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

1686 TERAMOTO T et al. Circ J 2017; 81: 1686 – 1692 ORIGINAL ARTICLE doi: 10.1253/circj.CJ-16-1325 Ischemic Heart Disease

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

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

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.

Key Words: Cholesteryl ester transfer protein inhibitor; Evacetrapib; High-density lipoprotein cholesterol; Hypercholesterolemia; Low-density lipoprotein cholesterol

he ability of 3-hydroxy-3-methylglutaryl-coenzyme or higher, respectively, compared with the group with reductase inhibitors (statins) to reduce levels of total cholesterol levels between 4.14 and 4.63 mmol/L T low-density lipoprotein cholesterol (LDL-C) has (160–179 mg/dL).4 A more recent epidemiological study resulted in reports of 20–30% reductions in cardiovascular in Japan showed that the hazard ratio of total CAD events.1–3 Current guidelines for lipid-modulating therapy increases 1.4-, 1.7-, 2.2-, and 2.8-times when LDL-C levels for both primary and secondary prevention of atheroscle- were 2.07–2.56, 2.59–3.08, 3.10–3.59, and 3.62 mmol/L rosis have defined LDL-C goal levels for lipid management (80–99, 100–119, 120–139, and 140 mg/dL) or higher, on the basis of these findings. respectively, compared with an LDL-C level <2.07 mmol/L In Japan, the relative risk of coronary artery disease (80 mg/dL).5 Consequently, the Japan Atherosclerosis (CAD) has been shown in epidemiological studies to Society (JAS) defines high LDL-C as >3.62 mmol/L increase incrementally with increasing levels of LDL-C and (140 mg/dL).2 total cholesterol. Results from the NIPPON DATA 80 Although LDL-C management has provided significant study demonstrated that the relative risk of death from clinical benefits, atherosclerosis remains a major health CAD increases 1.4-, 1.7-, 1.8-, and 3.8-times when the total burden. Statins are effective in lowering LDL-C and reduc- cholesterol levels were 5.17–5.66, 5.69–6.18, 6.21–6.70, and ing the risk of CAD, yet many patients on statins do not 6.72 mmol/L (200–219, 220–239, 240–259, and 260 mg/dL) reach their LDL-C goal6 and other patients cannot tolerate

