Nexlizet (Page 4 of 6)

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Bempedoic acid

Bempedoic acid was negative for mutagenicity in an in vitro Ames assay and negative for clastogenicity in the vitro human lymphocyte chromosome aberration assay. Bempedoic acid was negative in both in vivo mouse micronucleus and in vivo rat bone marrow micronucleus/liver comet assay. In a 2-year rat carcinogenicity study, Wistar rats were given oral doses of bempedoic acid at 3, 10 and 30 mg/kg/day. An increased incidence of liver hepatocellular adenomas and hepatocellular adenomas combined with carcinomas, thyroid gland follicular cell adenoma and follicular cell adenomas combined with carcinomas, and pancreatic islet cell adenomas combined with carcinomas were observed in male rats at the dose of 30 mg/kg/day (exposure equivalent to the maximum recommended human dose (MRHD), based on AUC). In a 2-year mice carcinogenicity study, CD-1 mice were given oral doses of bempedoic acid at 25, 75 and 150 mg/kg/day. Bempedoic acid-related increases in the incidence of liver hepatocellular adenomas, hepatocellular carcinomas and hepatocellular adenomas combined with carcinomas in male mice were observed at 75 and 150 mg/kg/day (exposures equivalent to the MRHD). Observations of liver and thyroid tumors are consistent with PPAR alpha agonism in rodents. The human relevance of pancreatic islet cell tumor findings is unknown.

In fertility and early embryofetal development study in rats, bempedoic acid was given orally to male and female rats at 10, 30 and 60 mg/kg/day. Males were dosed for 28 days prior to mating and females were dosed 14 days prior to mating through gestation day 7. No adverse effects on fertility were observed in females in the absence of maternal toxicity. No effects were observed on male fertility outcomes, but decreases in sperm counts were observed at 60 mg/kg/day (9 times the MRHD).

Ezetimibe

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (approximately 20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (approximately 7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

14. CLINICAL STUDIES

The efficacy of NEXLIZET was investigated in a single, multi-center, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 301 patients with heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease, or multiple risk factors for cardiovascular disease on maximally tolerated statin therapy. The efficacy of NEXLIZET in patients with multiple risk factors for cardiovascular disease has not been established.

Study 1 (NCT03337308) was a 4-arm, 12-week trial that assessed the efficacy of NEXLIZET in 301 patients randomized 2:2:2:1 to receive either NEXLIZET (180 mg of bempedoic acid and 10 mg of ezetimibe) (n = 86), bempedoic acid 180 mg (n = 88), ezetimibe 10 mg (n = 86), or placebo (n = 41) once daily as add-on to maximally tolerated statin therapy. Patients were stratified by cardiovascular risk and baseline statin intensity. Patients on simvastatin 40 mg per day or higher and patients taking non-statin lipid-lowering therapy (including fibrates, niacin, bile acid sequestrants, ezetimibe, and PCSK9 inhibitors) were excluded from the trial.

Overall, the mean age at baseline was 64 years (range: 30 to 87 years), 50% were ≥ 65 years old, 50% were women, 12% Hispanic, 81% White, 17% Black, and 1% Asian. Sixty-two percent (62%) of patients had clinical atherosclerotic cardiovascular disease (ASCVD) and/or a diagnosis of heterozygous familial hypercholesterolemia (HeFH). The mean baseline LDL-C was 149.7 mg/dL. At the time of randomization, 65% of patients were receiving statin therapy; and 35% were receiving high intensity statin therapy.

The primary efficacy outcome measure of the study was the percent change from baseline to Week 12 in LDL-C. The difference between NEXLIZET and placebo in mean percent change in LDL-C from baseline to Week 12 was -38% (95% CI: -47%, -30%; p < 0.001). High-density lipoprotein (HDL) and triglycerides (TG) were examined as exploratory endpoints and were not included in the statistical hierarchy. The difference between NEXLIZET and placebo in mean percent change from baseline to Week 12 was -5% for HDL and median percent change from baseline to Week 12 was -11% for TG. The maximum LDL-C lowering effect was observed at Week 4. For additional results see Table 3.

Table 3. Effects of NEXLIZET on Lipid Parameters in Patients on Maximally Tolerated Statin Therapy (Mean % Change from Baseline to Week 12 in Study 1)*
LDL-C LS Mean non-HDL-C LS Mean apo B LS Mean TC LS Mean
apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol; LS = least squares; SE = standard error; TC = total cholesterol.
Background statin: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.
*
3.5% of subjects on NEXLIZET, 6.8% of subjects on bempedoic acid, 7% of subjects on ezetimibe and 2.4% of subjects on placebo had missing LDL-C data at Week 12. Percent change from baseline was analyzed using analysis of covariance (ANCOVA), with treatment and randomization strata (high intensity statin versus other and ASCVD and/or HeFH versus multiple CV risk factors) as factors and baseline lipid parameter as a covariate. Missing data for LDL-C, non-HDL-C, TC and apo B were imputed through multiple imputation using a pattern mixture model (PMM) account for treatment adherence.
Number of randomized subjects at baseline
NEXLIZET (180 mg/10 mg; n = 86) -36 -32 -25 -26
Bempedoic acid (180 mg; n = 88) -17 -14 -12 -12
Ezetimibe (10 mg; n = 86) -23 -20 -15 -16
Placebo (n = 41) 2 2 6 1
Mean Difference of NEXLIZET versus Placebo (95% CI) -38 (-47, -30) -34 (-44, -23) -30 (-40, -20) -27 (-35, -19)

Examination of age, gender, and race subgroups did not identify differences in response to NEXLIZET among these subgroups in any of the trials.

Bempedoic Acid

In two 52-week trials that included 3009 adult patients with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease on maximally tolerated statin therapy, the difference between bempedoic acid and placebo in mean percent change in LDL-C from baseline to Week 12 was -17% to -18%. Bempedoic acid also significantly lowered non-HDL-C (-13%), apo B (-12% to -13%), and TC (-11%) compared with placebo.

Ezetimibe

Ezetimibe Added to On-going Statin Therapy: In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal, were randomized to receive either ezetimibe or placebo in addition to their on-going statin therapy.

Ezetimibe, added to on-going statin therapy, significantly lowered TC (-17%), LDL-C (-25%), apo B (-19%), non-HDL-C (-23%), and TG (-14%), and increased HDL-C (+3%) relative to baseline and compared with a statin administered alone. LDL-C reductions induced by ezetimibe were generally consistent across all statins.

Ezetimibe Initiated Concurrently with a Statin: In four, multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ezetimibe or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin. When all patients receiving ezetimibe with a statin were compared to all those receiving the corresponding statin alone, ezetimibe significantly lowered LDL-C (ezetimibe + all atorvastatin doses [-56%] versus all atorvastatin doses alone [-44%]; ezetimibe + all simvastatin doses [- 51%] versus all simvastatin doses alone [-36%]; ezetimibe + all pravastatin doses [-39%] versus all pravastatin doses alone [-25%]; ezetimibe + all lovastatin doses [-40%] versus all lovastatin doses alone [-25%]). LDL-C reductions induced by ezetimibe were generally consistent across all statins.

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