Effect of ETC-1002 on Serum Low-Density Lipoprotein Cholesterol in Hypercholesterolemic Patients Receiving Statin Therapy

Abstract

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 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.1Berkhout T.A. Havekes L.M. Pearce N.J. Groot P.H. The effect of (-)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2.Biochem J. 1990; 272: 181-186Crossref PubMed Scopus (69) Google Scholar, 2Filippov S. Pinkosky S.L. Newton R.S. LDL-cholesterol reduction in patients with hypercholesterolemia by modulation of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase.Curr Opin Lipidol. 2014; 25: 309-315Crossref PubMed Scopus (32) Google Scholar, 3Pinkosky S.L. Filippov S. Srivastava R.A. Hanselman J.C. Bradshaw C.D. Hurley T.R. Cramer C.T. Spahr M.A. Brant A.F. Houghton J.L. Baker C. Naples M. Adeli K. Newton R.S. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.J Lipid Res. 2013; 54: 134-151Crossref PubMed Scopus (147) Google Scholar 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. Hypercholesterolemic men and women aged 18 through 80 years with a body mass index from 18 to 45 kg/m2 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. 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%).Table 1Baseline demographic and clinical characteristics, safety populationCharacteristicPlacebo(n = 45)ETC-1002 120 mg(n = 43)ETC-1002 180 mg(n = 45)Age (years)56 ± 1059 ± 957 ± 10Women22 (49%)26 (61%)31 (69%)White37 (82%)37 (86%)37 (82%)Not Hispanic/Latino38 (84%)33 (77%)35 (78%)NCEP ATP III Risk Category Very high6 (13%)2 (5%)1 (2%) High2 (4%)3 (7%)8 (18%) Moderate13 (29%)23 (54%)22 (49%) Low24 (53%)15 (35%)14 (31%)LDL-C (mg/dl)131 ± 22134 ± 20142 ± 28Total cholesterol (mg/dl)212 ± 24216 ± 24229 ± 29HDL-C (mg/dl)54 ± 1455 ± 1555 ± 14Triglycerides (mg/dl) ∗Values are median (interquartile range).119 (82-159)112 (88-178)145 (122-196)High-sensitivity C-reactive protein (mg/l)∗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.1.8 (1.10-4.60)1.8 (0.90-3.10)1.8 (1.20-4.00)Systolic blood pressure (mm Hg)126 ± 12128 ± 11129 ± 14Diastolic blood pressure (mm Hg)78 ± 780 ± 878 ± ± ± ± index ± ± ± of statin of statin intolerance was defined as discontinuation of ≥1 at any because of muscle-related symptoms. patients with a history of statin intolerance were AEs at are mean ± Baseline defined as the mean of the values from weeks and = high-density lipoprotein LDL-C = low-density lipoprotein ATP III = are median (interquartile For CRP, baseline defined as the last value before the first dose of study drug; n = 42 for ETC-1002 120 of statin intolerance was defined as discontinuation of ≥1 at any because of muscle-related symptoms. patients with a history of statin intolerance were AEs at in a are mean ± Baseline defined as the mean of the values from weeks and = high-density lipoprotein LDL-C = low-density lipoprotein ATP III = ETC-1002 120 and 180 mg added to stable statin therapy reduced mean LDL-C significantly more than with the reduction observed in patients who received ETC-1002 180 mg (Table The least-square mean ± standard error percent from baseline in LDL-C were ± with ± with ETC-1002 120 mg = and ± with ETC-1002 180 mg LDL-C reductions in the ETC-1002 treatment groups were significantly greater than in the placebo group by week 2 and significantly greater through week 12. The reduction in LDL-C was not significantly in patients treated with ETC-1002 180 and 120 mg in least-square mean percent p = in lipid and levels from baseline to week mITT = 43)ETC-1002 120 mg(n = 180 mg(n = end point LDL-C ± ± ± end points B ± ± ± placebo. ± ± ± placebo. cholesterol ± ± ± placebo. LDL particle number ± ± ± placebo. ± ± ± HDL particle number ± ± ± placebo. ± ± ± are median (interquartile p values placebo are from Wilcoxon rank-sum particle number are median (interquartile p values placebo are from Wilcoxon rank-sum are median (interquartile p values placebo are from Wilcoxon rank-sum are least-squares mean ± standard Baseline was defined as the mean of the values from weeks and 0 for LDL-C, non–HDL-C, total cholesterol, HDL-C, and Baseline was defined as the last value before the first dose of study drug for apolipoprotein B, LDL particle number, HDL particle number, apolipoprotein A-1, particle number, and = high-sensitivity C-reactive = high-density lipoprotein LDL-C = low-density lipoprotein mITT = modified = very-low-density p p p are median (interquartile p values placebo are from Wilcoxon rank-sum in a are least-squares mean ± standard Baseline was defined as the mean of the values from weeks and 0 for LDL-C, non–HDL-C, total cholesterol, HDL-C, and Baseline was defined as the last value before the first dose of study drug for apolipoprotein B, LDL particle number, HDL particle number, apolipoprotein A-1, particle