Colesevelam Hydrochloride (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).

Mutagenesis: Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylaminohexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.

Impairment of Fertility: Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Colesevelam hydrochloride reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with a statin in patients with primary hyperlipidemia.

Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.

Monotherapy: In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), colesevelam hydrochloride was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 6, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Colesevelam hydrochloride at both doses increased HDL-C by 3%. Increases in TG of 9 to 10% were observed at both colesevelam hydrochloride doses but the changes were not statistically different from placebo.

Table 6 Response to Colesevelam Hydrochloride Monotherapy in a 24-Week Trial — Percent Change in Lipid Parameters from Baseline

Grams/Day	N	TC	LDL-C	Apo B	HDL-C *	Non-HDL-C	TG *
* Median % change from baseline. † p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
Placebo	88	+1	0	0	-1	+1	+5
3.8 g (6 tablets)	95	-7 †	-15 †	-12 †	+3 †	-10 †	+10
4.5 g (7 tablets)	94	-10 †	-18 †	-12 †	+3	-13 †	+9

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.

Combination Therapy: Co-administration of colesevelam hydrochloride and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156 to 236 mg/dL), 171 mg/dL in the lovastatin study (range 115 to 247 mg/dL), and 188 mg/dL in the simvastatin study (range 148 to 352 mg/dL). As demonstrated in Table 7, colesevelam hydrochloride doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.

Table 7 Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin — Percent Change in Lipid Parameters

Dose/Day	N	TC	LDL-C	Apo B	HDL-C *	Non-HDL-C	TG *
* Median % change from baseline. † p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
Atorvastatin Trial (4-week)
Placebo	19	+4	+3	-3	+4	+4	+10
Atorvastatin 10 mg	18	-27 †	-38 †	-32 †	+8	-35 †	-24 †
Colesevelam Hydrochloride 3.8 g/ Atorvastatin 10 mg	18	-31 †	-48 †	-38 †	+11	-40 †	-1
Atorvastatin 80 mg	20	-39 †	-53 †	-46 †	+6	-50 †	-33 †
Simvastatin Trial (6-week)
Placebo	33	-2	-4	-4 †	-3	-2	+6 †
Simvastatin 10 mg	35	-19 †	-26 †	-20 †	+3 †	-24 †	-17 †
Colesevelam Hydrochloride 3.8 g/ Simvastatin 10 mg	34	-28 †	-42 †	-33 †	+10 †	-37 †	-12 †
Simvastatin 20 mg	39	-23 †	-34 †	-26 †	+7 †	-30 †	-12 †
Colesevelam Hydrochloride 2.3 g/ Simvastatin 20 mg	37	-29 †	-42 †	-32 †	+4 †	-37 †	-12 †
Lovastatin Trial (4-week)
Placebo	26	+1	0	0	+1	+1	+1
Lovastatin 10 mg	26	-14 †	-22 †	-16 †	+5	-19 †	0
Colesevelam Hydrochloride 2.3 g/ Lovastatin 10 mg Together	27	-21 †	-34 †	-24 †	+4	-27 †	-1
Colesevelam Hydrochloride 2.3 g/ Lovastatin 10 mg Apart	23	-21 †	-32 †	-24 †	+2	-28 †	-2

In all 3 studies, the LDL-C reduction achieved with the combination of colesevelam hydrochloride and any given dose of statin therapy was statistically superior to that achieved with colesevelam hydrochloride or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of colesevelam hydrochloride 3.8 g and atorvastatin 10 mg.

The effect of colesevelam hydrochloride when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either colesevelam hydrochloride 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 8.

Table 8 Response to Colesevelam Hydrochloride Added to Fenofibrate in Patients with Mixed Hyperlipidemia (Mean % Change from Treated Baseline * at 6 Weeks)

Treatment	N	TC	LDL-C	Apo B	HDL-C	Non-HDL-C	TG †
* Treated Baseline: following 8-week treatment with open-label fenofibrate 160 mg. † For triglycerides, median % change from baseline. ‡ p≤0.0002 compared to placebo.
Placebo + Fenofibrate 160 mg	61	2	2	1	-1	2	-3
Colesevelam Hydrochloride + Fenofibrate 160 mg	61	-6 ‡	-10 ‡	-7 ‡	0	-8 ‡	6