Received January 9, 2017; revised manuscript received April 20, 2017; accepted May 9, 2017; released online June 23, 2017 Time for primary review: 24 days Teikyo Academic Research Center, Teikyo University, Tokyo (T.T.); Tokyo-Eki Center-Building Clinic, Tokyo (A.K.); Department of Cardiovascular Medicine, University of Tokyo Hospital, Tokyo (A.K.); Eli Lilly Japan K.K., Kobe (T.I., Y.T.), Japan; and Eli Lilly and Company, Indianapolis, IN (J.S.R., M.M.), USA T.I. contributed to this work as a former full-time employee of Eli Lilly Japan K.K. T.I. is currently employed by Elsevier Japan K.K., Tokyo, Japan. Mailing address: Masahiro Murakami, MD, PhD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Circulation Journal Vol.81, November 2017 Evacetrapib for Hypercholesterolemia in Japan 1687 statin therapy. As a result, there is an unmet need for addi- performed. Eligible patients were instructed to start the diet tional LDL-C lowering therapies. lead-in and washout period within 2 weeks of the screening Inhibition of cholesteryl ester transfer protein (CETP) visit. Patients who were not taking lipid-modifying medica- represents a mechanism for increasing high-density lipo- tion at the screening visit (e.g., statins, ezetimibe, bile acid protein cholesterol (HDL-C) levels and lowering LDL-C sequestrant, eicosapentaenoic acid, or docosahexaenoic levels. CETP is a plasma glycoprotein secreted primarily acid) remained in the diet lead-in and washout period for from the liver that mediates the transfer of cholesteryl ester a minimum of 2 weeks, whereas those who were taking from HDL to apolipoprotein B (apoB)-containing lipopro- lipid-modifying medication remained in the diet lead-in teins (very low-density lipoprotein, intermediate-density and washout period for a minimum of 4 weeks. During this lipoproteins, and low-density lipoprotein) in exchange for period, patients began a diet in accordance with the JAS triglycerides. CETP also mediates the transfer of tri- guidelines2 to evaluate lipid levels and to minimize the glycerides/cholesteryl ester between apoB-containing effect of diet on lipid values throughout the study. lipoproteins. Evidence shows that CETP may be involved Patients who completed the diet lead-in and washout in reverse cholesterol transport.7 Inhibition of CETP may period and who met all enrollment criteria were random- also prevent transfer of cholesteryl esters from HDL to ized in a 1:1 ratio to double-blind treatment of evacetrapib apoB-containing lipoproteins. Animal model data indicate 130 mg or placebo. Randomization was performed at each that CETP is proatherogenic, supporting an antiathero- investigative site using an interactive web response system. genic effect of CETP inhibitors.7,8 Treatment with evacetrapib 130 mg or placebo QD began Clinical trial results demonstrate that potent CETP inhi- during the 12-week double-blind treatment period; patients bition results in increased HDL-C and decreased LDL-C. returned to the investigational sites 4 times for procedures Studies using intravascular ultrasound show that, in patients and assessments. All patients discontinued treatment dur- with or at high risk for CAD, high levels of HDL-C achieved ing the open-label extension period when the study was via CETP inhibition are associated with a reduction in per- terminated by the sponsor. The project was terminated cent atheroma volume,9 as well as a trend toward reduction after all patients’ primary endpoint data were collected; in major adverse cardiovascular events (MACE).10 therefore, there was no significant effect on the study The pharmacodynamic effect of CETP inhibition has results and this report focuses on the double-blind treat- been tested in clinical trials of several CETP inhibitors, ment period. including torcetrapib, anacetrapib (MK-0859), and dalcetrapib (JTT705). These trials clearly demonstrated that Patients CETP inhibition results in increased HDL-C and, with Japanese men and women ≥20 years of age were eligible for more potent agents, decreased LDL-C.8–10 this study if they were diagnosed with primary hypercho- Based on previous studies, the CETP inhibitor evacetra- lesterolemia and, at baseline sample collection, had fasting pib was expected to be a potential lipid-lowering mono- triglyceride levels ≤4.52 mmol/L (400 mg/dL), HDL-C levels therapy for patients with elevated LDL-C who were not <1.13 mmol/L (100 mg/dL), and LDL-C levels ≥4.14 mmol/L prescribed or could not tolerate statin therapy. Thus, eva- (160 mg/dL) and ≤5.17 mmol/L (200 mg/dL) (JAS Category cetrapib would address an unmet medical need for lipid- I2); LDL-C ≥3.62 mmol/L (140 mg/dL) and ≤4.53 mmol/L lowering therapy as an add-on or alternative to existing (175 mg/dL) (JAS Category II) or LDL-C ≥3.10 mmol/L standard-of-care statin treatment. This phase 3 study was (120 mg/dL) and ≤3.88 mmol/L (150 mg/dL) (JAS Category designed to evaluate the efficacy and safety of evacetrapib III). Patients were excluded from the study if they were when administered alone in Japanese patients with primary undergoing LDL apheresis or plasma apheresis, had sec- hypercholesterolemia. The study was terminated during its ondary hypercholesterolemia, familial hypercholesterol- open-label extension period because of a finding of futil- emia, clinically active hepatobiliary disease, or hemoglobin ity in the efficacy of evacetrapib in the ACCELERATE A1c (HbA1c) ≥8.4%, were taking CETP inhibitors, had a study11 evaluating MACE. However, this had no effect on history of New York Heart Association Class III or IV the evaluation of the primary endpoint for this study congestive heart failure or significant cardiovascular or because all patients had completed the double-blind phase cerebrovascular conditions, or had systolic blood pres- at the time of termination. The results from the primary sure (SBP) >160 mmHg or diastolic blood pressure (DBP) 12-week, double-blind treatment period are presented in >100 mmHg. this report. Patients were also excluded if they were suspected of having cancer or had a treatment history of malignancy Methods (except excised non-melanoma skin cancer/basal cell or squamous cell carcinoma of the skin) within the 3 years This was a multicenter, randomized, 12-week, double-blind, prior to screening. Based on laboratory tests performed at parallel group, placebo-controlled, outpatient, phase 3 screening, patients were also excluded if they had thyroid- study (ClinicalTrials.gov: NCT02260635). stimulating hormone below the lower limit of the normal The protocol was approved by the ethics review board or >1.5-fold of the upper limit of normal (ULN), serum of each participating study center, and all patients pro- creatinine >194.48 µmol/L (2.2 mg/dL), aspartate amino- vided written informed consent. Study treatment was eva- transferase/serum glutamic oxaloacetic transaminase cetrapib monotherapy (130 mg) or placebo once daily (AST/SGOT), alanine aminotransferase/serum glutamic (QD). Three consecutive study periods were planned: a pyruvic transaminase (ALT/SGPT), alkaline phosphatase, 2-week screening period; a 2–4-week diet lead-in and wash- total bilirubin >2.0×ULN, or an unexplained/documented out period; and a 12-week, double-blind treatment period. elevation in creatine kinase (CK) ≥3×ULN. Patients were asked to fast for at least 8 h before the screen- Additionally, women who were known to be pregnant ing visit, when laboratory samples were collected for cen- or breastfeeding, or who were not willing to use a reliable tral measurement and all other screening assessments were method of contraception during the study and for 12 weeks

