Circ J 2018; 82: 183 – 191 ORIGINAL ARTICLE doi: 10.1253/circj.CJ-16-1324 Ischemic Heart Disease

Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With 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 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; /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.

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

he use of 3-hydroxy-3-methyl-glutaryl-coenzyme A the hazard ratio for total CAD increases 1.4-, 1.7-, 2.2-, and reductase inhibitors () to reduce low-density 2.8-fold when LDL‑C is 2.06–2.57, 2.58–3.09, 3.10–3.61, lipoprotein cholesterol (LDL-C) has resulted in and ≥3.62 mmol/L, respectively, compared with LDL-C T 5 relative reductions in cardiovascular events of 20–30%. As <2.06 mmol/L. a result, current guidelines for dyslipidemia management Cholesteryl ester transfer protein (CETP) is a plasma and prevention of atherosclerotic cardiovascular diseases glycoprotein secreted primarily by the that mediates recommend reducing LDL-C.1–3 the transfer of cholesteryl ester (CE) from high-density Although LDL-C management has provided significant lipoprotein (HDL) to apolipoprotein (apo)B-rich lipopro- clinical benefits, atherosclerosis remains a major health teins (Lp; i.e., very-low-density lipoprotein [VLDL] and burden in Japan, where the relative risk of coronary artery LDL) in exchange for their , as well as the disease (CAD) has been confirmed by epidemiological transfer of triglycerides/CE between apo-B-rich lipopro- studies to increase in tandem with LDL-C and total teins. Inhibition of CETP represents a potent mechanism cholesterol (TC). The NIPPON DATA 80 study showed for increasing HDL cholesterol (HDL-C) and lowering that the relative risk of death due to CAD increases 1.4-, LDL-C. There is evidence that CETP inhibition prevents 1.7-, 1.8-, and 3.8-fold when TC is 5.18–5.68, 5.69–6.20, transfer of CE from HDL-C to apoB-containing lipopro- 6.21–6.70, and ≥6.71 mmol/L, respectively, compared with teins and may increase cholesterol efflux.6–8 The majority of TC 4.14–4.65 mmol/L, for men and women combined.4 A animal model data indicate that CETP is proatherogenic, more recent Japanese epidemiological study reported that supporting an anti-atherogenic effect of CETP inhibitors.8,9

Received January 9, 2017; revised manuscript received May 1, 2017; accepted June 21, 2017; released online August 3, 2017 Time for primary review: 31 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, Kobe (T.I., Y.T.), Japan; and Eli Lilly and Company, Indianapolis, IN (J.S.R., M.M.), USA Present address: Elsevier Japan, Tokyo, Japan (T.I.). 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.82, January 2018 184 TERAMOTO T et al.

