COLESEVELAM HYDROCHLORIDE (Page 5 of 6)

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 total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia. Approximately 1,600 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 7, 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 7 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 8, 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 8 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.

Pediatric Therapy

The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with HeFH, taking a stable dose of an FDA-approved statin (with LDL-C > 130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C > 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.

During the double-blind treatment period, patients were assigned randomly to treatment: Colesevelam hydrochloride 3.8 g/day (n = 64), colesevelam hydrochloride 1.9 g/day (n = 65), or placebo (n = 65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).

Table 9 Response to Colesevelam Hydrochloride 3.8 g Compared to Placebo in Pediatric Patients 10 to 17 Years of — Age Mean Percent Change in Lipid Parameters from Baseline to Week 8
*
For triglycerides, median % change from baseline
p 0.05 for lipid parameters compared to placebo Values represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication. Results were based on the ITT population with LOCF.
Treatment Difference TC
(N = 128)
LDL-C
(N = 128)
Apo B
(N = 124)
HDL-C
(N = 128)
Non-HDL-C
(N = 128)
TG *
(N = 128)
Colesevelam hydrochloride 3.8 g vs Placebo -7 -13 -8 +6 -11 +5

During the open-label treatment period patients were treated with colesevelam hydrochloride 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.

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