Pharmacology Update

Pegloticase Injection (Krystexxa™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A recombinant, polyethylene glycol (PEG) mammalian urate oxidase (uricase) has been approved by the FDA for treatment of hyperuricemia. Uricase metabolizes urate to allantoin, a water-soluble metabolite, which is cleared renally. Pegliticase is marketed by Savient Pharmaceuticals as Krystexxa™.

Indications

Pegliticase is indicated for the treatment of symptomatic hyperuricemia.1

Dosage

The recommended dose of pegloticase is 8 mg given as an intravenous infusion every 2 weeks. Patients should be premedicated with an antihistamine and corticosteroids, and serum uric acid levels should be monitored before each infusion.1 Gout flare prophylaxis with a nonsteroidal anti-inflammatory drug or colchicines is recommended starting at least 1 week before initiation of therapy.1

Pegloticase is available as an 8 mg vial.

Potential Advantages

Pegloticase reduced urate levels and resolved at least one target tophus in about 40% of patients that were refractory to conventional antigout drugs.

Potential Disadvantages

In a clinical trial, anaphylaxis was reported with a frequency of 6.5%. Infusion reactions occurred in 26% of patients that received pegloticase compared to 5% for placebo. Patients that receive retreatment may be at increased risk of anaphylaxis and infusion reactions.1 Anti-pegloticase antibodies have been detected in 92% of patients treated with pegloticase and high titers have been associated with treatment failure and a higher incidence of infusion reactions. Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency.

Comments

Pegloticase is a pegylated recombinant modified mammalian uricase product produced by Escherichia coli. The half-life is 1-2 weeks compared to 24 hours for the previously approved recombinant uricase, rasburicase.2 Efficacy was shown in two randomized, double-blind, placebo-controlled, 6-month studies in subjects with chronic gout with either treatment failure or contraindication to allopurinol.1 The study population had a mean age of 55 years, mean baseline serum urate level of 10 mg/dL, and symptomatic gout with at least three gout flares in the previous 18 months or at least one gout tophus or gouty arthritis; 82% were male. Subjects were randomized 2:2:1 to pegloticase 8 mg every 2 weeks, 8 mg every 4 weeks, or placebo. The primary endpoint was plasma urate levels below 6 mg/dL for 80% of the time in months 3 and 6. The secondary endpoint was response of tophi defined as 100% resolution of at least one target tophus, appearance of no new tophi, and no single tophus showing progression. In the first study, 47% of subjects (n = 104) randomized to 8 mg every 2 weeks met the primary endpoint compared to 20% for 8 mg every 4 weeks and 0% for placebo. In the second study, response rates were 38%, 49%, and 0%, respectively. In a pooled analysis, 45% of subjects on the high dose met criteria for the secondary endpoint compared to 26% for the lower dose and 8% for placebo. Reduction in urate levels can be observed within 6 hours.3 The most common adverse events were infusion reactions (26% vs 5% for placebo), nausea (12% vs 2%), and contusion or ecchymosis (11% vs 5%). Gout flares were reported in 77% of subjects in the clinical trials.

Clinical Implications

Gout is a common disorder that affects about 1% of adults and is much more prevalent in men.4 Chronic hyperuricemia (> 7 mg/dL) increases the risk of gout and may be an independent risk factor for renal and cardiovascular disease. Pegloticase provides another option for patients with hyperuricemia that have not adequately responded to standard therapy (e.g., allopurinol, febuxostat). It is successful in maintaining uric acid level below 6 mg/dL in about 40% of treatment refractory patients.

References

1. Krystexxa Prescribing Information. East Brunswick, NJ: Savient Pharmaceuticals; September 2010.

2. Burns CM, Wortmann RL. Gout therapeutics: New drugs for an old disease. Lancet 2010 Aug 16; Epub ahead of print.

3. Sundy JS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study. Arthritis Rheum 2008;58:2882-2891.

4. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther 2006;8(Suppl 1):S2.