Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia

Tamio Teramoto; Arihiro Kiyosue; Takeshi Iimura; Yasushi Takita; Jeffrey S. Riesmeyer; Masahiro Murakami

doi:10.1253/circj.CJ-16-1324

Abstract

Background: Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal.

Methods and Results: This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg daily for 12 weeks resulted in a statistically significant treatment difference of −25.70% compared with placebo in percentage decrease in LDL-C (95% CI: −34.73 to −16.68; P<0.001). Treatment with evacetrapib 130 mg also resulted in a statistically significant difference of 126.39% in the change in high-density lipoprotein cholesterol (HDL-C) compared with placebo (95% CI: 113.54–139.24; P<0.001). No deaths or serious adverse events were reported. Four patients (3 in the evacetrapib group and 1 in the ezetimibe group) discontinued due to adverse events.

Conclusions: Evacetrapib daily in combination with atorvastatin was superior to placebo in lowering LDL-C after 12 weeks, and resulted in a statistically significant increase of HDL-C compared with placebo. Also, no new safety risks were identified.

The use of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) to reduce low-density lipoprotein cholesterol (LDL-C) has resulted in relative reductions in cardiovascular events of 20–30%. As a result, current guidelines for dyslipidemia management and prevention of atherosclerotic cardiovascular diseases recommend reducing LDL-C.¹^–³

Although LDL-C management has provided significant clinical benefits, atherosclerosis remains a major health burden in Japan, where the relative risk of coronary artery disease (CAD) has been confirmed by epidemiological studies to increase in tandem with LDL-C and total cholesterol (TC). The NIPPON DATA 80 study showed that the relative risk of death due to CAD increases 1.4-, 1.7-, 1.8-, and 3.8-fold when TC is 5.18–5.68, 5.69–6.20, 6.21–6.70, and ≥6.71 mmol/L, respectively, compared with TC 4.14–4.65 mmol/L, for men and women combined.⁴ A more recent Japanese epidemiological study reported that the hazard ratio for total CAD increases 1.4-, 1.7-, 2.2-, and 2.8-fold when LDLC is 2.06–2.57, 2.58–3.09, 3.10–3.61, and ≥3.62 mmol/L, respectively, compared with LDL-C <2.06 mmol/L.⁵

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein secreted primarily by the liver that mediates the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to apolipoprotein (apo)B-rich lipoproteins (Lp; i.e., very-low-density lipoprotein [VLDL] and LDL) in exchange for their triglycerides, as well as the transfer of triglycerides/CE between apo-B-rich lipoproteins. Inhibition of CETP represents a potent mechanism for increasing HDL cholesterol (HDL-C) and lowering LDL-C. There is evidence that CETP inhibition prevents transfer of CE from HDL-C to apoB-containing lipoproteins and may increase cholesterol efflux.⁶^–⁸ The majority of animal model data indicate that CETP is proatherogenic, supporting an anti-atherogenic effect of CETP inhibitors.⁸^,⁹

Evacetrapib is a potent and selective CETP inhibitor. The effect of evacetrapib on LDL-C reduction has been evaluated in 2 phase 2 studies. A phase 2 study conducted outside Japan noted a 22.3% decrease in LDL-C in patients treated with evacetrapib 100 mg alone, and a 47.6% decrease when evacetrapib 100 mg was used with 20 mg atorvastatin.¹⁰ Similarly, a phase 2 study in Japanese patients noted a 22% reduction in LDL-C in patients treated with evacetrapib 100 mg alone, and a 52% decrease when evacetrapib 100 mg was used with 10 mg atorvastatin. The safety data on evacetrapib 30, 100, and 500 mg demonstrated that evacetrapib was safe and well tolerated.¹¹

Drugs that are added to statin therapy for the treatment of hypercholesterolemia and prevention of atherosclerotic cardiovascular disease include fibrates, resins (anion exchange resin), ezetimibe, and proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies. Statin use is accompanied by an increase in PCSK9, leading to lysosomal degradation of the LDL receptor. This may explain the observation that doubling the statin dose results in only a 6% additional reduction in LDL-C.¹² Ezetimibe is often used as a first-line drug for statin-intolerant patients. In patients requiring a more vigorous reduction in LDL-C, ezetimibe is frequently used. The reduction of LDL-C with ezetimibe 10 mg in patients with hypercholesterolemia is approximately 18%.¹³^,¹⁴ With regard to the effect of ezetimibe in combination with statins, a post-marketing clinical study in Japan showed that after treatment with ezetimibe 10 mg in patients who were receiving atorvastatin 10 mg, LDL-C decreased by approximately 26%.¹⁵ The IMPROVE-IT study showed that the addition of ezetimibe to simvastatin 40 mg resulted in an additional 6% reduction in the relative risk of major adverse cardiac events.¹⁶ We have chosen to use ezetimibe as a reference drug in this study to better characterize the clinical positioning of evacetrapib as an LDL-C-lowering drug.

