Triplet combination formulations and methods for treating or reducing the risk of cardiovascular disease

Abstract

Methods and compositions useful for treating or reducing the risk of cardiovascular disease are provided. [Solution] A triplet combination therapy comprising bempedoic acid (ETC-1002), ezetimibe, and a statin has a synergistic effect and provides outcomes in treating or reducing the risk of cardiovascular disease that are additive, and in some embodiments, greater than the sum of the benefits expected from the combination of any one or two of bempedoic acid, ezetimibe, and a statin; and further, the triplet combination produces fewer and less severe side effects and / or adverse events in patients suffering from or at risk of cardiovascular disease, or otherwise in need of treatment for cardiovascular disease.

Description

Technical Field

[0001] This application relates to methods and compositions useful for treating cardiovascular disease or reducing its risk. This application discloses methods for reducing low density lipoprotein cholesterol (LDL-C) and simultaneously treating cardiovascular disease or reducing its risk, and compositions therefor comprising ETC-1002, a statin, and ezetimibe.

Background Art

[0002] Statins are the cornerstone of the prevention and treatment of cardiovascular disease, but may cause statin-related muscle symptoms in 5% - 29% of patients. Muscle symptoms, which usually do not involve an increase in serum creatine kinase (CK), including pain, stiffness, cramps, or weakness, are the main signs of statin intolerance.

[0003] Regardless of aggressive intervention therapies and drug therapies, CVD is the leading cause of death worldwide (WHO 2015). According to the Global Burden of Disease study, in 2010, 29.6% of all deaths worldwide (about 15,600,000 deaths) were caused by CVD, more than the combination of all infectious diseases, maternal disorders, neonatal disorders, and nutritional disorders, and was estimated to be twice the number of deaths caused by cancer (Nichols 2014). In the United States (US), based on mortality data in 2011, more than 2150 Americans die of CVD every day, with an average of one death every 40 seconds (Mozffarian 2015). Of great concern is that approximately 155,000 Americans who die of CVD are under 65 years old (Mozffarian 2015). In Europe, CVD remains the most common cause of death, causing almost twice as many deaths as cancer (Townsend 2015).

[0004] An elevated LDL-C is a major modifiable risk factor for the development of atherosclerosis and CVD (Sharrett 2001). Evidence supporting LDL-C as a treatment target and surrogate for cardiovascular (CV) outcomes has been provided by interventional studies, epidemiological studies, and genetic variants (both gain-of-function and loss-of-function) using LDL-C lowering therapies. Large-scale randomized clinical studies aimed at reducing LDL-C have shown a consistent log-linear relationship between LDL-C reduction and CV risk reduction, independent of the mechanism of LDL-C lowering (Kathiresan 2008; Baigent 2010; Robinson 2005; Stamler 1986, Silverman 2016). Published patient-level meta-analyses, including 26 statin trials and over 160,000 participants, have shown a consistent relationship between LDL-C reduction and CV outcomes (Baigent 2010). This analysis demonstrated that a 1 mmol / L (~39 mg / dL) reduction in LDL-C was associated with a 22% reduction in the 5-year incidence of major coronary events, revascularization, and ischemic stroke. More recently, a meta-analysis of 312,175 patients in 49 trials evaluated the relationship between LDL-C reduction and CV outcomes when LDL-C reduction was achieved by statin therapy or established non-statin interventions that act primarily by upregulating the LDL receptor, such as diet, bile acid sequestrant, ileal bypass, and ezetimibe (Silverman 2016). This meta-analysis reported that the relationship between LDL-C reduction and CV outcomes was similar regardless of whether LDL-C reduction was achieved by statin therapy or non-statin interventions that upregulate the LDL receptor (Silverman 2016). Therefore, LDL-C reduction via upregulation of the LDL receptor is widely accepted by clinicians and regulatory authorities as a valid surrogate endpoint for CV risk reduction (Stone 2013).

[0005] Statins are central to the LDL-C reduction strategy and are supported by large-scale data demonstrating their strong effectiveness in reducing LDL-C and lowering the risk of CVD (Waters 2006, Grundy 2004). However, awareness of the limitations and risks of statin use is increasing. Many individuals at risk of CVD are unable to achieve their LDL-C targets (Martin 2013, Virani 2011). In 2011, the Food and Drug Administration (FDA) mandated a change in the safety labeling to restrict the use of high-dose (80 mg) simvastatin due to safety concerns regarding muscle injury or myopathy (Egan 2011). Myopathy events are rare, but the broader problem is various muscle side effects such as pain and weakness, particularly at high doses, leading to low tolerance and lack of persistence in statin therapy (Cohen 2012).

[0006] Patients with hypercholesterolemia have several treatment options for reducing LDL-C. Statin and non-statin therapies that reduce LDL-C via upregulation of the LDL receptor are associated with a reduction in cardiovascular disease (CVD) risk.