Circulation Journal Vol.81, November 2017 1688 TERAMOTO T et al. afterwards, were also excluded from enrolling in the study. study site 2, 4, 8, and 12 weeks after the randomization visit. At each visit, patients were required to fast for at least Efficacy Assessments 8 h before blood samples were collected. Blood samples During the double-blind period, patients returned to the 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 appli- cable, 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 Figure 1. Patient disposition through the 12-week double- with placebo using a 2-sample t-test with a 2-sided 0.05 blind treatment period of phase 3 study evaluating the efficacy significance level. Considering a 10% dropout rate, approx- and safety of evacetrapib in Japanese patients with hypercholesterolemia. imately 52 patients needed to be randomized to each treatment group in a 1:1 ratio.

Table 1. Baseline Characteristics (Randomized) of Japanese Hypercholesterolemia Patients Evacetrapib 130 mg Placebo Variable (N=27) (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 3.9±0.8 (148.8±25.3) (152.2±29.2) LDL-C (direct, mmol/L [mg/dL]), mean ± SD 4.1±0.6 4.2±0.6 (158.1±21.5) (162.3±23.3) HDL-C (mmol/L [mg/dL]), mean ± SD 1.4±0.3 1.5±0.3 (53.0±10.3) (58.8±11.9) Triglycerides (mmol/L [mg/dL]), mean ± SD 1.5±0.7 1.4±0.8 (131.6±61.9) (125.0±68.2) Non-HDL-C (mmol/L [mg/dL]), mean ± SD 4.7±0.6 4.8±0.7 (180.0±25.0) (185.9±28.6) Lp(a) (μmol/L [mg/dL]), mean ± SD 38.7±57.0 55.2±62.5 (1,084.0±1,596.6) (1,546.2±1,750.7) apoAI (g/L [mg/dL]), mean ± SD 1.5±0.2 1.6±0.2 (149.9±20.2) (161.0±19.4) apoB (g/L [mg/dL]), mean ± SD 1.2±0.2 1.2±0.2 (115.0±16.0) (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.