Atorvastatin is one of the statins most commonly used around the world, with a wealth of evidence on reducing the risk of cardiovascular events.¹⁷^,¹⁸ A systematic review and meta-analysis showed that LDL-C decreased by 28.9–42.0% with atorvastatin 10 mg once daily (QD).¹⁸ For Japanese patients with hypercholesterolemia, atorvastatin 10 mg QD is a standard dosage regimen.¹⁹ A phase 2 study in Japanese patients showed an additive reduction in LDL-C after use of evacetrapib in combination with atorvastatin (22% for evacetrapib 100 mg, 38% for atorvastatin 10 mg, and 52% for evacetrapib 100 mg in combination with atorvastatin 10 mg).¹¹ In addition, in another phase 2 study a similar additive effect was noted when evacetrapib was used in combination with other statins.¹⁰ Consequently, by using atorvastatin as a concomitant medication, additive effects of the other statin can be predicted based on the present results.

The present phase 3 study was designed to evaluate the safety and efficacy (LDL-C reduction) of evacetrapib 130 mg QD when added to atorvastatin 10 mg, as compared with atorvastatin 10 mg alone, in Japanese patients with hypercholesterolemia. In addition, this study evaluated the safety and efficacy of evacetrapib 130 mg QD relative to ezetimibe 10 mg QD with a background of atorvastatin 10 mg in the same population.

An independent data-monitoring committee recommended that the ACCELERATE study, a global phase 3 study conducted to evaluate the cardiovascular outcomes and safety of evacetrapib in participants with high-risk vascular disease,²⁰ be terminated due to futility. The decision was not based on safety concerns. As a consequence of these results, all ongoing studies of evacetrapib, including this study, were terminated by the sponsor.²¹

Methods

This was a multicenter, randomized, 12-week double-blind, parallel-group, placebo-controlled, phase 3 study (ClinicalTrials.gov: NCT02260648), with 3 consecutive periods (screening period; diet lead-in and washout period; and a 12-week, double-blind treatment period).

The study was performed in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice, all applicable laws, rules, and regulations. The protocol was approved by the ethics review board of each participating study center, and all patients provided written informed consent.

Study treatment included evacetrapib 130 mg QD, ezetimibe 10 mg QD, and placebo added to background therapy of atorvastatin 10 mg. Before screening, patients were asked to fast for at least 8 h before laboratory samples were collected for central measurement and other screening assessments were performed. All eligible patients were asked to begin the diet lead-in and washout period within 2 weeks of the screening visit. Patients taking lipid-modifying medication such as ezetimibe, bile acid sequestrant, eicosapentaenoic acid, and docosahexaenoic acid (except for atorvastatin 10 mg) were instructed to discontinue lipid-modifying medication during the washout period for 4 weeks before their first treatment visit. Patients were also instructed to start a diet therapy in accordance with Japan Atherosclerosis Society (JAS) guidelines³ during the washout period in order to evaluate lipid levels under the diet therapy, and to minimize the effect of diet on lipid values throughout the study period. Diet therapy was to continue throughout the study.

Patients who completed the diet lead-in and washout period and met all enrollment criteria were randomized to a treatment group (evacetrapib 130 mg QD, ezetimibe 10 mg QD, or placebo) in a 1:1:1 ratio. Randomization was performed at each investigative site using an interactive Web response system. Once treatment began during the 12-week double-blind treatment period, patients returned to the investigational sites 4 times for procedures and assessments.

Patients

Japanese men and women ≥20 years of age were eligible for this study if they were diagnosed with primary hypercholesterolemia and were treated with atorvastatin 10 mg QD for ≥30 days before their first treatment visit. At baseline sample collection, patients were required to have fasting triglyceride ≤4.52 mmol/L, HDL-C <2.59 mmol/L, and LDL-C ≥4.14 mmol/L (JAS Category I³); LDL-C ≥3.62 mmol/L (JAS Category II) or LDL-C ≥3.10 mmol/L (JAS Category III), and, as secondary prevention, LDL-C ≥2.56 mmol/L for patients with a history of CAD.

Patients were excluded if they were pregnant or breast-feeding, undergoing LDL apheresis or plasma apheresis, had secondary hypercholesterolemia, homozygous familial hypercholesterolemia, clinically active hepatobiliary disease, or hemoglobin A1c (HbA1c) ≥8.4%, or were exposed to CETP inhibitors. Certain exclusion criteria were established to avoid enrolling high-risk cardiovascular disease patients. These criteria included a history of New York Heart Association class III or IV congestive heart failure or significant cardiovascular or cerebrovascular conditions (such as acute coronary syndrome, symptomatic peripheral arterial disease, invasive treatment of carotid artery disease, ischemic stroke, or transient ischemic attack), or had systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg.