[0007] Therefore, there is a need to develop effective treatments for CVD and CV risk while minimizing the number of adverse side effects. SUMMARY OF THE INVENTION

[0008] Generally, the present application relates to methods for treating cardiovascular disease or reducing its risk, and compositions comprising bempedoic acid (ETC-1002), ezetimibe, and a statin. Triplet combinations comprising ETC-1002; ezetimibe; a statin; and one or more pharmaceutical excipients or carriers are disclosed herein. Kits comprising one or more compositions comprising one or more components of the triplet combination itself are also disclosed herein. The triplet combination is useful for treating cardiovascular disease or reducing its risk. Methods for treating or reducing the risk of cardiovascular disease, atherosclerotic cardiovascular disease, hyperlipidemia, dyslipidemia, or mixed dyslipidemia are disclosed using the triplet combination, optionally adding PCSK9 inhibitor antibody therapy or an approved lipid-lowering therapy to the combination, and optionally in patients having hypercholesterolemia or suffering from muscle-related adverse events associated with the use of a statin. Also disclosed are methods for treating or reducing the risk of cardiovascular disease that affect the low-density lipoprotein cholesterol (LDL-C) level, very-low-density lipoprotein (VLDL) level, number of VLDL particles, size of VLDL particles, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof in a subject compared to that in a matched control subject administered the same dose of a statin and ezetimibe but lacking ETC-1002.

[0009] Bempedoic acid, statin, and ezetimibe act by different mechanisms to reduce LDL-C via upregulation of the LDL receptor. The present invention provides methods, kits, and compositions useful for treating patients having elevated LDL-C to achieve reduction of LDL-C using triplet therapy.

[0010] The inventors have found that a triplet combination therapy comprising bempedoic acid (ETC-1002), ezetimibe, and a statin has a synergistic effect and provides an outcome that is additive and, in some aspects, exceeds the sum of the benefits predicted from any one or two combinations of bempedoic acid (ETC-1002), ezetimibe, and a statin when treating cardiovascular disease or reducing its risk. Further, the inventors have found that the triplet combination results in lower frequency and severity of side effects and / or adverse events that occur in patients with or at risk of cardiovascular disease or otherwise in need of treatment for cardiovascular disease.

[0011] As described herein, these triplet compositions provide a significant reduction in total cholesterol, specifically LDL-C, in patients in need of treatment for cardiovascular disease.

[0012] Accordingly, based on the results of the clinical studies disclosed herein demonstrating that the triplet combination is superior compared to the respective efficacy and safety of ETC-1002 monotherapy, ezetimibe monotherapy, therapy with ETC-1002 in combination with ezetimibe (EZE), and each with or without statin therapy, the present application discloses kits, compositions, and methods using ETC-1002, ezetimibe, and a statin. This result is particularly relevant among hypercholesterolemic patients with or without a history of statin-related muscle symptoms.

[0013] These and other features, aspects, and advantages of the present invention will be better understood with reference to the following description and the accompanying drawings.

Brief Description of the Drawings

[0014]

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Mode for Carrying Out the Invention

[0015] Advantages and Usefulness Bempedoic acid (ETC-1002) is an oral first-in-class small molecule designed to reduce low-density lipoprotein cholesterol (LDL-C). ETC-1002 has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by directly inhibiting hepatic adenosine triphosphate citrate lyase, reducing de novo cholesterol synthesis, and increasing LDL receptor expression.

[0016] The general classification of "statins" is compounds that inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, concomitantly, reduce cholesterol levels in the body by inhibiting the pathway for synthesizing cholesterol in the liver. Examples of compounds that are part of the "statin" classification include, but are not limited to, atorvastatin, simvastatin, rosuvastatin, and pravastatin. In treatment, usually, a statin compound in an amount of about 1 mg to 80 mg is administered.

[0017] As described above, bempedoic acid (ETC-1002) is a small molecule that inhibits adenosine triphosphate citrate lyase (ACL), an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterol biosynthetic pathway. Bempedoic acid upregulates the LDL-C receptor, similar to both statins and ezetimibe. However, unlike statins, bempedoic acid does not inhibit cholesterol synthesis in muscle tissue, and it is predicted that negative muscle-related adverse events associated with statin use can be avoided by the use of bempedoic acid.

[0018] Briefly, as described in more detail below, compositions, methods of making the compositions, and methods for treating cardiovascular disease or reducing the risk of cardiovascular disease using a triplet combination of ezetimibe, a statin, and ETC-1002 are described herein. There are numerous advantages to this approach, including, but not limited to, increased reduction in total cholesterol and low density lipoprotein cholesterol levels in patients. Patients treated with the triplet combination experience at least equivalent outcomes, if not exceeding the merely additive beneficial effects of these three components. In some embodiments, the triplet combination demonstrates a synergistic effect. In other words, the triplet combination is more effective than predicted, as many results significantly exceed those when patients are treated with ezetimibe monotherapy, ETC-1002 monotherapy, and each of the combinations of ezetimibe and ETC-1002, with or without statin therapy.

[0019] As noted above, statins are the cornerstone of cardiovascular disease prevention and treatment, but can cause statin-related myalgias in 5% - 29% of patients. Since discontinuation of statins in patients with hypercholesterolemia increases cardiovascular risk, statin-related myalgias are an important clinical problem. Patients who discontinue statin therapy due to intolerance tend to have a reduced 8-year survival rate compared to patients who continue statin therapy. Thus, there is a significant need for cardiovascular therapies for patients who exhibit muscle-related statin intolerance.

