Pegylated Recombinant Mammalian Uricase (PEG-uricase) as Treatment for Refractory Gout
Summary
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.
Description
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.
Study Design
Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Conditions
Gout
Intervention
Pegloticase
Location
Duke University Medical Center
Durham
North Carolina
United States
27710
Status
Completed
Source
Duke University
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00111657
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Gout Suppressants
Agents that increase uric acid excretion by the kidney (URICOSURIC AGENTS), decrease uric acid production (antihyperuricemics), or alleviate the pain and inflammation of acute attacks of gout.
Benzbromarone
Uricosuric that acts by increasing uric acid clearance. It is used in the treatment of gout.
Apazone
An anti-inflammatory agent used in the treatment of rheumatoid arthritis. It also has uricosuric properties and has been used to treat gout.
Uricosuric Agents
Gout suppressants that act directly on the renal tubule to increase the excretion of uric acid, thus reducing its concentrations in plasma.
Sulfinpyrazone
A uricosuric drug that is used to reduce the serum urate levels in gout therapy. It lacks anti-inflammatory, analgesic, and diuretic properties.
Clinical Trials
Re-exposure Study of Pegloticase Intravenous (i.v.) in Symptomatic Gout Patients
The purpose of the study is to evaluate the safety and clinical effect of re-exposure to a 24 week course of treatment of pegloticase i.v. in subjects whose last exposure to pegloticase i....
Study of the Safety and Effectiveness of Rilonacept for the Prevention of Gout Flares
This is a clinical research study to determine the safety and effectiveness of an experimental drug called rilonacept in subjects with gout who are beginning another additional treatment....
Assessment of Primary Care Providers' Knowledge and Beliefs Regarding Gout Management
This is a questionnaire study aimed at learning about physicians' views on the treatment of Gout.
PREventative Study Against URate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2)
The purpose of this clinical research study is to determine the safety and effectiveness of an experimental drug called rilonacept in subjects with gout who are beginning allopurinol treat...
PREventative Study Against URate-lowering Drug-induced Gout Exacerbations 1
The purpose of this clinical research study is to determine the safety and effectiveness of an experimental drug called rilonacept in subjects with gout who are beginning allopurinol treat...
PubMed Articles
Pegloticase: in treatment-refractory chronic gout.
Intravenous pegloticase offers a novel approach to treating chronic gout refractory to conventional therapy. Pegloticase is a recombinant polyethylene glycol-conjugated form of uricase (a uric acid-sp...
A high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support...
Gout therapeutics: new drugs for an old disease.
The approval of febuxostat, a non-purine-analogue inhibitor of xanthine oxidase, by the European Medicines Agency and the US Food and Drug Administration heralds a new era in the treatment of gout. Th...
To identify association of IL18-607 C/A and -137 G/C polymorphism with susceptibility to gout in Chinese Han male population, We evaluate the genetic contribution of the IL18-607 C/A and -137 G/C poly...
