Efficacy and Safety of Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib Administered as Monotherapy in Japanese Patients With Primary Hypercholesterolemia

Abstract

Background: Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.

Methods and Results: This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia. Primary efficacy measure was the percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg once daily for 12 weeks resulted in statistically significant (P<0.001) change in LDL-C (β quantification) compared with placebo. Least-squares mean percentage changes from baseline were −34.3% in the evacetrapib group vs. 0.0% in the placebo group. Treatment with evacetrapib 130 mg also resulted in a statistically significant (P<0.001) increase in high-density lipoprotein cholesterol compared with placebo in mean percent change from baseline, with a least-squares mean difference of 124.0% (95% confidence interval: 104.6–143.5). No deaths, serious adverse events, or discontinuations because of adverse events were reported; 5 patients (18.5%) in the evacetrapib group and 7 patients (26.9%) in the placebo group experienced treatment-emergent adverse events.

Conclusions: Once-daily evacetrapib 130 mg monotherapy was superior to placebo in lowering LDL-C after 12 weeks. No new safety risks were identified.

The ability of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors (statins) to reduce levels of low-density lipoprotein cholesterol (LDL-C) has resulted in reports of 20–30% reductions in cardiovascular events.^1–3 Current guidelines for lipid-modulating therapy for both primary and secondary prevention of atherosclerosis have defined LDL-C goal levels for lipid management on the basis of these findings.

In Japan, the relative risk of coronary artery disease (CAD) has been shown in epidemiological studies to increase incrementally with increasing levels of LDL-C and total cholesterol. Results from the NIPPON DATA 80 study demonstrated that the relative risk of death from CAD increases 1.4-, 1.7-, 1.8-, and 3.8-times when the total cholesterol levels were 5.17–5.66, 5.69–6.18, 6.21–6.70, and 6.72 mmol/L (200–219, 220–239, 240–259, and 260 mg/dL) or higher, respectively, compared with the group with total cholesterol levels between 4.14 and 4.63 mmol/L (160–179 mg/dL).⁴ A more recent epidemiological study in Japan showed that the hazard ratio of total CAD increases 1.4-, 1.7-, 2.2-, and 2.8-times when LDL-C levels were 2.07–2.56, 2.59–3.08, 3.10–3.59, and 3.62 mmol/L (80–99, 100–119, 120–139, and 140 mg/dL) or higher, respectively, compared with an LDL-C level <2.07 mmol/L (80 mg/dL).⁵ Consequently, the Japan Atherosclerosis Society (JAS) defines high LDL-C as >3.62 mmol/L (140 mg/dL).²

Although LDL-C management has provided significant clinical benefits, atherosclerosis remains a major health burden. Statins are effective in lowering LDL-C and reducing the risk of CAD, yet many patients on statins do not reach their LDL-C goal⁶ and other patients cannot tolerate statin therapy. As a result, there is an unmet need for additional LDL-C lowering therapies.

Inhibition of cholesteryl ester transfer protein (CETP) represents a mechanism for increasing high-density lipoprotein cholesterol (HDL-C) levels and lowering LDL-C levels. CETP is a plasma glycoprotein secreted primarily from the liver that mediates the transfer of cholesteryl ester from HDL to apolipoprotein B (apoB)-containing lipoproteins (very low-density lipoprotein, intermediate-density lipoproteins, and low-density lipoprotein) in exchange for triglycerides. CETP also mediates the transfer of triglycerides/cholesteryl ester between apoB-containing lipoproteins. Evidence shows that CETP may be involved in reverse cholesterol transport.⁷ Inhibition of CETP may also prevent transfer of cholesteryl esters from HDL to apoB-containing lipoproteins. Animal model data indicate that CETP is proatherogenic, supporting an antiatherogenic effect of CETP inhibitors.^7,8

Clinical trial results demonstrate that potent CETP inhibition results in increased HDL-C and decreased LDL-C. Studies using intravascular ultrasound show that, in patients with or at high risk for CAD, high levels of HDL-C achieved via CETP inhibition are associated with a reduction in percent atheroma volume,⁹ as well as a trend toward reduction in major adverse cardiovascular events (MACE).¹⁰

