ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia. This phase 2b, multicenter, double-blind trial ( NCT02072161 ) randomized 134 hypercholesterolemic patients (LDL-C, 115 to 220 mg/dl) on stable background statin therapy to 12 weeks of add-on treatment with ETC-1002 120 mg, ETC-1002 180 mg, or placebo. The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12. For LDL-C, the least-squares mean percent change ± standard error from baseline to week 12 was significantly greater with ETC-1002 120 mg (−17 ± 4%, p = 0.0055) and ETC-1002 180 mg (−24 ± 4%, p <0.0001) than placebo (−4 ± 4%). ETC-1002 also dose dependently reduced apolipoprotein B by 15% to 17%, non–high-density lipoprotein cholesterol by 14% to 17%, total cholesterol by 13% to 15%, and LDL particle number by 17% to 21%. All these reductions in ETC-1002–treated cohorts were significantly greater than those with placebo. Rates of adverse events (AEs), muscle-related AEs, and discontinuations for AEs with ETC-1002 were similar to placebo. In conclusion, ETC-1002 120 mg or 180 mg added to stable statin therapy significantly reduced LDL-C compared to placebo and has a similar tolerability profile.
ETC-1002 (bempedoic acid) is an oral, once-daily therapy that lowers low-density lipoprotein cholesterol (LDL-C) by direct inhibition of adenosine triphosphate (ATP) citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. This inhibition leads to reduced cholesterol biosynthesis and increased LDL receptor activity. The present phase 2b trial ( NCT02072161 ) evaluated whether add-on ETC-1002 would lead to further reductions in LDL-C in patients with persistently elevated LDL-C, despite stable, ongoing statin therapy.
Methods
Hypercholesterolemic men and women aged 18 through 80 years with a body mass index from 18 to 45 kg/m 2 who were on stable statin therapy were eligible for inclusion. Stable statin therapy was defined as use of atorvastatin (10 or 20 mg), simvastatin (5, 10, or 20 mg), rosuvastatin (5 or 10 mg), or pravastatin (10, 20, or 40 mg) for at least 3 months before screening. Included participants had fasting, calculated LDL-C levels from 115 to 220 mg/dl and a fasting triglyceride level of ≤400 mg/dl after washout of lipid-regulating agents other than the statins listed previously. Patients were excluded if they had a history of clinically significant cardiovascular disease within 12 months of screening, including but not limited to acute coronary syndromes, stroke, transient ischemic attack, carotid or peripheral artery disease, or cardiac arrhythmias; current clinically significant cardiovascular disease including decompensated heart failure, uncontrolled hypertension, or cardiac arrhythmias; a history of liver or muscle enzyme elevation that occurred during statin therapy and resolved after statin discontinuation; type 1 diabetes or uncontrolled type 2 diabetes; a history of long-term muscle symptoms difficult to differentiate from myalgia; current muscle symptoms that may have been due to ongoing statin therapy; uncontrolled hypothyroidism; liver or renal dysfunction; gastrointestinal disorders affecting drug absorption; unexplained creatine kinase elevations; or use of anticoagulants, colchicine, systemic corticosteroids, digoxin, potent cytochrome P450 3A4 inhibitors or inducers, metformin, or thiazolidinediones within 4 weeks of screening.
This was a double-blind, parallel-group, placebo-controlled, multicenter, phase 2b trial consisting of a 6-week screening and washout phase and a 12-week treatment phase. Patients were randomized in a 1:1:1 ratio to ETC-1002 120 mg, ETC-1002 180 mg, or matching placebo once daily for 12 weeks in addition to ongoing statin therapy. Participants were stratified by history of statin intolerance, defined as discontinuation of ≥1 statins at any dose because of muscle-related symptoms. Patients supplied background statin therapy from their usual source and ingested study drug and statin once daily. Study visits occurred every 2 weeks through week 8, with a final visit at week 12. Clinical laboratory assessments and basic fasting lipid blood tests (total cholesterol, calculated LDL-C, high-density lipoprotein cholesterol [HDL-C], and triglycerides) were performed at screening and at all treatment-phase study visits; all other fasting lipid and biomarker measurements were performed at week 0 (day 1) and week 12. Adverse events (AEs) were monitored throughout the study, beginning with the first screening visit, and were observed until resolution or for 30 days after the last dose of study drug.
The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12 in patients treated with ETC-1002 versus those treated with placebo. Secondary efficacy end points included the percent change from baseline to week 12 in apolipoprotein B, non–HDL-C, total cholesterol, LDL particle number, HDL-C, HDL particle number, apolipoprotein A-1, triglycerides, very-low-density lipoprotein particle number, and high-sensitivity C-reactive protein (CRP).