[0020] Definitions The terms used in the claims and the specification are defined as follows, unless otherwise specified.

[0021] As used in this specification and the appended claims, in the context of describing an element (especially in the context of the following claims), singular articles such as "a", "an", and "the" and similar references shall be construed to include both the singular and the plural unless the specification indicates otherwise or the context clearly dictates otherwise. Descriptions of ranges of values herein are merely intended to serve as a convenient method of referring individually to each individual value within the range, including the upper and lower limits of the range, and each individual value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless the specification indicates otherwise or the context clearly dictates otherwise. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is merely intended to clarify the embodiments and does not impose a limitation on the claims. No language in this specification should be construed as indicating any non-claimed element as essential.

[0022] As used herein, the term "cardiovascular disease" refers to diseases of the heart and circulatory system. These diseases are often associated with abnormal lipoproteinemia and / or dyslipidemia. Cardiovascular diseases for which the compositions of the present disclosure are beneficial for prevention or treatment include, but are not limited to, atherosclerosis; atherosclerotic plaque; stroke; ischemia; endothelial dysfunction, particularly dysfunction that affects vascular elasticity; peripheral vascular disease; coronary heart disease; myocardial infarction; cerebral infarction and restenosis.

[0023] As used herein, the term "dyslipidemia" refers to a disorder that results in or is manifested by abnormal levels of circulating lipids. Within a range where the levels of lipids in the blood are too high, the compositions of the present disclosure are administered to a patient to restore normal levels. Normal levels of lipids are reported in medical papers known to those of ordinary skill in the art. For example, the recommended blood levels of LDL, HDL, free triglycerides, and other parameters related to lipid metabolism can be found on the websites of the American Heart Association (http: / / www.americanheart.org / cholesterol- / about_level.html) and the National Cholesterol Education Program of the National Heart, Lung and Blood Institute (http: / / www.nhlbi.nih.gov / health / public / heart / chol / hb-c_what.html). At present, the recommended level of HDL cholesterol in the blood is 35 mg / dL or higher, the recommended level of LDL cholesterol in the blood is 130 mg / dL or lower, the recommended LDL:HDL cholesterol ratio in the blood is 5:1 or lower, ideally 3.5:1, and the recommended level of free triglycerides in the blood is less than 200 mg / dL. Dyslipidemia includes, but is not limited to, hyperlipidemia and low blood levels of high-density lipoprotein (HDL) cholesterol. In certain embodiments, hyperlipidemia for prevention or treatment with the compounds of the present disclosure includes familial hypercholesterolemia; familial combined hyperlipidemia; a decrease or deficiency in lipoprotein lipase level or activity, including a decrease or deficiency resulting from a mutation in lipoprotein lipase; hypertriglyceridemia; hypercholesterolemia; high blood levels of urea bodies (e.g., β-OH butyric acid); high blood levels of Lp(a) cholesterol; high blood levels of low-density lipoprotein (LDL) cholesterol; high blood levels of very-low-density lipoprotein (VLDL) cholesterol, and high blood levels of non-esterified fatty acids.

[0024] Generally, reference to a particular element, such as hydrogen or H, means all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it includes deuterium and tritium. Thus, compounds containing radioactive isotopes such as tritium, 14 C, 32 P, and 35 S are within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0025] The term "ameliorate" refers to any therapeutically beneficial result in the treatment of a disease state, such as an inflammatory disease state, and includes attenuation of the severity or progression of the disease state, remission, or cure. In some embodiments, "ameliorate" includes prevention of the disease state.

[0026] As used herein, the term "IMP" means an investigational medicinal product. Such medicinal products include pharmaceutical forms or placebos of an active substance that are being tested in clinical trials or used as a reference, and products that already have marketing approval but are used or manufactured (formulated or packaged) in a manner different from the approved form, or are used for an indication for which approval has not been obtained, or are used to obtain further information about the approved form.

[0027] The term "in vitro" refers to processes occurring in living cells that are isolated and grown from an organism, such as grown in tissue culture.

[0028] The term "in vivo" refers to processes occurring within an organism.

[0029] The term "mammal" as used herein includes both human and non-human, including but not limited to humans, non-human primates, dogs, cats, mice, cows, horses, and pigs.

[0030] The term "sufficient amount" means an amount sufficient to produce the desired effect, e.g., an amount sufficient to modulate protein aggregation in cells.

[0031] The term "therapeutically effective amount" is an amount effective to ameliorate the symptoms of a disease. Since prevention can be considered treatment, the therapeutically effective amount may, in some embodiments, be a "prophylactically effective amount".

[0032] The compounds of the present technology can exist as solvates, particularly hydrates. Hydrates may form during the manufacture of the compound or a composition containing the compound, or hydrates may form over time due to the hygroscopicity of the compound. The compounds of the present technology can also exist as organic solvates including, inter alia, DMF, ether, and alcohol solvates. The identification and manufacture of any particular solvate are within the skill of those in the art of synthetic organic or pharmaceutical chemistry.

[0033] "Subject" refers to a mammalian organism being treated with the compounds of the present disclosure. The "subject" may be a human or non-human mammalian organism.