The pharmacodynamic effect of CETP inhibition has been tested in clinical trials of several CETP inhibitors, including torcetrapib, anacetrapib (MK-0859), and dalcetrapib (JTT705). These trials clearly demonstrated that CETP inhibition results in increased HDL-C and, with more potent agents, decreased LDL-C.^8–10

Based on previous studies, the CETP inhibitor evacetrapib was expected to be a potential lipid-lowering monotherapy for patients with elevated LDL-C who were not prescribed or could not tolerate statin therapy. Thus, evacetrapib would address an unmet medical need for lipid-lowering therapy as an add-on or alternative to existing standard-of-care statin treatment. This phase 3 study was designed to evaluate the efficacy and safety of evacetrapib when administered alone in Japanese patients with primary hypercholesterolemia. The study was terminated during its open-label extension period because of a finding of futility in the efficacy of evacetrapib in the ACCELERATE study¹¹ evaluating MACE. However, this had no effect on the evaluation of the primary endpoint for this study because all patients had completed the double-blind phase at the time of termination. The results from the primary 12-week, double-blind treatment period are presented in this report.

Methods

This was a multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study (ClinicalTrials.gov: NCT02260635).

The protocol was approved by the ethics review board of each participating study center, and all patients provided written informed consent. Study treatment was evacetrapib monotherapy (130 mg) or placebo once daily (QD). Three consecutive study periods were planned: a 2-week screening period; a 2–4-week diet lead-in and washout period; and a 12-week, double-blind treatment period. Patients were asked to fast for at least 8 h before the screening visit, when laboratory samples were collected for central measurement and all other screening assessments were performed. Eligible patients were instructed to start the diet lead-in and washout period within 2 weeks of the screening visit. Patients who were not taking lipid-modifying medication at the screening visit (e.g., statins, ezetimibe, bile acid sequestrant, eicosapentaenoic acid, or docosahexaenoic acid) remained in the diet lead-in and washout period for a minimum of 2 weeks, whereas those who were taking lipid-modifying medication remained in the diet lead-in and washout period for a minimum of 4 weeks. During this period, patients began a diet in accordance with the JAS guidelines² to evaluate lipid levels and to minimize the effect of diet on lipid values throughout the study.

Patients who completed the diet lead-in and washout period and who met all enrollment criteria were randomized in a 1:1 ratio to double-blind treatment of evacetrapib 130 mg or placebo. Randomization was performed at each investigative site using an interactive web response system. Treatment with evacetrapib 130 mg or placebo QD began during the 12-week double-blind treatment period; patients returned to the investigational sites 4 times for procedures and assessments. All patients discontinued treatment during the open-label extension period when the study was terminated by the sponsor. The project was terminated after all patients’ primary endpoint data were collected; therefore, there was no significant effect on the study results and this report focuses on the double-blind treatment period.

Patients

Japanese men and women ≥20 years of age were eligible for this study if they were diagnosed with primary hypercholesterolemia and, at baseline sample collection, had fasting triglyceride levels ≤4.52 mmol/L (400 mg/dL), HDL-C levels <1.13 mmol/L (100 mg/dL), and LDL-C levels ≥4.14 mmol/L (160 mg/dL) and ≤5.17 mmol/L (200 mg/dL) (JAS Category I²); LDL-C ≥3.62 mmol/L (140 mg/dL) and ≤4.53 mmol/L (175 mg/dL) (JAS Category II) or LDL-C ≥3.10 mmol/L (120 mg/dL) and ≤3.88 mmol/L (150 mg/dL) (JAS Category III). Patients were excluded from the study if they were undergoing LDL apheresis or plasma apheresis, had secondary hypercholesterolemia, familial hypercholesterolemia, clinically active hepatobiliary disease, or hemoglobin A1c (HbA1c) ≥8.4%, were taking CETP inhibitors, had a history of New York Heart Association Class III or IV congestive heart failure or significant cardiovascular or cerebrovascular conditions, or had systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg.

