OP0171 A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, MULTICENTER, STUDY OF METHOTREXATE COMBINED WITH PEGLOTICASE IN PATIENTS WITH UNCONTROLLED GOUT

Background Patients (pts) with gout refractory to oral urate-lowering therapy (ULT) have few treatment options. Pegloticase (pegylated uricase) lowers serum uric acid (sUA) in these pts, 1 but response rates are limited by anti-drug antibodies (ADAs), which decrease urate-lowering efficacy and increase infusion reaction (IR) risk. 2 Because methotrexate (MTX) is commonly used in RA and prevents ADA development against biologics, co-administering MTX with pegloticase in uncontrolled gout pts is of interest. A small open-label study of pegloticase+oral MTX suggested an increased efficacy rate, 3 so a randomized controlled trial (RCT) was conducted to compare pegloticase with/without MTX immunomodulation. Objectives To determine safety/efficacy of oral MTX as co-therapy with pegloticase for sustained urate-lowering response in a randomized placebo (PBO) controlled trial. Methods Pegloticase+MTX and pegloticase+PBO co-therapy were compared in uncontrolled gout pts (sUA≥7 mg/dL, ULT failure/intolerance, and ≥1 of the following: ≥1 tophus, ≥2 flares in past yr, chronic gouty arthritis). Primary endpoint was the proportion of Month 6 treatment responders (sUA<6 mg/dL for ≥80% of the time during Wks 20-24). Key exclusion criteria included MTX contraindication, immunosuppressant use, G6PD deficiency, and renal impairment (eGFR<40 ml/min/1.73 m 2 ). Pts were randomized 2:1 to oral MTX (15 mg/wk) or PBO. Following a 4 wk MTX/PBO run-in, pegloticase was initiated (Day 1). Both pegloticase (biweekly 8 mg infusions) and MTX/PBO were administered over 52-wks (treatment period). Efficacy was examined in the intent-to-treat population (ITT, all randomized pts); safety (AEs, laboratory values) in the safety population (all pts receiving ≥1 dose blinded MTX/PBO). Treatment was discontinued if pre-infusion sUA >6 mg/dL for 2 consecutive visits Wk 2 or later. Results 152 pts (88.8% male) were randomized at 42 sites; 100 to pegloticase+MTX, 52 to pegloticase+PBO. 4 MTX, 3 PBO pts discontinued before first pegloticase dose; 26 MTX, 30 PBO pts who received pegloticase discontinued treatment at or before Wk 24. The primary endpoint was met with a 6-month response rate of 71.0% (71/100) vs 38.5% (20/52) in the MTX vs PBO co-therapy groups (p<0.0001; modified ITT [all pts receiving ≥1 pegloticase dose]: 74.0% [71/96] vs 40.8% [20/49], p<0.0001). In the first 24 wks of therapy, 81.3% vs 95.9% experienced ≥1 AE (Table 1), with gout flare in 66.7% (64/96) vs 69.4% (34/49) of MTX vs PBO pts. Infusion reactions (IRs) were more frequent in the PBO group (30.6%) than in the MTX group (3.1% plus anaphylaxis [NIAID/FAAN criteria] in 1 MTX pt). A single cardiovascular event of cardiac arrest occurred in 1 MTX pt >2 wks after pegloticase infusion 3 (deemed unrelated to study drug by site investigator). MTX-associated AEs 4 did not occur more frequently in the MTX group (Table 1). Table 1. Key efficacy and safety findings through Month 6 of treatment. Pegloticase+MTX Pegloticase+PBO ITT population N=100 N=52 Age, yrs, mean±SD 55.6±12.7 53.0±12.1 Tophi at baseline, % 74.0% 78.8% sUA at baseline, mg/dL, mean±SD 8.7±1.6 9.1±1.7 6-mo treatment responders (primary endpoint), % 71.0% 38.5% Safety population N=96 N=49 ≥1 Serious AE, % 8.3% 10.2% ≥1 treatment-emergent AE, % 81.3% 95.9% Gout flare* 66.7% 69.4% IR*, anaphylaxis* 3.1%, 1.0% 30.6%, 0% Cardiac event* 1.0% 0% Infection/infestation † 10.4% 16.3% Gastrointestinal † 9.4% 16.3% Skin † 7.3% 12.2% Respiratory/thoracic † 5.2% 4.1% Blood/lymphatic † 2.1% 2.0% Renal/urinary † , hepatobiliary † 2.1%, 0% 2.0%, 2.0% *AE of special interest, † known MTX AE Conclusion This RCT demonstrated significantly higher rate of sustained urate-lowering response over 6 months in pts co-treated with pegloticase+MTX vs pegloticase+PBO. No new safety concerns were seen through Month 6 and IR incidence was markedly lower in patients co-administered MTX vs PBO. References [1]Sundy JS, et al. JAMA 2011;306:711-20 [2]Lipsky PE, et al. Arthritis Res Ther 2014;16:R60 [3]Botson JK, et al. J Rheumatol 2021;48:767-74 [4]MTX package insert Disclosure of Interests John Botson Speakers bureau: Horizon Therapeutics, Consultant of: Horizon Therapeutics, Grant/research support from: Horizon Therapeutics, Kenneth Saag Grant/research support from: Horizon Therapeutics, Alinea, Lg, Sobi., Jeff Peterson Grant/research support from: Horizon Therapeutics, Naval Parikh Grant/research support from: Horizon Therapeutics, Stephen Ong Grant/research support from: Horizon, Novo Nordisk, Sanofi, Lilly, NIH/Mount Sinai, Dan La Speakers bureau: Abbvie, Grant/research support from: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Stephen Sainati Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Suneet Grewal Speakers bureau: Horizon Therapeutics, UCB, Glaxo Smith Kline, Grant/research support from: Horizon Therapeutics, Amar Majjhoo Speakers bureau: Abbvie, Amgen, BMS, Horizon Therapeutics, Jansen, Glaxo Smith Kline, Astra Zeneca, Grant/research support from: Horizon Therapeutics, John Tesser Grant/research support from: Horizon Therapeutics, Michael E. Weinblatt Consultant of: Horizon Therapeutics