[0034] "Tautomers" refer to alternative forms of a compound where the position of a proton is different, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both the ring NH moiety and the ring =N moiety, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0035] "Treating" or "treatment" of a subject's disease or disorder means: 1) preventing the disease or disorder from occurring in a subject who is susceptible to the disease or disorder or who has not yet manifested symptoms of the disease or disorder; 2) inhibiting the disease or disorder or preventing its onset; or 3) ameliorating or alleviating the cause of regression of the disease or disorder.

[0036] As used herein, the terms "prevent", "preventing", "prevention", "prophylactic treatment", etc. refer to reducing the likelihood of developing a disease, disorder, or condition in a subject who does not have the disease, disorder, or condition but is at risk of developing it or is predisposed to developing it. Thus, in some embodiments, the agent can be administered prophylactically to prevent the onset of a disease, disorder, or condition or to prevent recurrence of a disease, disorder, or condition.

[0037] For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, ratios, shapes, compositions, parameters, percentages, parameters, amounts, features, and all other numerical expressions used in this specification and the claims are to be understood as being modified in all instances by the term "about", even when the term "about" is not explicitly recited with the value, amount, or range. Thus, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations and need not be exact, but may, as desired, reflect tolerance, conversion factors, rounding, measurement error, and other factors known to those of skill in the art, and may be greater than or less than as appropriate to the desired properties contemplated by the subject matter of the present disclosure. For example, when the term "about" refers to a value, in some embodiments it can mean a variation of ±100%, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the particular amount, as appropriate for carrying out the methods of the present disclosure or using the compositions of the present disclosure.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0039] Here, any and all heteroaryl and heterocycloalkyl substituents may contain up to four heteroatoms selected from the group consisting of O, N, and S.

[0040] Abbreviations: AE is the abbreviation for adverse event. CK is the abbreviation for creatine kinase. EZE is the abbreviation for ezetimibe. HDL-C is the abbreviation for high-density lipoprotein cholesterol. CRP is the abbreviation for high-sensitivity C-reactive protein. LDL-C is the abbreviation for low-density lipoprotein cholesterol. LS is the abbreviation for least squares. NCEP ATP-III is the abbreviation for National Cholesterol Education Program Adult Treatment Panel III. Non-HDL-C is the abbreviation for non-high-density lipoprotein cholesterol. VLDL is the abbreviation for very low-density lipoprotein. NCEP ATP-III is the abbreviation for National Cholesterol Education Program Adult Treatment Panel III.

[0041] Methods of treatment Disclosed herein is a method of treating or reducing the risk of cardiovascular disease in a subject in need thereof, the method comprising administering to the subject ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, wherein the administering treats or reduces the risk of cardiovascular disease in the subject.

[0042] Disclosed herein is a method for treating atherosclerotic cardiovascular disease or reducing its risk in a subject in need thereof, said method comprising administering to the subject ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, said administration being a method for treating atherosclerotic cardiovascular disease or reducing its risk in the subject.

[0043] Disclosed herein is a method for treating dyslipidemia in a subject in need thereof, said method comprising administering to the subject ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, said administration being a method for treating or alleviating dyslipidemia in the subject.

[0044] Disclosed herein is a method for treating hypercholesterolemia in a subject in need thereof, said method comprising administering to the subject ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, said administration being a method for treating or alleviating hypercholesterolemia in the subject.

[0045] Disclosed herein is a method for reducing cholesterol, said method comprising administering to the subject ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, said administration being a method for reducing cholesterol in the subject.

[0046] Disclosed herein is a method for treating cardiovascular disease or reducing its risk in a subject in need thereof, said method comprising administering to the subject ETC-1002, ezetimibe, a statin, PCSK9 inhibitor antibody therapy, and one or more pharmaceutical excipients or carriers, said administration being a method for treating cardiovascular disease or reducing its risk in the subject.

[0047] Disclosed herein is a method for treating cardiovascular disease or reducing its risk in a subject in need thereof, the method comprising administering to the subject ETC-1002, ezetimibe, a statin, an approved lipid-modifying therapy other than a statin and / or ezetimibe, and one or more pharmaceutical excipients or carriers, wherein the administration is a method for treating cardiovascular disease or reducing its risk in the subject.

[0048] In some embodiments, the method treats cardiovascular disease or reduces its risk in the subject. In some embodiments, the method treats atherosclerotic cardiovascular disease or reduces its risk in the subject.

[0049] In one embodiment, the triplet combination also exhibits a significantly superior efficacy and safety profile in patients / subjects with acute hypercholesterolemia or patients / subjects suffering from dyslipidemia.

[0050] In one embodiment, the methods and compositions of the present disclosure further reduce cholesterol in patients who have persistently elevated LDL-C despite being on stable statin therapy at high doses of statin, i.e., a statin dose of 40 - 80 mg.

[0051] The formulations of the present disclosure are also useful in methods for treating the following conditions in a subject: abnormal lipoproteinemia and / or dyslipidemia, arteriosclerosis, atherosclerosis, stroke, ischemia, and / or endothelial dysfunction.

[0052] The present disclosure also provides a method for the treatment or prevention of dyslipidemia comprising administering to a subject in need thereof ETC-1002, a statin, ezetimibe, and one or more pharmaceutical excipients.