number, and = high-sensitivity C-reactive = high-density lipoprotein LDL-C = low-density lipoprotein mITT = modified = very-low-density with treatment with ETC-1002 added to statin therapy also significantly reduced apolipoprotein B, non–HDL-C, total cholesterol, and LDL particle number (Table values were reduced by with ETC-1002 120 mg = and by with ETC-1002 180 mg = ETC-1002 did not significantly triglyceride levels or very-low-density lipoprotein particle All treatment groups demonstrated in and apolipoprotein which were not significantly between ETC-1002 and placebo. ETC-1002 treatment groups demonstrated small in HDL particle the difference in least-square mean percent change in HDL particle number was significant between ETC-1002 180 mg and placebo p = The of AEs and AEs was similar between ETC-1002 180 mg and placebo and with ETC-1002 120 mg (Table The percent of patients because of AEs was not between placebo 1 with and 1 with 1 with and ETC-1002 180 mg 1 with 1 with or ETC-1002 120 mg patients discontinued for AEs were or in AEs included 1 patient with and 1 patient with in the placebo group and 1 patient with who was treated with ETC-1002 180 all were to study drug. AE was reported by more than 1 patient in of the ETC-1002 treatment Muscle-related AEs were with ETC-1002 to than with placebo and study discontinuations (Table was reported in 2 patients, 1 patient treated with ETC-1002 120 mg, and patients treated with ETC-1002 180 adverse safety populationCharacteristicPlacebo(n = 45)ETC-1002 120 mg(n = 43)ETC-1002 180 mg(n = of AEs AEs included 1 patient with and 1 patient with in the placebo group and 1 patient with in the ETC-1002 all were to not to study (2%) were drug if to study drug was or or if to study drug was not (18%) due to common common AEs were those in patients in any group, excluding muscle-related AEs are of (2%) (4%)3 (2%) AEs from the system organ class musculoskeletal and connective tissue disorders except for arthralgia, back pain, bursitis, joint swelling, rotator cuff syndrome, and (13%)2 (5%)1 (2%) (2%) = adverse AEs included 1 patient with and 1 patient with in the placebo group and 1 patient with in the ETC-1002 all were to not to study AEs were drug if to study drug was or or if to study drug was not common AEs were those in patients in any group, excluding muscle-related AEs are of AEs from the system organ class musculoskeletal and connective tissue disorders except for arthralgia, back pain, bursitis, joint swelling, rotator cuff syndrome, and tendonitis. in a AE = adverse clinically in laboratory were laboratory was a AE or in study drug patient treated with ETC-1002 180 mg a in the of at week were other of liver enzyme and of creatine kinase in any treatment group. clinically differences were among the treatment groups with to mean in physical examination findings, vital sign measurements, electrocardiogram readings, weight, or ankle or waist circumference measurements from baseline to week 12. In patients with elevated LDL-C levels despite stable statin add-on treatment with ETC-1002 LDL-C with and 180 mg) LDL-C placebo. In this study, LDL-C was reduced to statin therapy in patients treated with The present trial is the first study of the effects of ETC-1002 added on to a of stable background statin of the efficacy apolipoprotein B, non–HDL-C, total cholesterol, and LDL particle number the primary end point of ETC-1002 significantly reduced each of these compared with placebo. are with those from previous phase 2 in which these 4 were significantly reduced with ETC-1002 monotherapy compared with J. Newton R.S. Efficacy and safety of a novel of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with of a multicenter, double-blind, placebo-controlled, 2013; PubMed Scopus Google Scholar and compared with Hanselman Newton ETC-1002 lowers LDL-C more than in patients with hypercholesterolemia with or statin intolerance and has a similar safety and tolerability profile. of the of Scholar M. J. J. C.D. C. S. T.A. A.F. B versus cholesterol in cardiovascular and in of the PubMed Scopus Google Scholar C. T.R. in Study of cardiovascular events in patients with coronary heart from the in PubMed Scopus Google Scholar and LDL particle M. R.S. R.A. T.A. in patients low-density lipoprotein cholesterol and particle 2014; PubMed Scopus Google Scholar have all been to have with the of cardiovascular events than is that ETC-1002 significantly apolipoprotein B, non–HDL-C, and LDL particle number when used as monotherapy or in with or was significant change in HDL-C, patients treated with ETC-1002 180 mg demonstrated a but significant in HDL particle number, which has been to with cardiovascular events in patients treated with statin S. lipoprotein cholesterol, particle number, and after potent statin 2013; PubMed Scopus