Patients were also excluded if they were suspected of having cancer or had a treatment history of malignancy (except excised non-melanoma skin cancer/basal cell or squamous cell carcinoma of the skin) within the 3 years prior to screening. Based on laboratory tests performed at screening, patients were also excluded if they had thyroid-stimulating hormone below the lower limit of the normal or >1.5-fold of the upper limit of normal (ULN), serum creatinine >194.48 µmol/L (2.2 mg/dL), 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 known to be pregnant or breastfeeding, or who were not willing to use a reliable method of contraception during the study and for 12 weeks afterwards, were also excluded from enrolling in the study.

Efficacy Assessments

During the double-blind period, patients returned to the study site 2, 4, 8, and 12 weeks after the randomization visit. At each visit, patients were required to fast for at least 8 h before blood samples were collected. Blood samples were collected at the site and serum lipids, lipoproteins, and apolipoproteins (HDL-C, LDL-C, non-HDL-C, lipoprotein [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, USA).

Safety Assessments

The safety of evacetrapib was evaluated over 12 weeks by means of adverse events (AEs), vital signs, and clinical laboratory tests including aldosterone, plasma renin activity, and serum potassium. Standard laboratory tests, including chemistry and hematology panels, were performed. If a patient experienced ALT or AST >3×ULN or total bilirubin >2×ULN, clinical and laboratory monitoring were initiated by the investigator. A pregnancy test, when applicable, was performed by a local laboratory at screening.

Statistical Analysis

The sample size was selected to detect the percent change in LDL-C from baseline to week 12. Assuming that the standard deviation (SD) of the percent change from baseline for LDL-C was 20%, 23 patients per group would provide 90% power to detect a 20% decrease from baseline in LDL-C in patients treated with evacetrapib as compared with placebo using a 2-sample t-test with a 2-sided 0.05 significance level. Considering a 10% dropout rate, approximately 52 patients needed to be randomized to each treatment group in a 1:1 ratio.

All efficacy analyses were performed on the full analysis set (FAS) on an intent-to-treat basis analyzed according to their randomized treatment. The FAS included all randomized patients who received at least 1 dose of study drug with evaluable LDL-C values measured by β quantification at baseline, and at least 1 post baseline visit. Safety analyses were conducted using the safety analysis set, which included all randomized patients who received at least 1 dose of study treatment.

The primary outcome variable for the double-blind treatment period was the percent change in LDL-C measured by β quantification from baseline to week 12. The primary efficacy analysis was a restricted maximum likelihood-based mixed model for repeated measures (MMRM), with the 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 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 the last observation carried forward was applied. The model included baseline measurement as a covariate and treatment as a fixed effect. For categorical variables such as incidence of treatment-emergent adverse events (TEAEs), Fisher’s exact test was used for treatment comparison. For categorical variables such as incidence of TEAEs, Fisher’s exact test was used.

Results

This study was conducted at 3 sites in Japan (Tokyo-Eki Center-building Clinic, Tokyo; Tokyo Center Clinic, Tokyo; and the Nishi-Umeda Clinic for Asian Medical Collaboration, Osaka) between November 2014 and July 2015. A total of 85 patients were screened and 54 patients were randomized, of which 27 were treated with evacetrapib and 26 received placebo (Figure 1). A total of 51 patients (26 evacetrapib, 25 placebo) completed the double-blind treatment period; 3 randomized patients (evacetrapib, 1; placebo, 2) were disqualified during the double-blind treatment period because they had been inadvertently enrolled despite failing to meet the enrollment criteria. Baseline characteristics of patients were generally similar for each treatment group (Table 1). All patients were Asian, and 68.5% were male. The mean age was 52.8 years. At baseline, mean LDL-C (β quantification), HDL-C, and triglycerides were 3.9 mmol/L (150.5 mg/dL), 1.4 mmol (55.9 mg/dL), and 1.5 mmol/L (128.3 mg/dL), respectively (Figure 2).

Figure 1.

Patient disposition through the 12-week double-blind treatment period of phase 3 study evaluating the efficacy and safety of evacetrapib in Japanese patients with hypercholesterolemia.

