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Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study
David Geffen School of Medicine at UCLA and Cedars-Sinai Medical Center, Los Angeles, CA, USAWestside Medical Associates of Los Angeles, 99 La Cienega Blvd. #203, Beverly Hills, CA, 90211, USA
Division of Endocrinology & Metabolism, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, 61 Queen St East #6121, Toronto, M5C 2T2, Ontario, Canada
Bempedoic acid provides additional LDL-C lowering when added to ezetimibe.
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Bempedoic acid lowers atherogenic lipids and hsCRP in statin intolerant patients.
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Bempedoic acid is well tolerated including a low muscle-related adverse event rate.
Abstract
Background and aims
Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering.
Methods
This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C.
Results
The study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; −23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (−23.6%), total cholesterol (−18.0%), apolipoprotein B (−19.3%), and high-sensitivity C-reactive protein (−31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups.
Conclusions
Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.
Statins have established their role as a first-line option for low-density lipoprotein cholesterol (LDL-C) lowering through demonstrated efficacy and event risk reduction. Absolute cardiovascular (CV) risk reduction with lipid-lowering therapies depends on the patient's baseline CV risk and the extent of LDL-C reduction [
Statin-associated muscle symptoms: impact on statin therapy-european atherosclerosis society consensus panel statement on assessment, aetiology and management.
Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.
]. Statin intolerance has been linked to a lower likelihood of achieving LDL-C goals, increased risk for non-fatal CV events, and higher healthcare costs [
]. Statin intolerance ranges from “complete intolerance” of any statin at any dose to the more frequent scenario of inability to tolerate statins at doses that provide optimal reductions of LDL-C. Many statin intolerant individuals are at extreme or very high CV risk and, therefore, merit intensive intervention to reduce LDL-C [
]. Although ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used in this situation, additional LDL-C lowering and/or less expensive alternatives may still be required to reduce CV risk and reach guideline-recommended LDL-C treatment goals.
Bempedoic acid (ETC-1002) is an oral, once-daily, first-in-class, small-molecule cholesterol synthesis inhibitor in development for the treatment of hyperlipidemia. As an adenosine triphosphate (ATP)-citrate lyase inhibitor, bempedoic acid acts upstream of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase to inhibit cholesterol biosynthesis and increase LDL receptor expression [
Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
]. Improvements in lipid parameters were observed when bempedoic acid was administered as monotherapy or in addition to other lipid-modifying therapies. These studies encompassed a broad mix of primary and secondary prevention populations, including patients with primary hyperlipidemia or mixed dyslipidemia, some of whom also had a history of type 2 diabetes mellitus, coronary heart disease, and/or statin intolerance [
Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
]. Doses of bempedoic acid ranging from 40 to 240 mg/day were evaluated in phase 2 studies. The favorable efficacy and safety profile supported use of the 180 mg/day dose in phase 3 clinical trials [
Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
The first of the completed phase 3 studies, CLEAR Tranquility (NCT03001076), evaluated the efficacy and safety of bempedoic acid 180 mg daily when added to background therapy with ezetimibe 10 mg daily in patients with a history of not tolerating at least one statin and who required additional LDL-C lowering.
2. Patients and methods
2.1 Study population
The study population included men and women ages 18 years and older who had a history of statin intolerance, were on no more than low-dose statin therapy (which could also include no statin), and required additional LDL-C lowering. Patients were required to have fasting LDL-C ≥100 mg/dL (2.6 mmol/L) at screening. Low-dose statin therapy was defined as an average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg, which represents the lowest approved dose for each of these statins in the United States. Average daily doses less than these were considered very low-dose statin therapy. Patients with a recent history of clinically significant cardiovascular disease (CVD), including uncontrolled hypertension; a planned revascularization procedure; New York Heart Association class IV heart failure; or any one of the following within 3 months of screening: myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, coronary artery bypass graft surgery, stroke, transient ischemic attack, cerebrovascular event, symptomatic coronary artery disease, symptomatic peripheral arterial disease, or arrhythmia requiring medical intervention, were not eligible for study participation. Additional reasons for study exclusion included body mass index (BMI) > 50 kg/m2; fasting triglycerides ≥500 mg/dL; glycosylated hemoglobin (HbA1c) ≥10%; uncontrolled hypothyroidism; liver disease or dysfunction; renal dysfunction (estimated glomerular filtration rate <30 mL/min) or glomerulonephritis; gastrointestinal conditions or procedures that may affect drug absorption; hematologic or coagulation disorders; active malignancy; unexplained creatine kinase elevation >3 times the upper limit of normal (ULN) any time prior to randomization; or use of cholestin or red yeast rice–containing products within 2 weeks prior to screening, statin doses exceeding low dose within 4 weeks prior to screening, mipomersen, lomitapide, apheresis, probenecid, or cyclosporine within 3 months prior to screening, or a PCKS9 inhibitor within 4 months prior to screening.