Evacetrapib is a potent and selective CETP inhibitor. vascular disease,20 be terminated due to futility. The decision The effect of evacetrapib on LDL-C reduction has been was not based on safety concerns. As a consequence of evaluated in 2 phase 2 studies. A phase 2 study conducted these results, all ongoing studies of evacetrapib, including outside Japan noted a 22.3% decrease in LDL-C in patients this study, were terminated by the sponsor.21 treated with evacetrapib 100 mg alone, and a 47.6% decrease when evacetrapib 100 mg was used with 20 mg atorvas- Methods tatin.10 Similarly, a phase 2 study in Japanese patients noted a 22% reduction in LDL-C in patients treated with This was a multicenter, randomized, 12-week double- evacetrapib 100 mg alone, and a 52% decrease when blind, parallel-group, placebo-controlled, phase 3 study evacetrapib 100 mg was used with 10 mg atorvastatin. The (ClinicalTrials.gov: NCT02260648), with 3 consecutive safety data on evacetrapib 30, 100, and 500 mg demon- periods (screening period; diet lead-in and washout period; strated that evacetrapib was safe and well tolerated.11 and a 12-week, double-blind treatment period). Drugs that are added to therapy for the treatment The study was performed in accordance with the Inter- of hypercholesterolemia and prevention of atherosclerotic national Conference on Harmonisation guidelines for include , resins (anion Good Clinical Practice, all applicable laws, rules, and exchange resin), ezetimibe, and proprotein convertase regulations. The protocol was approved by the ethics review subtilisin kexin type 9 (PCSK9) monoclonal antibodies. board of each participating study center, and all patients Statin use is accompanied by an increase in PCSK9, leading provided written informed consent. to lysosomal degradation of the LDL receptor. This may Study treatment included evacetrapib 130 mg QD, ezeti- explain the observation that doubling the statin dose results mibe 10 mg QD, and placebo added to background therapy in only a 6% additional reduction in LDL-C.12 Ezetimibe of atorvastatin 10 mg. Before screening, patients were is often used as a first-line drug for statin-intolerant asked to fast for at least 8 h before laboratory samples were patients. In patients requiring a more vigorous reduction collected for central measurement and other screening in LDL-C, ezetimibe is frequently used. The reduction of assessments were performed. All eligible patients were LDL-C with ezetimibe 10 mg in patients with hypercholes- asked to begin the diet lead-in and washout period within terolemia is approximately 18%.13,14 With regard to the 2 weeks of the screening visit. Patients taking lipid- effect of ezetimibe in combination with statins, a post- modifying such as ezetimibe, bile acid seques- marketing clinical study in Japan showed that after treat- trant, eicosapentaenoic acid, and docosahexaenoic acid ment with ezetimibe 10 mg in patients who were receiving (except for atorvastatin 10 mg) were instructed to discon- atorvastatin 10 mg, LDL-C decreased by approximately tinue lipid-modifying medication during the washout period 26%.15 The IMPROVE-IT study showed that the addition for 4 weeks before their first treatment visit. Patients were of ezetimibe to 40 mg resulted in an additional also instructed to start a diet therapy in accordance with 6% reduction in the relative risk of major adverse cardiac Japan Atherosclerosis Society (JAS) guidelines3 during the events.16 We have chosen to use ezetimibe as a reference washout period in order to evaluate lipid levels under the drug in this study to better characterize the clinical posi- diet therapy, and to minimize the effect of diet on lipid tioning of evacetrapib as an LDL-C-lowering drug. values throughout the study period. Diet therapy was to Atorvastatin is one of the statins most commonly used continue throughout the study. around the world, with a wealth of evidence on reducing Patients who completed the diet lead-in and washout the risk of cardiovascular events.17,18 A systematic review period and met all enrollment criteria were randomized to and meta-analysis showed that LDL-C decreased by 28.9– a treatment group (evacetrapib 130 mg QD, ezetimibe 42.0% with atorvastatin 10 mg once daily (QD).18 For 10 mg QD, or placebo) in a 1:1:1 ratio. Randomization was Japanese patients with hypercholesterolemia, atorvastatin performed at each investigative site using an interactive 10 mg QD is a standard dosage regimen.19 A phase 2 study Web response system. Once treatment began during the in Japanese patients showed an additive reduction in 12-week double-blind treatment period, patients returned LDL-C after use of evacetrapib in combination with to the investigational sites 4 times for procedures and atorvastatin (22% for evacetrapib 100 mg, 38% for atorvas- assessments. tatin 10 mg, and 52% for evacetrapib 100 mg in combination with atorvastatin 10 mg).11 In addition, in another phase 2 Patients study a similar additive effect was noted when evacetrapib Japanese men and women ≥20 years of age were eligible was used in combination with other statins.10 Consequently, for this study if they were diagnosed with primary hyper- by using atorvastatin as a concomitant medication, additive cholesterolemia and were treated with atorvastatin 10 mg effects of the other statin can be predicted based on the QD for ≥30 days before their first treatment visit. At present results. baseline sample collection, patients were required to have The present phase 3 study was designed to evaluate the fasting ≤4.52 mmol/L, HDL-C <2.59 mmol/L, safety and efficacy (LDL-C reduction) of evacetrapib 130 mg and LDL-C ≥4.14 mmol/L (JAS Category I3); LDL-C QD when added to atorvastatin 10 mg, as compared with ≥3.62 mmol/L (JAS Category II) or LDL-C ≥3.10 mmol/L atorvastatin 10 mg alone, in Japanese patients with hyper- (JAS Category III), and, as secondary prevention, LDL-C cholesterolemia. In addition, this study evaluated the safety ≥2.56 mmol/L for patients with a history of CAD. and efficacy of evacetrapib 130 mg QD relative to ezetimibe Patients were excluded if they were pregnant or breast- 10 mg QD with a background of atorvastatin 10 mg in the feeding, undergoing LDL apheresis or plasma apheresis, same population. had secondary hypercholesterolemia, homozygous familial An independent data-monitoring committee recom- hypercholesterolemia, clinically active hepatobiliary disease, mended that the ACCELERATE study, a global phase 3 or hemoglobin A1c (HbA1c) ≥8.4%, or were exposed to study conducted to evaluate the cardiovascular outcomes CETP inhibitors. Certain exclusion criteria were established and safety of evacetrapib in participants with high-risk to avoid enrolling high-risk cardiovascular disease patients.

Circulation Journal Vol.82, January 2018 Evacetrapib/Atorvastatin for Hypercholesterolemia 185

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 (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 carci- noma 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, non‑HDL-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 Figure 1. Patient flow. Laboratory Services, Indianapolis, IN, US). Concentra- tion 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 1 post-baseline visit. This study was terminated by sponsor of LDL-C was also measured using the β-quantification due to futility observed in the ACCELERATE study21 and method. The ultracentrifugation and the assay were the on-going patients in the present study were forced to performed by Pacific Biomarkers (Seattle, WA, US). The discontinue the study treatment by sponsor request. calculation for LDL-C was cholesterol in >1.006 density Because of this early termination by the sponsor, lipid data fraction minus HDL-C obtained by chemical precipitation. were collected for some patients after stopping the study . Lipid data collected at the final visit for Safety Assessments patients discontinued by sponsor decision were excluded The safety of evacetrapib was evaluated over 12 weeks by from the efficacy analyses. As a result, efficacy analyses means of treatment-emergent adverse events (TEAE), were conducted on the on-treatment FAS. Safety analyses TEAEs related to study drug, TEAEs leading to study were conducted on the safety analysis set, defined as all discontinuation, serious adverse events (SAE), vital signs, randomized patients who received at least 1 dose of study and clinical laboratory tests including serum potassium, treatment. chloride, and bilirubin. Standard laboratory tests, including The primary efficacy analysis of the primary variable chemistry and hematology panels, were performed. If a was done using a restricted maximum likelihood-based patient had ALT or AST >3×ULN or total bilirubin mixed-effects model for repeated measures (MMRM), with >2×ULN, clinical and laboratory monitoring were to be percent changes in LDL-C from baseline as response initiated by the investigator. A pregnancy test, when appli- variables; baseline measurement as a covariate; treatment, cable, was performed by a local laboratory at screening. visit, and treatment by-visit interaction as fixed effects; and patient as a random effect. Statistical Analysis For continuous measurements such as secondary efficacy All efficacy analyses were performed on the full analysis measures and change from baseline of vital signs, the set (FAS) on an intent-to-treat basis according to their MMRM model specified for the primary variable was randomized treatment. The FAS included all randomized applied. For measures with only 1 scheduled post-baseline patients receiving at least 1 dose of study drug with measurement, an analysis of covariance (ANCOVA) model evaluable LDL-C (β quantification) at baseline, and at least using last observation carried forward (LOCF) was applied

Circulation Journal Vol.82, January 2018 186 TERAMOTO T et al.

Table 1. Baseline Characteristics Evacetrapib Placebo Ezetimibe Total Variable 130 mg (n=53) (n=46) 10 mg (n=50) (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).

to analyze percent changes from baseline. Mean body mass index was 25.9 kg/m2. Mean LDL-C For categorical variables such as TEAEs, Fisher’s exact (β quantification) was 3.62 mmol/L, triglycerides were test was used for treatment comparison of the proportion 1.68 mmol/L, HDL-C was 1.43 mmol/L, non-HDL-C was of patients. All statistical comparisons were at the 2-sided 4.42 mmol/L, and LDL-C (direct) was 3.84 mmol/L. There 0.05 statistical significance level. Given that the ezetimibe were no statistically significant differences between the 10-mg group was included to assess the relative efficacy treatment groups in characteristics at baseline, except and safety in the same patient population as the evacetrapib tobacco use. In the ezetimibe group, 32.0% of the patients or the placebo group, and the study was not adequately used tobacco, compared with 52.8% (P=0.033) in the powered for comparisons with ezetimibe, all hypothesis evacetrapib group; and 54.3% (P=0.027) in the placebo tests of comparisons between the evacetrapib and ezetimibe group. 10-mg group were used for exploratory purposes. Evacetrapib 130 mg QD, when added to atorvastatin 10 mg, demonstrated superiority to placebo in mean percent Results change from baseline to week 12 in LDL-C (β quantifica- tion) in patients with primary hypercholesterolemia. The This study was conducted at 16 study centers in Japan difference in least squares (LS) mean change in the evace- (Fukuwa Clinic, Tokyo; Shinagawa East One Medical trapib group compared with the placebo group was Clinic, Tokyo; Tokyo Center Clinic, Tokyo; Tokyo-Eki −25.70% (95% CI: −34.73 to −16.68; P<0.001). Evacetrapib Center-building Clinic, Tokyo; Yaesu Sakura-dori Clinic, 130 mg QD resulted in a difference in LS mean change Tokyo; Yutenji Medical Clinic, Tokyo; Minami Akatsuka from baseline of −1.35 (95% CI: −10.02 to 7.31) compared Clinic, Ibaraki; Nishiyamado-Keiwa Hospital, Ibaraki; with ezetimibe (Table 2). Taga General Hospital, Ibaraki; Musashino Medical Evacetrapib 130 mg QD demonstrated superiority to Clinic, Saitama; Namegata District General Hospital, placebo in mean percent change from baseline to week 12 Ibaraki; Sayama General Clinic, Saitama; Suruga Clinic, in HDL-C in patients. The difference in LS mean change Shizuoka; AMC Nishi-Umeda Clinic, Osaka; Kajiyama from baseline in the evacetrapib group was 126.39% (95% Clinic, Kyoto; Okamoto Clinic, Hyogo). Of the 149 patients CI: 113.54–139.24; P<0.001) compared with the placebo who were randomized and dispensed the study drug (53 group. Evacetrapib 130 mg QD resulted in a difference in patients in the evacetrapib group; 50 in the ezetimibe LS mean change from baseline of 127.62% (95% CI: group; and 46 in the placebo group), all received at least 1 115.17–140.07) compared with ezetimibe 10 mg. dose of study drug and were included in the FAS popula- Treatment with evacetrapib 130 mg QD also resulted in tion and the safety analysis set (Figure 1). A total of 110 a statistically significant difference (P<0.001, all time points) patients completed the study and 39 patients (18 from the compared with placebo in LS mean percent changes in evacetrapib group, 8 from the ezetimibe group; and 13 LDL-C (β quantification) from baseline at week 2 (−33.34%; from the placebo group) were discontinued. Four patients 95% CI: −40.98 to −25.71), week 4 (−32.75%; 95% CI: (2.7%; 3 in the evacetrapib group, 1 in the ezetimibe group) −41.50 to −23.99), week 8 (−25.67%; 95% CI: −34.33 to were discontinued as a result of AE; 2 patients (1.3%; 1 in −17.00), and week 12 (−25.70%; 95% CI: −34.73 to −16.68). the evacetrapib group, 1 in the placebo group) withdrew Evacetrapib 130 mg QD resulted in a significant difference consent; 1 (0.67%; in the evacetrapib group) was discontinued (P<0.001) in LS mean change compared with ezetimibe as a result of a protocol violation; and 32 patients (21.5%) 10 mg of −13.31% (95% CI: −20.76 to −5.85) at week 2 and were discontinued as a result of the study termination by a non-significant difference of −6.73% (95% CI: −15.27 to the sponsor. 1.80) at week 4 and −1.21% (95% CI: −9.67 to 7.25) at All patients were Asian. Overall, the majority of patients week 8 (Figure 2). were male (55.0%). Mean age was 58.2 years (Table 1). Treatment with evacetrapib 130 mg QD resulted in a

Circulation Journal Vol.82, January 2018 Evacetrapib/Atorvastatin for Hypercholesterolemia 187

Table 2. Serum Lipids Percent Change From Baseline at Week 12† Evacetrapib Placebo Ezetimibe Lab measure 130 mg (n=37) (n=33) 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.

statistically significant difference (P<0.001, all time points) apoB/apoAI ratio from baseline to week 12, as well as compared with placebo in LS mean percent changes in compared with ezetimibe 10 mg in mean percent changes HDL-C from baseline at week 2 (115.52%; 95% CI: in HDL-C, Lp(a), apoAI, non-HDL-C/LDL-C ratio, and 106.07–124.97), week 4 (125.43%; 95% CI: 114.51–136.34), apoB/apoAI ratio (Table 2; P<0.001). and week 8 (132.78%; 95% CI: 120.40–145.17). No deaths or SAEs were reported during the double- Evacetrapib 130 mg QD resulted in statistically significant blind treatment period. Forty-three patients (n=18, 34.0% differences in LS mean percent change compared with in the evacetrapib group; n=12, 24.0% in the ezetimibe ezetimibe 10 mg of 115.98% (95% CI: 106.69–125.26) at group; and n=13, 28.3% in the placebo group) had TEAEs, week 2; 122.67% (95% CI: 111.96–133.38) at week 4; and of whom 9 patients (evacetrapib group, n=5, 9.4%; 129.62% (95% CI: 117.46–141.77) at week 8 (P<0.001, all ezetimibe group, n=3, 6.0%; placebo group, n=1, 2.2%) had time points). TEAEs that were deemed related to study drug (Table 3). Treatment with evacetrapib 130 mg resulted in statisti- There were no significant treatment differences in the cally significant differences compared with placebo in mean incidence of any TEAE. In the evacetrapib group, percent changes in LDL-C (direct), HDL-C, non-HDL-C, nasopharyngitis (n=3, 5.7%) and rash (n=2, 3.8%) were non-HDL-C/HDL-C ratio, Lp(a), apoAI, apoB, and the only TEAEs occurring in >3% of patients.

Circulation Journal Vol.82, January 2018 188 TERAMOTO T et al.

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 termina- tion 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. Figure 2. Percentage changes from baseline for (A) low- For the primary objective, to demonstrate the superiority density lipoprotein cholesterol (LDL-C; β quantification) and of evacetrapib 130 mg, when added to atorvastatin 10 mg, (B) high-density lipoprotein cholesterol (HDL-C) using mixed- vs. placebo on the mean percent change from baseline to model repeated measures, double-blind treatment period, full week 12 in LDL-C (β quantification), the evacetrapib group analysis set minus on-treatment analysis, excluding data at showed a statistically significant treatment difference of the discontinuation visit of the discontinued patients due to 25.70% improvement in LDL-C compared with placebo study termination. Atorvostatin 10 mg was background therapy for all patients. LS mean, least-squares mean. (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 Four patients (evacetrapib group, n=3, 5.7%; ezetimibe seen in the placebo group. group, n=1, 2.0%) were discontinued due to an AE. In the For the secondary objectives, treatment with evacetrapib evacetrapib group, TEAE of drug eruption, ulcerative colitis, 130 mg, when added to atorvastatin 10 mg, resulted in a and vertigo (1 patient each) resulted in discontinuation of statistically significant treatment difference of 126.39% study drug. All these events were mild in severity. improvement in HDL-C compared with placebo (P<0.001). Treatment with evacetrapib for 12 weeks, when added Statistically significant treatment differences were seen at to atorvastatin 10 mg, did not result in any adverse effects all time points compared with placebo for LDL-C (direct), on blood pressure. No statistically significant differences in non-HDL-C, non-HDL-C/HDL-C ratio, Lp(a), apoAI, SBP or DBP were observed between evacetrapib and apoB, and apoB/apoAI ratio (P<0.001). When compared placebo at weeks 2, 4, 8, or 12. With regard to pulse rate, with ezetimibe 10 mg, statistically significant differences there were no statistically significant differences, except at were seen in the evacetrapib group for HDL-C, Lp(a), week 8, when the LS mean change in pulse rate was apoAI, non-HDL-C/LDL-C ratio, and apoB/apoAI ratio −3.35 beats/min in the placebo group, compared with (P<0.001; Table 2). −0.57 beats/min in the evacetrapib group (P=0.036). The LDL-C reduction observed in this study is largely No clinically significant differences were observed at week consistent with the results of other evacetrapib studies,10,11 12 between the evacetrapib and placebo groups in mean including the phase 3 ACCENTUATE study of 366 change from baseline in serum sodium, serum potassium, patients, in which atorvastatin 40 mg QD plus evacetrapib

Circulation Journal Vol.82, January 2018 Evacetrapib/Atorvastatin for Hypercholesterolemia 189

Table 3. Safety Data Evacetrapib Placebo Ezetimibe 130 mg (total n=53) (total n=46) 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.

Table 4. BP and Mineralocorticoid Activity: Change From Baseline to Week 12 Evacetrapib Placebo Ezetimibe Lab measure 130 mg (n=42) (n=40) 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.

Circulation Journal Vol.82, January 2018 190 TERAMOTO T et al.

130 mg QD resulted in greater reductions in LDL-C, monotherapy group or in combination with atorvastatin. compared with ezetimibe (−27%, P=0.045).22 Similarly, in Additionally, a significant but small increase in mean SBP a phase 2 study with 165 Japanese patients, evacetrapib with evacetrapib treatment was detected in the 12,000-patient 30 mg QD monotherapy resulted in a statistically significant ACCELERATE study.20 Considering this small increase treatment difference compared with placebo of −15% (90% and the inherent variability in blood pressure measurements, CI: −24 to 7.4; P=0.002). These results were similar to it is not surprising that no increase in SBP was noted in the those for atorvastatin 10 mg QD plus evacetrapib 100 mg present small study. Additionally, a similar SBP increase QD, which resulted in a statistically significant treatment was reported in the atorvastatin monotherapy group in the difference of −15% (90% CI: −23 to −6.6) in LDL-C present study. No clinically significant changes in serum compared with placebo (P=0.003).11 sodium, serum potassium, chloride, or serum bicarbonate In a separate phase 2, multicenter, randomized, double- were reported, and there was no evidence of any adverse blind, parallel, placebo-controlled study of 398 patients with effect of evacetrapib on hepatic safety. elevated LDL-C or low HDL-C, evacetrapib monotherapy As for safety issues of particular interest in a Japanese (100 mg, QD, for 12 weeks) significantly increased pre-β patient population or findings in previous studies, 1 patient HDL compared with placebo (P<0.001).23 Increases in the evacetrapib group had a muscle-related TEAE compared with placebo were seen in the 30- and 500-mg (increased blood phosphokinase) of mild intensity that was doses as well. In the same study, evacetrapib significantly considered not related to the study treatment, but no reduced the concentration of apoB-containing lipoproteins, evacetrapib patients had CK >5×ULN. No clinically including Lp(a), total LDL particle, and small LDL particle. significant changes in CK compared with placebo were Treatment with evacetrapib resulted in a significant reported at any time point. increase in LDL particle size but had no consistent effect 24 on intermediate LDL or large LDL particle concentration. Conclusions It should be noted, however, that different methods for measuring LDL particle size have produced varied results Evacetrapib 130 mg QD, when added to atorvastatin 10 mg, for LDL particle subfractions. Yamashita et al, using was superior to placebo in lowering LDL-C and increasing polyacrylamide gel electrophoresis, reported that LDL HDL-C after 12 weeks in patients with primary hypercho- particles are large in heterozygotes and polydispersed in lesterolemia. Evacetrapib 130 mg QD was generally well homozygotes with CETP deficiency;25 Nicholls et al, using tolerated, and no new safety risks were identified. nuclear magnetic resonance spectroscopy, reported reduc- tions of total LDL particle (LDL-P) and small LDL particle Acknowledgment 24 (sLDL) concentration with evacetrapib treatment, whereas The authors wish to acknowledge Kent Steinriede, MS, of inVentiv Krauss et al, using ion mobility for measurement, reported Health Clinical for assistance with the manuscript. reductions of total LDL-P and sLDL 3a particle as well as increases in very small LDL 4b particle concentration with Disclosures 26 treatment. T.I. and Y.T. are employees of Eli Lilly Japan and own stock in the Use of evacetrapib in patients with hypocholesteremia company. J.S.R. and M.M. are employees of Eli Lilly and Company in another phase 2 study resulted in significant placebo- and own stock in the company. T.T. has receive remuneration from adjusted, dose-dependent decreases of sLDL concentration Bayer Yakuhin, Pfizer Japan, Daiichi Sankyo, Takeda Pharmaceutical 24 Company, Astellas Pharma, Kowa Pharmaceutical Company, Kissei up to 95%. Pharmaceutical., Sanofi, MSD, and AABP. A.K. has received Similarly, improvements in serum Lp(a) compared with remuneration from Astra Zeneca. T.T.’s institution has received placebo that we report are consistent with a separate phase scholarship funds or donations from Daiichi Sankyo, Kowa 2 study of 393 patients with hypercholesterolemia in which Pharmaceutical Company, Eli Lilly Japan, Takeda Pharmaceutical Company, and Shionogi. T.T.’s institution has received funding for evacetrapib as monotherapy or with statins, significantly department endowments from Bayer Yakuhin, Astellas Pharma, reduced Lp(a) concentration.24 Gaining an understanding ASKA Pharmaceutical, Kissei Pharmaceutical, Kowa Pharmaceutical of the causes of these changes, however, will require further Company, Mochida Pharmaceutical and MSD. study. The safety results from this study showed that 12-week Funding therapy with daily evacetrapib 130 mg, when added to This was a clinical study sponsored by Eli Lilly Japan. atorvastatin 10 mg, was safe and well-tolerated in Japanese patients with primary hypercholesterolemia. No deaths or References SAEs were reported, and there were no significant treatment 1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, differences in the incidence of any TEAE. Nine patients (5 Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the in the evacetrapib group, 3 in the ezetimibe group, and 1 in treatment of blood cholesterol to reduce atherosclerotic cardio- vascular risk in adults: A report of the American College of the placebo group) had TEAEs that were considered related Cardiology/American Heart Association Task Force on Practice to study drug (Table 3). Guidelines. Circulation 2014; 129: S1 – S45. In contrast to the phase 2 study of evacetrapib in 2. Reiner Z, Catapano AL, De BG, Graham I, Taskinen MR, Japanese patients, in which SBP significantly increased in Wiklund O, et al. ESC/EAS guidelines for the management of the evacetrapib 500-mg treatment group compared with dyslipidaemias: The Task Force for the management of dyslipi- 11 daemias of the European Society of Cardiology (ESC) and the placebo (5.9 [90% CI: −1.7 to 2.2]; P=0.021), treatment European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: with evacetrapib for 12 weeks, when added to atorvastatin 1769 – 1818. 10 mg, did not result in any adverse effects on blood pressure 3. Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et (Table 4). We interpret the SBP changes seen in the previous al. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic phase 2 study as an incidental occurrence for the reasons cardiovascular diseases in Japan–2012 version. J Atheroscler 11 described by Teramoto et al. In the phase 2 study, there Thromb 2013; 20: 517 – 523. was no dose-dependent effect on SBP in the evacetrapib 4. Okamura T, Tanaka H, Miyamatsu N, Hayakawa T, Kadowaki

Circulation Journal Vol.82, January 2018 Evacetrapib/Atorvastatin for Hypercholesterolemia 191

T, Kita Y, et al. The relationship between serum total cholesterol Exp 2012; 73: 16 – 40. and all-cause or cause-specific mortality in a 17.3-year study of a 16. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Japanese cohort. Atherosclerosis 2007; 190: 216 – 223. Theroux P, et al. Ezetimibe added to statin therapy after acute 5. Imano H, Noda H, Kitamura A, Sato S, Kiyama M, Sankai T, coronary syndromes. N Engl J Med 2015; 372: 2387 – 2397. et al. Low-density lipoprotein cholesterol and risk of coronary 17. Adams SP, Tsang M, Wright JM. Lipid lowering efficacy of heart disease among Japanese men and women: The Circulatory atorvastatin. Cochrane Database Syst Rev 2015; (3): CD008226. Risk in Communities Study (CIRCS). Prev Med 2011; 52: 381 – 18. Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and 386. meta-analysis on the therapeutic equivalence of statins. J Clin 6. Yvan-Charvet L, Kling J, Pagler T, Li H, Hubbard B, Fisher T, Pharm Ther 2010; 35: 139 – 151. et al. Cholesterol efflux potential and antiinflammatory properties 19. Teramoto T, Kashiwagi A, Mabuchi H, Lap I. Status of lipid- of high-density lipoprotein after treatment with or lowering therapy prescribed based on recommendations in the anacetrapib. Arterioscler Thromb Vasc Biol 2010; 30: 1430 – 1438. 2002 report of the Japan Atherosclerosis Society Guideline for 7. Castro-Perez J, Briand F, Gagen K, Wang SP, Chen Y, McLaren Diagnosis and Treatment of Hyperlipidemia in Japanese Adults: DG, et al. Anacetrapib promotes reverse cholesterol transport A study of the Japan Lipid Assessment Program (J-LAP). Curr and bulk cholesterol excretion in Syrian golden hamsters. J Lipid Ther Res Clin Exp 2005; 66: 80 – 95. Res 2011; 52: 1965 – 1973. 20. Nicholls SJ, Lincoff AM, Barter PJ, Brewer HB, Fox KAA, 8. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader Gibson CM, et al. Impact of the cholesteryl ester transfer protein DJ, Tall AR. Cholesteryl ester transfer protein: A novel target inhibitor evacetrapib on cardiovascular events: Results of the for raising HDL and inhibiting atherosclerosis. Arterioscler ACCELERATE trial (abstract). http://www.abstractsonline. Thromb Vasc Biol 2003; 23: 160 – 167. com/pp8/#!/3874/presentation/47087 (accessed April 4, 2017). 9. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, 21. Casteel B. Evacetrapib fails to reduce major adverse cardio- Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates vascular events. https://www.acc.org/about-acc/press-releases/ atherosclerosis in rabbits. Nature 2000; 406: 203 – 207. 2016/04/03/13/02/evacetrapib-fails-to-reduce-major-adverse- 10. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, cardiovascular-events (accessed April 6, 2017). Shao M, et al. Effects of the CETP inhibitor evacetrapib 22. Nicholls S, Ray K, Ballantyne C, Beacham L, Miller D, Rutolo administered as monotherapy or in combination with statins on G, et al. Comparative effects of cholesteryl ester transfer protein HDL and LDL cholesterol: A randomized controlled trial. inhibition, statin and ezetimibe therapy on atherogenic and JAMA 2011; 306: 2099 – 2109. protective lipid factors: The ACCENTUATE trial (abstract). 11. Teramoto T, Takeuchi M, Morisaki Y, Ruotolo G, Krueger KA. Atherosclerosis 2016; 252: e237 – e238. Efficacy, safety, tolerability, and pharmacokinetic profile of 23. Nicholls SJ, Ruotolo G, Brewer HB, Kane JP, Wang MD, evacetrapib administered as monotherapy or in combination Krueger KA, et al. Cholesterol efflux capacity and pre-beta-1 with atorvastatin in Japanese patients with dyslipidemia. Am J HDL concentrations are increased in dyslipidemic patients Cardiol 2014; 113: 2021 – 2029. treated with evacetrapib. J Am Coll Cardiol 2015; 66: 2201 – 2210. 12. Konrad RJ, Troutt JS, Cao G. Effects of currently prescribed 24. Nicholls SJ, Ruotolo G, Brewer HB, Wang MD, Liu L, Willey LDL-C-lowering drugs on PCSK9 and implications for the next MB, et al. Evacetrapib alone or in combination with statins lowers generation of LDL-C-lowering agents. Lipids Health Dis 2011; lipoprotein(a) and total and small LDL particle concentrations 10: 38. in mildly hypercholesterolemic patients. J Clin Lipidol 2016; 10: 13. Merck. Zetia package insert. https://www.merck.com/product/ 519 – 527. usa/pi_circulars/z/zetia/zetia_pi.pdf (accessed July 18, 2017). 25. Yamashita S, Matsuzawa Y, Okazaki M, Kako H, Yasugi T, 14. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Akioka H, et al. Small polydisperse low density lipoproteins in Suresh R, et al. Effect of ezetimibe coadministered with atorvas- familial hyperalphalipoproteinemia with complete deficiency of tatin in 628 patients with primary hypercholesterolemia: A cholesteryl ester transfer activity. Atherosclerosis 1988; 70: 7 – 12. prospective, randomized, double-blind trial. Circulation 2003; 26. Krauss RM, Pinto CA, Liu Y, Johnson-Levonas AO, Dansky 107: 2409 – 2415. HM. Changes in LDL particle concentrations after treatment 15. Teramoto T, Sawada T, Iwamoto K, Daida H. Clinical efficacy with the cholesteryl ester transfer protein inhibitor anacetrapib and tolerability of ezetimibe in combination with atorvastatin in alone or in combination with atorvastatin. J Clin Lipidol 2015; 9: Japanese patients with hypercholesterolemia. Curr Ther Res Clin 93 – 102.

Circulation Journal Vol.82, January 2018