Pegloticase and Methotrexate Cotherapy in Patients With Uncontrolled Gout With Prior Pegloticase Monotherapy Failure: Findings of an Open-Label Trial

Abstract

Objective: Patients with uncontrolled gout have few treatment options. Pegloticase lowers serum urate (SU) levels, but antidrug antibodies limit SU-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) cotherapy increases pegloticase response rates and lowers IR risk in pegloticase-naïve patients. Therefore, the question of re-treating patients with previous pegloticase monotherapy failure has arisen. The ADVANCE open-label trial examined pegloticase plus MTX cotherapy efficacy and safety following pegloticase monotherapy failure.

Methods: Patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate-lowering therapy failure or intolerance, and ≥1 gout sign or symptom) who previously lost SU-lowering response to pegloticase monotherapy were included. Key exclusion criteria were moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate <30 mL/min/1.73m². After a 6-week subcutaneous MTX run-in (at 25 mg/wk), patients entered 24-week pegloticase (at 8 mg biweekly) plus MTX treatment. The primary end point was SU-lowering response rate during month 6 (SU levels <6 mg/dL for ≥80% of weeks 20-24). Safety was assessed via adverse events (AEs) and laboratory monitoring.

Results: Eleven patients began pegloticase plus MTX treatment (91% male patients, mean age 58.6 ± 11.3 years, mean ± SD SU levels 8.5 ± 3.2 mg/dL, 91% tophaceous). Previous pegloticase course was 2 to 27 infusions, with the last infusion admins being a mean ± SD of 3.7 ± 2.4 years before. One patient (9%) maintained response during month 6; 10 patients prematurely discontinued treatment (loss of SU lowering [n = 8], IR [n = 2]). Eight patients (73%) experienced ≥1 AE, most commonly gout flare. All AEs were mild or moderate.

Conclusion: Pegloticase plus MTX response rate following failed monotherapy was lower (9% vs 71%) and IR rate was higher (18% vs 4%) than in pegloticase-naïve patients. These findings demonstrate the challenge of overcoming established antipegloticase antibodies and emphasize the importance of initiating immunomodulation before the first pegloticase exposure.

Figure 1

Study schema. Individual patients who met serum urate discontinuation criteria ended pegloticase therapy, completed the end‐of‐trial procedures, and remained in the trial on observation. Key efficacy and safety assessments conducted at weeks 10, 12, 14, 20, 21, 22, 23, and 24. Offered at the treating investigator's discretion. *15 mg/wk if screening estimated glomerular filtration rate <30 mL/min/1.73m². IV, intravenous; MTX, methotrexate; subQ, subcutaneous.

Figure 2

(A) Treatment response and (B) IR rate in patients undergoing pegloticase plus MTX cotherapy following pegloticase monotherapy treatment failure (loss of urate‐lowering response; n = 11). Response rates in pegloticase‐naïve MIRROR RCT participants undergoing pegloticase plus MTX cotherapy (n = 96) or pegloticase monotherapy (n = 49) are shown for comparison (MIRROR RCT modified intent‐to‐treat population [≥1 pegloticase infusion received]). Treatment response defined as SU level <6 mg/dL for ≥80% of the time during the month examined. IR, infusion reaction; MTX, methotrexate; SU, serum urate.

Figure 3

On‐treatment observed SU levels in patients treated with pegloticase plus methotrexate after pegloticase monotherapy treatment failure (loss of urate‐lowering response). SU, serum urate.

Figure 4

Pegloticase concentration in pegloticase plus methotrexate treatment responders and nonresponders with previous pegloticase monotherapy failure (loss of urate‐lowering response). The week 6 preinfusion value for the single‐treatment responder was missing. Mean values are shown. Error bars represent one SD. For treatment nonresponders, the open number represents preinfusion n, and the closed number represents postinfusion n at the specified time point.

Figure 5

Anti‐PEG antibody titers measured during pegloticase plus methotrexate cotherapy in patients with previous loss of serum urate–lowering response to pegloticase monotherapy. On‐treatment measurements are denoted by closed circles and solid lines; off‐treatment measurements by open circles and dotted lines. Red‐filled circles indicate infusion reaction. On infusion visits, titers shown represent preinfusion measurements. anti‐PEG, anti–polyethylene glycol.