Patients were also excluded if they had suspected cancer or had a history of malignancy (except excised non-melanoma skin cancer/basal cell or squamous cell carcinoma of the skin) within the last 3 years. Based on laboratory tests performed at screening, patients could also be excluded if they had thyroid-stimulating hormone below the lower limit of the normal (LLN) or >1.5×upper limit of normal (ULN), serum creatinine >194.48 µmol/L, aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT), alkaline phosphatase, total bilirubin >2.0×ULN, or an unexplained/documented elevation in creatine kinase (CK) ≥3×ULN.

Additionally, women who were not willing to use a reliable method of contraception during the study and for 12 weeks afterwards were also excluded.

Efficacy Assessments

After the randomization visit, patients returned to the study site at 2, 4, 8, and 12 weeks. At each visit, patients were required to have fasted for at least 8 h before blood samples were collected. Blood samples were collected at the site, and serum lipids (HDL-C, LDL-C, nonHDL-C, Lp(a), apoAI, apoB, non-HDL-C/HDL-C ratio, and apoB/apoAI ratio) were measured at all visits. Laboratory tests were performed at a central laboratory (Covance Central Laboratory Services, Indianapolis, IN, US). Concentration of LDL-C was measured on direct homogeneous enzymatic assay using the LDL-C Plus, 2nd generation, kit (Roche Diagnostics, Indianapolis, IN, US). The assay was performed by Covance (Princeton, NJ, US). Concentration of LDL-C was also measured using the β-quantification method. The ultracentrifugation and the assay were performed by Pacific Biomarkers (Seattle, WA, US). The calculation for LDL-C was cholesterol in >1.006 density fraction minus HDL-C obtained by chemical precipitation.

Safety Assessments

The safety of evacetrapib was evaluated over 12 weeks by means of treatment-emergent adverse events (TEAE), TEAEs related to study drug, TEAEs leading to study discontinuation, serious adverse events (SAE), vital signs, and clinical laboratory tests including serum potassium, chloride, and bilirubin. Standard laboratory tests, including chemistry and hematology panels, were performed. If a patient had ALT or AST >3×ULN or total bilirubin >2×ULN, clinical and laboratory monitoring were to be initiated by the investigator. A pregnancy test, when applicable, was performed by a local laboratory at screening.

Statistical Analysis

All efficacy analyses were performed on the full analysis set (FAS) on an intent-to-treat basis according to their randomized treatment. The FAS included all randomized patients receiving at least 1 dose of study drug with evaluable LDL-C (β quantification) at baseline, and at least 1 post-baseline visit. This study was terminated by sponsor due to futility observed in the ACCELERATE study²¹ and the on-going patients in the present study were forced to discontinue the study treatment by sponsor request. Because of this early termination by the sponsor, lipid data were collected for some patients after stopping the study medications. Lipid data collected at the final visit for patients discontinued by sponsor decision were excluded from the efficacy analyses. As a result, efficacy analyses were conducted on the on-treatment FAS. Safety analyses were conducted on the safety analysis set, defined as all randomized patients who received at least 1 dose of study treatment.

The primary efficacy analysis of the primary variable was done using a restricted maximum likelihood-based mixed-effects model for repeated measures (MMRM), with percent changes in LDL-C from baseline as response variables; baseline measurement as a covariate; treatment, visit, and treatment by-visit interaction as fixed effects; and patient as a random effect.

For continuous measurements such as secondary efficacy measures and change from baseline of vital signs, the MMRM model specified for the primary variable was applied. For measures with only 1 scheduled post-baseline measurement, an analysis of covariance (ANCOVA) model using last observation carried forward (LOCF) was applied to analyze percent changes from baseline.

For categorical variables such as TEAEs, Fisher’s exact test was used for treatment comparison of the proportion of patients. All statistical comparisons were at the 2-sided 0.05 statistical significance level. Given that the ezetimibe 10-mg group was included to assess the relative efficacy and safety in the same patient population as the evacetrapib or the placebo group, and the study was not adequately powered for comparisons with ezetimibe, all hypothesis tests of comparisons between the evacetrapib and ezetimibe 10-mg group were used for exploratory purposes.

