Pegloticase for the Treatment of Gout
November 1, 2010
On September 14, 2010 the FDA approved pegloticase (Krystexxa) for chronic gout that is refractory to conventional therapy. Approval was based upon the results of two pivotal trials, an open-label extension trial (not yet published), and earlier open label trials (1-2).
Pegloticase is a recombinant mammalian urate oxidase (uricase) modified by polyethylene glycol. Its therapeutic effect results from the oxidation of urate to allantoin, a highly soluble purine metabolite that is excreted by the kidney. Pegloticase is administered intravenously at a dose of 8 mg every two weeks; treatment reduces plasma urate to a mean of < 1 mg/dl within 24 hours.
In pivotal studies, pegloticase 8 mg or placebo was administered intravenously every 2 weeks (Q2W) or 4 weeks (Q4W). Subjects received gout flare prophylaxis with colchicine or NSAIDs unless contraindicated. As prophylaxis against infusion reactions subjects received fexofenadine 60 mg the evening before and the day of infusion, hydrocortisone 200 mg IV and acetaminophen 1000 mg on the day of infusion. Those who completed the 6 month placebo-controlled trial were eligible for a 2 year open label extension trial.
Subjects had chronic, symptomatic gout; serum urate of ≥ 8 mg/dL; and were refractory to allopurinol – either because of intolerance or failure to normalize serum urate to less than 6 mg/dL. 71% had tophi. Mean baseline serum urate level was 10 mg/dL. The participants were predominantly men (82%), with longstanding gout, and a substantial burden of cardiovascular and metabolic disease.
The primary efficacy endpoint was the percentage of subjects with a plasma urate < 6 mg/dL for at least 80% of the time during Month 3 and 6. Dosing every 2 weeks was more effective, with the endpoint achieved in ~ 40% of patients compared with none in the placebo group. Failure to achieve the primary efficacy endpoint was associated with high titer antibody to pegloticase (see below). Resolution of at least one tophus was seen in almost half of patients on 8 mg Q2W.
Important Safety Considerations
- Glucose-6-Phosphate Dehydrogenase Deficiency. Pegloticase is contraindicated in patients with G6PD deficiency because of the risk for methemaglobinemia and hemolytic anemia.
- Gout Flares. As with other urate lowering therapies, treatment with pegloticase appeared to increase gout flare rates, particularly during months 1-3 of treatment.
- Infusion Reactions. Infusion reactions were reported in 26% of Q2W subjects, 41% of Q4W subjects, and 5% of placebo subjects despite pre-infusion treatment with antihistamines, corticosteroids and acetaminophen. Reactions, some severe, included one or more of urticaria, dyspnea, chest discomfort, erythema or pruritis.
- Anaphylaxis. In a post-hoc analysis, 5% of subjects who received pegloticase and none on placebo were determined to have anaphylaxis. Only 1 subject was treated with epinephrine.
- Congestive Heart Failure. Exacerbation of congestive heart failure was observed in 2 patients who received pegloticase 8 mg Q2W in the placebo controlled trial and 4 patients in the open-label extension. About 12% of subjects who entered the Phase 3 trials had a history of cardiac failure. The label advises caution in patients with congestive heart failure who receive pegloticase.
Immunogenicity
Antibodies to pegloticase were present in 92% of patients receiving pegloticase 8 mg Q2W compared to 28% for placebo. High titer pegloticase antibody was associated with increased clearance of pegloticase, loss of the urate lowering response, and increased risk of infusion reactions and anaphylaxis. Although assays for antibodies to pegloticase are not commercially available, elevations in pre-infusion plasma urate levels (e.g. > 6 mg/dL) may serve as a marker. In clinical trials, this finding indicated patients at higher risk for infusion reactions.
Dosing and Administration
Pegloticase is diluted into 250 mL of saline and administered intravenously over 2 hours. It is recommended that patients receive pre-treatment with antihistamines and corticosteroids in order to try to reduce the risk of infusion reactions and anaphylaxis. Patients should be observed for signs of infusion reactions for at least 1 hour after dosing. Treatment is administered every 2 weeks. The optimal duration of therapy has not been defined, nor has the potential efficacy and safety of repeated courses of pegloticase. The potential utility of following pegloticase therapy with conventional hypouricemic therapy has not been studied. At this time the cost of pegloticase has not been announced.
The Bottom Line
Pegloticase presents a novel and effective option for the subset of patients with severe, refractory gout who are unable to normalize serum urate levels with conventional therapy.
There are several important considerations in selecting patients for pegloticase:
- Patients with gout who respond to and can tolerate conventional urate lowering therapies such as allopurinol or febuxostat should be treated with these drugs before considering pegloticase.
- Pegloticase should be used with caution in patients with CHF
- Patients with G6PD deficiency should not receive pegloticase
- Pre-medication with an antihistamine and a corticosteroid prior to dosing should be used to help reduce the risk of infusion-related reactions.
- Measurement of a routine serum urate level several days prior to each infusion may be helpful in identifying patients who have lost a therapeutic response to pegloticase and may be at increased risk of infusion reactions and anaphylaxis. Consider discontinuing treatment in patients with a pre-treatment serum urate level > 6 mg/dL; definitely discontinue if this occurs more than once.
- Clinicians administering pegloticase should have the capabilities and experience to manage infusion reactions and anaphylaxis.
References
- Sundy JS, et al. Arthritis Rheum 2007;56(3):1021-8. PMID 17328081
- Sundy JS, et al. Arthritis Rheum 2008; 58(9):2882-91. PMID 18759308
Hotline Author: John Sundy, MD, PhD, Associate Professor of Medicine, Director, Duke Clinical Research Unit, Duke University School of Medicine, Durham, NC.
Disclosure: Research Support: Ardea Biosciences; Celgene; Genentech; Neopharm; Nuon Therapeutics; Regeneron; Savient Pharmaceuticals. Scientific Advisory Board: Ardea Biosciences. Consultant: BioCryst; Novartis; Pharmos; Roche; Savient Pharmaceuticals. Speakers Bureau: Takeda. Duke University and Mountain View Pharmaceuticals hold patent rights in pegylated urate oxidase and its use which have been licensed to Savient Pharmaceuticals.
Hotline Editors: Arthur Kavanaugh, MD and Eric Ruderman, MD. Disclosure: Dr. Kavanaugh has served as an investigator on clinical research studies of pegloticase. Dr. Ruderman has nothing to disclose.
In addition to review by the editors, this Hotline has been reviewed by all members of the ACR Executive Committee, Communications and Marketing Committee and Drug Safety Committee.
The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author(s) and does not represent a position statement of the American College of Rheumatology.