Table 1. Baseline Characteristics (Randomized) of Japanese Hypercholesterolemia Patients

Variable	Evacetrapib 130 mg (N=27)	Placebo (N=27)
Age (years), mean±SD	52.2±10.2	53.3±10.1
Male (n, %)	20 (74.1)	17 (63.0)
Female (n, %)	7 (25.9)	10 (37.0)
Height (cm), mean±SD	165.7±7.8	162.9±8.2
Weight (kg), mean±SD	72.4±14.6	68.5±13.8
Body mass index (kg/m2), mean±SD	26.2±4.0	25.7±4.0
LDL-C (β quantification, mmol/L [mg/dL]), mean±SD	3.9±0.7 (148.8±25.3)	3.9±0.8 (152.2±29.2)
LDL-C (direct, mmol/L [mg/dL]), mean±SD	4.1±0.6 (158.1±21.5)	4.2±0.6 (162.3±23.3)
HDL-C (mmol/L [mg/dL]), mean±SD	1.4±0.3 (53.0±10.3)	1.5±0.3 (58.8±11.9)
Triglycerides (mmol/L [mg/dL]), mean±SD	1.5±0.7 (131.6±61.9)	1.4±0.8 (125.0±68.2)
Non-HDL-C (mmol/L [mg/dL]), mean±SD	4.7±0.6 (180.0±25.0)	4.8±0.7 (185.9±28.6)
Lp(a) (μmol/L [mg/dL]), mean±SD	38.7±57.0 (1,084.0±1,596.6)	55.2±62.5 (1,546.2±1,750.7)
apoAI (g/L [mg/dL]), mean±SD	1.5±0.2 (149.9±20.2)	1.6±0.2 (161.0±19.4)
apoB (g/L [mg/dL]), mean±SD	1.2±0.2 (115.0±16.0)	1.2±0.2 (116.0±19.8)
Non-HDL-C/HDL-C ratio mean±SD	3.6±1.0	3.3±0.9
apoB/apoAI ratio mean±SD	0.8±0.2	0.7±0.2

apoAI, apolipoprotein AI; apoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); N, number of patients in the randomized population within treatment group; n, number of patients; SD, standard deviation.

Figure 2.

Percent change from baseline for LDL-C and HDL-C (β quantification) using mixed model repeated measures, double-blind treatment period, and full analysis set. LDL-C, low-density lipoprotein cholesterol; LS, least-squares; HDL-C, high-density lipoprotein cholesterol; SD, standard error.

Treatment with evacetrapib 130 mg for 12 weeks for primary hypercholesterolemia resulted in a statistically significant decrease (P<0.001) in the percent change from baseline to week 12 in LDL-C (β quantification) compared with placebo (Table 2). The least-squares (LS) mean changes from baseline were −34.3% in the evacetrapib group and 0.0% in the placebo group. The LS mean difference (evacetrapib vs. placebo) at week 12 was −34.3% (95% confidence interval [CI]: −45.5 to −23.0). Treatment with evacetrapib 130 mg also resulted in a statistically significant (P<0.001) increase in HDL-C compared with placebo in mean percent change from baseline to week 12, with an LS mean difference (evacetrapib vs. placebo) at week 12 of 124.0% (95% CI: 104.6 to 143.5).

Table 2. Analysis of Percent Change From Baseline of Serum Lipids at Week 12 (Full Analysis Set) in Phase 3 Study of Japanese Hypercholesterolemia Patients

Laboratory measure	Evacetrapib 130 mg (N=27)	Placebo (N=26)
LDL-C (β quantification, mg/dL)
LS mean percent change	−34.3 (3.9)	0.00 (4.0)
LS mean difference (95% CI)*		−34.3 (−45.5, −23.0)
P value*		<0.001a
HDL-C (mg/dL)
LS mean percent change	123.6 (6.7)	−0.5 (6.8)
LS mean difference (95% CI)*		124.0 (104.6, 143.5)
P value*		<0.001a
LDL-C (direct, mg/dL)
LS mean percent change	−33.9 (3.2)	0.2 (3.2)
LS mean difference (95% CI)*		−34.1 (−43.2, −25.0)
P value*		<0.001a
Non-HDL-C (mg/dL)
LS mean percent change	−26.48 (3.2)	−0.03 (3.2)
LS mean difference (95% CI)*		−26.5 (−35.6, −17.3)
P value*		<0.001a
Lp(a) (nmol/L)
LS mean percent change	−35.71 (6.6)	3.54 (5.5)
LS mean difference (95% CI)*		−39.25 (−56.7, −21.9)
P value*		<0.001b
apoAI (mg/dL)
LS mean percent change	49.1 (3.4)	−2.5 (3.5)
LS mean difference (95% CI)*		51.7 (41.6, 61.7)
P value*		<0.001b
apoB (mg/dL)
LS mean percent change	−29.0 (2.7)	−1.3 (2.7)
LS mean difference (95% CI)*		−27.7 (−35.3, −20.1)
P value*		<0.001b
Non-HDL-C/HDL-C ratio
LS mean percent change	−64.4 (3.4)	3.37 (3.4)
LS mean difference (95% CI)*		−67.8 (−77.5, −58.0)
P value*		<0.001a
apoB/apoAI ratio
LS mean percent change	−49.4 (3.5)	2.52 (3.5)
LS mean difference (95% CI)*		−51.9 (−61.9, −41.9)
P value*		<0.001b