Results

This study was conducted at 16 study centers in Japan (Fukuwa Clinic, Tokyo; Shinagawa East One Medical Clinic, Tokyo; Tokyo Center Clinic, Tokyo; Tokyo-Eki Center-building Clinic, Tokyo; Yaesu Sakura-dori Clinic, Tokyo; Yutenji Medical Clinic, Tokyo; Minami Akatsuka Clinic, Ibaraki; Nishiyamado-Keiwa Hospital, Ibaraki; Taga General Hospital, Ibaraki; Musashino Medical Clinic, Saitama; Namegata District General Hospital, Ibaraki; Sayama General Clinic, Saitama; Suruga Clinic, Shizuoka; AMC Nishi-Umeda Clinic, Osaka; Kajiyama Clinic, Kyoto; Okamoto Clinic, Hyogo). Of the 149 patients who were randomized and dispensed the study drug (53 patients in the evacetrapib group; 50 in the ezetimibe group; and 46 in the placebo group), all received at least 1 dose of study drug and were included in the FAS population and the safety analysis set (Figure 1). A total of 110 patients completed the study and 39 patients (18 from the evacetrapib group, 8 from the ezetimibe group; and 13 from the placebo group) were discontinued. Four patients (2.7%; 3 in the evacetrapib group, 1 in the ezetimibe group) were discontinued as a result of AE; 2 patients (1.3%; 1 in the evacetrapib group, 1 in the placebo group) withdrew consent; 1 (0.67%; in the evacetrapib group) was discontinued as a result of a protocol violation; and 32 patients (21.5%) were discontinued as a result of the study termination by the sponsor.

Figure 1.

Patient flow.

All patients were Asian. Overall, the majority of patients were male (55.0%). Mean age was 58.2 years (Table 1). Mean body mass index was 25.9 kg/m². Mean LDL-C (β quantification) was 3.62 mmol/L, triglycerides were 1.68 mmol/L, HDL-C was 1.43 mmol/L, non-HDL-C was 4.42 mmol/L, and LDL-C (direct) was 3.84 mmol/L. There were no statistically significant differences between the treatment groups in characteristics at baseline, except tobacco use. In the ezetimibe group, 32.0% of the patients used tobacco, compared with 52.8% (P=0.033) in the evacetrapib group; and 54.3% (P=0.027) in the placebo group.

Table 1. Baseline Characteristics

Variable	Evacetrapib 130 mg (n=53)	Placebo (n=46)	Ezetimibe 10 mg (n=50)	Total (n=149)
Age (years)	58.5±11.5	57.9±10.8	58.0±10.4	58.2±10.9
Male	32 (60.4)	24 (52.2)	26 (52.0)	82 (55.0)
BMI (kg/m²)	25.65±3.92	25.86±4.07	26.23±3.48	25.91±3.81
LDL-C (β quantification; mmol/L)	3.70±0.77	3.52±0.61	3.62±0.59	3.62±0.67
LDL-C (direct; mmol/L)	3.94±0.78	3.73±0.56	3.83±0.69	3.84±0.69
HDL-C (mmol/L)	1.40±0.29	1.43±0.27	1.47±0.34	1.43±0.30
Triglycerides (mmol/L)	1.81±1.16	1.68±0.84	1.54±0.78	1.68±0.95
Non-HDL-C (mmol/L)	4.56±1.02	4.27±0.72	4.40±0.77	4.42±0.86
Lp(a) (nmol/L)	75.36±88.29	62.34±58.58	55.48±53.98	64.38±68.78
apoAI (g/L)	1.56±0.24	1.54±0.22	1.58±0.23	1.56±0.23
apoB (g/L)	1.14±0.22	1.08±0.18	1.11±0.17	1.11±0.19
Non-HDL-C/HDL-C ratio	3.40±1.04	3.11±0.86	3.15±0.93	3.23±0.95
apoB/apoAI ratio	0.74±0.15	0.72±0.16	0.71±0.15	0.72±0.16

Data given as mean±SD or n (%). apoAI, apolipoprotein AI; apoB, apolipoprotein B; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a).

Evacetrapib 130 mg QD, when added to atorvastatin 10 mg, demonstrated superiority to placebo in mean percent change from baseline to week 12 in LDL-C (β quantification) in patients with primary hypercholesterolemia. The difference in least squares (LS) mean change in the evacetrapib group compared with the placebo group was −25.70% (95% CI: −34.73 to −16.68; P<0.001). Evacetrapib 130 mg QD resulted in a difference in LS mean change from baseline of −1.35 (95% CI: −10.02 to 7.31) compared with ezetimibe (Table 2).