Safety assessments included reported or observed treatment-emergent AEs, clinical laboratory tests (hematology, serum chemistry, coagulation, urinalysis), physical examination findings, vital sign measurements, electrocardiogram readings, weight, and ankle and waist circumference measurements. AEs were coded using the Medical Dictionary for Regulatory Activities version 16.1, and the severity and relation to study drug was assessed by the investigator. Muscle-related AEs were defined as those from the system organ class of musculoskeletal and connective tissue disorders, except for those that were not obviously muscle related. Terms included in the muscle-related AE analysis were selected after database lock and before unblinding; excluded terms were arthralgia, back pain, bursitis, joint swelling, rotator cuff syndrome, and tendonitis.
The planned sample size was 44 patients per treatment group, which provided 90% power to detect a difference of 15% in the percent change in calculated LDL-C from baseline to week 12 between at least 1 ETC-1002 treatment group and the placebo group. This calculation was based on a 2-sided t test at the 5% level of significance and assumed a common standard deviation of 20% and a dropout rate of 10%.
Efficacy analyses were performed on the modified intent-to-treat (mITT) population, which consisted of all randomized patients who received at least 1 dose of study drug, had a baseline assessment, and at least 1 postbaseline assessment, excluding any assessment taken more than 2 days after a dose of study drug. Safety analyses were performed on the safety population, which consisted of all randomized patients who received at least 1 dose of study drug.
For LDL-C, non–HDL-C, total cholesterol, HDL-C, and triglycerides, baseline was defined as the mean of the values from the last screening visit (day −10 to −7) and day 1. For all other efficacy measurements, baseline was defined as the last value before the first dose of study drug. Missing values at week 12 were imputed using the last-observation-carried-forward procedure.
An analysis of covariance was performed on the mITT population to compare each dose of ETC-1002 with placebo for the efficacy end points and evaluated the effects of treatment and history of statin intolerance with the baseline value as a covariate. Least-square means and standard errors were calculated for each treatment group, and differences in least-square means, corresponding 2-sided 95% confidence intervals, and p values were obtained for the treatment comparisons using Wilcoxon rank-sum tests.
Individual institutional review boards approved the clinical study protocol and informed consent documents. Written informed consent was obtained from all participants before any study-related procedures.
Results
Of the 134 randomized patients, 115 (86%) completed the trial and 19 patients (14%) discontinued early, most often for withdrawn consent ( Figure 1 ). Because 1 patient who was randomized did not receive study drug, the safety population included 133 patients. The number of patients included in the mITT population varied according to the end point assessed; 127 patients were included for the primary efficacy end point.
Baseline demographic and clinical characteristics were similar among the treatment groups ( Table 1 ). Overall, 10% of the population reported a history of statin intolerance, defined as a previous discontinuation of at least 1 statin medication because of muscle-related symptoms. The most commonly used protocol-specified background statin medication was simvastatin 20 mg (30%).
| Characteristic | Placebo (n = 45) | ETC-1002 120 mg (n = 43) | ETC-1002 180 mg (n = 45) |
|---|---|---|---|
| Age (years) | 56 ± 10 | 59 ± 9 | 57 ± 10 |
| Women | 22 (49%) | 26 (61%) | 31 (69%) |
| White | 37 (82%) | 37 (86%) | 37 (82%) |
| Not Hispanic/Latino | 38 (84%) | 33 (77%) | 35 (78%) |
| NCEP ATP III Risk Category | |||
| Very high | 6 (13%) | 2 (5%) | 1 (2%) |
| High | 2 (4%) | 3 (7%) | 8 (18%) |
| Moderate | 13 (29%) | 23 (54%) | 22 (49%) |
| Low | 24 (53%) | 15 (35%) | 14 (31%) |
| LDL-C (mg/dl) | 131 ± 22 | 134 ± 20 | 142 ± 28 |
| Total cholesterol (mg/dl) | 212 ± 24 | 216 ± 24 | 229 ± 29 |
| HDL-C (mg/dl) | 54 ± 14 | 55 ± 15 | 55 ± 14 |
| Triglycerides (mg/dl) ∗ | 119 (82-159) | 112 (88-178) | 145 (122-196) |
| High-sensitivity C-reactive protein (mg/l) ∗ † | 1.8 (1.10-4.60) | 1.8 (0.90-3.10) | 1.8 (1.20-4.00) |
| Systolic blood pressure (mm Hg) | 126 ± 12 | 128 ± 11 | 129 ± 14 |
| Diastolic blood pressure (mm Hg) | 78 ± 7 | 80 ± 8 | 78 ± 9 |
| Weight (kg) | 90 ± 20 | 83 ± 20 | 83 ± 19 |
| Body-mass index (kg/m 2 ) | 31 ± 6 | 30 ± 6 | 30 ± 6 |
| History of statin intolerance ‡ | 3 (7%) | 6 (14%) | 4 (9%) |
∗ Values are median (interquartile range).
† For CRP, baseline defined as the last value before the first dose of study drug; n = 42 for ETC-1002 120 mg.
