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

This is a Phase 2, multicenter, study of KRYSTEXXA® (pegloticase) plus MTX in adult
participants with uncontrolled gout.

The study design will include: 1) Screening Period which includes a MTX Run in Period; 2) 24
week Dual Therapy Period (KRYSTEXXA® + MTX); 3) an End of study/Early Termination Visit; 4)
Safety Follow-up after last dose of KRYSTEXXA; and 5) For subjects that are non-vasectomized
males; a 3- month follow up regarding partner pregnancy.

Interim analysis of the first 15 subjects will have the potential to influence the remainder
of the study.

Inclusion Criteria:

1. Willing and able to give informed consent.

2. Willing and able to comply with the prescribed treatment protocol and evaluations for
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 years
prior to screening, non-therapy-induced amenorrhea for <12 months prior to screening,
or not surgically sterile [absence of ovaries and/or uterus]) must have negative
serum/urine pregnancy tests during the Screening/(methotrexate) MTX Run in Period;
participants must agree to use 2 reliable forms of contraception during the study, 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 MTX dosing) and
continue for 30 days after the last dose of KRYSTEXXA® or at least one ovulatory cycle
after the last dose of MTX (whichever is the longest duration after the last dose of
KRYSTEXXA® or MTX). 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, or
vasectomized partner.

5. Men who are not vasectomized must not impregnant their female partner during the study
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 Run in
Period, as documented by sUA ≥6 mg/dL.

7. Uncontrolled gout, defined as meeting the following criteria:

sUA ≥6 mg/dL prior to entry into the Dual Therapy Period (any laboratory 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 other urate-lowering therapy;
intolerable side effects associated with current urate-lowering therapy; functionally
limiting tophaceous deposits (including those detected clinically or by DECT imaging)

8. Able to tolerate MTX 15 mg for 4 weeks during the Screening/MTX Run-in Period prior to
the first dose of KRYSTEXXA®.

Exclusion Criteria:

1. Weight >160 kg (352 pounds).

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

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

4. Current immunocompromised condition, including current or chronic treatment with
systemic immunosuppressive agents, including prednisone >10 mg/day or equivalent dose
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 DNA
positivity.

7. Known history of hepatitis C virus RNA positivity.

8. Human immunodeficiency virus 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) or
currently on dialysis.

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

12. Pregnant, planning to become pregnant, breastfeeding, planning to impregnant female
partner, or not on an effective form of birth control, as determined by the
Investigator.

13. Prior treatment with 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 a
recombinant 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 is
longer, prior to MTX administration at Week -4 or plans to take an investigational
drug during the study.

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

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

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

21. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening that is
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 as
Lesch-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 the
participant or interfere with the participant's ability to comply with the protocol
requirements 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 to
MTX dosing at Week -4 and unable to discontinue treatment during the duration of the
study.