Higher Dose Pegloticase Q4W Feasible for Uncontrolled Gout

New research suggests that monthly (Q4W), higher doses of pegloticase are feasible for people with uncontrolled gout while maintaining safety and efficacy comparable to that of pegloticase 8 mg Q2W in the MIRROR randomized control trial (RCT).1

The MIRROR RCT previously evaluated pegloticase Q2W dosing with MTX coadminstration. These findings, from the phase 4 FORWARD trial, were presented at the European Alliance of Associations for Rheumatology (EULAR) Congress 2025 in Barcelona, Spain, taking place June 11-14, 2025.

“Pegloticase, when co-administered with methotrexate (MTX) decreases pegloticase immunogenicity, thus increasing serum urate (SU)-lowering response rate and decreasing infusion reaction (IR) risk in patients with uncontrolled gout. However, the current treatment regimen of infusions administered every 2 weeks for >2 hours can be burdensome on patients,” lead investigator Orrin Troum, MD, clinical professor of medicine, Keck School of Medicine, University of Southern California, and director, clinical rheumatology research, Providence St John's Hospital, Santa Monica, California, and colleagues wrote in their abstract. “The recent results from the AGILE trial demonstrated the safety and efficacy of a shorter infusion time (60 min) of pegloticase with MTX coadminitration.2 In addition to a shorter infusion time, decreasing the frequency of pegloticase to a Q4W intravenous dose will further improve treatment logistics, patient adherence and infusion efficiency.”

FORWARD is a phase 4, multicenter, open-label study (FORWARD I, NCT04762498) that enrolled patients with uncontrolled gout (serum uric acid [sUA] ≥6 mg/dL, intolerance or failure of urate-lowering therapy, and ≥1 gout symptom: ≥2 flares in 12 months, a tophus, or gouty arthropathy). Key exclusion criteria included MTX contraindication, serious bacterial infection, G6PD deficiency, and eGFR <40 mL/min/1.73 m². Patients completed a 4-week MTX run-in (15 mg/week with 1 mg/day folic acid) followed by pegloticase plus MTX for 24 weeks (6 infusions). Enrollment began with the 16-mg cohort, and following 4- and 8-week safety and efficacy reviews, the 30-mg cohort was opened. Patients who completed treatment through week 24 could enter an optional 24-week extension (up to 12 infusions).1

Co-primary endpoints included the proportion of month 6 responders (sUA <6 mg/dL for ≥80% of Month 6) and time to first sUA ≥6 mg/dL after achieving <6 mg/dL. Secondary endpoints included pharmacokinetics, sUA response rates, area under the sUA curve (Day 1–Week 24 and Day 1–Week 48), sustained sUA control at weeks 24 and 48, and pegloticase immunogenicity. Investigators also monitored for adverse events of interest.

The study treated 51 patients with Q4W pegloticase with MTX, 25 with 16 mg and 26 with 3- mg. In these 2 cohorts, 72.0% and 69.2% completed treatment through week 24, and 94.1% and 68.4% completed week 48, respectively. Overall, 70.6% continued in the optional extension phase (17 in 16 mg and 19 in 30 mg).1

Troum and colleagues found that 68.0% (95% CI, 46.5-85.1) of the 16-mg cohort and 73.1% (95% CI, 52.2-88.4) of the 30-mg cohort achieved the Month 6 sUA-lowering response primary endpoint. A total of 8 patients in each cohort (32.0% in 16-mg and 30.8% in 30-mg) had an sUA ≥ 6 mg/dL after achieving sUA < 6 mg/dL from first infusion until week 24, with a median time of of 50.5 days (IQR, 11.5-86.5) and 22.5 days (IQR, 18.5-82.0), respectively.1

Of the 36 patients who continued into the extension period, 88.2% (n = 15 of 17) of the 16-mg cohort and 68.4% (n = 13 of 19) of the 30-mg cohort were sUA responders during Month 12. Both cohorts had a median of 100% of time patients sustained sUA < 6 mg/dL from day 1 to week 24 or day 1 to week 48.1

In terms of safety, the IR rate, including anaphylaxis, period was 16.0% in the 16-mg cohort and 11.5% in the 30-mg cohort at week 48. Notably, no IRs occurred after week 24, which was consistent with the safety profile in the MIRROR RCT. Pegloticase standard stopping rule (sUA > 6 mg/dL at 2 consecutive visits) was not implemented until enrollment was complete in the 16-mg cohort, and 1 patient in the 30-mg cohort with IR was dosed despite meeting this rule, inflating IR rate. Investigators noted that if the discontinuation criteria had been properly applied, the IR rate would be around 8% in both groups.1

The investigators identified major adverse cardiac events (MACE; edema, peripheral edema, transient ischemic attack) in 8.0% of 16-mg cohort and 3.8% of the 30-mg cohort respectively, but these were not considered by the Sponsor to be MACE upon further review.1

REFERENCES

1. Troum O, Botson J, Fang F, et al. Safety and Efficacy of Monthly Dosing of Pegloticase (Every 4 Weeks Every 4 Weeks) With Methotrexate Co-administration in With Methotrexate Co-administration in Patients With Uncontrolled Gout: Phase 4 FORWARD Open-label Trial Patients With Uncontrolled Gout: Phase 4 FORWARD Open-label Trial. Presented at: EULAR Congress 2025; Barcelona, Spain; June 11-14. Abstract # POS1153

2. Troum O, Botson J, Fang F, et al. Safety, Tolerability and Efficacy of Pegloticase Administered with a Shorter Infusion Duration in Subjects with Uncontrolled Gout Receiving Methotrexate: Primary Findings of the AGILE Open-label Trial. Presented at: Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract 2012.