[0053] The lipid disorders in which the compositions of the present disclosure are beneficial for prevention or treatment include, but are not limited to, hyperlipidemia and low blood levels of high-density lipoprotein (HDL) cholesterol. In certain embodiments, the hyperlipidemia for prevention or treatment by the compounds of the present disclosure is familial hypercholesterolemia; familial combined hyperlipidemia; a decrease or deficiency in lipoprotein lipase level or activity, including a decrease or deficiency due to a mutation in lipoprotein lipase; hypertriglyceridemia; hypercholesterolemia; high blood levels of urea bodies (e.g., β-OH butyric acid); high blood levels of Lp(a) cholesterol; high blood levels of low-density lipoprotein (LDL) cholesterol; high blood levels of very-low-density lipoprotein (VLDL) cholesterol and high blood levels of non-esterified fatty acids.

[0054] The present disclosure further provides a method of altering lipid metabolism in a subject, e.g., reducing LDL in the patient's blood, reducing free triglycerides in the patient's blood, increasing the ratio of HDL to LDL in the patient's blood, and inhibiting saponification and / or non-saponification fatty acid synthesis, the method comprising administering a compound of the present disclosure to the patient.

[0055] Clinical endpoint In some embodiments, the administration reduces the C-reactive protein (CRP) level by 20%, or 30% or more compared to the baseline.

[0056] In some embodiments, the administration dose-dependently reduces apolipoprotein B by 15% to 17% or more, non-high-density lipoprotein cholesterol by 14% to 17% or more, total cholesterol by 13% to 15% or more, and the number of LDL particles by 17% to 21% or more.

[0057] In some embodiments, due to said administration, LDL-C in the subject is reduced by up to 24% or more compared to the baseline. In some embodiments, due to said administration, non-HDL-C in the subject is reduced by at least 30, 35, 37, 40, 42, 45% or more compared to the baseline. In some embodiments, due to said administration, hsCRP in the subject is reduced by at least 20, 25, 26, 30, 35, 38, 40% or more compared to the baseline.

[0058] In some embodiments, due to said administration, non-HDL-C in the subject is reduced by at least 30, 35, 40, 43, 45, 48, 50% or more compared to the baseline. In other embodiments, due to said administration, HDL-C in the subject is reduced compared to the baseline.

[0059] In one embodiment, due to said administration, the following are decreased: the level of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof in the subject.

[0060] In some embodiments, LDL-C is reduced in the subject by at least 30, 35, 40, 43, 45, 48, or 50% compared to baseline. In some embodiments, the LDL-C level in the subject is reduced by 40% compared to baseline by the method. In some embodiments, the LDL-C level in the subject is reduced by 45% compared to baseline by the method. In some embodiments, the LDL-C level in the subject is reduced by 50% compared to baseline by the method. In some embodiments, non-HDL-C is reduced in the subject by at least 30, 35, 37, 40, 42, or 45% compared to baseline. In some embodiments, hsCRP is reduced in the subject by at least 20, 25, 26, 30, 35, 38, or 40% compared to baseline.

[0061] In some embodiments, by the method, the LDL-C level in the subject is reduced by 61% compared to the baseline. In some embodiments, by the method, the LDL-C level in the subject is reduced by 64% compared to the baseline LDL-C level in the subject. In some embodiments, by the method, 6 weeks after administration, the LDL-C level in the subject is reduced by 50% compared to the baseline. In some embodiments, by the method, 6 weeks after administration, the LDL-C level in the subject is reduced by 64% compared to the baseline LDL-C level in the subject. In some embodiments, by the method, the hsCRP level in the subject is reduced by 40% compared to the baseline. In some embodiments, by the method, the hsCRP level in the subject is reduced by 45% compared to the baseline. In some embodiments, by the method, the hsCRP level in the subject is reduced by 48% compared to the baseline. In some embodiments, by the method, the non-HDL-C level in the subject is reduced by 40% compared to the baseline. In some embodiments, by the method, the non-HDL-C level in the subject is reduced by 50% compared to the baseline. In some embodiments, by the method, the non-HDL-C level in the subject is reduced by 60% compared to the baseline non-HDL-C level in the subject. In some embodiments, by the method, the apoB level in the subject is reduced by 40% compared to the baseline. In some embodiments, by the method, the apoB level in the subject is reduced by 50% compared to the baseline. In some embodiments, by the method, the apoB level in the subject is reduced by 54% compared to the baseline ApoB level in the subject. In some embodiments, by the method, the total cholesterol level in the subject is reduced by 40% compared to the baseline. In some embodiments, by the method, the total cholesterol level in the subject is reduced by 47% compared to the baseline TC level in the subject. In some embodiments, by the method, the triglyceride level in the subject is reduced by 25% compared to the baseline. In some embodiments, by the method, the total cholesterol level in the subject is reduced by 27% compared to the baseline.In some embodiments, by the method, the triglyceride (TG) level in the subject is reduced by 27% compared to the baseline TG level in the subject.

[0062] In one embodiment, upon said administration, the following do not significantly change or decrease: the low-density lipoprotein cholesterol (LDL-C) level, very low-density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof in the subject.

