CINACALCET (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity
Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given cinacalcet at dietary doses of 15, 50, and 125 mg/kg/day in males and 30, 70, and 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, and 35 mg/kg/day in males and 5, 20, and 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.

Mutagenicity
Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay, nor in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation, nor in the in vivo mouse micronucleus assay.

Impairment of Fertility Female rats were given oral gavage doses of 5, 25, and 75 mg/kg/day cinacalcet beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks postmating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.

14 CLINICAL STUDIES

14.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to cinacalcet and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P product was 61 mg 2 /dL 2. The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Cinacalcet (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of ≤ 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH ≤ 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the cinacalcet arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on cinacalcet and 5% of placebo-treated patients achieved an iPTH ≤ 250 pg/mL (p < 0.001) (Table 7, Figure 1). These studies showed that cinacalcet reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 7, Figure 2). The median dose of cinacalcet at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.

Table 7. Effects of Cinacalcet on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)
Study 1Study 2Study 3
PlaceboCinacalcet PlaceboCinacalcetPlaceboCinacalcet
(n = 205)(n = 205)(n = 165)(n = 166)(n = 101)(n = 294)
iPTH
Baseline (pg/mL): Median Mean (SD) 535 651 (398) 537 636 (341) 556 630 (317) 547 652 (372) 670 832 (486) 703 848 (685)
Evaluation Phase (pg/mL) 563275592238737339
Median Percent Change +3.8-48.3+8.4-54.1+2.3-48.2
Patients Achieving Primary Endpoint (iPTH ≤ 250 pg/mL) (%) a 4%41%**7%46%**6%35%**
Patients Achieving ≥ 30% Reduction in iPTH (%) a 11%61%12%68%10%59%
Patients Achieving iPTH ≤ 250 pg/mL and Ca x P < 55 mg 2 /dL 2 (%) 1%32%5%35%5%28%
Ca x P
Baseline (mg 2 /dL 2) 626161616159
Evaluation Phase (mg 2 /dL 2) 595259475748
Median Percent Change-2.0-14.9-3.1-19.7-4.8-15.7
Calcium
Baseline (mg/dL) 9.89.89.910.09.99.8
Evaluation Phase (mg/dL) 9.99.19.99.110.09.1
Median Percent Change +0.5-5.5+0.1-7.4+0.3-6.0
Phosphorus
Baseline (mg/dL) 6.36.16.16.06.16.0
Evaluation Phase (mg/dL) 6.05.65.95.15.65.3
Median Percent Change -1.0-9.0-2.4-12.4-5.6-8.6
** p < 0.001 compared with placebo; p-values presented for primary endpoint only. a iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3). Values shown are medians unless indicated otherwise.

Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)

Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)
(click image for full-size original)

Data are presented for patients who completed the studies; Placebo (n = 342), Cinacalcet (n = 439).

Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)

Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)
(click image for full-size original)

Data are presented for patients who completed the studies; Placebo (n = 342), Cinacalcet (n = 439).

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.

Cinacalcet decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH ≥ 300 to ≤ 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of ≤ 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

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