About Uricase-PEG 20
Uricase-PEG 20 is a pegylated recombinant Candida utilis uricase. This particular enzyme was chosen because at a physiological pH it has the highest affinity for uric acid and the greatest catalytic rate compared with multiple other uricases. The 20 kD PEG-succinimydyl succinate conjugate has a demonstrated safety record in humans and has been shown to have excellent pharmacological properties.
Phase I Data for Uricase-PEG 20
A single dose, open label, cohort dose escalation Phase 1 study enrolled 12 subjects with gout who were treated with 0.5, 1 or 2 IU/kg intramuscularly; there was no washout of the existing chronic gout regimen and patients continued on their gout medications through the trial. Pharmacokinetics, pharmacodynamics and immunogenicity of Uricase-PEG 20 were measured. The circulating half-life of Uricase-PEG 20 was approximately 8-10 days, as seen in the figure below.
Single-Dose Pharmacokinetics of Intramuscular Uricase-PEG 20
Treatment resulted in a dose dependent decrease in peripheral blood uric acid, with doses of 1-2 IU/kg sufficient to eliminate most, if not all, detectable plasma uric acid for 7 days and to maintain levels under 6 mg/dL for 15 days (see next figure). Subjects with tophi noted shrinking of tophi and decreased pain.
Plasma Uric Acid Levels After Single Doses of Uricase-PEG 20
The safety profile of uricase-PEG 20 was excellent in this single dose phase I study. . No grade 2 or greater adverse events attributed to the drug were observed. Only two laboratory abnormalities were observed: one subject treated with 0.5 IU/kg had a minor increase in fibrinogen from a pretreatment level of 345 to a level of 490 on day 15 (upper limit of normal was 423), and another subject treated at 1 IU/kg had a minor increase in AST from a pretreatment AST level of 32 to 39 on day 8 (upper limit of normal was 35). There were no clinical findings associated with these laboratory abnormalities. There were 4 clinical adverse events, all of which were Grade 1 in severity, and there were no serious adverse events. One subject had redness at the injection site, one subject complained of fatigue and malaise, and two subjects had arthritic complaints that possibly represented gout flares 9-10 days following treatment.
All subjects were tested for the presence of antibodies to Uricase-PEG 20 using two different assays (the first an ELISA assay for antibody to uricase-PEG 20, the second an enzyme assay to determine if neutralizing antibodies are present in a sample). None of the individuals had any measurable antibodies to Uricase-PEG 20 nor did any patient show evidence of neutralizing antibodies.
Clinical Development Program : Proof of Principle Phase II Trial in Resistant/Refractory Gout
The phase II trial will enroll patients with resistant/refractory gout, defined as intolerant to chronic gout medications or insufficiently controlled on those medications (i.e., serum urate > 8 mg/dL). The trial will study 3-4 doses/dosing regimens. The primary endpoint of the trial will likely be the percent responders at three months. Secondary endpoints would include the change in uric acid levels over time, percent of time with normal uric acid levels, number of gout flares, shrinkage of tophi, and assessments of pain, disability and quality of life. In addition to the typical clinical and laboratory monitoring of adverse events, careful assessment of anti-PEG and anti-uricase-PEG 20 antibodies must be performed.