2.2 Study design
This phase 3, randomized, double-blind, placebo-controlled, parallel-group study was conducted at 90 sites in the United States, Canada, and Europe from November 29, 2016, to January 11, 2018. The study comprised 3 phases: a 1-week screening period; a 4-week, single-blind run-in period; and a 12-week, double-blind treatment period (Fig. 1). During the run-in phase, patients received open-label ezetimibe 10 mg once daily and single-blind placebo to confirm tolerance to ezetimibe and compliance with protocol-directed therapy. Patients with poor adherence to ezetimibe or placebo (i.e. ingesting <80% of planned doses) during the run-in phase or who experienced an ezetimibe–related adverse event (AE) were not eligible for randomization. At the end of the screening phase, patients were randomized 2:1 to double-blind treatment with oral bempedoic acid 180 mg or placebo once daily for 12 weeks. Randomization for treatment assignments was determined using an interactive web response system; patients, investigators, pharmacists, and study personnel remained blinded to treatment group assignments through the duration of the study. Random allocation sequences were generated by dynamic allocation using Rave Balance (Medidata Solutions, New York, New York). Stable background lipid-modifying therapy (inclusive of a low-dose or very low-dose statin and/or permitted non-statin agents) and study-provided open-label ezetimibe 10 mg once daily were maintained throughout the study.
aPatients with ≤80% adherence and/or who experienced a study drug-related adverse event during the placebo and ezetimibe run-in period did not proceed to randomization.
The study protocol and informed consent documents received appropriate institutional review board/independent ethics committee approval, and the study was conducted in accordance with ethical principles established by the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.
2.3 Assessments and endpoints
Basic fasting lipid levels (LDL-C, total cholesterol, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglycerides) were measured at the first screening visit (week −5), during the run-in period (week −1), and at all study visits during the double-blind treatment period. LDL-C was calculated directly using the Friedewald formula, except in cases of triglycerides >400 mg/dL (4.5 mmol/L) or calculated LDL-C ≤50 mg/dL (1.3 mmol/L); in these instances, a direct measure of LDL-C was conducted. Apolipoprotein B (apoB) and hsCRP measurements were performed at week 0 (day 1) and week 12 (end of study). Analyses of lipid, lipoprotein, biomarker, and clinical safety parameters were performed at a central laboratory (Q2 Solutions, Morrisville, NC).
Safety assessments included continuous monitoring of treatment-emergent AEs (TEAEs), clinical safety laboratory results (hematology, blood chemistry, HbA1c, fasting glucose, and urinalysis), physical examination findings, vital sign measurements, electrocardiograph readings, and weight measurements. Given patients' histories of statin intolerance, muscle-related AEs—predefined as muscle spasms, myalgia, muscular weakness, myoglobin blood increased, myoglobin blood present, myoglobin urine present, myoglobinemia, myoglinuria, myopathy, myopathy toxic, muscle necrosis, necrotizing myositis, pain in extremity, and rhabdomyolysis—were identified from among TEAEs.
The primary endpoint was the percent change from baseline to week 12 in LDL-C. Secondary endpoints included percent changes from baseline to week 12 in non-HDL-C, total cholesterol, apoB, hsCRP, triglycerides, and HDL-C. Tertiary endpoints included percent and absolute changes from baseline to weeks 4 and 8 in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C; and absolute changes from baseline to week 12 in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C.
2.4 Statistical analysis
A sample size of 150 randomized patients in the bempedoic acid group and 75 in the placebo group was expected to provide more than 95% power to detect a difference of 15% in the percent change from baseline to week 12 in calculated LDL-C between treatment groups. This calculation is based on a 2-sided t-test at the 5% level of significance and a common standard deviation of 15%.