n=number of subjects in the population with non-missing baseline and at least 1 post baseline value. In Lp(a), the number of patients analyzed was less because of missing values (evacetrapib: 17; placebo: 24). *Versus evacetrapib. ^aFrom MMRM model, percent change from baseline=baseline+treatment+visit+treatment*visit, where patient is a random effect; covariance structure=unstructured; denominator degrees of freedom were estimated using the Kenward-Roger method. ^bFrom ANCOVA model, percent change from baseline=baseline+treatment. ANCOVA, analysis of covariance; LS, least-squares; MMRM, mixed-effect model repeated measure; SE, standard error. Other abbreviations as in Table 1.

For the secondary endpoints, treatment with evacetrapib 130 mg resulted in statistically significant improvements compared with placebo in mean percent changes from baseline to week 12 in LDL-C (direct), non-HDL-C, non-HDL-C/HDL-C ratio, Lp(a), apoAI, apoB, and apoB/apoAI ratio (Table 2).

No deaths, serious adverse events (SAEs), or discontinuations because of AEs were reported during the double-blind treatment period; 5 patients (18.5%) in the evacetrapib group and 7 patients (26.9%) in the placebo group experienced TEAEs (Table 3). None of these events was assessed by the investigator to be related to the study drug. Nasopharyngitis (2 patients, 7.4%) was the most frequent TEAE in the evacetrapib group. All other TEAEs occurred in only 1 patient each. There were no significant treatment differences in the incidence of any TEAE.

Table 3. Safety Data (Safety Analysis Set) in Phase 3 Study of Japanese Hypercholesterolemia Patients

	Evacetrapib 130 mg (n=27)	Placebo (n=26)	P valuea
TEAEs, n (%)	5 (18.5)	7 (26.9)	0.526
Drug-related TEAEs, n (%)	0 (0.0)	0 (0.0)	N/A
TEAEs leading to discontinuation, n (%)	0 (0.0)	0 (0.0)	N/A
Serious adverse events, n (%)	0 (0.0)	0 (0.0)	N/A
ALT >3×ULN, n (%)	0 (0.0)	0 (0.0)	N/A
AST >3×ULN, n (%)	0 (0.0)	0 (0.0)	N/A
Creatine kinase >5×ULN, n (%)	0 (0.0)	0 (0.0)	N/A
Elevation in SBP ≥15 mmHg, n (%)	6 (22.2)	4 (15.4)	0.728
Elevation in DBP ≥10 mmHg, n (%)	7 (25.9)	3 (11.5)	0.293

^aFrom Fisher’s exact test. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; n, number of patients; SBP, systolic blood pressure; TEAE, treatment-emergent adverse event; ULN, upper limit of normal.

No statistically significant differences were observed at week 12 between groups in the mean changes from baseline in plasma renin activity, serum sodium, serum potassium, serum chloride, or serum bicarbonate (Table 4). However, treatment with evacetrapib resulted in a statistically significant decrease from baseline in aldosterone at week 12 (ANCOVA) compared with placebo: the LS mean difference (evacetrapib vs. placebo) was −53.3pmol/L (−1.92 ng/dL) (P=0.009). For potassium, there was no statistically significant treatment difference between evacetrapib and placebo at week 12. The LS mean difference (evacetrapib vs. placebo) was −0.08 mmol/L (−0.08 mEq/L) (P=0.344).

