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

Abstract

BackgroundPatients (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.ObjectivesTo determine safety/efficacy of oral MTX as co-therapy with pegloticase for sustained urate-lowering response in a randomized placebo (PBO) controlled trial.MethodsPegloticase+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 m2). 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.Results152 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 AEs4 did not occur more frequently in the MTX group (Table 1).Table 1.Key efficacy and safety findings through Month 6 of treatment.Pegloticase+MTXPegloticase+PBOITT populationN=100N=52Age, yrs, mean±SD55.6±12.753.0±12.1Tophi at baseline, %74.0%78.8%sUA at baseline, mg/dL, mean±SD8.7±1.69.1±1.76-mo treatment responders (primary endpoint), %71.0%38.5%Safety populationN=96N=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 AEConclusionThis 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.