Table 2. Serum Lipids Percent Change From Baseline at Week 12^†

Lab measure	Evacetrapib 130 mg (n=37)	Placebo (n=33)	Ezetimibe 10 mg (n=42)
LDL-C (β quantification, mg/dL)
LS mean percent change	−29.51	−3.81	−28.16
LS mean difference (95% CI)^‡		−25.70 (−34.73 to −16.68)	−1.35 (−10.02 to 7.31)
P-value^‡		<0.001	0.758
HDL-C (mg/dL)
LS mean percent change	124.28	−2.11	−3.34
LS mean difference (95% CI)^‡		126.39 (113.54 to 139.24)	127.62 (115.17 to 140.07)
P-value^‡		<0.001	<0.001
LDL-C (direct, mg/dL)
LS mean percent change	−31.17	−4.47	−30.10
LS mean difference (95% CI)^‡		−26.70 (−34.52 to −18.88)	−1.07 (−8.58 to 6.44)
P-value^‡		<0.001	0.778
Non-HDL-C (mg/dL)
LS mean percent change	−25.99	−7.68	−28.79
LS mean difference (95% CI)^‡		−18.31 (−25.32 to −11.31)	2.80 (−3.92 to 9.52)
P-value^‡		<0.001	0.412
Lp(a) (nmol/L)
LS mean percent change	−37.36	9.20	3.19
LS mean difference (95% CI)^‡		−46.57 (−60.28 to −32.86)	−40.56 (−53.40 to −27.71)
P-value^‡		<0.001	<0.001
ApoAI (mg/dL)
LS mean percent change	46.6	−0.1	−1.2
LS mean difference (95% CI)^‡		46.7 (39.1 to 54.4)	47.8 (40.6 to 55.0)
P-value^‡		<0.001	<0.001
ApoB (mg/dL)
LS mean percent change	−26.1	−4.3	−23.6
LS mean difference (95% CI)^‡		−21.8 (−29.3 to −14.3)	−2.5 (−9.6 to 4.5)
P-value^‡		<0.001	0.480
Non-HDL-C/HDL-C ratio
LS mean percent change	−63.21	−5.54	−24.27
LS mean difference (95% CI)^‡		−57.68 (−65.69 to −49.67)	−38.95 (−46.68 to −31.21)
P-value^‡		<0.001	<0.001
ApoB/apoAI ratio
LS mean percent change	−46.82	−2.92	−21.39
LS mean difference (95% CI)^‡		−43.91 (−52.96 to −34.85)	−25.43 (−34.02 to −16.84)
P-value^‡		<0.001	<0.001

^†Full analysis set minus on-treatment analysis. ^‡vs. evacetrapib. The mixed-effects model for repeated measures was used for the least squares (LS) mean estimates at week 12 for LDL C, HDL-C, and non-HDL-C. The analysis of covariance model was used for the LS mean estimates at week 12 for apoAI, apoB, and Lp(a). On-treatment analysis excludes data collected at the final visit for any ongoing patients who stopped study medications because of early termination of the study by the sponsor. Abbreviations as in Table 1.

Evacetrapib 130 mg QD demonstrated superiority to placebo in mean percent change from baseline to week 12 in HDL-C in patients. The difference in LS mean change from baseline in the evacetrapib group was 126.39% (95% CI: 113.54–139.24; P<0.001) compared with the placebo group. Evacetrapib 130 mg QD resulted in a difference in LS mean change from baseline of 127.62% (95% CI: 115.17–140.07) compared with ezetimibe 10 mg.

Treatment with evacetrapib 130 mg QD also resulted in a statistically significant difference (P<0.001, all time points) compared with placebo in LS mean percent changes in LDL-C (β quantification) from baseline at week 2 (−33.34%; 95% CI: −40.98 to −25.71), week 4 (−32.75%; 95% CI: −41.50 to −23.99), week 8 (−25.67%; 95% CI: −34.33 to −17.00), and week 12 (−25.70%; 95% CI: −34.73 to −16.68). Evacetrapib 130 mg QD resulted in a significant difference (P<0.001) in LS mean change compared with ezetimibe 10 mg of −13.31% (95% CI: −20.76 to −5.85) at week 2 and a non-significant difference of −6.73% (95% CI: −15.27 to 1.80) at week 4 and −1.21% (95% CI: −9.67 to 7.25) at week 8 (Figure 2).

Figure 2.

Percentage changes from baseline for (A) low-density lipoprotein cholesterol (LDL-C; β quantification) and (B) high-density lipoprotein cholesterol (HDL-C) using mixed-model repeated measures, double-blind treatment period, full analysis set minus on-treatment analysis, excluding data at the discontinuation visit of the discontinued patients due to study termination. Atorvostatin 10 mg was background therapy for all patients. LS mean, least-squares mean.

Treatment with evacetrapib 130 mg QD resulted in a statistically significant difference (P<0.001, all time points) compared with placebo in LS mean percent changes in HDL-C from baseline at week 2 (115.52%; 95% CI: 106.07–124.97), week 4 (125.43%; 95% CI: 114.51–136.34), and week 8 (132.78%; 95% CI: 120.40–145.17).

