PARICALCITOL (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg given three times weekly (2 to 15 times the AUC at a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg. In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg (< 1 to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Paricalcitol had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose (equivalent to 13 times a human dose of 14 mcg based on surface area, mcg/m2).

14 CLINICAL STUDIES

14.1 Chronic Kidney Disease Stages 3 and 4

The safety and efficacy of Paricalcitol Capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stages 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A total of 107 patients received Paricalcitol Capsules and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin D levels were not measured.

The initial dose of Paricalcitol Capsules was based on baseline iPTH. If iPTH was ≤ 500 pg/mL, Paricalcitol Capsules were administered 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was > 500 pg/mL, Paricalcitol Capsules were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was increased by 1 mcg daily or 2 mcg three times a week every 2 to 4 weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of Paricalcitol Capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times a week regimen.

In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to < 60 pg/mL, or decreased > 60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased < 30% from baseline and serum calcium was ≤ 10.3 mg/dL and serum phosphorus was ≤ 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were ≤ 10.3 mg/dL and ≤ 5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was > 11.0 mg/dL. If serum phosphorus was > 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the Paricalcitol Capsules dose was decreased. Seventy-seven percent (77%) of the Paricalcitol Capsules treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 91% of Paricalcitol Capsules treated patients and 13% of the placebo treated patients (p < 0.001). The proportion of Paricalcitol Capsules treated patients achieving two consecutive ≥ 30% reductions was similar between the daily and the three times a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%).

The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), and hyperphosphatemia in Paricalcitol Capsules treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the Paricalcitol Capsules group. No increases in urinary calcium or phosphorous were detected in Paricalcitol Capsules treated patients compared to placebo.

The pattern of change in the mean values for serum iPTH during the studies is shown in Figure 1.

Figure 1. Mean Values for Serum iPTH Over Time in the Three Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies Combined
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(click image for full-size original)

The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, calcium-phosphorus product, and bone-specific alkaline phosphatase are shown in Table 4.

Table 4. Mean Changes from Baseline to Final Treatment Visit in Serum iPTH, Bone Specific Alkaline Phosphatase, Calcium, Phosphorus, and Calcium x Phosphorus Product in Three Combined Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies
Paricalcitol Capsules Placebo
iPTH (pg/mL) n = 104 n = 110
Mean Baseline Value 266 279
Mean Final Treatment Value 162 315
Mean Change from Baseline (SE) -104 (9.2) +35 (9.0)
Bone Specific Alkaline Phosphatase (mcg/L) n = 101 n = 107
Mean Baseline 17.1 18.8
Mean Final Treatment Value 9.2 17.4
Mean Change from Baseline (SE) -7.9 (0.76) -1.4 (0.74)
Calcium (mg/dL) n = 104 n = 110
Mean Baseline 9.3 9.4
Mean Final Treatment Value 9.5 9.3
Mean Change from Baseline (SE) +0.2 (0.04) -0.1 (0.04)
Phosphorus (mg/dL) n = 104 n = 110
Mean Baseline 4.0 4.0
Mean Final Treatment Value 4.3 4.3
Mean Change from Baseline (SE) +0.3 (0.08) +0.3 (0.08)
Calcium x Phosphorus Product (mg2 /dL2) n = 104 n = 110
Mean Baseline 36.7 36.9
Mean Final Treatment Value 40.7 39.7
Mean Change from Baseline (SE) +4.0 (0.74) +2.9 (0.72)

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