Efficacy analyses were performed using the intention-to-treat population, which included all randomized patients. The primary and secondary efficacy endpoints were analyzed using analysis of covariance (ANCOVA), with treatment group as a factor and relevant baseline value as a covariate. If non-normality of the data was detected at any time point for any parameter, a non-parametric test was used instead of the planned ANCOVA. Baseline for LDL-C, HDL-C, non-HDL-C, triglycerides, and total cholesterol was defined as the mean of the last two non-missing values on or before day 1. Baseline for apoB and hsCRP was defined as the last non-missing value on or before day 1. Baseline for all other parameters was defined as last measurement before the first dose of double-blind study medication. For each lipid parameter at each time point, the least-squares (LS) mean and standard error were calculated for both treatment groups, as well as the placebo-corrected LS mean, 95% confidence interval (CI), and associated p value. Missing values at week 12 were imputed using the multiple imputation method taking into account ongoing treatment. Patients who had missing values and were off treatment were imputed with placebo patient data only. Percent change from baseline statistics (LS means and p value) are based on the final combined estimators from Rubin's method.
A gatekeeping or stepdown approach was used to test the primary efficacy endpoint and specific secondary efficacy endpoints sequentially. Percent change from baseline to week 12 in lipid/biomarker parameters were tested in the following sequence: LDL-C, non-HDL-C, total cholesterol, apoB, and hsCRP. In this hierarchical testing structure, each hypothesis is tested at a significance level of 0.05, 2-sided. Statistical significance at each step is required to test the next hypothesis. For the remaining secondary and tertiary efficacy endpoints, a significance level of 0.05 was used; given the large number of remaining endpoints, the p values for those endpoints are considered descriptive.
Completer, on-treatment, and observed data analyses were performed as sensitivity analyses for primary and key secondary efficacy endpoints. The completer analysis set included all patients who completed the study. There was no imputation for missing data in the sensitivity analyses. Subgroup analyses for the primary efficacy variable were performed using ANCOVA without imputation for missing data for the following groups: baseline LDL-C category (<130 mg/dL, ≥130 to <160 mg/dL, ≥160 mg/dL), history of diabetes, age (<65 years, ≥65 to <75 years, ≥75 years), race (white vs. non-white), sex, region (North America vs. Europe), BMI category (<25 kg/m2, 25 to <30 kg/m2, ≥30 kg/m2), and background lipid-modifying therapy (statin vs. other).
The safety analysis population included all randomized patients who received at least one dose of study medication. Safety parameters, including AEs, clinical safety laboratory results, physical examination findings, vital sign measurements, electrocardiograph readings, and weight, were summarized using descriptive statistics for each treatment group and time point.
3. Results
3.1 Patient disposition and characteristics
Of the 616 patients who were screened, 269 met study criteria, completed the single-blind run-in period, and were randomized to treatment with bempedoic acid (n = 181) or placebo (n = 88; Fig. 2). One patient randomized to placebo did not receive any dose of study medication during the double-blind treatment period and was excluded from the safety analysis. Discontinuation rates during the double-blind treatment period were similar in the bempedoic acid (9.4%, 17 patients) and placebo (9.1%, 8 patients) treatment groups.
The study population was predominantly white (89.2%) and female (61.3%), with a mean age of 63.8 years (Table 1). Mean baseline LDL-C was 127.6 mg/dL and approximately 25% of patients had pre-existing atherosclerotic cardiovascular disease (ASCVD; defined as coronary heart disease, stroke, and/or peripheral arterial disease [
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
]). Demographics and baseline characteristics were well matched between treatment groups in most respects. Mean baseline LDL-C, non-HDL-C, apoB, and triglycerides were marginally higher in the bempedoic acid treatment group compared with placebo. Concomitant lipid-modifying therapy (in addition to ezetimibe) was used by 44.8% of patients (47.5% bempedoic acid, 39.1% placebo). Thirty-one percent of patients (32.6% bempedoic acid, 27.6% placebo) were receiving concomitant statin therapy. The most common background statin was atorvastatin 10 mg, used by 11.6% of patients.
Table 1Patient demographics and baseline characteristics.
Data are means (standard deviations) unless otherwise specified.
Baseline for LDL-C, HDL-C, non-HDL-C, triglycerides, and total cholesterol was defined as the mean of the last two non-missing values on or prior to day 1. Baseline for apoB and hsCRP was defined as the last non-missing value on or prior to day 1. Baseline for all other parameters was defined as last measurement before the first dose of double-blind study medication.
a Data were available from 86 to 180 patients in the placebo and bempedoic acid treatment groups, respectively.
b Data are medians (interquartile ranges).
c Includes fish oil, eicosapentaenoic acid ethyl ester, omega-3 fatty acids, salmon oil, and sitosterol.