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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 likeli- hood-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 for- ward 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 Figure 2. Percent change from baseline for LDL-C and HDL-C Center-building Clinic, Tokyo; Tokyo Center Clinic, (β quantification) using mixed model repeated measures, Tokyo; and the Nishi-Umeda Clinic for Asian Medical double-blind treatment period, and full analysis set. LDL-C, Collaboration, Osaka) between November 2014 and July low-density lipoprotein cholesterol; LS, least-squares; HDL-C, 2015. A total of 85 patients were screened and 54 patients high-density lipoprotein cholesterol; SD, standard error. 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 (evace- For the secondary endpoints, treatment with evacetrapib trapib, 1; placebo, 2) were disqualified during the 130 mg resulted in statistically significant improvements double-blind treatment period because they had been inad- compared with placebo in mean percent changes from vertently enrolled despite failing to meet the enrollment baseline to week 12 in LDL-C (direct), non-HDL-C, non- criteria. Baseline characteristics of patients were generally HDL-C/HDL-C ratio, Lp(a), apoAI, apoB, and apoB/ similar for each treatment group (Table 1). All patients apoAI ratio (Table 2). were Asian, and 68.5% were male. The mean age was 52.8 No deaths, serious adverse events (SAEs), or discon- years. At baseline, mean LDL-C (β quantification), HDL-C, tinuations because of AEs were reported during the dou- and triglycerides were 3.9 mmol/L (150.5 mg/dL), 1.4 mmol ble-blind treatment period; 5 patients (18.5%) in the (55.9 mg/dL), and 1.5 mmol/L (128.3 mg/dL), respectively evacetrapib group and 7 patients (26.9%) in the placebo (Figure 2). group experienced TEAEs (Table 3). None of these events Treatment with evacetrapib 130 mg for 12 weeks for was assessed by the investigator to be related to the study primary hypercholesterolemia resulted in a statistically sig- drug. Nasopharyngitis (2 patients, 7.4%) was the most nificant decrease (P<0.001) in the percent change from frequent TEAE in the evacetrapib group. All other TEAEs baseline to week 12 in LDL-C (β quantification) compared occurred in only 1 patient each. There were no significant with placebo (Table 2). The least-squares (LS) mean changes treatment differences in the incidence of any TEAE. from baseline were −34.3% in the evacetrapib group and No statistically significant differences were observed at 0.0% in the placebo group. The LS mean difference (evace- week 12 between groups in the mean changes from baseline trapib vs. placebo) at week 12 was −34.3% (95% confidence in plasma renin activity, serum sodium, serum potassium, interval [CI]: −45.5 to −23.0). Treatment with evacetrapib serum chloride, or serum bicarbonate (Table 4). However, 130 mg also resulted in a statistically significant (P<0.001) treatment with evacetrapib resulted in a statistically signifi- increase in HDL-C compared with placebo in mean per- cant decrease from baseline in aldosterone at week 12 cent change from baseline to week 12, with an LS mean (ANCOVA) compared with placebo: the LS mean difference difference (evacetrapib vs. placebo) at week 12 of 124.0% (evacetrapib vs. placebo) was −53.3pmol/L (−1.92 ng/dL) (95% CI: 104.6 to 143.5). (P=0.009). For potassium, there was no statistically

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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 Evacetrapib 130 mg Placebo Laboratory measure (N=27) (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. significant treatment difference between evacetrapib and Discussion placebo at week 12. The LS mean difference (evacetrapib vs. placebo) was −0.08 mmol/L (−0.08 mEq/L) (P=0.344). This study evaluated the efficacy and safety profile of eva- No patients reported any hepatic-related TEAEs and no cetrapib 130 mg QD as monotherapy in Japanese patients patients experienced ALT or AST values >3×ULN or total with primary hypercholesterolemia. This study differed bilirubin >2×ULN. Additionally, no patients reported any from a previous phase 2 study in Japanese patients that muscle-related TEAEs, and no patients experienced CK included evacetrapib monotherapy in ranging doses of 30, values >5×ULN. Greater percentages of patients in the 100, and 500 mg QD or evacetrapib 100 mg QD in combi- evacetrapib group experienced increases from baseline in nation with 10 mg atorvastatin.12 SBP (≥15 mmHg) or DBP (≥10 mmHg), although none of A total of 85 patients entered the study and 54 patients these increases was statistically significant (Table 3). 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

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Table 3. Safety Data (Safety Analysis Set) in Phase 3 Study of Japanese Hypercholesterolemia Patients Evacetrapib 130 mg Placebo P valuea (n=27) (n=26) 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.