Evacetrapib 130 mg QD resulted in statistically significant differences in LS mean percent change compared with ezetimibe 10 mg of 115.98% (95% CI: 106.69–125.26) at week 2; 122.67% (95% CI: 111.96–133.38) at week 4; and 129.62% (95% CI: 117.46–141.77) at week 8 (P<0.001, all time points).

Treatment with evacetrapib 130 mg resulted in statistically significant differences compared with placebo in mean percent changes in LDL-C (direct), HDL-C, non-HDL-C, non-HDL-C/HDL-C ratio, Lp(a), apoAI, apoB, and apoB/apoAI ratio from baseline to week 12, as well as compared with ezetimibe 10 mg in mean percent changes in HDL-C, Lp(a), apoAI, non-HDL-C/LDL-C ratio, and apoB/apoAI ratio (Table 2; P<0.001).

No deaths or SAEs were reported during the double-blind treatment period. Forty-three patients (n=18, 34.0% in the evacetrapib group; n=12, 24.0% in the ezetimibe group; and n=13, 28.3% in the placebo group) had TEAEs, of whom 9 patients (evacetrapib group, n=5, 9.4%; ezetimibe group, n=3, 6.0%; placebo group, n=1, 2.2%) had TEAEs that were deemed related to study drug (Table 3). There were no significant treatment differences in the incidence of any TEAE. In the evacetrapib group, nasopharyngitis (n=3, 5.7%) and rash (n=2, 3.8%) were the only TEAEs occurring in >3% of patients.

Table 3. Safety Data

	Evacetrapib 130 mg (total n=53)	Placebo (total n=46)	Ezetimibe 10 mg (total n=50)
TEAE
n (%)	18 (34.0)	13 (28.3)	12 (24.0)
P-value^†		0.665	0.287
Drug-related TEAE
n (%)	5 (9.4)	1 (2.2)	3 (6.0)
P-value^†		0.211	0.716
TEAE leading to discontinuation
n (%)	3 (5.7)	0 (0.0)	1 (2.0)
P-value^†		0.246	0.618
Serious AE
n (%)	0 (0.0)	0 (0.0)	0 (0.0)
P-value^†		NA	NA
Common TEAE (≥3% in any treatment group)
Nasopharyngitis	3 (5.7)	2 (4.3)	2 (4.0)
Rash	2 (3.8)	0 (0.0)	0 (0.0)
Pruritus	0 (0.0)	2 (4.3)	0 (0.0)
ALT >3×ULN
n (%)	0 (0.0)	0 (0.0)	0 (0.0)
P-value^†		NA	NA
AST >3×ULN
n (%)	0 (0.0)	0 (0.0)	0 (0.0)
P-value^†		NA	NA
Creatine kinase >5×ULN
n (%)	0 (0.0)	0 (0.0)	1 (2.0)
P-value^†		NA	0.485
Elevation in SBP ≥15 mmHg
n (%)	9 (17.0)	10 (21.7)	7 (14.0)
P-value^†		0.614	0.788
Elevation in DBP ≥10 mmHg
n (%)	13 (24.5)	11 (23.9)	8 (16.0)
P-value^†		>0.999	0.333

^†vs. evacetrapib. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; AE, adverse event; NA, not applicable; SBP, systolic blood pressure; TEAE, treatment-emergent adverse event; ULN, upper limit of normal.

Four patients (evacetrapib group, n=3, 5.7%; ezetimibe group, n=1, 2.0%) were discontinued due to an AE. In the evacetrapib group, TEAE of drug eruption, ulcerative colitis, and vertigo (1 patient each) resulted in discontinuation of study drug. All these events were mild in severity.

Treatment with evacetrapib for 12 weeks, when added to atorvastatin 10 mg, did not result in any adverse effects on blood pressure. No statistically significant differences in SBP or DBP were observed between evacetrapib and placebo at weeks 2, 4, 8, or 12. With regard to pulse rate, there were no statistically significant differences, except at week 8, when the LS mean change in pulse rate was −3.35 beats/min in the placebo group, compared with −0.57 beats/min in the evacetrapib group (P=0.036).

No clinically significant differences were observed at week 12 between the evacetrapib and placebo groups in mean change from baseline in serum sodium, serum potassium, chloride, or serum bicarbonate. For HbA1c, mean change from baseline to week 12 was 0.14% (SD, 0.747) in the evacetrapib group, 0.2% (SD, 0.477) in the ezetimibe group, and 0.05% (SD, 0.256) in the placebo group.

There was no evidence of any adverse effect of evacetrapib on hepatic safety through 12 weeks: no patients reported any hepatic-related TEAEs, and no patients had ALT or AST >3×ULN and total bilirubin >2×ULN.