‡ History of statin intolerance was defined as patient-reported discontinuation of ≥1 statin, at any dose, because of muscle-related symptoms. No patients with a history of statin intolerance were experiencing statin-related AEs at baseline.
ETC-1002 120 and 180 mg added to stable statin therapy reduced mean LDL-C significantly more than placebo, with the greatest reduction observed in patients who received ETC-1002 180 mg ( Table 2 ). The least-square mean ± standard error percent changes from baseline in LDL-C were −4.2 ± 4.2% with placebo, −17.3 ± 4.0% with ETC-1002 120 mg (p = 0.0055 vs placebo), and −24.3 ± 4.2% with ETC-1002 180 mg (p <0.0001 vs placebo; Figure 2 ). LDL-C reductions in the ETC-1002 treatment groups were significantly greater than in the placebo group by week 2 and remained significantly greater through week 12. The reduction in LDL-C was not significantly different in patients treated with ETC-1002 180 and 120 mg (difference in least-square mean percent change, 7.0%; p = 0.14).
| Placebo (n = 43) | ETC-1002 120 mg (n = 41) | ETC-1002 180 mg (n = 43) | |
|---|---|---|---|
| Primary end point | |||
| LDL-C (mg/dl) | -4.2 ± 4.2 | -17.3 ± 4.0 ∗ | -24.3 ± 4.2 † |
| Secondary end points | |||
| Apolipoprotein B (mg/dl) | -5.5 ± 3.4 | -15.0 ± 3.3 ‡ | -17.2 ± 3.4 ∗ |
| Non–HDL-C (mg/dl) | -1.8 ± 3.9 | -14.3 ± 3.7 ∗ | -16.6 ± 3.9 ∗ |
| Total cholesterol (mg/dl) | -3.2 ± 2.9 | -12.8 ± 2.7 ∗ | -15.3 ± 2.9 ∗ |
| LDL particle number (nmol/l) | -2.3 ± 4.3 | -17.4 ± 4.1 ∗ | -21.3 ± 4.3 ∗ |
| HDL-C (mg/dl) | -2.0 ± 2.7 | -6.1 ± 2.6 | -4.0 ± 2.7 |
| HDL particle number (μmol/l) | -1.6 ± 2.8 | 4.0 ± 2.7 | 10.1 ± 2.8 ∗ |
| Apolipoprotein A-1 (mg/dl) | -3.7 ± 2.2 | -2.0 ± 2.1 | -0.1 ± 2.2 |
| Triglycerides (mg/dl) § | -3.0 (37) | -4.8 (28) | -9.1 (47) |
| VLDL particle number (nmol/l) § | 10.9 (76) | 10.0 (67) | -8.3 (91) |
| CRP (mg/l) § | 0 (89) | -21.8 (44) | -29.8 (50) |
§ Values are median (interquartile range); p values vs placebo are from Wilcoxon rank-sum test.
Compared with placebo, treatment with ETC-1002 added to statin therapy also significantly reduced apolipoprotein B, non–HDL-C, total cholesterol, and LDL particle number ( Table 2 ). Median CRP values were reduced by 22% with ETC-1002 120 mg (p = 0.26 vs placebo) and by 30% with ETC-1002 180 mg (p = 0.08 vs placebo). ETC-1002 did not significantly affect triglyceride levels or very-low-density lipoprotein particle number. All treatment groups demonstrated slight decreases in HDL-C and apolipoprotein A-1 levels, which were not significantly different between ETC-1002 and placebo. Both ETC-1002 treatment groups demonstrated small increases in HDL particle number; the difference in least-square mean percent change in HDL particle number was significant between ETC-1002 180 mg and placebo (10.1% increase vs 1.6% decrease; p = 0.0004).
The overall incidence of AEs and drug-related AEs was similar between ETC-1002 180 mg and placebo and lowest with ETC-1002 120 mg ( Table 3 ). The percent of patients discontinuing because of AEs was not different between placebo (3 patients; 1 with dizziness and headache, 1 with cholelithiasis, 1 with constipation) and ETC-1002 180 mg (2 patients; 1 with rash, 1 with abdominal distention) or ETC-1002 120 mg (no patients discontinued for AEs). Most AEs were mild or moderate in severity. Serious AEs included 1 patient with noncardiac-related chest pain and 1 patient with cholelithiasis in the placebo group and 1 patient with ovarian adenoma who was treated with ETC-1002 180 mg; all were determined unrelated to study drug. No specific drug-related AE was reported by more than 1 patient in either of the ETC-1002 treatment groups. Muscle-related AEs were less frequent with ETC-1002 (2% to 5%) than with placebo (13%) and caused no study discontinuations ( Table 3 ). Myalgia was reported in 2 placebo-treated patients, 1 patient treated with ETC-1002 120 mg, and no patients treated with ETC-1002 180 mg.