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 Evacetrapib 130 mg Placebo Laboratory measure P value (n=26) (n=25) 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) 1.2 (0.5) 0.009b −19.42 (13.9) 33.3 (13.9) Plasma renin, ng/mL/h, pmol/L, LS mean change (SE) −0.4 (0.4) 0.7 (0.4) 0.079b −0.01 (0.0) −0.02 (0.0) Serum sodium, mEq/L, mmol/L, LS mean change (SE) 0.7 (0.3) 0.1 (0.3) 0.154a 0.7 (0.3) 0.1 (0.3) Serum potassium, mEq/L, mmol/L, LS mean change (SE) −0.1 (0.1) 0.0 (0.1) 0.344a −0.1 (0.1) −0.1 (0.1) Serum bicarbonate, mEq/L, mmol/L, LS mean change (SE) 0.4 (0.4) 0.3 (0.4) 0.749a 0.4 (0.4) 0.4 (0.4) 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. double-blind treatment period. The treatment groups were study also found that evacetrapib monotherapy increased well balanced with regard to demographics and baseline ABCA1-specific cholesterol efflux capacity up to 26%.13 characteristics, including BP, LDL-C, HDL-C, and triglyc- The LDL-C lowering effect of evacetrapib 130 mg erides. observed in this phase 3 study was greater than the effect The primary objective of the study, to demonstrate the of evacetrapib 500 mg observed in the phase 2 study, which superiority of evacetrapib 130 mg vs. placebo on mean per- shows the potential of evacetrapib. Changes in LDL-C and cent change from baseline to week 12 in LDL-C (measured HDL-C were observed as early as week 2. Other lipid by β quantification) in patients with primary hypercholes- parameters also showed favorable changes. terolemia, was achieved: A statistically significant treatment Improvements in serum LP(a) levels compared with difference of −34.3% (P<0.001) was observed in the evace- both placebo and ezetimibe are consistent with results of trapib 130 mg group compared with the placebo group. other evacetrapib studies. In a previous phase 2 study of In comparison, in the phase 2 study in Japanese patients, evacetrapib in mildly hypercholesterolemic patients, mono- 12 weeks of monotherapy QD with evacetrapib resulted in therapy or combination therapy with statins significantly a treatment difference of 15% (30 mg), 23% (100 mg), and reduced Lp(a) concentrations.15 However, understanding 22% (500 mg) decrease in LDL-C compared with placebo.12 the causes of these changes will require further study. However, in the present study, for HDL-C, a treatment No deaths, SAEs, discontinuations of study drug because difference of 124.0% was observed in evacetrapib com- of AEs, or study drug-related TEAEs were reported during pared with placebo. The present study did not assess the double-blind treatment period. changes in cholesterol efflux capacity. However, in a sepa- Because of safety concerns associated with another rate phase 2, multicenter, randomized, double-blind, paral- CETP inhibitor (torcetrapib)8 and the results of a phase 2 lel, placebo-controlled study of 398 patients with elevated study of evacetrapib in the Japanese population,12 the pres- LDL-C or low HDL-C, evacetrapib monotherapy (30, ent study rigorously evaluated the effects of evacetrapib on 100, or 500 mg QD for 12 weeks) increased total and non- BP, serum electrolytes, aldosterone, and plasma renin activ- adenosine triphosphate-binding cassette transporter A1 ity. In a phase 2 study of evacetrapib in Japanese patients, (ABCA1)-specific cholesterol efflux capacity up to 34% increased SBP was observed in the evacetrapib 500 mg and 47%, respectively, compared with placebo.13,14 The group.12 In the present study, no statistically significant

