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

Inclusion Criteria:

1. Willing and able to give informed consent.

2. Willing and able to comply with the prescribed treatment protocol and evaluationsfor the duration of the trial.

3. Adult men or women ≥18 years of age.

4. 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 atthe maximum medically appropriate dose or with a contraindication to xanthineoxidase 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 toScreening

• Presence of chronic gouty arthritis

5. Subject was previously treated with pegloticase without concomitant immunomodulationand stopped pegloticase due to failure to maintain sUA reduction response (had ≥1sUA >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-relatedclinically mild IR (Cohort 2).

6. Subject for whom the last pegloticase infusion occurred >6 months prior toScreening.

7. Willing to discontinue any oral urate-lowering therapy for at least 7 days prior toDay 1 and remain off other urate-lowering therapy during the Pegloticase + MTXTreatment Period.

8. Women of childbearing potential (including those with an onset of menopause <2 yearsprior to Screening, non-therapy-induced amenorrhea for <12 months prior to Screeningor not surgically sterile [absence of ovaries and/or uterus]) must have negativeserum pregnancy tests during Screening: Subjects must agree to use 2 reliable forms of contraception during the trial, 1 ofwhich is recommended to be hormonal, such as an oral contraceptive. Hormonalcontraception must be started ≥1 full cycle prior to Week -6 (start of MTX) andcontinue for 30 days after the last dose of pegloticase, or at least 1 ovulatorycycle after the last dose of MTX (whichever is the longer duration after the lastdose of pegloticase). Highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include implants, injectables,combined oral contraceptives, some intrauterine devices, sexual abstinence orvasectomized partner.

9. Men who are not vasectomized must agree to use appropriate contraception so as tonot impregnate a female partner of reproductive potential during the trial,beginning with the initiation of MTX at Week -6 and continuing for at least 3 monthsafter the last dose of MTX.

10. Able to tolerate MTX at SC doses of at least 15 mg during the MTX Run-in Period,regardless of estimated glomerular filtration rate (eGFR) status.

Exclusion Criteria:

1. Known history of medically confirmed prior anaphylactic reaction.

2. Known history of moderate or severe IR (including but not limited to difficulty inbreathing, hypotension, generalized urticaria, generalized erythema, angioedemaand/or required treatment with IV steroids or epinephrine; or other serious adverseevents (SAEs) related to pegloticase or any other pegylated product treatment.

3. Weight >160 kg (352 pounds) at Screening.

4. Any serious acute bacterial infection, unless treated and completely resolved withantibiotics at least 2 weeks prior to the Week 6 Visit.

5. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia orchronic bronchiectasis.

6. Current or chronic treatment with systemic immunosuppressive agents, such as MTX,azathioprine, cyclosporine, leflunomide, cyclophosphamide or mycophenolate mofetil.

7. Current treatment with prednisone >10 mg/day or equivalent dose of anothercorticosteroid on a chronic basis (defined as 3 months or longer).

8. Known history of any solid organ transplant surgery requiring maintenanceimmunosuppressive therapy.

9. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNApositivity, unless treated, viral load is negative and no chronic or activeinfection confirmed by hepatitis B virus serology.

10. Known history of hepatitis C virus RNA positivity, unless treated and viral load isnegative.

11. Known history of human immunodeficiency virus positivity.

12. glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit).

13. Severe chronic renal impairment (eGFR <30 mL/min/1.73 m^2) at the Screening Visitbased on 4 variable Modification of Diet in Renal Disease [MDRD] formula orcurrently on dialysis.

14. Non-compensated congestive heart failure, hospitalization for congestive heartfailure or treatment for acute coronary syndrome (myocardial infarction or unstableangina) within 3 months of the Screening Visit, current uncontrolled arrhythmia orcurrent uncontrolled blood pressure (>160/100 mm Hg) prior to Week -6.

15. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate femalepartner, or not on an effective form of birth control, as determined by theInvestigator.

16. Prior treatment with another recombinant uricase (rasburicase) or concomitanttherapy with a PEG-conjugated drug.

17. Known allergy to pegylated products or history of anaphylactic reaction to arecombinant protein or porcine product.

18. Contraindication to MTX treatment or MTX treatment considered inappropriate.

19. Known intolerance to MTX.

20. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever islonger, prior to MTX administration at Week -6 or plan to take an investigationaldrug during the trial.

21. Current liver disease, as determined by alanine transaminase (ALT) or aspartatetransaminase (AST) >1.25 × upper limit of normal (ULN) or albumin <lower limit ofnormal at the Screening Visit.

22. Currently receiving systemic or radiologic treatment for ongoing cancer, excludingnonmelanoma skin cancer.

23. History of malignancy within 5 years other than non-melanoma skin cancer or in situcarcinoma of cervix.

24. White blood cell count <4.0 × 10^9/L, hematocrit <32% or platelet count <75 × 10^9/L.

25. Diagnosis of osteomyelitis.

26. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such asLesch-Nyhan and Kelley-Seegmiller syndrome.

27. Unsuitable candidate for the trial (e.g., cognitive impairment), based on theopinion of the Investigator, such that participation might create undue risk to thesubject or interfere with the subject's ability to comply with the protocolrequirements or complete the trial.

28. Alcohol use in excess of 3 alcoholic beverages per week.

29. A known intolerance to all protocol standard gout flare prophylaxis regimen (i.e.,unable to tolerate any of the following 3 agents: colchicine,nonsteroidalanti-inflammatory drugs (NSAIDs) or low- dose prednisone (≤10 mg/day).

30. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemednecessary by the Investigator, a chest x-ray may be performed during Screening.