[0063] In one embodiment, an effective amount of each of ETC-1002, ezetimibe, and a statin is administered, wherein the combination results in the following changes: the low-density lipoprotein cholesterol (LDL-C) level, very low-density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof in the subject.

[0064] In one embodiment, an effective amount of each of ETC-1002, ezetimibe, and a statin is administered, where the combination results in the following changes in a subject compared to that of a matched control subject receiving a placebo and / or the same dose of ezetimibe and / or the same dose of statin but lacking ETC-1002: low density lipoprotein cholesterol (LDL-C) level, very low density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof.

[0065] In one embodiment, an effective amount of each of ETC-1002, ezetimibe, and a statin is administered, where the combination results in the following changes in a subject compared to that of a matched control subject receiving a placebo: low density lipoprotein cholesterol (LDL-C) level, very low density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof.

[0066] In one embodiment, an effective amount of each of ETC-1002, ezetimibe, and a statin is administered, where the combination results in the following changes in a subject compared to that of a matched control subject to whom the same dose of ezetimibe and the same dose of ETC-1002 are administered: low density lipoprotein cholesterol (LDL-C) level, very low density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, or any combination thereof.

[0067] In some aspects, by the methods disclosed herein, the following levels do not change: the low density lipoprotein cholesterol (LDL-C) level, very low density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, non-HDL-C level, and / or any combination thereof in a subject.

[0068] In one embodiment, the method provides any combination of the following increased, decreased, or unchanged values: low density lipoprotein cholesterol (LDL-C) level, very low density lipoprotein (VLDL) level, VLDL particle number, VLDL particle size, apolipoprotein A-1 (ApoA1) level, apolipoprotein B (ApoB) level, the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1), triglyceride (TG) level, total cholesterol (TC) level, high-sensitivity C-reactive protein (hs-CRP) level, and non-HDL-C level.

[0069] In other aspects, by the method, the number of drug-related AEs is reduced by at least 25%, 35%, 45%, or 50% or more. In other aspects, by the method, the number of muscle-related AEs is reduced by at least 50%, 65%, 75%, 85% or more. In some aspects, by the method, the number of drug-related AEs is reduced compared to a therapy using ETC-1002, ezetimibe, a statin, or any combination of two of them. In some aspects, by the method, the number of drug-related AEs is reduced compared to a therapy using ETC-1002, ezetimibe, a statin, or any combination of two of them.

[0070] In other aspects, by the method disclosed herein, the risk of cardiovascular events in a subject is significantly reduced. In some aspects, this risk is reduced by 35% or more.

[0071] In some aspects, the method herein provides for the treatment of cardiovascular disease and / or the reduction of the risk of cardiovascular disease in a subject, and administers an amount of a composition comprising ETC-1002, ezetimibe, and a statin that has a T max of less than 4 hours and is rapidly absorbed.

[0072] In some aspects, the method disclosed herein provides for the treatment of cardiovascular disease and / or the reduction of the risk of cardiovascular disease in a subject, and administers an amount of a composition comprising ETC-1002, ezetimibe, and a statin that does not prolong QTc or QT / QTc (TQT study). In one aspect, the triplet combination does not affect the heart rate of the subject and the PR and QRS intervals. In one aspect, the triplet combination clinically significantly has a positive effect on the heart rate of the subject and the PR and QRS intervals.

[0073] In some aspects, the method herein provides for the treatment of cardiovascular disease and / or the reduction of the risk of cardiovascular disease in a subject, and the systemic exposure, AUC tau,ss is about 15-27 hours for t 1 / 2administering an effective amount of a composition comprising ETC-1002, ezetimibe, and a statin, which occurs in

[0074] In some embodiments, the methods herein provide for the treatment of cardiovascular disease and / or reduction of the risk of cardiovascular disease in a subject, and exposure measurements, AUC, and / or C that show no pharmacokinetic interactions between the two regimens are max administering an amount of a composition comprising ETC-1002, ezetimibe, and a statin that provides. In one embodiment, none of the statin, ETC-1002, and ezetimibe exposure measurements are outside the range of safe values established by the confidence interval.

[0075] In one aspect, the composition comprises a statin defined by a dosage of atorvastatin (10 mg or 20 mg), simvastatin (5 mg, 10 mg, or 20 mg), rosuvastatin (5 mg or 10 mg), and / or pravastatin (10 mg, 20 mg, or 40 mg). In other aspects, the method comprises a statin defined by a dosage of atorvastatin (10 mg or 20 mg), simvastatin (5 mg, 10 mg, or 20 mg), rosuvastatin (5 mg or 10 mg), and / or pravastatin (10 mg, 20 mg, or 40 mg).

[0076] In one aspect, the composition comprises a statin defined by the fixed dosages in Table 1 below:

[0077]

Table 1

[0078] Component In one embodiment, ETC-1002 is administered at a dosage of 0.001 mg to 2000 mg.

[0079] In one embodiment, ETC-1002 is administered at a dose of 120 mg. In one embodiment, ETC-1002 is administered at a dose of 180 mg. In one embodiment, ETC-1002 is administered at a dose of 40 mg to 90 mg. ETC-1002 is administered at a dose of 40 mg. ETC-1002 is administered at a dose of 60 mg. ETC-1002 is administered at a dose of 90 mg.