Circulation Journal Vol.81, November 2017 1692 TERAMOTO T et al. differences in the change from baseline to week 12 in 2. Teramoto T, Sasaki J, Ueshima H, Egusa G, Kinoshita M, SBP and DBP were observed, although more cases with Shimamoto K, et al. Executive summary of Japan Atherosclerosis increased SBP ≥15 mmHg and DBP ≥10 mmHg were Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler observed in the evacetrapib group. Also, no statistically Thromb 2007; 14: 45 – 50. significant difference in electrolytes was observed, and 3. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, there was no sign of elevation of aldosterone or renin levels Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the in the evacetrapib group. These findings are consistent treatment of blood cholesterol to reduce atherosclerotic cardio- 12,16 vascular risk in adults: A report of the American College of with data from phase 2 studies of evacetrapib and with Cardiology/American Heart Association Task Force on Practice other more recently studied CETP inhibitors, anacetra- Guidelines. Circulation 2014; 129(Suppl 2): S1 – S45. pib10 and dalcetrapib.17 The results of the ACCELERATE 4. Okamura T, Tanaka H, Miyamatsu N, Hayakawa T, Kadowaki study11 also revealed an increase in SBP of 1.2 mmHg in the T, Kita Y, et al. The relationship between serum total cholesterol and all-cause or cause-specific mortality in a 17.3-year study of a evacetrapib group, which was statistically significant Japanese cohort. Atherosclerosis 2007; 190: 216 – 223. (P<0.001) but clinically insignificant. All these findings 5. Imano H, Noda H, Kitamura A, Sato S, Kiyama M, Sankai T, et support the conclusion that administration of evacetrapib al. Low-density lipoprotein cholesterol and risk of coronary heart is unlikely to lead to clinically significant elevation in BP as disease among Japanese men and women: The Circulatory Risk 8,18,19 in Communities Study (CIRCS). Prev Med 2011; 52: 381 – 386. was demonstrated with torcetrapib. 6. Kurihara Y, Douzono T, Kawakita K, Nagasaka Y. A large-scale, Additional safety issues of particular interest in this long-term prospective post-marketing surveillance of pitavas- patient population or based on findings in previous studies tatin (Livalo): Livalo effectiveness and safety study (LIVES). Jpn of evacetrapib included severe rash, diarrhea, hepatic tox- Pharmacol Ther 2008; 36: 709 – 731. 7. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, icity, muscle toxicity, arrhythmogenic risk, and MACE. Shinkai H. A cholesteryl ester transfer protein inhibitor attenu- Although a patient in the phase 2 evacetrapib study in ates atherosclerosis in rabbits. Nature 2000; 406: 203 – 207. Japan12 experienced an SAE of toxic skin eruption, no 8. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, events of rash were reported in the present study. In addi- Komajda M, et al. Effects of torcetrapib in patients at high risk tion, no arrhythmia was reported, and there was no evi- for coronary events. N Engl J Med 2007; 357: 2109 – 2122. 9. Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE. dence of hepatic, muscular or cardiovascular AEs related Cholesteryl ester transfer protein inhibition, high-density lipo- to evacetrapib. protein raising, and progression of coronary atherosclerosis: Insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction Conclusions of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008; 118: 2506 – 2514. The results from this study showed that evacetrapib 130 mg 10. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto QD monotherapy was superior to placebo in lowering AM, et al. Safety of anacetrapib in patients with or at high risk LDL-C after 12 weeks, and no new safety risks were iden- for coronary heart disease. N Engl J Med 2010; 363: 2406 – 2415. 