A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings

Abstract

Objective: To assess efficacy, safety, pharmacokinetics, and immunogenicity of pegloticase plus methotrexate (MTX) versus pegloticase plus placebo cotreatment for uncontrolled gout in a randomized, placebo-controlled, double-blind trial.

Methods: This study included adults with uncontrolled gout, defined as serum urate ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of ongoing gout symptoms including ≥1 tophus, ≥2 flares in the past 12 months, or gouty arthritis. Key exclusion criteria included MTX contraindication, current immunosuppressant use, G6PDH deficiency, and estimated glomerular filtration rate <40 ml/minute/1.73 m² . Patients were randomized 2:1 to 52 weeks of pegloticase (8 mg biweekly) with either oral MTX (15 mg/week) or placebo. The primary end point was the proportion of treatment responders during month 6 (defined as serum urate <6 mg/dl for ≥80% of visits during weeks 20-24). Efficacy was evaluated in all randomized patients (intent-to-treat population), and safety was evaluated in all patients receiving ≥1 blinded MTX or placebo dose.

Results: A total of 152 patients were randomized, 100 to receive pegloticase plus MTX, 52 to receive pegloticase plus placebo. Significantly higher treatment response occurred during month 6 in the MTX group versus the placebo group (71.0% [71 of 100 patients] versus 38.5% [20 of 52 patients], respectively; between-group difference 32.3% [95% confidence interval 16.3%, 48.3%]) (P < 0.0001 for between-group difference). During the first 6 months of pegloticase plus MTX or pegloticase plus placebo treatment, 78 (81.3%) of 96 MTX patients versus 47 (95.9%) of 49 placebo patients experienced ≥1 adverse event (AE), most commonly gout flare (64 [66.7%] of 96 MTX patients and 34 [69.4%] of 49 placebo patients). Reports of AEs and serious AEs were comparable between groups, but the infusion reaction rate was considerably lower with MTX cotherapy (4.2% [4 of 96 MTX patients, including 1 patient who had anaphylaxis]) than with placebo cotherapy (30.6% [15 of 49 placebo patients, 0 who had anaphylaxis]) (P < 0.001). Antidrug antibody positivity was also lower in the MTX group.

Conclusion: MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals. These findings verify higher treatment response rate, lower infusion reaction incidence, and lower immunogenicity when pegloticase is coadministered with MTX.

Trial registration: ClinicalTrials.gov NCT03994731.

Figure 1

Overview of the study design for assessing pegloticase plus methotrexate (MTX) versus pegloticase plus placebo (PBO) cotreatment for uncontrolled gout in a randomized, placebo‐controlled, double‐blind trial. Following screening, patients underwent a 2‐week MTX tolerability period before randomization then entered a 4‐week run‐in period and 52‐week pegloticase plus MTX or PBO treatment period. Patients with pre‐infusion serum urate >6 mg/dl at 2 consecutive study visits beginning at week 2 discontinued study treatment and remained in the study on observation. Key efficacy and safety assessments were conducted during months 6 and 12.

Figure 2

Flow chart depicting patient distribution and study disposition for a randomized, placebo‐controlled, double‐blind trial assessing pegloticase plus methotrexate (MTX) versus pegloticase plus placebo (PBO) cotreatment for uncontrolled gout. * = 1 patient in each treatment group discontinued MTX/PBO but continued to receive biweekly pegloticase infusions. † = withdrawal due to COVID‐19 concerns, not infection. ITT = intent‐to‐treat; mITT = modified intent‐to‐treat.

Figure 3

A, Key treatment efficacy end points through week 24 in the intent‐to‐treat (ITT) and modified intent‐to‐treat (mITT) populations of patients randomized to receive pegloticase plus methotrexate (MTX) or pegloticase plus placebo (PBO) for treatment of uncontrolled gout. Treatment response was defined as serum urate (SU) <6 mg/dl for ≥80% of visits during month 6 (weeks 20–24). B, Least squares (LS) mean change from baseline in SU at each study visit. The shaded region represents 95% confidence intervals (95% CIs). C, Kaplan‐Meier curve for time to 2 consecutive SU measurements >6 mg/dl through week 24. Median time to 2 consecutive SU >6 mg/dl was not estimable in the pegloticase plus MTX group and 69 days (9.9 weeks) in the pegloticase plus PBO group (mITT population). In A, * = primary efficacy end point. † = determined through week 24 using mixed model repeated measures analysis. ‡ = assessed during pegloticase treatment; MTX/PBO was discontinued when pegloticase was discontinued. In B, asterisks denote a statistically significant difference between treatment groups (P ≤ 0.0001). In C, circles represent patient censoring due to 2 consecutive SU measurements >6 mg/dl.

Figure 4

A, Summary of treatment‐emergent adverse events (AEs) occurring in ≥5% of either treatment group through week 24 of the pegloticase plus methotrexate (MTX) or placebo (PBO) treatment period (safety population). All AEs of special interest and serious AEs are also shown. Elevated liver function test (LFT) includes elevated aspartate aminotransferase, alanine aminotransferase, bilirubin, and hepatic enzymes. B, Proportion of patients in each treatment group who experienced ≥1 gout flare during each month of the pegloticase plus MTX or pegloticase plus PBO treatment period. Month 0 represents the proportion of patients with ≥1 flare during the MTX/PBO 4‐week run‐in period. In A, * = AE of special interest, adjudicated. † = known MTX AE (ref. 17). ‡ = nervous system disorders included dizziness (2 MTX), headache (1 MTX, 1 PBO), hypoesthesia (2 MTX), neuropathy peripheral (1 MTX), paresthesia (1 MTX). § = general disorders included fatigue (5 MTX, 1 PBO), chest discomfort (1 PBO), feeling hot (1 MTX), peripheral edema (1 PBO), peripheral swelling (1 MTX), pain (1 MTX), foreign body sensation (1 MTX), non‐cardiac chest pain (1 PBO). ‖ = infections included COVID‐19 (1 MTX) and soft tissue abscess (1 PBO).

Figure 5

Comparison of peak (C_max [A]) and trough (C_min [B]) concentrations of pegloticase at week 14 in patients who received cotreatment with methotrexate (MTX) or placebo (PBO). C, Kaplan‐Meier curve for time to anti–polyethylene glycol (anti‐PEG) IgG antibody positivity. Median time to anti‐PEG antibody positivity was not estimable in patients treated with pegloticase plus MTX and 155 days (lower quartile [Q1] 44, upper quartile [Q3] not estimable) in patients treated with pegloticase plus PBO. The below quantitation limit (BQL) was 0.6 μg/ml (imputed as 0.3 μg/ml in analysis). In A and B, circles represent treatment responders; triangles represent treatment nonresponders. Lines represent the median; whiskers represent Q1 and Q3. Dashed horizontal lines show the pegloticase BQL. In C, circles represent patient censoring. Numbers below the plot show the number of patients remaining in the analysis at each time point. ADA = antidrug antibody.