Table 4. Change From Baseline to Week 12 in Blood Pressure, Mineralocorticoid Activity, and Electrolytes (Safety Analysis Set) in Phase 3 Study of Japanese Hypercholesterolemia Patients

Laboratory measure	Evacetrapib 130 mg (n=26)	Placebo (n=25)	P value
SBP, mmHg, LS mean change (SE)	1.3 (2.2)	−2.9 (2.2)	0.184a
DBP, mmHg, LS mean change (SE)	1.7 (1.3)	0.4 (1.3)	0.485a
Aldosterone, ng/dL, pmol/L, LS mean change (SE)	−0.7 (0.5) −19.42 (13.9)	1.2 (0.5) 33.3 (13.9)	0.009b
Plasma renin, ng/mL/h, pmol/L, LS mean change (SE)	−0.4 (0.4) −0.01 (0.0)	0.7 (0.4) −0.02 (0.0)	0.079b
Serum sodium, mEq/L, mmol/L, LS mean change (SE)	0.7 (0.3) 0.7 (0.3)	0.1 (0.3) 0.1 (0.3)	0.154a
Serum potassium, mEq/L, mmol/L, LS mean change (SE)	−0.1 (0.1) −0.1 (0.1)	0.0 (0.1) −0.1 (0.1)	0.344a
Serum bicarbonate, mEq/L, mmol/L, LS mean change (SE)	0.4 (0.4) 0.4 (0.4)	0.3 (0.4) 0.4 (0.4)	0.749a

^aFrom MMRM model, percent change from baseline=baseline+treatment+visit+treatment*visit, where patient is a random effect; covariance structure=unstructured; denominator degrees of freedom were estimated using the Kenward-Roger method. ^bFrom ANCOVA model, percent change from baseline=baseline+treatment. Abbreviations as in Tables 1–3.

No patients reported any hepatic-related TEAEs and no patients experienced ALT or AST values >3×ULN or total bilirubin >2×ULN. Additionally, no patients reported any muscle-related TEAEs, and no patients experienced CK values >5×ULN. Greater percentages of patients in the evacetrapib group experienced increases from baseline in SBP (≥15 mmHg) or DBP (≥10 mmHg), although none of these increases was statistically significant (Table 3).

Discussion

This study evaluated the efficacy and safety profile of evacetrapib 130 mg QD as monotherapy in Japanese patients with primary hypercholesterolemia. This study differed from a previous phase 2 study in Japanese patients that included evacetrapib monotherapy in ranging doses of 30, 100, and 500 mg QD or evacetrapib 100 mg QD in combination with 10 mg atorvastatin.¹²

A total of 85 patients entered the study and 54 patients were randomized (27 to evacetrapib and 27 to placebo); 3 patients were disqualified for failure to meet randomization criteria, so a total of 51 patients completed the 12-week double-blind treatment period. The treatment groups were well balanced with regard to demographics and baseline characteristics, including BP, LDL-C, HDL-C, and triglycerides.

The primary objective of the study, to demonstrate the superiority of evacetrapib 130 mg vs. placebo on mean percent change from baseline to week 12 in LDL-C (measured by β quantification) in patients with primary hypercholesterolemia, was achieved: A statistically significant treatment difference of −34.3% (P<0.001) was observed in the evacetrapib 130 mg group compared with the placebo group.

In comparison, in the phase 2 study in Japanese patients, 12 weeks of monotherapy QD with evacetrapib resulted in a treatment difference of 15% (30 mg), 23% (100 mg), and 22% (500 mg) decrease in LDL-C compared with placebo.¹² However, in the present study, for HDL-C, a treatment difference of 124.0% was observed in evacetrapib compared with placebo. The present study did not assess changes in cholesterol efflux capacity. However, 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 (30, 100, or 500 mg QD for 12 weeks) increased total and nonadenosine triphosphate-binding cassette transporter A1 (ABCA1)-specific cholesterol efflux capacity up to 34% and 47%, respectively, compared with placebo.^13,14 The study also found that evacetrapib monotherapy increased ABCA1-specific cholesterol efflux capacity up to 26%.¹³

The LDL-C lowering effect of evacetrapib 130 mg observed in this phase 3 study was greater than the effect of evacetrapib 500 mg observed in the phase 2 study, which shows the potential of evacetrapib. Changes in LDL-C and HDL-C were observed as early as week 2. Other lipid parameters also showed favorable changes.