[0080] In one embodiment, ezetimibe is administered at a dose of 0.001 mg to 100 mg.

[0081] In one embodiment, ezetimibe is administered at a dose of 10 mg.

[0082] In some embodiments, ETC-1002 is administered at a dose of 120 mg or 180 mg, and ezetimibe is administered at a dose of 10 mg.

[0083] In some embodiments, ETC-1002 is administered at a dose of 120 mg or 180 mg, a statin is administered at a dose of 1 mg to 80 mg, and ezetimibe is administered at a dose of 10 mg.

[0084] In some embodiments, the subject has hypercholesterolemia. In some embodiments, the method further comprises treating hypercholesterolemia.

[0085] In some embodiments, the subject has a baseline LDL-C level of 130 to 220 mg / dL. In some embodiments, the subject has a baseline triglyceride level of 400 mg / dL or less.

[0086] In some embodiments, ezetimibe, a statin, and ETC-1002 are administered simultaneously. In some embodiments, any two or more of ezetimibe, a statin, and ETC-1002 are administered sequentially. In some embodiments, all three of ezetimibe, a statin, and ETC-1002 are administered sequentially.

[0087] In some embodiments, statin, ezetimibe, and ETC-1002 are each administered at least once a day. In some embodiments, statin, ezetimibe, and ETC-1002 are each administered at least once a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, ezetimibe is administered at least once every other day. In some embodiments, ezetimibe is administered at least once every other day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, ETC-1002 is administered at least once every other day. In some embodiments, ETC-1002 is administered at least once every other day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, statin is administered at least once every other day. In some embodiments, statin is administered at least once every other day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0088] In some embodiments, statin, ezetimibe, and ETC-1002 are each co-administered in one composition. In some embodiments, statin, ezetimibe, and ETC-1002 are co-administered separately in two compositions. In some embodiments, statin, ezetimibe, and ETC-1002 are co-administered separately in three compositions.

[0089] In some embodiments, statin, ezetimibe, and ETC-1002 are each administered separately and continuously over 12 hours. In some embodiments, two of statin, ezetimibe, and ETC-1002 are administered in one composition, and then one other composition containing the remaining components of the combination of statin, ezetimibe, and ETC-1002 is administered continuously over 12 hours.

[0090] patient In some embodiments, the subject has dyslipidemia. In some embodiments, the subject has hypercholesterolemia. In some embodiments, the subject is obese, where optionally the subject's BMI is 18 - 45 kg / m 2 is.

[0091] In one embodiment, the subject is statin - resistant.

[0092] In some embodiments, the subject is statin - intolerant. In some embodiments, the subject cannot tolerate at least two statins, including one statin at the lowest FDA - approved dose, due to muscle - related symptoms such as pain, ache, weakness, or spasm that start or increase during statin therapy and resolve when statin therapy is discontinued.

[0093] In some embodiments, the subject suffers from muscle - related adverse events associated with the use of statins.

[0094] In some embodiments, the subject has mixed dyslipidemia.

[0095] In one embodiment, the subject has hypercholesterolemia.

[0096] In some embodiments, the subject has atherosclerotic cardiovascular disease.

[0097] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0098] In some embodiments, the subject is obese, where optionally the subject's BMI is 18 - 45 kg / m 2 is.

[0099] In some embodiments, the subject experiences adverse events when using statin therapy at the minimum FDA-approved dose, and the adverse events are selected from the group consisting of muscle-related pain, ache, weakness, and spasm. The inventors have observed that such muscle-related adverse events that start or increase during statin therapy can be significantly reduced or even eliminated when using treatment with a triplet combination.

[0100] In some embodiments, the subject has a baseline LDL-C level of 115-220 mg / dL. In some embodiments, the subject has a baseline triglyceride level of 400 mg / dL or less.

[0101] Compound Compositions or formulations of ezetimibe, statin, and ETC-1002 are described herein.

[0102] Statins and ETC-1002 are described herein. In one embodiment, the statin is a natural product isolated from natural sources such as fungi of the genus Penicillium and Aspergillus. In other embodiments, the statin is a synthetic substance, meaning that they are made by converting petrochemical starting materials into the desired statin compound via organic synthesis.

[0103] The following formula I shows the structure of an ETC-1002 derivative that can be used in place of ETC-1002 according to the present disclosure:

Chemical formula

Chemical formula

[0104] The chemical structure of ETC-1002 (bempedoic acid) is as follows:

Chemical formula

[0105] ETC-1002 may also be referred to as bempedoic acid or 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.

