Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect

Study Overview
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Brief Summary
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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.

Detailed Description
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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 therapy. 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.

Official Title
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Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect

Conditions
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Gout

Intervention / Treatment
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* Biological: Pegloticase
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 contraindicated. Hyperuricemic - Screening visit SUA must be >6 mg/dL On gout flare prophylactic regimen for 7 days prior to the first dose. 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: Glucose-6-phosphate dehydrogenase (G6PD) deficiency (confirmed at Screening visit) 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 ) 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. Prior treatment with pegloticase or another recombinant uricase Prior treatment or concomitant therapy with a polyethylene glycol (PEG) conjugated drug Known allergy to PEG products or history of anaphylactic reaction to a recombinant protein or porcine product 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 Recipient of an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study Current liver disease as determined by alanine transaminase (ALT) or aspartate transaminase (AST) levels >3 times upper limit of normal (ULN) History of malignancy within 5 years other than basal cell skin cancer or carcinoma in situ of the cervix 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 Solid organ transplant recipients Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening Currently on dialysis Additional Exclusion Criteria for Imaging Sub-study Only Contraindication to receiving a gadolinium-based contrast agent (GBCA) or > 2 previous lifetime exposures to a GBCA 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. 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 Contraindication to FDG Additional Exclusion Criteria for Pegloticase and AZA Therapy Arm Only Any active serious bacterial infection (2 weeks prior to screening) requiring antibiotic treatment Severe chronic or recurrent bacterial infections, such as recurrent pneumonia, chronic bronchiectasis Current immunocompromised condition, including current or chronic treatment with systemic immunosuppressive agents (e.g., prednisone or equivalent dose >510 mg/day) 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 Known history of hepatitis B surface antigen-positivity or hepatitis B DNA positivity Known history of hepatitis C RNA-positivity Known history of human immunodeficiency virus positivity Severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m2) AZA treatment is contraindicated or considered inappropriate Subject has a homozygous or heterozygous thiopurine methyltransferase (TPMT) variant genotype Diagnosis of osteomyelitis Known hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome Concurrent use of a xanthine oxidase inhibitor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pegloticase regimen <120 kg - Main Study<br>Subjects weighing <120 kg will receive a tolerizing dose of pegloticase 8 mg IV weekly for the first 3 weeks of dosing followed by an 8 mg IV dose every 2 weeks for a total of 10 doses. | Biological: Pegloticase<br>* Pegloticase, IV<br>* Other names: Krystexxa;|
| Experimental: Pegloticase regimen ≥120kg<br>Subjects weighing ≥ 120 kg will be sequentially assigned to 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. | Biological: Pegloticase<br>* Pegloticase, IV<br>* Other names: Krystexxa;|
| Experimental: Pegloticase PK Sub-Study<br>Subjects weighing <120 kg and ≥120 kg will be assigned to 1 of 2 different loading doses (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 have multiple blood sampled for PK levels over the 17 week dosing period. | Biological: Pegloticase<br>* Pegloticase, IV<br>* Other names: Krystexxa;|
| Experimental: Pegloticase Imaging Sub-Study<br>A subset of subjects participating in the Main Study and weighing <120 kg will have dual-energy computed tomography (DECT) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) performed at Screen and at Week 17. | Biological: Pegloticase<br>* Pegloticase, IV<br>* Other names: Krystexxa;|
| Experimental: Pegloticase FDG-PET-CT Sub-Study<br>A subset of subjects participating in the Main Study and weighing <120 kg will have fluorodeoxyglucose-positron emission tomography (FDG-PET-CT) to evaluate carotid and aortic (chest) atherosclerosis at Screen and at Week 17. | Biological: Pegloticase<br>* Pegloticase, IV<br>* Other names: Krystexxa;|
| Experimental: Pegloticase and Azathioprine<br>Subjects weighing <120 kg will receive azathioprine (AZA) daily for a 2-week run-in period, followed by daily AZA plus pegloticase 8 mg IV every 2 weeks through Week 25 for a total of 13 doses. | Biological: Pegloticase<br>* Pegloticase, IV<br>* Other names: Krystexxa;Drug: Azathioprine<br>* Azathioprine (1.25 mg/kg, followed by 2.5 mg/kg) oral, daily<br>* Other names: Imuran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization of serum uric acid (SUA) in subjects receiving a tolerizing regimen of pegloticase | Determine response rate; the last 3 consecutive levels of SUA must be <6 mg/dL | Week 17 | 
| Normalization of serum uric acid (SUA) in subjects receiving pegloticase and azathioprine (AZA) immunosuppressive therapy | Determine response rate; the last 3 consecutive levels of SUA must be <6 mg/dL | Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in SUA to end of Treatment | Change from baseline | Baseline and Week 17 | 
| Change from baseline in SUA to end of Treatment | Change from baseline - AZA arm | Baseline and Week 25 | 
| Proportion of subjects with SUA <5 mg/dL | Proportion of subjects | Week 17 | 
| Proportion of subjects with SUA <5 mg/dL | Proportion of subjects - AZA arm | Week 25 | 
| Proportion of subjects with SUA <2 mg/dL | Proportion of subjects | Week 17 | 
| Proportion of subjects with SUA <2 mg/dL | Proportion of subjects - AZA arm | Week 25 | 
| Infusion reactions (IRs) and anaphylaxis | Incidence - AZA arm | Week 17 | 
| Infusion reactions (IRs) and anaphylaxis | Incidence | Week 25 | 
| Incidence of anti-pegloticase antibodies | Anti-pegloticase antibodies | Week 17 | 
| Incidence of anti-pegloticase antibodies | Anti-pegloticase antibodies - AZA arm | Week 25 | 
| Mean titer of anti-pegloticase antibodies | Anti-pegloticase antibodies | Week 17 | 
| Mean titer of anti-pegloticase antibodies | Anti-pegloticase antibodies AZA arm | Week 25 | 
| Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs | Incidence | Week 17 | 
| Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs | Incidence - AZA arm | Week 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory gout, Chronic gout