Study of Pegloticase (KRYSTEXXA®) Plus Methotrexate in Patients With Uncontrolled Gout

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 study.

3. Adult men or women ≥18 to ≤65 years of age.

4. Women of childbearing potential (including those with an onset of menopause <2 yearsprior to screening, non-therapy-induced amenorrhea for <12 months prior toscreening, or not surgically sterile [absence of ovaries and/or uterus]) must havenegative serum/urine pregnancy tests during the Screening/(methotrexate) MTX Run inPeriod; participants must agree to use 2 reliable forms of contraception during thestudy, one of which is recommended to be hormonal, such as an oral contraceptive.Hormonal contraception must be started ≥1 full cycle prior to Week -4 (start of MTXdosing) and continue for 30 days after the last dose of pegloticase or at least oneovulatory cycle after the last dose of MTX (whichever is the longest duration afterthe last dose of pegloticase or MTX). Highly effective contraceptive methods (with afailure rate <1% per year), when used consistently and correctly, include implants,injectables, combined oral contraceptives, some intrauterine devices, sexualabstinence, or vasectomized partner.

5. Men who are not vasectomized must not impregnant their female partner during thestudy and for at least 3 months after the last dose of MTX.

6. Hyperuricemia at the Screening, Week -4, or Week -2 Visit of the Screening/MTX Runin Period, as documented by sUA ≥6 mg/dL.

7. Uncontrolled gout, defined as meeting the following criteria: serum uric acid (sUA) ≥6 mg/dL prior to entry into the pegloticase +IMM Period (anylaboratory tests during screening up to and including during the MTX Run in Period)and at least 1 of the following: inability to maintain sUA <6 mg/dL on otherurate-lowering therapy; intolerable side effects associated with currenturate-lowering therapy; functionally limiting tophaceous deposits (including thosedetected clinically or by dual-energy computed tomography [DECT] imaging)

8. Able to tolerate MTX 15 mg for 4 weeks during the MTX Run-in Period prior to thefirst dose of pegloticase.

Exclusion Criteria:

1. Weight >160 kg (352 pounds).

2. Any serious acute bacterial infection, unless treated and completely resolved withantibiotics at least 2 weeks prior to the Week -4 Visit of the MTX Run-in Period.

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

4. Current immunocompromised condition, including current or chronic treatment withsystemic immunosuppressive agents, including prednisone >10 mg/day or equivalentdose of other corticosteroid.

5. History of any transplant surgery requiring maintenance immunosuppressive therapy.

6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNApositivity.

7. Known history of hepatitis C virus RNA positivity.

8. Human immunodeficiency virus (HIV) positivity (tested at the Screening Visit).

9. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit).

10. Severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m^2) orcurrently on dialysis.

11. Non-compensated congestive heart failure or hospitalization for congestive heartfailure within 3 months of the Screening Visit, uncontrolled arrhythmia, treatmentfor acute coronary syndrome (myocardial infarction or unstable angina), oruncontrolled blood pressure (>160/100 mmHg) at the end of the Screening/MTX Run-inPeriod.

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

13. Prior treatment with pegloticase (KRYSTEXXA®), another recombinant uricase (rasburicase), or concomitant therapy with a polyethylene glycol-conjugated drug.

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

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

16. Known intolerance to MTX.

17. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever islonger, prior to MTX administration at Week -4 or plans to take an investigationaldrug during the study.

18. Current liver disease, as determined by alanine transaminase or aspartatetransaminase levels >3 times upper limit of normal at the Screening Visit.

19. Currently receiving systemic or radiologic treatment for ongoing cancer, excludingnon melanoma skin cancer.

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

21. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening thatis not subsequently controlled by the end of the Screening/MTX Run-in Period.

22. Diagnosis of osteomyelitis.

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

24. Unsuitable candidate for the study, based on the opinion of the Investigator (e.g.,cognitive impairment), such that participation might create undue risk to theparticipant or interfere with the participant's ability to comply with the protocolrequirements or complete the study.

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

26. Currently receiving allopurinol and unable to discontinue medication 7 days prior toMTX dosing at Week -4 and unable to discontinue treatment during the duration of thestudy.