Bempedoic acid 180 mg once daily added to background lipid-lowering therapy that included ezetimibe 10 mg daily resulted in a placebo-corrected LS mean change in LDL-C of −28.5% (95% CI: −34.4%, −22.5%; p < 0.001) from baseline to week 12 (Fig. 3A). Whereas mean LDL-C decreased to <100 mg/dL among patients in the bempedoic acid treatment group (from 129.8 mg/dL at baseline to 96.2 mg/dL at week 12), patients who received placebo experienced a modest net increase in LDL-C from baseline (from 123.0 mg/dL at baseline to 128.8 mg/dL at week 12). Significant reductions in LDL-C with bempedoic acid vs. placebo were observed at the first post-baseline study visit (week 4) and were maintained throughout the 12-week study (p < 0.001; Fig. 3B).
Fig. 3Effect of treatment on lipid parameters and other secondary endpoints.
(A) Percent change from baseline to week 12. (B) Absolute change in low-density lipoprotein cholesterol (LDL-C) over time. Data for LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), and apolipoprotein B (apoB) are least-squares means ± standard error; p values are based on analysis of covariance. Data are medians for high-sensitivity C-reactive protein (hsCRP); p value is based on the Wilcoxon Rank Sum Test. an = 81 for apoB and hsCRP. bn = 176 for TC. n = 174 for apoB. *p < 0.001 for the comparison of bempedoic acid vs. placebo.
Exploratory analyses were performed to evaluate LDL-C lowering across subgroups, and although some numerical differences were observed, there were no clinically significant differences based on baseline LDL-C, history of diabetes, age, race, sex, BMI, or region (Supplemental Fig. 1). Heterogeneity in LDL-C reduction was observed (p = 0.032 for treatment and subgroup interaction) in the background statin use subgroups. The difference in LDL-C reduction between the bempedoic acid and placebo treatment groups was statistically significant in both subgroups; however, the LDL-C lowering effect was greater among those who received non-statin or no background therapy compared with those on a low-dose or very low-dose statin (−34.7% ± 3.1%; p < 0.001 for bempedoic acid vs. placebo, and −20.5% ± 6.4%; p = 0.003, respectively).
Least-squares mean non-HDL-C, total cholesterol, and apoB decreased significantly from baseline to week 12 in the bempedoic acid treatment group but increased slightly among those who received placebo (p < 0.001) (Fig. 3A). Placebo-corrected changes from baseline were −23.6% ± 2.8%, −18.0% ± 2.0%, and −19.3% ± 2.3% for non-HDL-C, total cholesterol, and apoB, respectively. Significant differences between treatment groups for non-HDL-C and total cholesterol were observed at the first post-baseline assessment (week 4) and were maintained throughout the study (apoB was only measured at baseline and week 12). Marked reductions from baseline in median hsCRP were also observed in the bempedoic acid treatment group, with a placebo-corrected decrease of 31.0% (p < 0.001) (Fig. 3A). HDL-C decreased from baseline to week 12 in both the bempedoic and placebo treatment groups, although to a large extent in the former (−7.3% ± 1.2 and −1.4% ± 1.4, respectively; p = 0.002). Changes in triglyceride levels were modest and comparable between treatment groups (median change: bempedoic acid, −1.4%; placebo, +7.8%).
Results for primary and secondary efficacy endpoints were consistent across sensitivity analyses, which included completer, on-treatment, and observed data analyses.
3.3 Safety
TEAEs were reported by 48.6% and 44.8% of patients in the bempedoic acid and placebo treatment groups, respectively, during the double-blind treatment period (Table 2). Most TEAEs were mild or moderate in intensity and were judged to be not related or unlikely related to investigational study drug. Rates of discontinuation due to a TEAE were similar in the bempedoic acid (6.1%, 11 patients) and placebo (5.7%, 5 patients) treatment groups. Serious TEAEs occurred in 2.8% and 3.4% of patients in the bempedoic acid and placebo treatment groups, respectively. Each of the serious TEAEs (bempedoic acid: bronchitis, dysuria, hepatic cancer, intestinal obstruction, osteoarthritis, and syncope; placebo: breast cancer, bacterial pneumonia, deliberate poisoning, subdural hematoma, and subdural hemorrhage) occurred in no more than one patient, and none were considered to be related to study medication. No fatal TEAEs occurred during the study.
