Pegloticase and Methotrexate Co-administered in Participants With Uncontrolled Gout Who Previously Failed Pegloticase Monotherapy

Inclusion Criteria

• Willing and able to give informed consent.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
• Adult men or women ≥18 years of age.
• Uncontrolled gout, defined by the following criteria:
• Hyperuricemia during the Screening Period, defined as sUA ≥6 mg/dL, and;
• Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the maximum medically appropriate dose or with a contraindication to xanthine oxidase inhibitor therapy based on medical record review or subject interview, and;
• Symptoms of gout, including at least 1 of the following:
• Presence of at least 1 tophus
• Recurrent flares, defined as 2 or more flares in the 12 months prior to Screening
• Presence of chronic gouty arthritis
• Subject was previously treated with pegloticase without concomitant immunomodulation and stopped pegloticase due to failure to maintain sUA reduction response (had ≥1 sUA >6 mg/dL within 2 weeks post pegloticase infusion) and did not experience an IR (Cohort 1) and/or stopped pegloticase treatment due to pegloticase-related clinically mild IR (Cohort 2).
• Subject for whom the last pegloticase infusion occurred >6 months prior to Screening.
• Willing to discontinue any oral urate-lowering therapy for at least 7 days prior to Day 1 and remain off other urate-lowering therapy during the Pegloticase + MTX Treatment Period.
• Women of childbearing potential (including those with an onset of menopause 160 kg (352 pounds) at Screening.
• Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week 6 Visit.
• Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.
• Current or chronic treatment with systemic immunosuppressive agents, such as MTX, azathioprine, cyclosporine, leflunomide, cyclophosphamide or mycophenolate mofetil.
• Current treatment with prednisone >10 mg/day or equivalent dose of another corticosteroid on a chronic basis (defined as 3 months or longer).
• Known history of any solid organ transplant surgery requiring maintenance immunosuppressive therapy.
• Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity, unless treated, viral load is negative and no chronic or active infection confirmed by hepatitis B virus serology.
• Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative.
• Known history of human immunodeficiency virus positivity.
• glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit).
• Severe chronic renal impairment (eGFR 160/100 mm Hg) prior to Week -6.
• Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female partner, or not on an effective form of birth control, as determined by the Investigator.
• Prior treatment with another recombinant uricase (rasburicase) or concomitant therapy with a PEG-conjugated drug.
• Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product.
• Contraindication to MTX treatment or MTX treatment considered inappropriate.
• Known intolerance to MTX.
• Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to MTX administration at Week -6 or plan to take an investigational drug during the trial.
• Current liver disease, as determined by alanine transaminase (ALT) or aspartate transaminase (AST) >1.25 × upper limit of normal (ULN) or albumin <lower limit of normal at the Screening Visit.
• Currently receiving systemic or radiologic treatment for ongoing cancer, excluding nonmelanoma skin cancer.
• History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.
• White blood cell count <4.0 × 10^9/L, hematocrit <32% or platelet count <75 × 10^9/L.
• Diagnosis o