Pegloticase: Mechanism and Function
Pegloticase is a pegylated recombinant uricase enzyme that catalyzes the oxidation of uric acid into allantoin, a more soluble end product that can be readily excreted. 1, 2
Mechanism of Action
Pegloticase functions as a uric acid-specific enzyme that enzymatically degrades uric acid, distinguishing it from all other urate-lowering therapies which work by reducing uric acid production or increasing renal excretion 2, 3
The enzyme is produced by a genetically modified strain of Escherichia coli and is conjugated with polyethylene glycol (PEGylated) to extend its half-life and reduce immunogenicity 1, 4
By converting uric acid to allantoin through oxidation, pegloticase rapidly and profoundly lowers serum urate levels, typically achieving levels below 6 mg/dL within 6 hours of infusion 5
Clinical Indications
Pegloticase is reserved exclusively for patients with crystal-proven severe debilitating chronic tophaceous gout and poor quality of life in whom the serum uric acid target cannot be reached with any other available drug at maximal dosage, including combinations 1, 6
The FDA specifically indicates pegloticase for chronic gout in adult patients refractory to conventional therapy—defined as patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at maximum medically appropriate doses or for whom these drugs are contraindicated 2
Pegloticase is not recommended as first-line urate-lowering therapy for any gout scenario and should not be used for asymptomatic hyperuricemia 1, 2
Efficacy Profile
In pivotal phase III trials, pegloticase 8 mg every 2 weeks achieved serum uric acid levels below 6 mg/dL in 42% of patients on average, compared to 0% in the placebo group at 6 months 1
The therapy demonstrates disease-modifying benefits including 45% of patients achieving complete resolution of one or more tophi versus 8% with placebo, along with significant improvements in chronic arthropathy and health-related quality of life 1
Pegloticase profoundly lowers serum urate, resolves tophi, reduces tender and swollen joint counts, decreases pain, and improves patients' global assessments and quality of life 3
Critical Safety Considerations
The major limitation is immunogenicity: anti-drug antibodies emerge in many patients, resulting in increased drug clearance, loss of efficacy, and infusion reactions 3, 7
Allergic reactions and infusion-related reactions occur in approximately 25-30% of patients receiving pegloticase biweekly, with most reactions occurring in patients who have lost therapeutic response 1, 7
Monitoring serum uric acid levels prior to each infusion is essential: 91% of all infusion reactions occurred in patients with preinfusion serum uric acid concentrations greater than 6 mg/dL 7
Treatment should be discontinued if serum uric acid levels increase above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed, as this indicates loss of efficacy and increased risk of infusion reactions 1, 2
Administration Requirements
Pegloticase must be administered in healthcare settings by providers prepared to manage anaphylaxis and infusion reactions 2
Patients require premedication with antihistamines and corticosteroids before each infusion 2
Oral urate-lowering medications should be discontinued during pegloticase therapy to avoid masking increases in serum uric acid levels that warn of increased infusion reaction risk 6, 2
The recommended dose is 8 mg administered as an intravenous infusion over no less than 120 minutes every two weeks 2