Table 2Treatment-emergent adverse events.
Parameter
Patients, % (n)
Placebo (n = 87)
Bempedoic acid (n = 181)
Overview of AEs
Any AEs
44.8 (39)
48.6 (88)
Serious AEs
3.4 (3)
2.8 (5)
Investigational study drug–related AEs
9.2 (8)
21.5 (39)
Discontinuation of investigational study drug due to an AE
Muscle-related TEAEs occurred at equal frequency in the bempedoic acid and placebo treatment groups (3.3% and 3.4%, respectively). Three patients discontinued due to muscle-related TEAEs: muscle spasms and pain in extremity were experienced by one patient each in the bempedoic acid treatment group; myalgia was experienced by one patient who received placebo. Both patients in the bempedoic acid treatment group who withdrew due to muscle-related TEAEs were receiving concomitant statin therapy (pravastatin 20 mg and rosuvastatin 5 mg).
Mean changes in clinical chemistry, hematology, and urinalysis parameters were generally similar between treatment groups. Asymptomatic blood uric acid increases reported as TEAEs were experienced by 7.7% of patients (n = 14) in the bempedoic acid treatment group and 2.3% of patients (n = 2) in the placebo group. Of these 16 patients, 13 had blood uric acid levels greater than the ULN prior to randomization. In the bempedoic acid treatment group, a slight increase in mean uric acid concentration was observed during the first 4 weeks of treatment (5.8 ± 1.4 mg/dL at baseline, 6.4 ± 1.5 mg/dL at week 4), which remained stable over the course of the study (6.3 ± 1.5 mg/dL at week 12). Similar mean changes were observed among patients receiving bempedoic acid who had a TEAE of blood uric acid increased. Notably, no TEAEs of new-onset or worsening gout were reported during the study. Elevations in ALT and/or AST reported by the investigator as TEAEs occurred in 3.9% of patients (n = 7) who received bempedoic acid and no patients in the placebo treatment group. Transaminase elevations >3 times ULN were present in repeated confirmatory measurements for only two patients (1.1%); in both cases, ALT and AST were elevated prior to randomization, with the increase to >3 times ULN occurring at weeks 8 (n = 1) and 12 (n = 1). For the patient with values > 3 times ULN at week 8, study drug was discontinued at week 9 and transaminases remained elevated through the week 12 end-of-study visit. The patient who experienced elevations of >3 times ULN at the week 12 end-of-study visit had decreasing transaminases within a week of completing the last study drug dose. Neither patient was receiving background statin therapy. The investigator assessed these events as possibly related to investigational study drug. Overall in the bempedoic acid treatment group, median ALT was generally unchanged (baseline: 21.0 U/L [interquartile range, 16.0, 27.0]; week 12: 21.5 U/L [16.0, 32.0]) and a modest increase in AST was observed (baseline: 20.0 U/L [17.0, 26.0]; week 12: 23.5 U/L [19.0, 30.5]). No patients experienced increases in total bilirubin >2 times ULN or met Hy's law criteria, and no clinically meaningful changes in physical examination findings, vital sign measurements, electrocardiograph readings, or weight were reported.
4. Discussion
In this phase 3 clinical trial, bempedoic acid 180 mg once daily was effective in reducing LDL-C when added to background therapy with ezetimibe 10 mg per day with or without additional lipid-modifying therapy in patients unable to tolerate more than low-dose statin therapy. Bempedoic acid generated an additional 28.5% LDL-C lowering compared with placebo. Marked reductions in LDL-C were observed at the first post-baseline study visit (week 4) and were maintained throughout the study. Bempedoic acid also improved other lipid and lipoprotein parameters, including non-HDL-C, total cholesterol, and apoB. These findings are consistent with results from phase 2 studies in which bempedoic acid significantly reduced LDL-C and other atherogenic lipids across a variety of clinical scenarios, including among patients with statin intolerance and as an add-on to statins or ezetimibe [
Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
]. In the current study, bempedoic acid had minimal effect on triglyceride levels. There was a small, but statistically significant decrease in HDL-C. Reductions in HDL-C with bempedoic acid have not been reported consistently in previous studies, although apolipoprotein A-I levels have generally been unchanged and HDL particle number, when measured, was increased [
Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
]. The clinical significance of these small changes in HDL-C is unknown.