Google Scholar phase 2 with ETC-1002 monotherapy have demonstrated in of Hanselman J.C. M.A. Newton R.S. Efficacy and safety of ETC-1002, a novel low-density therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes 2014; PubMed Scopus Google Scholar to J. Newton R.S. of ETC-1002 to hypercholesterolemia in patients with statin Lipidol. PubMed Scopus Google Scholar In the present study, reduction in was observed for patients in the placebo group statin the addition of ETC-1002 120 or 180 mg to stable statin therapy reduced by and from ETC-1002 was and in the present study, with a similar of AEs between ETC-1002 180 mg and placebo and the observed in patients treated with ETC-1002 120 The of muscle-related AEs during the trial was and patients discontinued because of muscle-related This of muscle safety with ETC-1002 is by in previous phase 2 in patients with a history of muscle symptoms in which the of muscle-related AEs was not with ETC-1002 monotherapy compared with J. Newton R.S. of ETC-1002 to hypercholesterolemia in patients with statin Lipidol. PubMed Scopus Google Scholar or Hanselman Newton ETC-1002 lowers LDL-C more than in patients with hypercholesterolemia with or statin intolerance and has a similar safety and tolerability profile. of the of Scholar used in with statins for LDL-C which further reduce LDL-C by 10% to S. S. J. J. for and for the of the for the of of the of and the J. PubMed Scopus Google Scholar and which lowers LDL-C by and by R.S. J. efficacy of statin and statin monotherapy and of with treatment a analysis of from clinical PubMed Scopus Google Scholar In of the approved type inhibitors added to statin has been to reduce LDL-C by C. Efficacy and safety of the type among cardiovascular patients on statin the J. PubMed Scopus Google Scholar to C. Safety and efficacy of a to type in patients with primary hypercholesterolemia ongoing stable atorvastatin PubMed Scopus Google Scholar from with effect on C. Efficacy and safety of in cardiovascular patients with on of the randomized J. PubMed Scopus Google Scholar and has reductions of to from J. J.C. of or added to or statin therapy on LDL-C in patients with the randomized clinical 2014; PubMed Scopus Google Scholar The protein lowers LDL-C by and has effect on when added to S. M. M. J. the Efficacy and Safety of in patients with or at for coronary heart PubMed Scopus Google Scholar that differences in study patient baseline LDL-C and cardiovascular of and in the direct comparisons of ETC-1002 inhibits ATP citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis S.L. Filippov S. Srivastava R.A. Hanselman J.C. Bradshaw C.D. Hurley T.R. Cramer C.T. Spahr M.A. Brant A.F. Houghton J.L. Baker C. Naples M. Adeli K. Newton R.S. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.J Lipid Res. 2013; 54: 134-151Crossref PubMed Scopus (147) Google Scholar Because ETC-1002 and statins in the cholesterol the end is cholesterol The cholesterol leads to of and reduction in the levels of LDL-C, that the by which LDL-C is Patients who have an on statin therapy an in the clinical of hypercholesterolemia. is that cardiovascular in patients despite statin therapy and that are to this J.C. C. J.C. J. to lipid with atorvastatin in patients with stable coronary PubMed Scopus Google Scholar, for lipid-lowering effect of on and of PubMed Scopus Google Scholar, to from add-on lipid J. 2013; PubMed Scopus Google Scholar This has further in the clinical use of agents as add-on therapy for cholesterol reduction and on long-term cardiovascular clinical trial with the that LDL-C in the statin is with cardiovascular M.A. K. C. T.A. added to statin therapy after acute coronary PubMed Scopus Google Scholar, that is cholesterol and PubMed Scopus Google Scholar The present study was to a clinical in which a drug is added to ongoing or statin therapy to LDL-C and the efficacy and safety in this study a for ETC-1002 in these the study a phase 2 the sample size was small and the of treatment was 12 The safety and efficacy demonstrated in the present study further of ETC-1002 as add-on to statins in clinical in the despite the randomized trial were differences in baseline characteristics among the treatment including level of cardiovascular and levels of LDL-C and In patients with elevated LDL-C levels despite stable statin the addition of ETC-1002 120 or 180 mg daily significant and clinically LDL-C and is that once-daily ETC-1002 to stable statin therapy may a clinical in the The all their and all patient also of for their of patient clinical laboratory clinical safety clinical and The J. and of The for in this for based on the and The for all The that they have all the for has received from of and has as a for and is an of Clinical which has received for lipid from and has also received from and are of