Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect

Therapuetic Areas:Rheumatology
Age Range:18 - Any
Start Date:December 2015
End Date:April 2020
Contact:Maggie Pugh, MS

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The purpose of this study is to evaluate the effect of a high zone tolerizing regimen of
pegloticase on clinical outcome, as defined by an serum uric acid level <6 mg/dL, in patients
with chronic, refractory gout.

This is an exploratory open-label, multicenter study to evaluate the effectiveness of a
16-week high zone tolerance regimen of pegloticase on response to therapy (serum uric acid <6
mg/dL) with this drug in adult hyperuricemic patients with gout refractory to conventional

Eligible subjects will receive 1 of 3 different loading doses (8, 12, and 16 mg) on Study Day
1, and then receive 8 mg on Week 2 and 3, followed by 8 mg every 2 weeks through Week 17 for
a total of 10 doses.

Subjects will be monitored for efficacy and safety endpoints through Week 17. Subjects will
also have blood drawn for pegloticase levels prior to each dose on Weeks 2, 3, 5, 7, 9, 11,
13,15, and 17. Following Study Week 17, subjects will have an option to continue dosing for
an additional 8 weeks.

A subset of subjects will participate in additional pharmacokinetic (PK) assessments.

The study duration, per enrolled patient, will be approximately 26 weeks including a 2-week
screening period, a 16-week treatment period (end of treatment [EOT] visit Week 17), and an
optional 8-week dosing extension.

Inclusion Criteria:

1. Adult (age ≥18 years) men and women of non-childbearing potential, with chronic gout
refractory to conventional therapy, defined as patients who have failed to normalize
SUA and whose signs and symptoms are inadequately controlled with xanthine oxidase
inhibitors at the maximum medically appropriate dose, or for whom these drugs are

2. Hyperuricemic - Screening visit SUA must be >6 mg/dL

3. On gout flare prophylactic regimen for 7 days prior to the first dose.

4. Willing and able to give informed consent and adhere to visit/protocol schedules
(informed consent must be given before the first study procedure is performed)

Exclusion Criteria:

1. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (confirmed at Screening visit)

2. Non-compensated congestive heart failure, uncontrolled arrhythmia, treatment for acute
coronary syndrome (ACS) (myocardial infarction or unstable angina) or hospitalization
for congestive heart failure within 3 months of screening or uncontrolled blood
pressure (>160/100 mm Hg) at baseline (Screening and pre-dose at Week 1 visit )

3. Women of childbearing potential defined as:

- Pre- or perimenopausal (<24 months of natural [spontaneous] amenorrhea).

- <6 weeks after surgical bilateral oophorectomy with or without hysterectomy.

4. Prior treatment with pegloticase or another recombinant uricase

5. Prior treatment or concomitant therapy with a polyethylene glycol (PEG) conjugated

6. Known allergy to PEG products or history of anaphylactic reaction to a recombinant
protein or porcine product

7. Concurrent treatment with urate lowering agents (ULAs), such as allopurinol and
febuxostat. Patients treated with these medications must discontinue treatment 7 days
prior to the first dose of study drug

8. Recipient of an investigational drug within 4 weeks prior to study drug administration
or plans to take an investigational agent during the study

9. Current liver disease as determined by alanine transaminase (ALT) or aspartate
transaminase (AST) levels >3 times upper limit of normal (ULN)

10. History of malignancy within 5 years other than basal cell skin cancer or carcinoma in
situ of the cervix

11. Has any other medical or psychological condition which, in the opinion of the
Investigator, might create undue risk to the patient or interfere with the patient's
ability to comply with the protocol requirements, or to complete the study

12. Solid organ transplant recipients

13. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening

14. Currently on dialysis

Additional Exclusion Criteria for Imaging Sub-study Only

15. Contraindication to receiving a gadolinium-based contrast agent (GBCA) or > 2 previous
lifetime exposures to a GBCA

16. Implanted pacemaker, certain older intracranial aneurysm clips, cochlear implants,
certain prosthetic devices, implanted drug infusion pumps, neurostimulators,
bone-growth stimulators, certain intrauterine contraceptive devices, or any other type
of iron-based metal implants.

17. Any internal metallic objects such as bullets or shrapnel, as well as most surgical
clips, pins, plates, screws, metal sutures, or wire mesh.

Additional Exclusion Criteria for FDG-PET-CT Sub-study Only

18. Contraindication to FDG

Additional Exclusion Criteria for Pegloticase and AZA Therapy Arm Only

19. Any active serious bacterial infection (2 weeks prior to screening) requiring
antibiotic treatment

20. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia, chronic

21. Current immunocompromised condition, including current or chronic treatment with
systemic immunosuppressive agents (e.g., prednisone or equivalent dose >510 mg/day)

22. At risk for tuberculosis. Specifically, subjects with: a) current clinical,
radiographic, or laboratory evidence of active or latent tuberculosis; b) a history of
active tuberculosis within the last 31 years even if it was treated; c) a history of
active tuberculosis >31 years ago unless there is documentation that the prior
anti-tuberculosis treatment was appropriate in duration and type

23. Known history of hepatitis B surface antigen-positivity or hepatitis B DNA positivity

24. Known history of hepatitis C RNA-positivity

25. Known history of human immunodeficiency virus positivity

26. Severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m2)

27. AZA treatment is contraindicated or considered inappropriate

28. Subject has a homozygous or heterozygous thiopurine methyltransferase (TPMT) variant

29. Diagnosis of osteomyelitis

30. Known hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan
and Kelley-Seegmiller syndrome

31. Concurrent use of a xanthine oxidase inhibitor
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Duncansville, Pennsylvania 16635
Duncansville, PA
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1720 2nd Avenue South
Birmingham, Alabama 35294
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Detroit, Michigan 48202
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Eagan, Minnesota 55121
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Huntsville, AL
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Orangeburg, South Carolina 29118
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Orchard Park, New York 14127
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Santa Maria, California 93454
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Wheaton, MD
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Worcester, Massachusetts 01610
Worcester, MA
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