Treatment with bempedoic acid has consistently produced reductions in the inflammatory biomarker hsCRP, with phase 2 studies reporting decreases from baseline of as much as 42% [
Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
]. Elevated C-reactive protein (CRP) levels are associated with increased risk for coronary heart disease and adverse CV outcomes, both in the general population and among patients receiving lipid-modifying therapy, including maximally tolerated statin treatment [
Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).
C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy.
]. The CANTOS study further strengthened the relationship between inflammation, CRP, and ASCVD. In patients with a history of myocardial infarction and elevated hsCRP, canakinumab (a monoclonal antibody targeting interleukin-1β) 150 mg every 3 months decreased hsCRP by 37% vs. placebo and statistically significantly reduced the occurrence of major CV events (hazard ratio, 0.85 [95% CI, 0.74 to 0.98]; p = 0.021) without reducing lipid levels [
]. In the current study, bempedoic acid reduced median hsCRP by 33% (from 2.21 mg/L at baseline to 1.35 mg/L at week 12) in a population of patients already receiving ezetimibe.
In our study population—all of whom reported a history of statin intolerance—69% of patients were not currently receiving statin therapy. A subgroup analysis revealed, although not definitively, a greater magnitude of LDL-C lowering benefit with bempedoic acid in patients receiving no background statin therapy (−34.7%) compared with those receiving a low-dose or very low-dose statin (−20.5%). One plausible explanation for the attenuation of effect in patients already receiving background statin therapy is that both statins and bempedoic acid act on the same pathway, lowering LDL-C by reducing hepatic cholesterol synthesis and subsequently increasing LDL receptor activity [
], may have deteriorated over the course of the study, thus reducing the overall LDL-C-lowering benefit. The latter possibility is strictly hypothetical, as adherence to background therapy was not measured during the study.
Bempedoic acid was safe and well tolerated. Rates of TEAEs, muscle-related TEAEs, and discontinuations due to TEAEs were similar in the bempedoic acid and placebo treatment groups. Notably, the study population had a history of statin intolerance and only 32.6% of patients in the bempedoic acid treatment group were on background low- or very low-dose statin therapy. Statin intolerance frequently presents as muscle-related complaints, which are a major cause of treatment discontinuation [
Statin-associated muscle symptoms: impact on statin therapy-european atherosclerosis society consensus panel statement on assessment, aetiology and management.
]. The lack of a muscle-related side effect signal with bempedoic acid vs. placebo may be due to a lack of exposure in muscle to the active metabolite [
]. Bempedoic acid is a prodrug that requires very long-chain acyl-CoA synthetase-1 (ASCV1L) for conversion to active drug (bempedoic acid-coenzyme A), and ASCV1L expression is predominantly limited to the liver. Therefore, although statins and bempedoic acid both act on the cholesterol biosynthesis pathway, the absence of active bempedoic acid in muscle limits the potential for myotoxic effects.
Most TEAEs occurred at similar frequencies in the bempedoic acid and placebo treatment groups; however, elevations in uric acid were observed more frequently among patients who received bempedoic acid. Mean uric acid values stabilized within the first 4 weeks of treatment and were not accompanied by new onset or worsening gout. Repeated and confirmed transaminase elevations were infrequent, occurring in only two patients (1.1%) in the bempedoic acid treatment group and no patients in the placebo group. This frequency of repeated transaminase elevations is similar to that observed in trials of statins [
], which also inhibit cholesterol synthesis in the liver.
There are several limitations to consider when interpreting these data. First, this was a short-term study. The 12-week duration, combined with the exclusion of patients who experienced tolerability issues during the placebo run-in phase and the inclusion of patients who could tolerate a low-dose or very low-dose statin, may have contributed to the low overall rate of muscle-related adverse events. Questions regarding the long-term use of bempedoic acid, including the occurrence of muscle-related adverse events, are being addressed by ongoing phase 3 clinical trials, including two 52-week studies (CLEAR Harmony [NCT02666664]; CLEAR Wisdom [NCT02991118]); a 1.5-year, open-label extension study (NCT03067441); and a CV outcomes trial (CLEAR Outcomes [NCT02993406]). In addition, a 24-week study is currently evaluating the efficacy and safety of bempedoic acid in patients with a history of not tolerating two or more statins, one at the lowest dose (CLEAR Serenity [NCT02988115]). Second, there was a slight imbalance in baseline lipid parameters between treatment groups, with a more unfavorable atherogenic profile among those randomized to bempedoic acid. Third, compliance to background therapy was not measured, thereby precluding assessment of the influence of statin adherence on treatment response. Lastly, the enrollment criterion of a history of statin intolerance/inability to tolerate more than low-dose/very low-dose statin therapy was based on patient self-report, which is less rigorous than a challenge/rechallenge approach to defining statin intolerance, but nevertheless represents a common scenario in practice.