Improvements in serum LP(a) levels compared with both placebo and ezetimibe are consistent with results of other evacetrapib studies. In a previous phase 2 study of evacetrapib in mildly hypercholesterolemic patients, monotherapy or combination therapy with statins significantly reduced Lp(a) concentrations.¹⁵ However, understanding the causes of these changes will require further study.

No deaths, SAEs, discontinuations of study drug because of AEs, or study drug-related TEAEs were reported during the double-blind treatment period.

Because of safety concerns associated with another CETP inhibitor (torcetrapib)⁸ and the results of a phase 2 study of evacetrapib in the Japanese population,¹² the present study rigorously evaluated the effects of evacetrapib on BP, serum electrolytes, aldosterone, and plasma renin activity. In a phase 2 study of evacetrapib in Japanese patients, increased SBP was observed in the evacetrapib 500 mg group.¹² In the present study, no statistically significant differences in the change from baseline to week 12 in SBP and DBP were observed, although more cases with increased SBP ≥15 mmHg and DBP ≥10 mmHg were observed in the evacetrapib group. Also, no statistically significant difference in electrolytes was observed, and there was no sign of elevation of aldosterone or renin levels in the evacetrapib group. These findings are consistent with data from phase 2 studies of evacetrapib^12,16 and with other more recently studied CETP inhibitors, anacetrapib¹⁰ and dalcetrapib.¹⁷ The results of the ACCELERATE study¹¹ also revealed an increase in SBP of 1.2 mmHg in the evacetrapib group, which was statistically significant (P<0.001) but clinically insignificant. All these findings support the conclusion that administration of evacetrapib is unlikely to lead to clinically significant elevation in BP as was demonstrated with torcetrapib.^8,18,19

Additional safety issues of particular interest in this patient population or based on findings in previous studies of evacetrapib included severe rash, diarrhea, hepatic toxicity, muscle toxicity, arrhythmogenic risk, and MACE. Although a patient in the phase 2 evacetrapib study in Japan¹² experienced an SAE of toxic skin eruption, no events of rash were reported in the present study. In addition, no arrhythmia was reported, and there was no evidence of hepatic, muscular or cardiovascular AEs related to evacetrapib.

Conclusions

The results from this study showed that evacetrapib 130 mg QD monotherapy was superior to placebo in lowering LDL-C after 12 weeks, and no new safety risks were identified.

Acknowledgments

The authors wish to acknowledge the investigators and patients who participated in this study and Kent Steinriede, MS, of inVentiv Health Clinical for providing writing assistance.

Disclosures

T.T. has received remuneration from Bayer Yakuhin, Ltd., Pfizer Japan Inc., Daiichi Sankyo, Inc., Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc., Kowa Pharmaceutical Company Ltd., Kissei Pharmaceutical Co Ltd., Sanofi, MSD, and AABP. Additionally, he reports that his institution has received scholarship funds or donations from Daiichi Sankyo, Inc., Kowa Pharmaceutical Company Ltd., Eli Lilly Japan, Takeda Pharmaceutical Company Ltd., and Shionogi & Co., Ltd. and funding for department endowments from Bayer Yakuhin, Ltd., Astellas Pharma Inc., ASKA Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co Ltd., Kowa Pharmaceutical Company Ltd., Mochida Pharmaceutical Co. Ltd., and MSD. A.K. has received remuneration from Astra Zeneca. T.I. contributed to this work as a former full-time employee of Eli Lilly Japan K.K. The opinions expressed in this work are solely his and do not represent his current affiliation, Elsevier Japan K.K. He also owns stock in Eli Lilly Japan K.K. Y.T. is an employee of Eli Lilly Japan K.K. and owns stock in Eli Lilly Japan K.K. J.S.R. and M.M. are employees of Eli Lilly and Company and own stock in the company.

Funding

This clinical study was sponsored by Eli Lilly Japan K.K.

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