Official Title: “A Phase II Multidose Study of Intravenous PEG-Uricase in Patients With Refractory Gout”

The purpose of this study is to determine whether PEG-uricase (a chemically modified recombinant mammalian enzyme that degrades uric acid) is effective in controlling hyperuricemia in patients with chronic gout, who cannot tolerate, or have not responded adequately, to conventional therapy for gout.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Inflammatory arthritis in patients with gout is caused by crystals of monosodium urate (MSU) that form as a result of chronically elevated levels of uric acid in plasma and extracellular fluids. Recurrent attacks can usually be prevented by treatment with drugs that block urate synthesis by inhibiting xanthine oxidase, or that promote uric acid excretion. If for various reasons (noncompliance, drug intolerance, inadequate dosage, or inefficacy) therapy fails to maintain serum urate concentration below about 6 mg/dL, gout can progress to a chronic stage characterized by destructive arthropathy, deposition of urate crystals in soft tissues (tophi), and nephropathy. The management of chronic gout in such patients is often complicated by co-morbidities such as hypertension, heart disease, diabetes, and renal insufficiency, which may limit the use of anti-inflammatory agents to treat arthritis.

Urate levels are low and gout does not occur in species that express the enzyme urate oxidase (uricase), which converts urate to the more soluble and easily excreted compound allantoin.

Humans do not express this enzyme owing to a mutation of the uricase gene during evolution.

Parenteral uricase is thus a potential means of controlling hyperuricemia and depleting urate stores in patients with chronic, refractory gout. Infusion of recombinant fungal uricase is effective in preventing acute uric acid nephropathy due to tumor lysis in patients with malignancies. However, the short circulating life and potential immunogenicity of fungal uricase prevents its chronic use for treating gout.

PEG-uricase is a recombinant porcine urate oxidase to which multiple strands of polyethylene glycol (PEG) of average molecular weight 10,000 have been attached. "PEGylation" is intended to reduce the immunogenicity of uricase, and greatly prolong its circulating life. This "mammalian" PEG-uricase was non-immunogenic and effective in preventing uric acid nephropathy in a uricase-deficient strain of mice (Kelly et al, J Am Soc Nephrol 12:1001-09, 2001). It has been licensed to Savient Pharmaceuticals for clinical development, and has received Orphan Drug designation for the treatment of refractory gout by the FDA Office of Orphan Product Development.

In a Phase I trial sponsored by Savient Pharmaceuticals in 24 subjects with symptomatic gout, single intravenous (IV) infusions of 0.5 to 12 mg of PEG-uricase were well tolerated, and at doses of 4 mg to 12 mg, were effective in normalizing plasma and urinary uric acid levels over a 21-day period post-infusion. Some subjects in this trial developed antibodies to PEG-uricase, but the only serious adverse events observed were attacks of gout. The present Phase II clinical trial in subjects with refractory gout will evaluate the efficacy, safety, and immunogenicity of PEG-uricase when administered at a dose of 8 mg by IV infusion once every 3 weeks, for a total of 5 infusions. The primary measure of efficacy will be a reduction in plasma uric acid to less than 6 mg/dL, and reduction in the ratio of uric acid to creatinine in urine to <0.2. In addition, the ability of PEG-uricase to lower the total uric acid pool size will be evaluated in a subset of treatment subjects. Uric acid pool size will be measured by a method that involves an infusion of uric acid labeled with N15, a stable (non-radioactive) isotope of nitrogen.

Primary:

• Reduction in plasma uric acid to less than 6 mg/dL
• Reduction of the ratio of uric acid:creatinine in urine
• Development of antibodies to PEG-uricase
• Pharmacokinetics of PEG-uricase

Secondary:

• Clinical response will be evaluated, including the frequency of gout flares, number and distribution of swollen/tender joints, change in size of tophi, change in functional status
• In a subset of subjects who volunteer separately, change in uric acid pool size will be assessed by a method that involves infusion of uric acid labeled with N15, a stable (nonradioactive) isotope of nitrogen.

Inclusion Criteria:

• Age >18 years
• Symptomatic gout
• Serum uric acid >7 mg/dL
• Intolerance of, or inadequate response to, conventional therapy for gout
• Women of childbearing potential must have a negative serum pregnancy test and must use an approved birth control method

Exclusion Criteria:

• End stage renal failure that requires dialysis
• Concurrent use of uric-acid lowering agents
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• A history of anaphylactic reaction to a recombinant protein
• Concurrent use of immunosuppressive therapy (except as needed for prevention of rejection of a transplanted organ, or prednisone at 10 mg a day or less for treatment of gout flares)
• A medical or psychological condition which, in the opinion of the investigator, might create undue risk to the subject

Lead Sponsor: FDA Office of Orphan Products Development

Duke University Medical Center

Durham North Carolina 27710 United States

Overall Clinical Trial Officials and Contacts

John S. Sundy, MD, PhD Principal Investigator Duke University  

Information obtained from ClinicalTrials.gov on July 23, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00111657

Study ID Number: FD-R-02537

ClinicalTrials.gov Identifier: NCT00111657

Health Authority: United States: Food and Drug Administration