Background: Pegloticase is a recombinant intravenous uricase enzyme that effectively treats uncontrolled gout in combination with methotrexate (MTX), which prevents anti-drug antibodies, increases efficacy and minimizes infusion reactions. An open-label trial of monthly pegloticase 16 mg with MTX (FORWARD I) showed a response rate of 68% (95% CI 46.5-85.1), with a 16% IR rate without implementation of standard serum uric acid discontinuation criteria [1]. Based on these results, the present randomized controlled trial (FORWARD II) directly compared pegloticase administration at 8 mg every-2-weeks with 16 mg every-4-weeks with weekly oral methotrexate in all subjects to test whether intravenous uricase therapy with immunomodulation remains as efficacious at the less-frequent monthly dosing interval.

Objectives: To report the safety, efficacy, and non-inferiority results of FORWARD II, a randomized double-blind trial of pegloticase Q2W 8 mg compared to Q4W 16 mg, each with weekly methotrexate.

Methods: This randomized, double-blind, multi-center, non-inferiority trial (FORWARD II, NCT06229145) enrolled participants with uncontrolled gout: serum urate [SU] ≥7 mg/dL, oral urate-lowering failure/intolerance, and at least one gout clinical manifestation of 2 or more flares per year, 1 or more visible tophi, or gouty arthropathy. Key exclusion criteria included G6PD deficiency, methotrexate contraindication, serious bacterial infection, and eGFR < 40 mL/min/1.73 m ² . After screening, participants underwent a 4-week MTX run-in period (with folic acid supplementation) followed by randomization with double-blinding to pegloticase 16 mg every-4-weeks or pegloticase 8 mg every-2-weeks with continuation of weekly MTX and folic acid throughout the trial. The primary efficacy endpoint was the 24-week response rate of SU < 6 mg/dL at least 80% of the time during month 6 (weeks 20,21,22,23 and 24). An SU stopping-rule was employed where pegloticase was discontinued if two consecutive pre-infusion SU values were > 6 mg/dL starting at week two, and an open-label extension to week 48 was included. The secondary endpoint was tophus resolution at Week 24. Safety parameters included incidence of AEs and AEs of special interest (gout flares, IRs, anaphylaxis, MACE).

Results: A total of 306 participants were screened, of which 44 had MTX run-in failure with just 9 of those due to MTX intolerance. For the trial 262 participants were randomized, and 261 received study treatment (131 receiving pegloticase 16 mg every-4-weeks (Q4W) and 130 receiving pegloticase 8 mg every-2-weeks (Q2W)). Enrolled participant demographics reflected prior uncontrolled gout clinical trials: 95% were male and the Q4W and Q2W dosing groups had a mean age of 53.2 and 56.4 years, 55.7% and 53.8% had visible tophi, 8.0 and 6.2 mean flares in the prior 12 months, and 86.2% and 82.3% had detectable anti-PEG anti-drug antibodies at baseline, respectively. Overall 58% (76/131) and 70% (91/130) of participants completed the 24-week dosing period in the Q4W and Q2W arms, respectively, and entered the open-label extension. The 24-week SU-lowering response rate was 56.5% (74/131) in the 16 mg Q4W dosing group and 70.8% (92/130) in the 8 mg Q2W dosing group for a non-inferiority margin of 20%. The adjusted response rate difference (Q2W-Q4W) was 12.7% (95% CI 1.2, 24.1) with p-value 0, using G computation method for adjusted difference of proportion accounting for baseline covariates; non-inferiority was not established. The secondary endpoint of tophi resolution at week 24 was 46.6% (34/73) in the Q4W group and 32.9% (23/70) in the Q2W group (non-inferiority margin 15%); sequential non-inferiority testing for this endpoint was not performed after failure to establish non-inferiority for the primary endpoint. With respect to safety, gout flares occurred in 61.8% and 47.7% of participants dosed Q4W and Q2W, respectively, while adjudicated infusion reactions (including anaphylaxis) occurred in 9.2% (12/131) and 7.7% (10/130) of participants, respectively. There were no deaths in the study and a single MACE event occurred (1 out of 261 participants) that was deemed unrelated to study treatment.

Conclusions: In this randomized, double-blind trial including co-administration with MTX, Q4W dosing of 16 mg pegloticase (56.5% response rate) did not demonstrate non-inferiority to standard Q2W dosing of 8 mg pegloticase which showed a 70.8% response rate consistent with prior trials [2]. Non-inferiority was not established primarily due to higher non-response/discontinuation rates in the Q4W arm driven by the protocol SU stopping rule. Consistent with established data, this study demonstrated that every-two-week dosing of pegloticase with MTX coadministration remains the standard of care for uncontrolled gout.

REFERENCES: [1] Troum et al. Ann Rhuem Dis 2025; 84 (suppl 1):1225.

[2] Botson et al. Arthritis Rheumatol 2022;75:293-304.

Acknowledgments: NIL.

Disclosure of Interests: Amar Majjhoo: None declared, Orrin M. Troum AbbVie, Amgen, Amgen, Inc., Novartis, Pfizer Inc, Sanofi-Genzyme, AbbVie, Amgen, Bristol-Myers Squibb, Amgen, Inc., Lilly, and Pfizer, AbbVie, Amgen, Bristol Myers Squibb, Revitas, Horizon, Novartis, and Sanofi-Genzyme, Chad Boomershine Amgen, Inc., Amgen, Inc., Supra Verma Amgen, Inc., Amgen, Inc., Fang Fang Amgen, Inc., Amgen, Inc., Junzhi Ji Amgen, Inc., Amgen, Inc., Quinnie Yang Amgen, Inc., Amgen, Inc., Brian LaMoreaux Amgen, Inc., Amgen, Inc., Andre Gabriel Amgen, Inc., Amgen, Inc.