Patients with indications for LDL-C lowering who have statin intolerance represent an at-risk population in need of therapeutic alternatives that effectively lower LDL-C and its associated CV risk. In our study population, which consisted of patients who had a history of intolerance to at least one statin, less than one-third were receiving a statin despite a high prevalence of ASCVD risk factors and persistently elevated LDL-C while receiving non-statin therapies. The ability to significantly reduce LDL-C in these patients while avoiding muscle-associated symptoms supports the potential for bempedoic acid as a complementary lipid-lowering agent to ezetimibe in patients who cannot tolerate more than low-dose statin therapy and require additional LDL-C lowering.
Clinical trial
NCT03001076.
Conflicts of interest
Dr. Ballantyne has received research grant(s)/support from Abbott Diagnostic, Amarin, Amgen, Esperion, Ionis, Novartis, Pfizer, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, NIH, AHA, and ADA (all paid to institution, not individual). He has also served as a consultant for Abbott Diagnostics, Amarin, Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma Inc, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. Dr. Banach has received research grant(s)/support from Sanofi and Valeant, and has served as a consultant for Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis, Servier, Valeant, Daichii Sankyo, Esperion, Lilly, and Resverlogix. Dr. Mancini has received research grant(s)/support from Merck, Astra Zeneca, Amgen, Sanofi, Novo Nordisk, and Boehringer Ingelheim, and has served as a consultant for these companies as well as Esperion, Novartis, and Servier. Dr. Lepor has received research grant(s)/support from Regeneron and Sanofi; has served as a consultant for Astra Zeneca, Amgen, Sanofi and Regeneron; and has participated in speakers' bureaus for Regeneron, Sanofi, Amgen, Boehringer Ingelheim, Bristol Myers Squib, and Pfizer. Mr. Hanselman and Ms. Zhou are full-time employees of Esperion Therapeutics, Inc. Dr. Leiter has received research grant(s)/support from Astra Zeneca, Amgen, Kowa, Merck, The Medicines Company, and Sanofi/Regeneron. He has also served as a consultant for Astra Zeneca, Amgen, Esperion, Kowa, Merck, The Medicines Company, and Sanofi/Regeneron.
Financial support
This clinical trial was funded by Esperion Therapeutics, Inc. Medical writing/editorial support for preparation of this article was also provided to the JB Ashtin Group, Inc. by Esperion Therapeutics, Inc.
Author contributions
Christie M. Ballantyne and Norman E. Lepor: data acquisition, data interpretation, critical review of the manuscript throughout the editorial process, and approval of the final manuscript draft submitted for publication. Maciej Banach, G. B. John Mancini, and Lawrence A. Leiter: data interpretation, critical review of the manuscript throughout the editorial process, and approval of the final manuscript draft submitted for publication. Jeffrey C. Hanselman: study concept and design, data acquisition, data interpretation, critical review of the manuscript throughout the editorial process, and approval of the final manuscript draft submitted for publication. Xin Zhao: statistical analysis, critical review of the manuscript throughout the editorial process, and approval of the final manuscript draft submitted for publication. All authors agree to be accountable for all aspects of the work, ensuring the accuracy and integrity of the publication.
Acknowledgements
The authors offer their appreciation to all the investigators, study site staff, and patient volunteers who participated in the study. They also thank IQVIA for their oversight of patient randomization, clinical laboratory services, statistical analyses, clinical monitoring, data management, and clinical programming. The authors thank Crystal Murcia, PhD, and Lamara D. Shrode, PhD, CMPP, of the JB Ashtin Group, Inc., who developed the first draft of the manuscript based on an author-approved outline and assisted in implementing revisions based on the authors' input and direction.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
Supplemental Fig 1. Subgroup analysis of percent change from baseline to week 12 in low-density lipoprotein cholesterol (LDL-C). Data are least-squares (LS) mean differences and 95% confidence intervals (CIs); p values for interaction are based on analysis of covariance. BMI, body mass index.
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