KRYSTEXXA Solution for infusion Ref.[10152] Active ingredients: Pegloticase

Approximately 24 hours following the first dose of KRYSTEXXA, mean plasma uric acid levels for subjects in the KRYSTEXXA groups were 0.7 mg/dL for the KRYSTEXXA 8 mg every 2 weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2 mg/dL.

In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12 mg of pegloticase in 24 patients with symptomatic gout (n=4 subjects/dose group), plasma uric acid decreased with increasing pegloticase dose or concentrations. The duration of suppression of plasma uric acid appeared to be positively associated with pegloticase dose. Sustained decrease in plasma uric acid below the solubility concentration of 6 mg/dL for more than 300 hours was observed with doses of 8 mg and 12 mg.

Pegloticase levels were determined in serum based on measurements of uricase enzyme activity.

Absorption

Following single intravenous infusions of 0.5 mg to 12 mg pegloticase in 23 patients with symptomatic gout, maximum serum concentrations of pegloticase increased in proportion to the dose administered. The population pharmacokinetic analysis showed that age, sex, weight, and creatinine clearance did not influence the pharmacokinetics of pegloticase.

Distribution

Significant covariates included in the model for determining clearance and volume of distribution were found to be body surface area and anti-pegloticase antibodies.

Special Populations

Pediatric Populations

The pharmacokinetics of pegloticase has not been studied in children and adolescents.

Patients with Renal or Hepatic Impairment

No formal studies were conducted to examine the effects of either renal or hepatic impairment on pegloticase pharmacokinetics.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of pegloticase.

The genotoxic potential of pegloticase has not been evaluated.

There was no evidence of impairment on fertility at pegloticase doses up to 40 mg/kg (approximately 50 times the MRHD on mg/m² basis) every other day in rats.

Pegloticase at similar to and higher than the maximum recommended human dose (MRHD) on a plasma AUC basis [at intravenous (IV) doses of ≥0.4 mg/kg in dogs] caused cytoplasmic vacuoles in multiple organs, and edema and histiocyte infiltration in the aortic outflow tract in dogs. Organs with cytoplasmic vacuoles included the spleen, adrenal gland, liver, heart, duodenum, and jejunum. Vacuoles in the spleen, adrenal glands, and heart persisted after a 1-year recovery period at pegloticase doses (≥1.5 mg/kg in dogs) approximately 5 times the MRHD, but were absent at a dose similar to the MRHD. Vacuoles in the liver, duodenum, and jejunum persisted after a 3-month recovery period at a pegloticase dose (10 mg/kg in dogs) approximately 30 times the MRHD, but were absent at doses (≤1.5 mg/kg) approximately 5 times and similar to the MRHD. The edema and histiocyte infiltration in the aortic outflow tract was absent after recovery periods of 6 and 12 months, respectively.

Vacuoles in the spleen, liver, duodenum, and jejunum were within macrophages and most likely represented phagocytic removal of pegloticase from the circulation. However, the vacuolated cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of the heart, vacuoles were in the cytoplasm of endothelial cells in the intimal lining of the aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and zona fasciculata. The clinical significance of these findings and the functional consequences are unknown.

The efficacy of KRYSTEXXA was studied in adult patients with chronic gout refractory to conventional therapy in two replicate, multicenter, randomized, double-blind, placebo- controlled studies of six months duration: Trial 1 and Trial 2. Patients were randomized to receive KRYSTEXXA 8 mg every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio.

Studies were stratified for the presence of tophi. Seventy-one percent (71%) of patients had baseline tophi. All patients were prophylaxed with an oral antihistamine, intravenous corticosteroid and acetaminophen. Patients also received prophylaxis for gout flares with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine, or both, beginning at least one week before KRYSTEXXA treatment unless medically contraindicated or not tolerated. Patients who completed the randomized clinical trials were eligible to enroll in a 2-year open label extension study.

Entry criteria for patients to be eligible for the trials were: baseline serum uric acid (SUA) of at least 8 mg/dL; had symptomatic gout with at least 3 gout flares in the previous 18 months or at least 1 gout tophus or gouty arthritis; and had a self-reported medical contraindication to allopurinol or medical history of failure to normalize uric acid (to less than 6 mg/dL) with at least 3 months of allopurinol treatment at the maximum medically appropriate dose.

The mean age of study subjects was 55 years (23-89); 82% were male, mean body mass index (BMI) was 33 kg/m², mean duration of gout was 15 years, and mean baseline SUA was 10 mg/dL.

To assess the efficacy of KRYSTEXXA in lowering uric acid, the primary endpoint in both trials was the proportion of patients who achieved plasma uric acid (PUA) less than 6 mg/dL for at least 80% of the time during Month 3 and Month 6. As shown in Table 2, a greater proportion of patients treated with KRYSTEXXA every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. Although the 4 week regimen also demonstrated efficacy for the primary endpoint, this regimen was associated with increased frequency of anaphylaxis and infusion reactions and less efficacy with respect to tophi.

Table 2. Plasma Uric Acid <6 mg/dL for at Least 80% of the Time During Months 3 and 6:

Note: Based on post-hoc analyses of the clinical trial data, if KRYSTEXXA had been stopped when a patient’s uric acid level rose to greater than 6 mg/dL on a single occasion, the incidence of infusion reactions would have been reduced by approximately 67%, but the success rates for the primary efficacy endpoint would have been reduced by approximately 20%. If KRYSTEXXA had been stopped after 2 consecutive uric acid levels greater than 6 mg/dL, the incidence of infusion reactions would have been half, and there would have been little change in the efficacy outcome.
* 95% confidence interval for differences in responder rate between pegloticase group vs. placebo
^† P-value using Fisher’s exact test to compare pegloticase group vs. placebo

The effect of treatment on tophi was a secondary efficacy endpoint and was assessed using standardized digital photography, image analysis, and a Central Reader blinded to treatment assignment. Approximately 70% of patients had tophi at baseline. A pooled analysis of data from Trial 1 and Trial 2 was performed as pre-specified in the protocols. At Month 6, the percentage of patients who achieved a complete response (defined as 100% resolution of at least one target tophus, no new tophi appear and no single tophus showing progression) was 45%, 26%, and 8%, with KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The difference between KRYSTEXXA and placebo was statistically significant for the every 2 week dosing regimen, but not for the every 4 week dosing regimen.