Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
A Single Cohort, Dose Escalation Phase 1 Study of Intravenous Infusion of Pegsiticase (Formerly Uricase-PEG 20), a Drug for Managing Hyperuricemia in Refractory Gout.
Fiorino3, Tony, Kivitz1, Alan J., Pardo5, Patricia, Flores2, Rocelle, Zhang2, Zhihua, Bomalaski4, John S.
The enzyme uricase, found in most mammals but not humans, metabolizes uric acid into the highly soluble allantoin and represents a potential treatment for patients suffering from tophaceous and refractory gout. As a foreign protein, uricase is highly immunogenic and not suited for chronic use. Pegsiticase is a pegylated recombinant uricase designed to have an extended half life and reduced that has been previously studied as a single intramuscular dose in a phase 1 study in gout patients. It has not yet been studied as an intravenous agent.
This was an open label, single dose escalation phase 1 study in healthy volunteers and gout patients. Subjects of age 4075 with screening plasma uric acid >= 6 mg/dL for men and >=5 mg/dL for women were eligible to participate. The study enrolled five cohorts (4 subjects per cohort) at doses of 0.05, 0.1, 0.2, 0.3, and 0.4 mg/kg, respectively. Pegsiticase was administered via intravenous infusion over one hour without premedication, and subjects were followed for 24 days. The primary endpoint was safety and tolerability and the secondary endpoints were pharmacodynamics (plasma uric acid), and pharmacokinetics (serum uricase activity). Adverse events were graded according to the Common Toxicity Criteria for Rheumatology, version 2.0.
Pegsiticase was well tolerated in this study. No serious or grade 3 adverse events were observed, and no infusion or allergic reactions were observed in any subjects. The only observed grade 2 toxicities were gout flares. Plasma uric acid level decreased upon infusion of pegsiticase, with the rate of uric acid decrease exhibiting dose-dependence At 0.05 mg/kg, uric acid levels decreased from a baseline of 8.3 mg/dL to almost undetectable levels within 24 hours of the infusion, whereas at the highest dose (0.4 mg/dL), plasma uric acid decreased from a mean of 7.8 mg/dL to undetectable levels within 3 hours. All subjects responded to pegsiticase, and the duration of uric acid suppression below 2 mg/dL ranged from 7 to 24 days, in a dose-dependent manner. In the highest dose cohort, all four subjects maintained plasma uric acid at or near the limit of detection for the entire 24 day follow-up period.
A single intravenous infusion of pegsiticase was safe and well-tolerated in these 20 subjects, and was capable of profoundly suppressing uric acid levels for up to 24 days. Further study of intravenous pegsiticase as a chronic therapy in gout patients is warranted.
To cite this abstract, please use the following information:
Fiorino, Tony, Kivitz, Alan J., Pardo, Patricia, Flores, Rocelle, Zhang, Zhihua, Bomalaski, John S.; A Single Cohort, Dose Escalation Phase 1 Study of Intravenous Infusion of Pegsiticase (Formerly Uricase-PEG 20), a Drug for Managing Hyperuricemia in Refractory Gout. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :144