Abstract
Aim: We evaluated the efficacy and safety of bempedoic acid, an ATP-citrate lyase inhibitor, at doses of 60, 120, and 180 mg, administered for 12 weeks in conjunction with ongoing treatments (e.g., statin and/or other lipid-modifying therapy) and determined the phase 3 trial dosage in Japanese patients.
Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b trial included patients with hypercholesterolemia at risk for cardiovascular events and an inadequate response to statins/statin intolerance. The percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 12 was calculated.
Results: The bempedoic acid 60 mg, 120 mg, 180 mg, and placebo groups included 47, 46, 48, and 47 patients, respectively; 79% of patients had an inadequate response to statins and 21% had statin intolerance. Relative to placebo (–1.9%), LDL-C reduction from baseline to week 12 was significantly greater in the bempedoic acid treatment groups (least squares mean: 60 mg, −10.6%; 120 mg, −21.9%; 180 mg, −21.3%; p＜0.01 vs. placebo). Patients with an inadequate response and statin intolerance who were treated with bempedoic acid showed improved LDL-C levels by week 12. The incidence of treatment-emergent adverse events was higher in the bempedoic acid-treated groups (60 mg, 57.4%; 120 mg, 54.3%; and 180 mg, 58.3%) than in the placebo group (38.3%). There was no increasing trend with increasing doses. Adverse events related to muscular and hepatic disorders were infrequent, and no new or worsening cases of diabetes were reported.
Conclusions: The efficacy and safety of bempedoic acid in Japanese patients with elevated LDL-C levels were confirmed. The 180 mg dosage of bempedoic acid was found to be appropriate for a Japanese phase 3 trial.
Trial registration: NCT02072161
Introduction
In recent years, the incidence of cardiovascular disease, particularly high-risk atherosclerotic cardiovascular disease (ASCVD), has increased in Japan1-5). This is associated with contributing factors, such as a growing aging population and an increase in the frequency of hypercholesterolemia, and lifestyle changes6-8). In a recent study, the lifetime risk of coronary heart disease, a measure of disease burden, was found to be 47.2% in hypercholesterolemic men of 45 years of age and 44.5% in hypercholesterolemic men of 75 years of age. The study concluded that hypercholesterolemia increases the lifetime risk of coronary heart disease in the Japanese population9).
Preventing cardiovascular diseases is vital for reducing the healthcare burden, particularly given Japan’s large elderly population6). Many global trials have shown that lowering lipid levels, specifically low-density lipoprotein cholesterol (LDL-C), can reduce cardiovascular risk10). Indeed, LDL-C-modifying therapies lower the risk of cardiovascular events and mortality because they slow the progression of ASCVD, resulting in better cardiovascular outcomes11, 12).
The 2017/2022 guidelines from the Japan Atherosclerosis Society (JAS) for preventing ASCVDs recommend targeting LDL-C levels to reduce the risk of cardiovascular disease. Guidelines propose using statins as a first-line treatment to decrease LDL-C13). A recent cross-sectional study showed that among Japanese patients at high risk for ASCVD, 23.5% of patients without a history of coronary artery disease and 70.5% of patients with a history of coronary artery disease did not achieve their LDL-C targets14). In that study, many patients were treated with statin monotherapy; combination therapy may address the treatment gaps for these patients who are at high risk for ASCVD.
In cases in which statins are ineffective, combination therapy with drugs that have a different mechanism of action than statins has been used. However, some patients, such as those with familial hypercholesterolemia (FH), still have inadequate LDL-C levels. Furthermore, some statin users experience statin intolerance defined as the inability to use statins due to adverse events (AEs), such as those affecting skeletal muscle tissue15). For patients who still have inadequate control or who develop statin intolerance with statins alone or in combination, agents with new mechanisms of action are needed.
Bempedoic acid is a prodrug activated in the liver by very long-chain acyl-CoA synthetase-1 (ACSVL1). Activated bempedoic acid inhibits ATP-citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-CoA reductase, which is the target of statins, in the cholesterol biosynthesis pathway. In a global trial, bempedoic acid was administered as an add-on to patients who had an inadequate response to the maximum tolerated dose of statins, and it improved LDL-C levels16). Furthermore, bempedoic acid lowered LDL-C levels and prevented cardiovascular events in a high-risk group with statin intolerance17). Although bempedoic acid has been approved overseas, comprehensive studies evaluating its LDL-C-lowering effect and safety at 60, 120, and 180 mg dosages versus placebo have not been conducted in the Japanese population.
Aim
The objectives of this study were to: (1) assess the LDL-C-lowering effect and safety of bempedoic acid at 60, 120, and 180 mg versus placebo when administered for 12 weeks in combination with ongoing cholesterol-lowering drugs in patients with hypercholesterolemia who have inadequate control of LDL-C; (2) characterize the dose-response of bempedoic acid; and (3) investigate the appropriate doses for a phase 3 trial in a Japanese population.
Methods
Study Design
This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2b trial conducted was at 48 sites in Japan from March 24, 2021, to May 17, 2022. The trial consisted of screening, placebo run-in, treatment, and follow-up periods. Patients determined to be eligible during the screening period proceeded to the placebo run-in period. They received placebo tablets in a single-blind manner and continued with previous hypercholesterolemia treatment without changing the type, dose, and regimen taken before providing their informed consent.
Based on phase 3 studies overseas16, 18-20), the recommended clinical dose in the U.S. and Europe is 180 mg/day. A 120 mg/day group was included in this study, as this dose was included in several overseas phase 2 studies21, 22). A 60 mg/day group was established to confirm the dose response in Japanese patients.
Eligible patients underwent a 4-week placebo run-in phase before randomization. Patients who experienced adverse effects while on placebo, those who achieved the target LDL-C, and those who had low drug compliance during the placebo run-in phase were excluded. The rationale for this is described in the Supplementary Methods.
During the treatment period, patients continued taking cholesterol-lowering drugs that were taken before they provided their informed consent and received either placebo or bempedoic acid orally (60, 120, or 180 mg/day) for 12 weeks. The investigator performed a follow-up visit 28 days (±7 days) after the last administration date for all patients who proceeded to the treatment period (Supplementary Fig.1).
During the study, patients were required to maintain the following lifestyle limitations. To ensure an accurate evaluation of bempedoic acid, the patient’s diet, alcohol, and tobacco intake should not have changed from week −4 to week 12 of the study. Accordingly, exercise therapy should have remained consistent, and strenuous exercise should have been avoided during the study period to prevent any influence on clinical laboratory values.
Patients
The target population included patients with hypercholesterolemia who were at risk for cardiovascular events and were receiving treatment with cholesterol-lowering drugs, but who had inadequate control and who could not achieve their lipid management goals due to an insufficient response to statins or statin intolerance. The study population included adult patients (20–74 years of age) with hypercholesterolemia, an inadequate statin effect or statin intolerance, a risk of developing cardiovascular events, fasting triglyceride levels of ＜400 mg/dL, and a body mass index of 18–35 kg/m2.
Patients with an inadequate response to statins were those with hypercholesterolemia who had been taking statins (atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, or fluvastatin) with or without cholesterol-lowering drugs other than statins. Statin intolerance was defined as discontinuing ≥ 1 statin at any dose because of AEs (e.g., muscle-related symptoms) that resolved after discontinuation or dose reduction of statin. For the detailed selection criteria for LDL-C, and definitions of an inadequate response to statins and statin intolerance, see Supplementary Methods.
The main exclusion criteria were as follows: a diagnosis of homozygous familial hypercholesterolemia; a history of cardiovascular diseases within 3 months prior to week −5, uncontrolled hypertension, uncontrolled and serious hematologic diseases or complications of coagulopathy, hypothyroidism, liver disease or hepatic insufficiency, chronic musculoskeletal symptoms or complications challenging to distinguish from myalgia, renal dysfunction, nephritis syndrome, or history or complication of nephritis and with an estimated glomerular filtration rate of ≤ 30 mL/min/1.73 m2 at week −5 (Visit S1); patients with type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus; creatine kinase levels ＞3 times the upper reference limit at week −5 (Visit S1); gastrointestinal surgical procedures that could affect drug absorption; surgery, chemotherapy, or radiation therapy for active malignancy within the past 5 years prior to week −5 (Visit S1); use of drugs not approved in Japan within 4 weeks prior to week −5 (Visit S1) or within 5 times the half-life of the drug, whichever was longer; use of unapproved concomitant drugs; patients who had taken＜80% of single-blind placebo tablets by day 1 (Visit T1) or who were unable to continue taking placebo tablets because of safety issues; new or worsening myopathy-related AEs during the placebo run-in period; or other patients whom the investigator determined should not participate in this study. The full exclusion criteria are listed in the Supplementary Methods.
Randomization and Blinding
Patients were randomized in a 1:1:1:1 ratio to bempedoic acid 60 mg/day, 120 mg/day, 180 mg/day, or placebo once daily for 12 weeks, in addition to ongoing cholesterol-lowering drugs. To ensure that patients with statin intolerance were equally assigned to each treatment group, the statin response (inadequate response to statins or statin intolerance) was used as a stratification factor.
Study Endpoints
The primary endpoint was the percentage change in LDL-C level from baseline to week 12. The secondary endpoints were percentage changes from baseline in high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), triglyceride (TG), apolipoprotein B, high-sensitivity C-reactive protein (hs-CRP), and glycated hemoglobin (HbA1c) levels at 12 weeks, as well as the proportion of patients whose LDL-C levels met the lipid management goals based on risk assessment (＜100 mg/dL [history of coronary artery disease or heterozygous familial hypercholesterolemia],＜120 mg/dL [high risk], or ＜140 mg/dL [intermediate risk]).
Other Assessments
Time-course changes in LDL-C levels were assessed at each time point during the treatment period. Subgroup analyses by statin response, inadequate response to statins or intolerance to statins, and the presence of diabetes mellitus were also conducted.
The safety assessments included AEs, clinical laboratory tests, physical examination, vital signs (blood pressure, pulse rate, and body temperature), body weight, and 12-lead electrocardiogram.
Statistical Analysis
The difference in the percentage change in LDL-C from baseline at 12 weeks in the bempedoic acid group relative to the placebo group in two overseas phase 3 studies was −18.1% and −17.42% in patients with a history of ASCVD and/or heterozygous familial hypercholesterolemia (HeFH) taking maximally tolerated statins16, 19), and −21.41% and −28.45% in two studies on patients with statin intolerance18, 20). The difference between the bempedoic acid and placebo groups in patients with statin ineffectiveness was 17%, and the difference between the bempedoic acid and placebo groups in statin-intolerant patients was estimated to be 25%. In this trial, we assumed that statin-intolerant patients would be enrolled at a rate of 20%, and that the difference in the bempedoic acid group versus the placebo group in the overall population would be 19%. Based on the results of phase 3 studies16, 18-20), assuming a 19% difference and 25% standard deviation (SD) in the percentage change in LDL-C from baseline at 12 weeks in the bempedoic acid group versus the placebo group, 38 patients per group would be needed to ensure 90% power with a two-tailed test at a 5% significance level. Assuming that 12.5% of the patients would discontinue or drop out, the target number of patients to be randomly assigned was set at 44 patients per treatment group.
The safety analysis set was defined as patients who received at least one dose of bempedoic acid during treatment. The full analysis set was defined as all patients who received at least one dose of bempedoic acid during the treatment period and whose LDL-C levels were measured at baseline (baseline for efficacy endpoints) and at least one post-dose visit (up to 2 days after the final bempedoic acid administration).
An analysis of covariance (ANCOVA) was performed for the primary efficacy endpoint of the percentage change from baseline in LDL-C at week 12. The ANCOVA was performed using the treatment group and statin response (inadequate response to statins/statin intolerance) as factors, and the baseline value for each endpoint as a covariate.
For the primary analysis of the primary endpoint, missing LDL-C values were imputed using the last value observed after the initial bempedoic acid administration, up to 2 days after the final bempedoic acid administration. For the analysis of the percentage change from baseline to week 12 for secondary endpoints and the proportion of patients achieving the lipid management goals of LDL-C, missing values were handled in the same manner as above.
An ANCOVA was also used to analyze the percentage change from baseline in secondary efficacy parameters and the subgroup analysis by statin response, sex, familial hypercholesterolemia, diabetes mellitus, age, and cholesterol-lowering drugs. For a multiplicity analysis, the overall type I error rate was controlled by comparing the placebo group with the highest bempedoic acid dose group, using a closed testing procedure at a 2-sided significance level of 0.05. All statistical analyses were performed using SAS (version 9.4; SAS Institute Inc., Cary, NC, USA).
Ethical Considerations
This clinical trial followed the guidelines set by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice Consolidated Guidelines, and the local laws and regulatory requirements of Japan and its conduct adhered to the principles of the Declaration of Helsinki.
Before the trial began, the institutional review board reviewed and approved the protocol, amendments, and informed consent forms for each investigation site involved. All patients provided their informed consent before the commencement of the study.
Results
Patient Disposition and Baseline Characteristics
In this trial, 188 patients were randomly assigned to the following groups: bempedoic acid 60 mg (n = 47), bempedoic acid 120 mg group (n = 46), bempedoic acid 180 mg group (n = 48), and the placebo group (n = 47). A total of 182 patients completed the treatment period (44 patients in the 60 mg group, 46 patients in the 120 mg group, 46 patients in the 180 mg group, and 46 patients in the placebo group). A total of 6 patients discontinued during the treatment period (3 patients in the 60 mg group, 2 in the 180 mg group, and 1 in the placebo group). The reasons for discontinuation were treatment-emergent AEs (TEAEs) in 1 patient in the 60 mg group, 2 patients in the 180 mg group, and 1 patient in the placebo group; non-compliance with study drug in 1 patient in the 60 mg group; and protocol deviation in 1 patient in the 60 mg group (Fig.1).
The distribution of demographics and other baseline characteristics were similar among the treatment groups (Table 1). Most patients in each dose and placebo group were male (60 mg, 64.4%; 120 mg, 65.2%; 180 mg, 66.7%; placebo, 74.5%). The mean±SD age was 60.9±9.3 years (60 mg), 60.4±8.9 years (120 mg), 60.4±12.0 years (180 mg), and 63.0±10.7 years (placebo). The mean±SD body mass index (BMI) was 24.4±4.1 kg/m2 (60 mg), 26.0±3.9 kg/m2 (120 mg), 26.1±3.5 kg/m2 (180 mg), and 25.4±3.6 kg/m2 (placebo).
Table 1.Baseline demographic and clinical characteristics
| Characteristic |
Placebo
(n = 47)
|
Bempedoic acid 60 mg
(n = 45)
|
Bempedoic acid 120 mg
(n = 46)
|
Bempedoic acid 180 mg
(n = 48)
|
| Age, years, mean±SD |
63.0±10.7 |
60.9±9.3 |
60.4±8.9 |
60.4±12.0 |
| Male |
35 (74.5) |
29 (64.4) |
30 (65.2) |
32 (66.7) |
| Weight, kg, mean±SD |
68.9±12.5 |
65.5±13.6 |
70.4±13.1 |
69.3±12.2 |
| Body mass index, kg/m2, mean±SD
|
25.4±3.6 |
24.4±4.1 |
26.0±3.9 |
26.1±3.5 |
| Familial hypercholesterolemia |
| Yes - HeFH |
11 (23.4) |
10 (22.2) |
11 (23.9) |
16 (33.3) |
| Yes - HoFH |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
| Risk category |
|
HeFH or history of
coronary artery disease
|
33 (70.2) |
32 (71.1) |
34 (73.9) |
33 (68.8) |
| High risk |
14 (29.8) |
11 (24.4) |
8 (17.4) |
15 (31.3) |
| Diabetes mellitus |
| No |
25 (53.2) |
28 (62.2) |
28 (60.9) |
18 (37.5) |
| Yes |
22 (46.8) |
17 (37.8) |
18 (39.1) |
30 (62.5) |
| Statin response |
| Inadequate response to statins |
37 (78.7) |
35 (77.8) |
37 (80.4) |
38 (79.2) |
| Statin intolerance |
10 (21.3) |
10 (22.2) |
9 (19.6) |
10 (20.8) |
| Systolic blood pressure, mmHg, mean±SD |
123.9±13.7 |
126.3±21.2 |
128.8±12.6 |
127.3±18.5 |
| Diastolic blood pressure, mmHg, mean±SD |
76.8±10.6 |
77.1±12.1 |
79.8±10.1 |
77.4±11.9 |
| Apolipoprotein B, mg/dL, mean±SD |
100.7±12.1 |
99.6±15.2 |
98.3±14.9 |
97.8±13.0 |
| Non-HDL-C, mg/dL, mean±SD |
162.9±23.4 |
163.2±28.4 |
162.7±32.7 |
159.5±23.4 |
| Total cholesterol, mg/dL, mean±SD |
214.2±26.8 |
218.1±32.5 |
214.4±35.1 |
211.2±25.8 |
| HDL-C, mg/dL, mean±SD |
51.3±11.4 |
54.9±15.4 |
51.7±14.9 |
51.6±11.6 |
| Triglycerides, mg/dL, mean±SD |
140.0±57.6 |
126.0±72.3 |
131.2±45.0 |
120.7±46.6 |
| hs-CRP, mg/dL, mean±SD |
0.075±0.089 |
0.070±0.104 |
0.166±0.439 |
0.455±2.110 |
| HbA1c, %, mean±SD |
6.4±0.8 |
6.2±0.7 |
6.2±0.6 |
6.6±0.8 |
Data are presented as n (%) unless otherwise stated.
HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; hs-CRP, high-sensitivity C-reactive protein; SD, standard deviation.
The percentages of patients classified as having HeFH or with a history of coronary artery disease were 71.1% (60 mg), 73.9% (120 mg), 68.8% (180 mg), and 70.2% (placebo). The percentage of patients with an inadequate response to statins was 79%, and the percentage of patients classified as statin-intolerant was 21%. The treatment compliance in each bempedoic acid treatment group was ≥ 90%.
Study Endpoints
Primary Endpoint
In patients with an inadequate response to statins or statin intolerance, the baseline mean LDL-C values were 134.7±20.6 mg/dL (placebo), 135.4±25.4 mg/dL (60 mg), 134.9±31.8 mg/dL (120 mg), and 133.7±21.0 mg/dL (180 mg). At week 12, treatment with bempedoic acid resulted in greater reductions in LDL-C in each bempedoic acid treatment group (60 mg: −10.6%, 120 mg: −21.9%, 180 mg: −21.3%) relative to placebo (−1.9%), and the difference from placebo in the least squares means was statistically significant in each treatment group (p＜0.01) (Table 2). The extent of LDL-C reduction in the 120 mg and 180 mg groups was more marked than in the 60 mg group (Fig.2).
Table 2.Percentage change in LDL-C levels from baseline to week 12
|
Placebo (n = 47)
|
Bempedoic acid 60 mg
(n = 45)
|
Bempedoic acid 120 mg
(n = 46)
|
Bempedoic acid 180 mg
(n = 48)
|
| Primary endpoint
|
| LDL-C, mg/dL, mean±SD |
|
| Baseline |
134.7±20.6 |
135.4±25.4 |
134.9±31.8 |
133.7±21.0 |
| Week 12 (LOCF) |
133.9±19.3 |
121.9±25.0 |
107.4±27.9 |
106.8±24.5 |
|
Percentage change from baseline,
LS mean±SE
|
−1.9±2.1 |
−10.6±2.2 |
−21.9±2.2 |
−21.3±2.1 |
|
Treatment difference (treatment − placebo),
LS mean±SE
|
- |
−8.7±2.8 |
−19.9±2.8 |
−19.4±2.8 |
| 95% CI |
- |
(−14.2, −3.1) |
(−25.5, −14.4) |
(−24.8, −13.9) |
| p-value
|
- |
0.002 |
＜0.001 |
＜0.001 |
| Subgroup analyses
|
| Inadequate response to statins
|
| LDL-C, mg/dL |
|
| Baseline, n
|
37 |
35 |
37 |
38 |
| Baseline, mean±SD |
130.0±18.5 |
129.9±21.0 |
128.2±24.0 |
127.8±14.3 |
| Week 12 (LOCF), n
|
37 |
35 |
37 |
38 |
| Week 12 (LOCF), mean±SD |
128.5±16.0 |
122.0±25.6 |
104.6±21.2 |
107.0±26.8 |
|
Percentage change from baseline,
LS mean±SE
|
−0.3±2.3 |
−5.5±2.4 |
−18.1±2.3 |
−16.3±2.3 |
|
Treatment difference (treatment − placebo),
LS mean±SE
|
- |
−5.2±3.3 |
−17.8±3.3 |
−16.0±3.2 |
| 95% CI |
- |
(−11.7, 1.3) |
(−24.3, −11.4) |
(−22.4, −9.6) |
| p-value
|
- |
0.118 |
＜0.001 |
＜0.001 |
| Statin intolerance
|
| LDL-C, mg/dL |
|
| Baseline, n
|
10 |
10 |
9 |
10 |
| Baseline, mean±SD |
152.3±19.2 |
154.6±31.1 |
162.3±45.1 |
156.5±27.2 |
| Week 12 (LOCF), n
|
10 |
10 |
9 |
10 |
| Week 12 (LOCF), mean±SD |
153.8±17.8 |
121.5±24.1 |
119.1±46.6 |
106.0±13.6 |
|
Percentage change from baseline,
LS mean±SE
|
1.0±3.1 |
−20.4±3.1 |
−27.4±3.3 |
−31.3±3.1 |
|
Treatment difference (treatment − placebo),
LS mean±SE
|
- |
−21.4±4.4 |
−28.4±4.6 |
−32.3±4.4 |
| Two-sided 95% CI |
- |
(−30.4, −12.5) |
(−37.7, −19.2) |
(−41.2, −23.3) |
| p-value
|
- |
＜0.001 |
＜0.001 |
＜0.001 |
The baseline was defined as the mean of the values from week −1 and day 1. When LDL-C at week 12 was missing, the missing value was imputed using the LOCF from the start of IMP administration to 2 days after the final IMP administration. n is the number of patients with non-missing values at baseline and at week 12.
The LS mean, SE, 95% CI, and p-value were obtained from an analysis of covariance model with the treatment group as factors and the baseline as a covariate.
Common treatment differences and confidence intervals were calculated using the Mantel–Haenszel stratum weights and Sato variance estimator. When each value at week 12 was missing, the missing values were imputed using the LOCF from the start of IMP administration to 2 days after the final IMP administration.
LDL-C, low-density lipoprotein cholesterol; CI, confidence interval; IMP, investigational medicinal product; LOCF, last observation carried forward; LS, least squares; SD, standard deviation; SE, standard error.
Table 3 shows percentage changes from baseline in HDL-C, non-HDL-C, TC, TG, apolipoprotein B, hs-CRP, and HbA1c at week 12. The percentage changes in non-HDL-C, TC, and apolipoprotein B at week 12 were significantly larger in all bempedoic acid-treated groups than in the placebo group.
Table 3.Percentage changes in lipid, hs-CRP levels, and HbA1c from baseline to week 12, full analysis set (LOCF)
|
Placebo
(n = 47)
|
Bempedoic acid 60 mg
(n = 45)
|
Bempedoic acid 120 mg
(n = 46)
|
Bempedoic acid 180 mg
(n = 48)
|
| Secondary endpoints |
| Apolipoprotein B |
−2.1±1.7 |
−8.2±1.7＊＊
|
−14.6±1.7＊＊
|
−12.5±1.7＊＊
|
| Non-HDL-C |
−1.6±2.0 |
−8.9±2.0＊＊
|
−18.3±2.0＊＊
|
−16.0±2.0＊＊
|
| Total cholesterol |
−0.6±1.6 |
−6.4±1.7＊＊
|
−13.6±1.7＊＊
|
− 13.6±1.6＊＊
|
| HDL-C |
3.1±2.2 |
0.2±2.2 |
−0.7±2.2 |
−7.3±2.1＊＊
|
| Triglycerides |
−0.1±6.2 |
−9.1±6.3 |
−5.6±6.3 |
9.2±6.2 |
| hs-CRP |
1.0±61.5 |
150.5±62.5 |
1.0±62.4 |
−34.6±62.7 |
| HbA1c |
−0.1±0.6 |
0.1±0.6 |
−0.4±0.6 |
−0.2±0.6 |
Values represent the least squares mean±standard error unless otherwise indicated. For fasting lipid endpoints, the baseline was defined as the mean value from week −1 and day 1. For other endpoints, the baseline was defined as day 1. For week 12 (last observation carried forward [LOCF]), when each value at week 12 was missing, the missing value was imputed using the LOCF from the start of IMP administration to 2 days after the final IMP administration. The LS mean, SE, and p-value are from an analysis of the covariance model with the treatment group and statin response (inadequate response to statins/statin intolerance) as factors and the baseline as a covariate.
＊p＜0.05 vs. placebo, ＊＊p＜0.01 vs. placebo.
p values vs. placebo are from the Wilcoxon rank-sum test.
HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; IMP, investigational medicinal product; LS, least squares; hs-CRP, high-sensitivity C-reactive protein; mITT, modified intention-to-treat; SE, standard error.
The proportion of patients whose LDL-C levels reached the lipid management goals was significantly higher in the bempedoic acid 120 mg and 180 mg groups (p＜0.05, each) than in the placebo group at week 2 (Supplementary Table 1), and remained higher than in the placebo group until week 12 (Supplementary Table 1 and Table 2).
Supplementary Table 1.Number of patients who achieved target LDL-C values
|
Placebo
(n = 47)
|
Bempedoic acid 60 mg
(n = 45)
|
Bempedoic acid 120 mg
(n = 46)
|
Bempedoic acid 180 mg
(n = 48)
|
|
Number of patients who achieved the target value
/evaluated in LDL-C at week 2a (two-sided 95% CI)
|
6/47 (12.8) |
8/45 (17.8) |
22/46 (47.8) |
23/48 (47.9) |
|
(4.8, 25.7) |
(8.0, 32.1) |
(32.9, 63.1) |
(33.3, 62.8) |
|
Treatment difference (treatment − placebo)b
(two-sided 95% CI)
|
- |
5.1 (−9.6, 19.7) |
35.2 (17.9, 52.6) |
35.1 (18.1, 52.2) |
| p-value
|
- |
0.501 |
＜0.001 |
＜0.001 |
|
Number of patients who achieved the target value
/evaluated in LDL-C at week 4 a
|
2/46 (4.3) |
11/45 (24.4) |
21/46 (45.7) |
27/48 (56.3) |
|
(0.5, 14.8) |
(12.9, 39.5) |
(30.9, 61.0) |
(41.2, 70.5) |
|
Treatment difference
(treatment − placebo) b (two-sided 95% CI)
|
- |
20.1 (6.3, 34.0) |
41.5 (25.8, 57.2) |
51.8 (36.6, 67.0) |
| p-value
|
- |
0.007 |
＜0.001 |
＜0.001 |
|
Number of patients who achieved the target value
/evaluated in LDL-C at week 12 (LOCF) a
|
1/47 (2.1) |
15/45 (33.3) |
26/46 (56.5) |
28/48 (58.3) |
|
(0.1, 11.3) |
(20.0, 49.0) |
(41.1, 71.1) |
(43.2, 72.4) |
|
Treatment difference
(treatment−- placebo) b (two-sided 95% CI)
|
- |
31.1 (16.7, 45.5) |
54.5 (39.5, 69.4) |
56.2 (41.7, 70.7) |
| p-value
|
- |
＜0.001 |
＜0.001 |
＜0.001 |
95%CI, and p-value were from an analysis of covariance model with the treatment group as factors and the baseline as a covariate.
a Confidence interval was calculated using exact confidence limits. b Treatment difference was based on Cochran–Mantel–Haenszel test with statin response as a stratified factor. Common treatment differences and confidence intervals were calculated using the Mantel–Haenszel stratum weights and Sato variance estimator. When each value at week 12 was missing, the missing values were imputed using the LOCF from the start of IMP administration to 2 days after the final IMP administration.
LDL-C, low-density lipoprotein cholesterol; CI, confidence interval; IMP, investigational medicinal product; LOCF, last observation carried forward; SE, standard error.
Regarding the time-course changes in LDL-C during the treatment period, in each bempedoic acid dose group, the LDL-C level decreased from baseline at 2 weeks, and this reduction was maintained at each time point until 12 weeks.
Subgroup Analysis
Significant differences were observed in the percentage changes in LDL-C in the bempedoic acid 120 mg and 180 mg groups relative to placebo (p＜0.05, each) among the subpopulation with an inadequate response to statins and in all three groups (p＜0.05, each) of patients with statin intolerance (Table 2 and Fig.3).
The percentage change in LDL-C from baseline to week 12 was -0.3% (placebo); -5.5% (60 mg); -18.1% (120 mg); -16.3% (180 mg) in the inadequate response to statins subgroup, and 1.0% (placebo); -20.4% (60 mg); -27.4% (120 mg); -31.3% (180 mg) in the statin-intolerant subgroup.
Safety
The mean duration of exposure was 82.7 days (placebo), 80.1 days (60 mg), 83.9 days (120 mg), and 82.2 days (180 mg). The incidence of TEAEs was 38.3% (18/47 patients) (placebo), 57.4% (27/47 patients) (60 mg), 54.3% (25/46 patients) (120 mg), and 58.3% (28/48 patients) (180 mg) (Table 4). The incidence of study drug-related TEAEs was 4.3% (2/47 patients) (placebo), 10.6% (5/47 patients) (60 mg), 10.9% (5/46 patients) (120 mg), and 20.8% (10/48 patients) (180 mg). No deaths occurred during the trial.
Table 4.Overview of adverse events, treatment-emergent adverse events (TEAEs), and TEAEs occurring in ≥ 2 patients of any Group by MedDRA Preferred Term - Safety Analysis Set
| Characteristic |
Placebo
(n = 47)
|
Bempedoic acid 60 mg
(n = 47)
|
Bempedoic acid 120 mg
(n = 46)
|
Bempedoic acid 180 mg
(n = 48)
|
| Overview of AEs |
| Any AEs |
23 (48.9) |
32 (68.1) |
28 (60.9) |
30 (62.5) |
| Patients with TEAEs |
18 (38.3) |
27 (57.4) |
25 (54.3) |
28 (58.3) |
| Serious TEAEs＊
|
1 (2.1) |
0 (0.0) |
0 (0.0) |
1 (2.1) |
| Subjects with study-drug related TEAEs†
|
2 (4.3) |
5 (10.6) |
5 (10.9) |
10 (20.8) |
| Discontinuation due to AEs |
1 (2.1) |
1 (2.1) |
0 (0.0) |
2 (4.2) |
| Most common TEAEs‡
|
| Upper abdominal pain |
0 (0.0) |
4 (8.5) |
1 (2.2) |
0 (0.0) |
| Diarrhea |
1 (2.1) |
3 (6.4) |
1 (2.2) |
1 (2.1) |
| Large intestine polyp |
0 (0.0) |
0 (0.0) |
2 (4.3) |
0 (0.0) |
| Pyrexia |
2 (4.3) |
5 (10.6) |
4 (8.7) |
1 (2.1) |
| Malaise |
0 (0.0) |
1 (2.1) |
3 (6.5) |
3 (6.3) |
| Fatigue |
0 (0.0) |
2 (4.3) |
1 (2.2) |
1 (2.1) |
| Vaccination complication |
0 (0.0) |
2 (4.3) |
0 (0.0) |
2 (4.2) |
| Vaccination site pain |
1 (2.1) |
1 (2.1) |
3 (6.5) |
0 (0.0) |
| Vaccination site swelling |
0 (0.0) |
0 (0.0) |
2 (4.3) |
1 (2.1) |
| Abnormal hepatic function |
0 (0.0) |
2 (4.3) |
0 (0.0) |
5 (10.4) |
| Nasopharyngitis |
0 (0.0) |
2 (4.3) |
1 (2.2) |
1 (2.1) |
| Otitis externa |
0 (0.0) |
0 (0.0) |
2 (4.3) |
0 (0.0) |
| Increased alanine aminotransferase |
2 (4.3) |
0 (0.0) |
2 (4.3) |
3 (6.3) |
| Increased aspartate aminotransferase |
1 (2.1) |
0 (0.0) |
2 (4.3) |
2 (4.2) |
| Increased blood creatine phosphokinase |
0 (0.0) |
1 (2.1) |
1 (2.2) |
2 (4.2) |
| Increased blood lactate dehydrogenase |
0 (0.0) |
0 (0.0) |
0 (0.0) |
2 (4.2) |
| Increased blood uric acid |
0 (0.0) |
2 (4.3) |
3 (6.5) |
1 (2.1) |
| Hyperuricemia |
0 (0.0) |
0 (0.0) |
2 (4.3) |
3 (6.3) |
| Headache |
0 (0.0) |
0 (0.0) |
5 (10.9) |
2 (4.2) |
| Skin and subcutaneous tissue disorders |
2 (4.3) |
1 (2.1) |
0 (0.0) |
3 (6.3) |
| Eczema |
2 (4.3) |
1 (2.1) |
0 (0.0) |
3 (6.3) |
| Musculoskeletal and connective tissue disorders |
5 (10.6) |
5 (10.6) |
5 (10.9) |
5 (10.4) |
| Arthralgia |
0 (0.0) |
3 (6.4) |
2 (4.3) |
2 (4.2) |
| Back pain |
2 (4.3) |
1 (2.1) |
2 (4.3) |
0 (0.0) |
| Muscle spasms |
0 (0.0) |
1 (2.1) |
2 (4.3) |
0 (0.0) |
| Myalgia |
3 (6.4) |
1 (2.1) |
1 (2.2) |
3 (6.3) |
| Pain in extremity |
0 (0.0) |
0 (0.0) |
2 (4.3) |
0 (0.0) |
Data are presented as n (%). Adverse events were coded using MedDRA version 24.1. AE, adverse event.
＊Serious adverse events are events that meet any of the following criteria.
1.Life-threatening: An event that the investigator determines to be associated with an imminent risk of death to the subject as a result of the event’s occurrence. This does not include events that may result in death if the manifestation of the event is severe.
2.Permanent or serious disability or incapacity.
3.Requires hospitalization or prolonged hospitalization for treatment. It is important to note that hospitalization itself is not reported as a serious adverse event; however, whenever possible, the reason for hospitalization should be reported.
4.Hospitalization or prolonged hospitalization for reasons of social hospitalization (i.e., hospitalization for reasons of convenience or other non- medical necessity) was not considered a serious adverse event.
5.A pre-scheduled hospitalization for the treatment of a condition that existed before consent was obtained is not considered a serious adverse event.
6.Events that result in congenital anomalies.
7.A medically problematic event that places the subject at risk or requires medical or surgical treatment to prevent any of the above outcomes is considered serious, based on appropriate medical judgment.
†An adverse event is defined as any unfavorable medical event that occurs in a patient receiving an investigational drug and does not necessarily have to be causally related to the investigational drug.
Two patients experienced serious TEAEs during the study: 1 of 47 patients (2.1%) in the placebo group and 1 of 48 patients (2.1%) in the 180 mg group. Both cases were judged to be unrelated to the study drug. No severe TEAEs were reported during this trial. The incidence of AEs leading to treatment discontinuation was 2.1% (1 of 47 patients) in the placebo group, 2.1% (1 of 47 patients) in the 60 mg group, 0% (0 of 46 patients) in the 120 mg group, and 4.2% (2 of 48 patients) in the 180 mg group. Although the incidence of TEAEs was higher in each bempedoic acid-treated group than in the placebo group, no increasing trend was observed with increasing doses. Most TEAEs were mild. There were no significant differences in patient safety among the subpopulations with an inadequate response to statins or patients with statin intolerance.
The most frequently reported TEAEs, by preferred term, which occurred in ≥ 3 patients in any bempedoic acid group and at least twice the incidence in the placebo group were as follows: headache (0% [placebo], 0% [60 mg], 10.9% [120 mg, n = 5], 4.2% [180 mg, n = 2]); pyrexia (4.3% [placebo, n = 2], 10.6% [60 mg, n = 5], 8.7% [120 mg, n = 4], 2.1% [180 mg, n = 1]); abnormal hepatic function (0% [placebo], 4.3% [60 mg, n = 2], 0% [120 mg], 10.4% [180 mg, n = 5]); upper abdominal pain (0% [placebo], 8.5% [60 mg, n = 4], 2.2% [120 mg, n = 1], 0% [180 mg]); and diarrhea (2.1% [placebo, n = 1], 6.4% [60 mg, n = 3], 2.2% [120 mg, n = 1], 2.1% [180 mg, n = 1]) (Table 4). Although the incidence of abnormal hepatic function was higher in the 180 mg group than in the 120 mg group, the changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels from baseline in the two groups did not differ to a numerically extent. The mean change in ALT from baseline at 12 weeks was 7.6 U/L in the 120 mg group and 5.3 U/L in the 180 mg group, and the mean change in AST was 10.8 U/L and 9.7 U/L, respectively.
The incidence of AEs related to muscular disorders was comparable between the placebo (6.4% [3/47 patients]) and bempedoic acid-treated groups: 4.3% (60 mg [2/47 patients]), 6.5% (120 mg [3/46 patients]), and 6.3% (180 mg [3/48 patients]).
The incidence of AEs related to increased uric acid levels was 0% (n = 0) in the placebo group, 4.3% (n = 2) in the 60 mg group, 10.9% (n = 5) in the 120 mg group, and 8.3% (n = 4) in the 180 mg group. Notably, none of the patients in the trial presented with new-onset or worsening diabetes mellitus.
Discussion
This clinical trial evaluated the LDL-C-lowering effect of bempedoic acid (60 mg, 120 mg, and 180 mg) versus placebo after 12 weeks in combination with statin and/or other lipid-modifying therapies in patients with inadequately controlled LDL-C, as well as the appropriate doses for future phase 3 studies. This is the first phase 2b study to evaluate the LDL-C-lowering effect and dose-response of bempedoic acid in Japanese patients with hypercholesterolemia who have inadequately controlled LDL-C. Among the main findings, the superiority of bempedoic acid over placebo was verified in all treatment groups, and the change in LDL-C from baseline after 12 weeks of treatment was greater in the 120 mg and 180 mg groups than in the 60 mg group. The results for secondary endpoints, such as the achievement of lipid control targets and changes in apolipoprotein B, non-HDL-C, and TC levels, suggest that bempedoic acid is effective in the treatment of Japanese patients with hypercholesterolemia.
This phase 2b study showed that patients with an inadequate response to statin therapy who took bempedoic acid at doses of 120 mg and 180 mg experienced a significant reduction in LDL-C levels relative to the placebo group. It is worth noting that although both types of drugs suppress the cholesterol synthesis system, the use of bempedoic acid in conjunction with statins was associated with a significant reduction in LDL-C relative to the placebo group. This means that ATP-citrate lyase inhibition upstream of HMG-CoA reductase can further enhance cholesterol biosynthesis in the liver, thereby upregulating the synthesis of LDL receptors. The intolerant group also showed a significant improvement relative to the placebo group. Although there is no universally accepted definition, the criteria for statin intolerance used in this investigation are less strict than those proposed by the JAS23). The JAS definition specifies statin intolerance to at least two statins at specific dosage levels; statin intolerance includes statin-induced liver dysfunction and myopathy. This study differed from these criteria because patients who had tried at least one statin and were intolerant were enrolled.
Significantly more patients in the 120 mg and 180 mg groups achieved the LDL-C control targets set by the 2017 JAS guidelines in week 2 relative to the placebo group (placebo, 12.8%; 120 mg, 47.8%; 180 mg, 47.9%). The study included approximately 80% of patients who still failed to reach the target with statins and found that approximately half of the patients reached the target within a short period of 2 weeks by adding the study drug to the statin.
In a recent Japanese study, the proportion of patients receiving combination therapy with statins and ezetimibe was low (LDL-C target＜120 mg/dL, 1.0%;＜100 mg/dL, 5.4%;＜70 mg/dL, 6.6%)14). Factors, such as clinical inertia and physician hesitancy, may contribute to the low prevalence of combination therapy. Nevertheless, the presence of scenarios where current treatment options do not fully address a patient’s condition, as was the case for the patients in the present study, or where there is a gap in the timely adoption of available therapies, suggests that there is an ongoing need to resolve the clinical challenges faced by some patients. Bempedoic acid could contribute to the achievement of LDL-C targets as an adjunctive therapy for patients with an inadequate response to statins.
The safety profile of bempedoic acid indicated that this treatment was safe and well tolerated in all bempedoic acid treatment groups. There were no clinically meaningful differences in the safety profile of bempedoic acid between the 120 mg and 180 mg groups. Although the incidence of abnormal hepatic function was higher in the bempedoic acid 180 mg group than in the 120 mg group, there was no numerical difference in the degree of laboratory value fluctuation, and the risk was not considered particularly high relative to that in the bempedoic acid 120 mg group. The absolute values also varied within normal ranges in both groups. There were no major differences in the safety profile of bempedoic acid between the subpopulations of patients with an inadequate response to statins and statin intolerance. None of the patients had new or worsening diabetes mellitus. In addition, the incidence of AEs associated with muscular disorders in the bempedoic acid groups was similar to that in the placebo group. In the liver, bempedoic acid is activated by ACSVL1, which subsequently inhibits ATP citrate lyase. ACSVL1 is undetectable in skeletal muscle and is unable to convert bempedoic acid into its active form. Therefore, bempedoic acid is not thought to affect the cholesterol biosynthesis pathway in muscle cells or promote associated toxicity24).
Due to the small sample size and short length of this study, a long-term safety study in Japanese patients is currently ongoing (NCT05687071). A long-term study conducted overseas with the primary endpoint of safety in patients with an inadequate response to secondary prevention and statins showed no significant difference in the incidence of adverse events in the bempedoic acid 180 mg group relative to the placebo group19). Furthermore, this study was not designed to test for differences between doses; therefore, the differences between the 120 mg and 180 mg groups may not have been evident. There was no clear trend toward a higher incidence or severity of AEs in the 180 mg group relative to the 120 mg or lower dose group. Additionally, pharmacokinetic studies conducted in both Japanese and non-Japanese populations showed no clinically meaningful differences in mean plasma concentration profiles between White and Japanese participants after repeated dosing25). This suggests that the results of overseas phase 3 studies, which confirmed the efficacy and safety of bempedoic acid 180 mg, may be applicable to the Japanese population. Based on the background providing insight into appropriate dosing for the Japanese population, a dose of 180 mg not 120 mg, was chosen for the phase 3 study of bempedoic acid in Japan. Due to the limitations of sample size and study duration in the current study, the ongoing phase 3 clinical trial programs aim to provide more comprehensive efficacy and safety data on a 180 mg dose of bempedoic acid for Japanese patients with hypercholesterolemia.
Conclusion
In conclusion, the findings of the present study suggest that bempedoic acid is effective in treating Japanese patients with hypercholesterolemia, and no safety concerns have been raised. There was no dose-dependent increase in the incidence or severity of AEs in the 180 mg group relative to the 120 mg or lower dose groups. Following the results from the present study, a 180 mg dose of bempedoic acid was selected for further investigation in a subsequent phase 3 study in Japan.
Acknowledgements
The authors wish to thank Keyra Martinez Dunn, MD, of Edanz (www.edanz.com) for providing medical writing services, which were funded by Otsuka Pharmaceutical Co., Ltd., in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). The authors also express their gratitude to the investigators, research-site staff, and patients for their participation in this study.
Funding
This research was funded by Otsuka Pharmaceutical Co., Ltd.
Author Contributions
SY contributed to the study design, writing, and manuscript review. HF and DY contributed to (1) the study design, conduct, or collection; (2) data analysis and interpretation; and (3) writing or reviewing the manuscript. YI and RK wrote and reviewed the manuscript. All authors have read the final version and approved the manuscript for submission.
Data Sharing
The data that support the findings of this study are openly available at https://clinicaltrials.gov/study/NCT04784442?locStr=Japan&country=Japan&intr= Bempedoic%20Acid&rank=1
Conflicts of Interest
Shizuya Yamashita has received honoraria for lectures from Immuno-Biological Laboratories Co., Ltd., Kowa Company Ltd., Novartis Pharma, Otsuka Pharmaceutical Co., Ltd. Hitomi Fujita, Daisuke Yokota, Yuki Morikawa-Isogai, and Ryuki Kitamoto are full-time employees of Otsuka Pharmaceutical Co., Ltd.
Supplementary Methods
Placebo Run-in Phase
Patients who met the screening inclusion criteria and did not meet the exclusion criteria were included in a 4-week placebo run-in phase before randomization. During this phase, placebo tablets were administered in a single-blind manner for 4 weeks. When statin-intolerant patients were asked about their symptoms, they reported muscle-related adverse events such as myalgia and hepatic dysfunction-related adverse events1). Some patients even reported experiencing a nocebo effect, where they complained of muscle and other symptoms, even when taking drugs other than statins, such as placebo2, 3). A placebo run-in period was established to better evaluate the safety of bempedoic acid, similar to a clinical study of bempedoic acid. Patients who experienced adverse effects during the placebo run-in phase were excluded, in line with an overseas clinical study of bempedoic acid.
Inclusion Criteria
Patients were required to meet the following inclusion criteria when assessed:
1) Written informed consent obtained before the start of the trial
2) Patients, either male or female, who were 20–74 years of age at the time of giving their informed consent
3) Patients who met the following criteria for an inadequate response to statin or statin intolerance
Inadequate Response to Statin
Patients with hypercholesterolemia who had been taking statins (atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, or fluvastatin) and cholesterol-lowering drugs other than statins, if necessary, at the same dose and regimen from at least four weeks before week −5 (Visit S1) (at least six weeks, for fibrates and selective peroxisome proliferator-activated receptor [PPAR]-α modulators) to week −5 (Visit S1) according to the approved regimen, but who failed to achieve the lipid management goals of low-density lipoprotein cholesterol (LDL-C) based on the risk assessment shown in the inclusion criteria 4) at both week −5 (Visit S1) and week −1 (Visit S3).
Statin Intolerance
Patients with hypercholesterolemia who experienced safety issues when starting or increasing the dose of statins, which were resolved after discontinuation or dose reduction of statin administration, and who had been taking statins at or below the lowest approved daily dose and/or who had been taking at least one hypercholesterolemia drug other than statins at the same dose and regimen for at least 4 weeks before week −5 (Visit S1) (at least 6 weeks, for fibrates and selective PPAR-α modulators) to week −5 (Visit S1) according to the approved dosage regimen, but fail to achieve the lipid management goals of LDL-C4) based on risk assessment shown in the inclusion criteria 4) at both week −5 (Visit S1) and week −1 (Visit S3).
4) Patients considered at risk of developing cardiovascular events who met any of the following conditions: a), b), or c):
a) Patients with either of the following medical histories or complications and in whom LDL-C at week −5 (Visit S1) and week-1 (Visit S3) was ≥ 100 mg/dL.
- History of coronary artery disease.
- Diagnosis of heterozygous familial hypercholesterolemia
b) Patients with a medical history of any of the following conditions or complications and in whom LDL-C at week −5 (Visit S1) and week-1 (Visit S3) was ≥ 120 mg/dL.
- Diagnosis of peripheral arterial disease
- History of noncardiogenic cerebral infarction
- Diagnosed with chronic kidney disease without falling under the following exclusion criteria: patient with renal dysfunction or nephritic syndrome or a history or complication of nephritis and with an estimated glomerular filtration rate of ≤ 30 mL/min/1.73 m2 at week −5.
- Patients diagnosed with type 2 diabetes mellitus for more than 3 months before week −5 (Visit S1), without falling under the following exclusion criteria: patients with type 1 diabetes or uncontrolled type 2 diabetes with glycated hemoglobin ≥ 9% at week −5.
c) Patients who do not meet the inclusion criteria a) or b) but whose total score in the coronary artery disease risk prediction model using the Suita score specified by the Japan Atherosclerosis Society was ≥ 41 and ≤ 55 points (intermediate risk) and in whom the LDL-C level was ≥ 140 mg/dL at week −5 (Visit S1) and week −1 (Visit S3), or whose total score was ≥ 56 (high risk) and in whom each LDL-C level at week −5 (Visit S1) and week −1 (Visit S3) was ≥ 120 mg/dL4)
5) Patients with a fasting triglyceride level of ＜400 mg/dL at week −5 (Visit S1).
6) Patients with a body mass index of ≥ 18 kg/m2 and ＜35 kg/m2 at week −5 (Visit S1).
Exclusion Criteria
Patients were excluded if they met any of the following criteria at the time of the defined assessment:
Pregnant women, lactating women, or women with a positive pregnancy test (urine) at week −5 (Visit S1) or day 1 (Visit T1); sexually active men or sexually active women who did not agree to use two approved contraceptive methods or maintain complete abstinence (cyclic abstinence and extravaginal ejaculation were not appropriate methods of contraception) during the study period and for 30 days after the last dose of the study drug (if contraception was used, two of the following methods were to be used: vasectomy, tubal ligation, intrauterine device, oral contraceptives, or condoms [all methods approved or certified in Japan]); patients diagnosed as homozygous for familial hypercholesterolemia; patients with a history of the following cardiovascular diseases or complications within 3 months before week −5 (Visit S1) or patients who experienced the following adverse events during screening and placebo run-in periods: myocardial infarction, severe or unstable angina, coronary angioplasty, coronary artery bypass graft surgery, stroke, transient ischemic attack, symptomatic carotid artery stenosis, symptomatic peripheral artery disease, decompensated heart failure, abdominal aortic aneurysm, unexplained syncope or prolonged QT, patients with unexplained syncope or QT prolongation syndrome, family history of QT prolongation syndrome, or risk factors for torsade de pointes, such as persistent hypokalemia or degree II or III AV block (unless controlled by medication or other means); patients with uncontrolled hypertension with systolic blood pressure ＞160 mmHg or diastolic blood pressure ＞100 mmHg in the sitting position after 5 minutes of rest during week −5 (Visit S1); patients with serious uncontrolled hematologic diseases or complications of coagulopathy or hemoglobin ＜10.0 g/dL at week −5 (Visit S1); patients with type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus with glycated hemoglobin of ＞9% at week −5 (Visit S1); patients with poorly controlled hypothyroidism with a thyroid-stimulating hormone level ＞1.5 times the upper reference limit at week −5 (Visit S1); patients with liver disease or hepatic insufficiency including the following: positive hepatitis B surface antigen serology or hepatitis C virus antibody test at week −5 (Visit S1), aspartate aminotransferase or alanine aminotransferase level ＞3 times the upper reference limit or total bilirubin level ＞2 times the upper reference limit at week −5 (Visit S1); patients with a history of chronic musculoskeletal symptoms or complications that are difficult to distinguish from myalgia (e.g., fibromyalgia); patients with a creatine kinase level ＞3 times the upper reference limit at week −5 (Visit S1); patients with renal dysfunction, nephritis syndrome, or history of nephritis or its complications and an estimated glomerular filtration rate at week −5 (Visit S1) of ＜30 mL/min/1.73 m2; patients who had undergone gastrointestinal surgical procedures that may affect drug absorption, e.g., Lap-Band® or gastric bypass surgery; patients who had undergone surgery, chemotherapy, or radiation therapy for active malignancy (excluding appropriately treated non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin and epithelial carcinoma of the cervix) within 5 years before week −5 (Visit S1); patients with a history of drug, alcohol, or cocaine abuse within 2 years before week −5 (Visit S1); patients who had had ＞200 mL of blood drawn (e.g., blood donation) within 4 weeks, ＞400 mL within 12 weeks, or ＞1200 mL within 1 year before week −5 (Visit S1); patients who used drugs not approved in Japan within 4 weeks prior to week −5 (Visit S1) or within 5 times the half-life of the drug, whichever is longer; patients who had used or administered, or who were expected to use or administer by the end of week 12 (Visit T6) any of the following drugs (including food) or therapies within the specified period:
1. Initiation or dose modification of systemic corticosteroids from 3 months before week −5 (Visit S1) until the end of week 12 (Visit T6) (or until the end of Visit T6 if discontinued).
2. Lomitapide from 3 months before week −5 (Visit S1) to the end of week 12 (Visit T6) (or until the end of the examination at the time of discontinuation, if discontinued).
3. PCSK9 inhibitor from 4 weeks before week −5 (Visit S1) to the end of week 12 (Visit T6) (or until the end of Visit T6 if discontinued).
4. Probenecid from week −4 (Visit S2) to the end of week 12 (Visit T6) (or until the end of the examination at the time of discontinuation if discontinued).
5. Red yeast rice and foods containing red yeast rice from 2 weeks before week −5 (Visit S1) until the end of week 12 (Visit T6) (or until the end of the examination at the time of discontinuation, if discontinued).
6. LDL apheresis from 3 months before week −5 (Visit S1) to the end of week 12 (Visit T6) (or until the end of the examination at the time of discontinuation, if discontinued).
Patients who changed the following medications (therapies) before day 1 (Visit T1) or were scheduled to start the following medications (therapies) by the end of week 12 (Visit T6): hormone replacement within 6 weeks prior to day 1 (Visit T1), thyroid hormone replacement within 6 weeks prior to day 1 (Visit T1), diabetic medication within 4 weeks prior to day 1 (Visit T1), and anti-obesity medication within 3 months before day 1 (Visit T1); during the placebo run-in period, patients who had taken ＜80% of single-blind placebo tablets by day 1 (Visit T1) or who were unable to continue taking placebo tablets because of safety issues; patients who developed new or worsening myopathy-related adverse events during the placebo run-in period, other than for obvious reasons such as fatigue or trauma; and other patients the investigator or sub-investigator determined should not participate in this study.
Blinding
To maintain the blindness of the trial, endpoints (LDL-C, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, total cholesterol, triglycerides, apolipoprotein B, and high-sensitivity C-reactive protein) were not reported to the investigational site and the sponsor from the start of study drug administration on day 1 (Visit T1) to week 12 (Visit T6). The test results were kept by the central laboratories, submitted to the investigational site after the key was opened, and provided to the sponsor as an electronic file. In addition, the laboratory at the investigational site was prohibited from measuring the above endpoints from the start of the administration of the study drug on day 1 (Visit T1) to week 12 (Visit T6). Patients who discontinued treatment were not reported until the test was completed.
Supplementary References
1)Statin Intolerance Clinical Guide 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192817/
2)Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, Preiss D, Bruckert E, Ceška R, Lepor N, Ballantyne CM, Gouni-Berthold I, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA; GAUSS-3 Investigators: Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: TheGAUSS-3 Randomized Clinical Trial. JAMA, 2016; 315: 1580-1590
3)Tobert JA, Newman CB: Statin tolerability: In defence of placebo-controlled trials. Eur J Prev Cardiol, 2016; 23: 891-896
4)Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017. The Journal of Japan Atherosclerosis Society, 2018; 1: 73-80
Plain Language Summary
We looked at how well a medicine called bempedoic acid works and how safe it is for Japanese people with high levels of LDL (bad) cholesterol in their blood. We used three different amounts of the medicine and checked which amount is best for the next study. We conducted the study across several medical sites and included patients who had high cholesterol and were at risk of heart disease. These patients did not respond well to their current cholesterol medication (statins), and some could not tolerate them. We gave them bempedoic acid or a placebo (a fake pill) and measured the change in their LDL (bad) cholesterol level after 12 weeks. We had four groups, each given different amounts of bempedoic acid or a placebo. All groups showed a decrease in LDL (bad) cholesterol after 12 weeks, but the groups taking bempedoic acid had a greater decrease. However, more people in the bempedoic acid groups experienced side effects compared with the placebo group. These side effects were minor and did not increase with higher amounts of the medicine. Some of these side effects were related to liver problems, although these were rare. There were no reports of new or worsening cases of diabetes. Our study shows that bempedoic acid is effective and safe for Japanese people with high levels of LDL (bad) cholesterol in their blood. We found that 180 mg of bempedoic acid is the best amount to use in the next study.
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