventually led to guidance on monitoring uric acid (UA) levels as a biomarker of response to therapy¹. Here we describe the basis and outcomes of these risk mitigation analyses.

Methods: The 2 RCTs enrolled patients at 56 centers in the US, Mexico and Canada. Patients were > 18 yrs of age, had baseline UA ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the prior 18 mos; ≥1 tophi; or gouty arthropathy; and contraindication to allopurinol or failure to normalize UA during ≥3 mos of treatment at the maximum medically appropriate dose. Pegloticase was administered as 8 mg infusions q2wks or q4wks; plasma UA was sampled at baseline and immediately preceding each q2wk infusion. All patients received prophylaxis for IRs and flares. A responder was defined by plasma UA <6 mg/dL for 80% of time during mos 3 and 6.  IR was defined as any adverse event occurring during or within 2 hours after infusion.

Results: IRs were experienced by 26% and 42% of patients receiving pegloticase q2wks and q4wks, respectively. Post-hoc assessments revealed that the majority of these IRs (91% of IRs with q2wk dosing and 71% with q4wk dosing) occurred when UA exceeded 6mg/dL–suggesting that loss of urate-lowering response was predictive of risk for IRs. This relationship was not apparent to investigators during the 6 mos of RCT treatment because they were blinded to the pre-infusion UA levels.

Multiple benefit/risk scenarios were tested using UA concentration cut points and IRs to determine the most effective stopping rule for maximizing both safety and efficacy. The Table shows the number of patients reaching the two endpoints in the pooled trial population (no stopping rules) and the number of patients that would have reached these 2 endpoints if the specific stopping rule had been applied to the RCT population. Among the options tested, discontinuation of drug when patients had 2 consecutive serum UA levels >6 mg/dL appears to reduce the proportion of patients with IRs from 26% (observed) to 14% (estimated) with little impact on efficacy.

Conclusion: Post-hoc assessments from the 2 RCTs provided valuable information on the relationship between UA levels and IR risk that was not available during the trials. Multiple benefit/risk analyses informed the recommendation that patients discontinue pegloticase when serum UA is >6 mg/dL, particularly at 2 consecutive time points. Ongoing post-marketing surveillance will be important to assess the risk of IRs in clinical practice and adherence to these recommendations.

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