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  1. J. Botson1,
  2. K. Saag2,
  3. J. Peterson3,
  4. N. Parikh4,
  5. S. Ong5,
  6. D. La6,
  7. K. Obermeyer7,
  8. B. Lamoreaux8,
  9. S. Sainati9,
  10. S. Grewal10,
  11. A. Majjhoo11,
  12. J. Tesser12,
  13. M. E. Weinblatt13
  1. 1Orthopedic Physicians Alaska, Rheumatology, Anchorage, United States of America
  2. 2University of Alabama at Birmingham, Medicine, Clinical Immunology and Rheumatology, Birmingham, United States of America
  3. 3Western Washington Arthritis Clinic, Rheumatology, Bothell, United States of America
  4. 4Napa Research Center, Internal Medicine, Pompano Beach, United States of America
  5. 5MD Medical Research, Family Medicine, Oxon Hill, United States of America
  6. 6Keck USC Medical Center, Rheumatology, Los Angeles, United States of America
  7. 7Horizon Therapeutics plc, Biostatistics, Deerfield, United States of America
  8. 8Horizon Therapeutics plc, Medical Affairs, Deerfield, United States of America
  9. 9Horizon Therapeutics plc, Research and Development, Deerfield, United States of America
  10. 10East Bay Rheumatology Medical Group Inc, Rheumatology, San Leandro, United States of America
  11. 11Shores Rheumatology, Rheumatology, St. Clair Shores, United States of America
  12. 12Arizona Arthritis & Rheumatology Associates PC, Rheumatology, Phoenix, United States of America
  13. 13Brigham and Women’s Hospital, Division of Rheumatology, Immunology, and Allergy, Boston, United States of America


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 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.

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 AEs4 did not occur more frequently in the MTX group (Table 1).

Table 1.

Key efficacy and safety findings through Month 6 of treatment.

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

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