11. Nicholls SJ, Lincoff AM, Barter PJ, Brewer HB, Fox KAA, tified. Gibson CM, et al. Impact of the cholesteryl ester transfer protein inhibitor evacetrapib on cardiovascular events: Results of the Acknowledgments ACCELERATE trial [Abstract]. American College of Cardiology Annual Scientific Session, Chicago, ILL, April 3, 2016. http:// The authors wish to acknowledge the investigators and patients who www.abstractsonline.com/pp8/#!/3874/presentation/47087 participated in this study and Kent Steinriede, MS, of inVentiv Health (accessed on April 4, 2017). Clinical for providing writing assistance. 12. Teramoto T, Takeuchi M, Morisaki Y, Ruotolo G, Krueger KA. Efficacy, safety, tolerability, and pharmacokinetic profile of eva- Disclosures cetrapib administered as monotherapy or in combination with T.T. has received remuneration from Bayer Yakuhin, Ltd., Pfizer atorvastatin in Japanese patients with dyslipidemia. Am J Cardiol 113: Japan Inc., Daiichi Sankyo, Inc., Takeda Pharmaceutical Company 2014; 2021 – 2029. Ltd., Astellas Pharma Inc., Kowa Pharmaceutical Company Ltd., 13. Nicholls SJ, Ruotolo G, Brewer HB, Kane JP, Wang MD, Kissei Pharmaceutical Co Ltd., Sanofi, MSD, and AABP. Additionally, Krueger KA, et al. Cholesterol Efflux Capacity and Pre-Beta-1 he reports that his institution has received scholarship funds or dona- HDL Concentrations are increased in dyslipidemic patients 66: tions from Daiichi Sankyo, Inc., Kowa Pharmaceutical Company treated with evacetrapib. J Am Coll Cardiol 2015; 2201 – 2210. Ltd., Eli Lilly Japan, Takeda Pharmaceutical Company Ltd., and 14. Rohatgi A, Grundy SM. Cholesterol efflux capacity as a thera- Shionogi & Co., Ltd. and funding for department endowments from peutic target: Rationale and clinical implications. J Am Coll 66: Bayer Yakuhin, Ltd., Astellas Pharma Inc., ASKA Pharmaceutical Cardiol 2015; 2211 – 2213. Co., Ltd., Kissei Pharmaceutical Co Ltd., Kowa Pharmaceutical 15. Nicholls SJ, Ruotolo G, Brewer HB, Wang MD, Liu L, Willey Company Ltd., Mochida Pharmaceutical Co. Ltd., and MSD. A.K. MB, et al. Evacetrapib alone or in combination with statins low- has received remuneration from Astra Zeneca. T.I. contributed to this ers lipoprotein(a) and total and small LDL particle concentra- work as a former full-time employee of Eli Lilly Japan K.K. The tions in mildly hypercholesterolemic patients. J Clin Lipidol 2016; 10: opinions expressed in this work are solely his and do not represent his 519 – 527. current affiliation, Elsevier Japan K.K. He also owns stock in Eli Lilly 16. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Japan K.K. Y.T. is an employee of Eli Lilly Japan K.K. and owns Shao M, et al. Effects of the CETP inhibitor evacetrapib admin- stock in Eli Lilly Japan K.K. J.S.R. and M.M. are employees of Eli istered as monotherapy or in combination with statins on HDL Lilly and Company and own stock in the company. and LDL cholesterol: A randomized controlled trial. JAMA 2011; 306: 2099 – 2109. 17. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Funding Zwinderman AH, Posma JL, et al. Efficacy and safety of a novel This clinical study was sponsored by Eli Lilly Japan K.K. cholesteryl ester transfer protein inhibitor, JTT-705, in humans: A randomized phase II dose-response study. Circulation 2002; 105: 2159 – 2165. References 18. Vergeer M, Stroes ES. The pharmacology and off-target effects 1. Reiner Z, Catapano AL, De BG, Graham I, Taskinen MR, of some cholesterol ester transfer protein inhibitors. Am J Cardiol Wiklund O, et al. ESC/EAS Guidelines for the management of 2009; 104(10 Suppl): 32E – 38E. dyslipidaemias: The Task Force for the management of dyslipi- 19. Clerc RG, Stauffer A, Weibel F, Hainaut E, Perez A, Hoflack JC, daemias of the European Society of Cardiology (ESC) and the et al. Mechanisms underlying off-target effects of the cholesteryl European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: ester transfer protein inhibitor torcetrapib involve L-type cal- 1769 – 1818. cium channels. J Hypertens 2010; 28: 1676 – 1686.

Circulation Journal Vol.81, November 2017