Safety and Efficacy Study of Intramuscular Uricase-PEG 20

The purpose of this study is to assess the safety, pharmacokinetics and pharmacodynamics of single and multiple intramuscular doses of Uricase-PEG 20

Uricase is an enzyme (found in most mammals but not humans) that converts poorly soluble uric acid into highly soluble allantoin. Because humans lack uricase, they are prone to develop elevated levels of uric acid, which can form crystals in the joints and soft tissues. In those which chronically elevated uric acid, gout may develop. In the setting of acute rises in uric acid, seen for example in tumor lysis syndrome, uric acid crystals can damage the renal tubules. Uricase-PEG 20 is a recombinant uricase conjugated with multiple PEG molecules designed to prolong the half-life and decrease the immunogenicity of uricase. This study will characterize the safety, pharmacokinetics and pharmacodynamics of intramuscular Uricase-PEG 20, the anticipated route of administration to be used in future clinical development in gout.

Cohorts will receive ascending doses of Uricase-PEG 20 in a sequential manner. The study will enroll both single dose cohorts and multi-dose cohorts.

Safety (assessment of signs and symptoms and clinical laboratory measurements following administration of Uricase-PEG 20, graded according to the Common Toxicity Criteria for Rheumatology, version 2.0)

Inclusion Criteria: Serum uric acid > 6 mg/dL (men) or > 5 mg/dL (women) Clinical laboratory values within normal limits or not clinically significant Women should be menopausal or peri-menopausal Exclusion Criteria: Prior exposure to uricase History of severe allergic reactions, or any allergy to PEG or pegylated products G6PD or catalase deficiency Medical condition that may interfere with ability to complete the study (e.g., uncontrolled diabetes or hypertension, congestive heart failure NYHA Class III or IV, history of myocardial infarction, immunosuppression, pregnancy)

Bomalaski JS, Holtsberg FW, Ensor CM, Clark MA. Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies. J Rheumatol. 2002 Sep;29(9):1942-9.