Evacetrapib had few adverse effects on muscles through 12 weeks: a muscle-related TEAE (blood CK increased) was reported in 1 patient in the evacetrapib group and in 1 patient in the ezetimibe group. No patients had CK >5×ULN.

Discussion

The goal of this study was to evaluate the efficacy and safety of evacetrapib 130 mg when added to atorvastatin 10 mg vs. placebo in a population of Japanese adults with primary hypercholesterolemia. A total of 149 patients were randomized and dispensed the study drug (53 patients in the evacetrapib group; 50 patients in the ezetimibe group; and 46 patients in the placebo group) in combination with atorvastatin, of whom 110 patients completed the study and 39 (18 receiving evacetrapib, 8 receiving ezetimibe, and 13 receiving placebo) were discontinued. The majority (32 of 39) of these discontinuations were due to early termination of the study by the sponsor as a result of insufficient efficacy in the global phase 3 ACCELERATE study, which was conducted in 36 countries.²⁰ Because of the early termination, lipid data from the ongoing patients were collected for some patients after stopping study medications. On-treatment analyses were performed for the primary and secondary efficacy objectives on the FAS in the study. At the same time, the fact that 32 patients (21.5%) were discontinued due to study termination is a limitation of this study.

For the primary objective, to demonstrate the superiority of evacetrapib 130 mg, when added to atorvastatin 10 mg, vs. placebo on the mean percent change from baseline to week 12 in LDL-C (β quantification), the evacetrapib group showed a statistically significant treatment difference of 25.70% improvement in LDL-C compared with placebo (P<0.001). Statistically significant differences compared with placebo were also seen at all time points (P<0.001). Initial decrease in LDL-C in the evacetrapib 130 mg group, however, may be a result of lifestyle modification related to participation in the study, given that similar trends were seen in the placebo group.

For the secondary objectives, treatment with evacetrapib 130 mg, when added to atorvastatin 10 mg, resulted in a statistically significant treatment difference of 126.39% improvement in HDL-C compared with placebo (P<0.001). Statistically significant treatment differences were seen at all time points compared with placebo for LDL-C (direct), non-HDL-C, non-HDL-C/HDL-C ratio, Lp(a), apoAI, apoB, and apoB/apoAI ratio (P<0.001). When compared with ezetimibe 10 mg, statistically significant differences were seen in the evacetrapib group for HDL-C, Lp(a), apoAI, non-HDL-C/LDL-C ratio, and apoB/apoAI ratio (P<0.001; Table 2).

The LDL-C reduction observed in this study is largely consistent with the results of other evacetrapib studies,¹⁰^,¹¹ including the phase 3 ACCENTUATE study of 366 patients, in which atorvastatin 40 mg QD plus evacetrapib 130 mg QD resulted in greater reductions in LDL-C, compared with ezetimibe (−27%, P=0.045).²² Similarly, in a phase 2 study with 165 Japanese patients, evacetrapib 30 mg QD monotherapy resulted in a statistically significant treatment difference compared with placebo of −15% (90% CI: −24 to 7.4; P=0.002). These results were similar to those for atorvastatin 10 mg QD plus evacetrapib 100 mg QD, which resulted in a statistically significant treatment difference of −15% (90% CI: −23 to −6.6) in LDL-C compared with placebo (P=0.003).¹¹

In a separate phase 2, multicenter, randomized, double-blind, parallel, placebo-controlled study of 398 patients with elevated LDL-C or low HDL-C, evacetrapib monotherapy (100 mg, QD, for 12 weeks) significantly increased pre-β HDL compared with placebo (P<0.001).²³ Increases compared with placebo were seen in the 30- and 500-mg doses as well. In the same study, evacetrapib significantly reduced the concentration of apoB-containing lipoproteins, including Lp(a), total LDL particle, and small LDL particle. Treatment with evacetrapib resulted in a significant increase in LDL particle size but had no consistent effect on intermediate LDL or large LDL particle concentration.²⁴

It should be noted, however, that different methods for measuring LDL particle size have produced varied results for LDL particle subfractions. Yamashita et al, using polyacrylamide gel electrophoresis, reported that LDL particles are large in heterozygotes and polydispersed in homozygotes with CETP deficiency;²⁵ Nicholls et al, using nuclear magnetic resonance spectroscopy, reported reductions of total LDL particle (LDL-P) and small LDL particle (sLDL) concentration with evacetrapib treatment,²⁴ whereas Krauss et al, using ion mobility for measurement, reported reductions of total LDL-P and sLDL 3a particle as well as increases in very small LDL 4b particle concentration with anacetrapib treatment.²⁶

Use of evacetrapib in patients with hypocholesteremia in another phase 2 study resulted in significant placebo-adjusted, dose-dependent decreases of sLDL concentration up to 95%.²⁴

Similarly, improvements in serum Lp(a) compared with placebo that we report are consistent with a separate phase 2 study of 393 patients with hypercholesterolemia in which evacetrapib as monotherapy or with statins, significantly reduced Lp(a) concentration.²⁴ Gaining an understanding of the causes of these changes, however, will require further study.

