A phase 4, open-label efficacy and safety study of methotrexate and monthly pegloticase co-administration in patients with uncontrolled gout

Abstract Background Pegloticase is an infused pegylated uricase enzyme indicated for the treatment of uncontrolled gout in adults who did not respond to or cannot tolerate oral urate-lowering therapies; pegloticase is administered as 8-mg infusions every 2 weeks (Q2W). However, frequent infusions can create a logistical burden for patients. The phase 4, FORWARD open-label trial (NCT04762498) assessed the efficacy and safety of less frequent and higher dose pegloticase infusions in patients with uncontrolled gout. Methods Adults with uncontrolled gout received either 16-mg or 30-mg pegloticase infusions, co-administered with methotrexate, every 4 weeks (Q4W) through the 24-week trial, with an optional extension through Week 48. The primary endpoints were the percentage of responders during Month 6 (those with serum uric acid [sUA] < 6 mg/dL for ≥ 80% of the time during Month 6) and the time to the first sUA level ≥ 6 mg/dL after achieving sUA < 6 mg/dL through Week 24. Other key endpoints included pharmacokinetic parameters, adverse events (AEs), and antidrug antibody profiles. Results The percentages of Month 6 responders in the 16-mg cohort ( n = 25) and 30-mg cohort ( n = 26) were 68.0% and 73.1%, respectively. The median time to the first sUA level ≥ 6 mg/dL after achieving sUA < 6 mg/dL was 50.5 days in the 16-mg cohort and 22.5 days in the 30-mg cohort for those with events, but the median time to this endpoint among all patients was not estimable using Kaplan–Meier due to the low number of events. Safety results were similar between cohorts. Gout flares occurred in 72.0% and 77.0% of patients in the 16- and 30-mg cohorts, respectively. Serious treatment-emergent AEs occurred in three patients in the 16-mg cohort. Immunogenicity findings were similar to those established with 8-mg pegloticase Q2W with methotrexate. Conclusions The efficacy and safety findings from this study of monthly 16- and 30-mg pegloticase dosing are consistent with results from standard biweekly 8-mg dosing, indicating that a less frequent and higher dosed pegloticase treatment schedule co-administered with methotrexate is feasible for patients with uncontrolled gout. Trial registration ClinicalTrials.gov NCT04762498 (registered on 17 February 2021).