The safety results from this study showed that 12-week therapy with daily evacetrapib 130 mg, when added to atorvastatin 10 mg, was safe and well-tolerated in Japanese patients with primary hypercholesterolemia. No deaths or SAEs were reported, and there were no significant treatment differences in the incidence of any TEAE. Nine patients (5 in the evacetrapib group, 3 in the ezetimibe group, and 1 in the placebo group) had TEAEs that were considered related to study drug (Table 3).

In contrast to the phase 2 study of evacetrapib in Japanese patients, in which SBP significantly increased in the evacetrapib 500-mg treatment group compared with placebo (5.9 [90% CI: −1.7 to 2.2]; P=0.021),¹¹ treatment with evacetrapib for 12 weeks, when added to atorvastatin 10 mg, did not result in any adverse effects on blood pressure (Table 4). We interpret the SBP changes seen in the previous phase 2 study as an incidental occurrence for the reasons described by Teramoto et al.¹¹ In the phase 2 study, there was no dose-dependent effect on SBP in the evacetrapib monotherapy group or in combination with atorvastatin. Additionally, a significant but small increase in mean SBP with evacetrapib treatment was detected in the 12,000-patient ACCELERATE study.²⁰ Considering this small increase and the inherent variability in blood pressure measurements, it is not surprising that no increase in SBP was noted in the present small study. Additionally, a similar SBP increase was reported in the atorvastatin monotherapy group in the present study. No clinically significant changes in serum sodium, serum potassium, chloride, or serum bicarbonate were reported, and there was no evidence of any adverse effect of evacetrapib on hepatic safety.

Table 4. BP and Mineralocorticoid Activity: Change From Baseline to Week 12

Lab measure	Evacetrapib 130 mg (n=42)	Placebo (n=40)	Ezetimibe 10 mg (n=43)
SBP (mmHg)
LS mean change±SE	0.72±1.480	2.33±1.536	−1.54±1.473
P-value^†		0.452	0.282
DBP (mmHg)
LS mean change±SE	1.15±1.088	0.63±1.129	−1.39±1.086
P-value^†		0.738	0.100
Sodium (mEq/L)
LS mean change±SE	−0.2±0.23	−0.0±0.24	0.7±0.23
P-value^†		0.620	0.008
Potassium (mEq/L)
LS mean change±SE	−0.09±0.041	−0.00±0.042	−0.07±0.040
P-value^†		0.134	0.711
Bicarbonate (mEq/L)
LS mean change±SE	−0.77±0.262	−0.39±0.270	−0.33±0.261
P-value^†		0.309	0.229

^†vs. evacetrapib. BP, blood pressure. Other abbreviations as in Tables 2,3.

As for safety issues of particular interest in a Japanese patient population or findings in previous studies, 1 patient in the evacetrapib group had a muscle-related TEAE (increased blood phosphokinase) of mild intensity that was considered not related to the study treatment, but no evacetrapib patients had CK >5×ULN. No clinically significant changes in CK compared with placebo were reported at any time point.

Conclusions

Evacetrapib 130 mg QD, when added to atorvastatin 10 mg, was superior to placebo in lowering LDL-C and increasing HDL-C after 12 weeks in patients with primary hypercholesterolemia. Evacetrapib 130 mg QD was generally well tolerated, and no new safety risks were identified.

Acknowledgment

The authors wish to acknowledge Kent Steinriede, MS, of inVentiv Health Clinical for assistance with the manuscript.

Disclosures

T.I. and Y.T. are employees of Eli Lilly Japan and own stock in the company. J.S.R. and M.M. are employees of Eli Lilly and Company and own stock in the company. T.T. has receive remuneration from Bayer Yakuhin, Pfizer Japan, Daiichi Sankyo, Takeda Pharmaceutical Company, Astellas Pharma, Kowa Pharmaceutical Company, Kissei Pharmaceutical., Sanofi, MSD, and AABP. A.K. has received remuneration from Astra Zeneca. T.T.’s institution has received scholarship funds or donations from Daiichi Sankyo, Kowa Pharmaceutical Company, Eli Lilly Japan, Takeda Pharmaceutical Company, and Shionogi. T.T.’s institution has received funding for department endowments from Bayer Yakuhin, Astellas Pharma, ASKA Pharmaceutical, Kissei Pharmaceutical, Kowa Pharmaceutical Company, Mochida Pharmaceutical and MSD.

Funding

This was a clinical study sponsored by Eli Lilly Japan.

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