[0106] The following formula (II) shows the structure of an ezetimibe derivative that can be used in place of ezetimibe according to the present disclosure: [Chemical formula] [In the above formula (II) or a salt thereof, Ar 1 and Ar 2 are independently selected from the group consisting of aryl and R 4 -substituted aryl, Ar 3 is aryl or R 5 -substituted aryl, X, Y and Z are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(di-lower alkyl)-, R and R 2 are independently selected from the group consisting of -OR 6 , -O(CO)R 6 , -O(CO)OR 9 and -O(CO)NR 6 R 7 selected from the group consisting of, R 1 and R 3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl, q is 0 or 1, r is 0 or 1, m, n and p are independently selected from 0, 1, 2, 3 or 4, provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6, provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5, R 4 is lower alkyl, -OR 6 , -O(CO)R 6 , -O(CO)OR 9 , -O(CH2) 1-5 OR 6 , -O(CO)NR 6 R 7 , -NR 6 R 7 , -NR 6 (CO)R 7 , -NR 6 (CO)OR 9 , -NR 6 (CO)NR 7 R 8 , -NR 6SO2R 9 、 -COOR 6 、 -CONR 6 R 7 、 -COR 6 、 -SO2NR 6 R 7 、 S(O) 0-2 R 9 、 -O(CH2) 1-10 -COOR 6 、 -O(CH2) 1-10 CONR 6 R 7 、 -(lower alkylene)COOR 6 、 -CH=CH-COOR 6 、 1 - 5 substituents independently selected from the group consisting of -CF3, -CN, -NO2 and halogen, and R 5 is, -OR 6 、 -O(CO)R 6 、 -O(CO)OR 9 、 -O(CH2) 1-5 OR 6 、 -O(CO)NR 6 R 7 、 -NR 6 R 7 、 -NR 6 (CO)R 7 、 -NR 6 (CO)OR 9 、 -NR 6 (CO)NR 7 R 8 、 -NR 6 SO2R 9 、 -COOR 6 、 -CONR 6 R 7 、 -COR 6 、 -SO2NR 6 R 7 、 S(O) 0-2 R 9 、 -O(CH2) 1-10 -COOR 6 、 -O(CH2) 1-10 CONR 6 R 7 、 -(lower alkylene)COOR 6 and -CH=CH-COOR 6 are 1 - 5 substituents independently selected from the group consisting of, and R 6 、 R7 and R 8 are each independently selected from the group consisting of hydrogen, lower alkyl, aryl, and aryl-substituted lower alkyl, and R 9 is lower alkyl, aryl, or aryl-substituted lower alkyl.]

[0107] Statins inhibit HMGR enzyme activity in the liver. Structurally, all statins have a dihydroxyheptanoic acid group or its lactone and a substituted ring system (shown below).

Chemical formula

[0108] However, statins vary with respect to the substituted ring structure. There are statins with a substituted decalin ring structure and those with a substituted aryl and heteroaryl ring system. The structures of exemplary statin compounds are shown below, but this list is in no way limiting.

Chemical formula

[0109] It is recognized that any and all analogs or derivatives of ezetimibe, and any and all analogs or derivatives of ETC-1002 according to formula I, can be used in any of the methods and / or compositions or formulations disclosed herein. It is further recognized that any and all analogs of the statins as described above can be used in any of the methods and / or compositions or formulations disclosed herein.

[0110] Ezetimibe is referred to as 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone, or (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0111] The structure of ezetimibe is as follows:

Chemical formula

[0112] Synthesis of ETC-1002, ezetimibe, and statin ETC-1002 and the method for synthesizing ETC-1002 are disclosed in U.S. Patent No. 7,335,799 issued. Details of this method can be found in paragraphs

[0247] to

[0343] of the published U.S. Patent Application Publication No. 2005-0043278, each of which is incorporated herein by reference.

[0113] Ezetimibe and the method for synthesizing ezetimibe are disclosed in U.S. Patent No. 5,631,365 issued. Details of this method can be found starting from line 43 of the right column on page 4 to line 65 of the right column on page 11 of the specification, each of which is incorporated herein by reference.

[0114] The synthesis of statins is known in the art. In a strategic and general disclosure, the synthesis of statins is disclosed in International Publication No. WO 2005 / 047276, which is incorporated herein by reference. Any other synthetic modifications to statins (or, for that matter, analogs of ETC-1002) that may include unique or alternative ring systems are within the scope of those skilled in the art. For example, one skilled in the art could use reference texts on synthesis and incorporate unique or desired substituted aryl, heteroaryl, and decalin ring systems into the final statin compound. Such reference works include, but are not limited to, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), T. W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999.

[0115] Pharmaceutical composition Also disclosed herein are pharmaceutical compositions or pharmaceutical formulations comprising ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers.

[0116] The combination of ezetimibe, a statin, and a triplet of ETC-1002 may be formulated in two or more separate pharmaceutical compositions or may be formulated in a single pharmaceutical composition.

[0117] In some embodiments, the composition comprises one or more pharmaceutically acceptable carriers or vehicles.

[0118] In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is formulated for once-daily administration.

[0119] Each of these compositions may include one or more pharmaceutically acceptable excipients, carriers, buffers, stabilizers or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the effectiveness of the active ingredient. The exact nature of the carrier or other materials may vary depending on the route of administration, for example oral, intravenous, dermal or subcutaneous, nasal, intramuscular, intraperitoneal route.

[0120] Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powders or liquids. Tablets may contain solid carriers such as gelatin or adjuvants. Generally, liquid pharmaceutical compositions include liquid carriers such as water, petroleum, animal or vegetable oils, mineral oils or synthetic oils. Saline solutions, dextrose or other sugar solutions, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

[0121] For intravenous, dermal or subcutaneous injection, or injection at the site of the lesion, the active ingredient will be in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity and stability. Those skilled in the relevant art in the art can adequately prepare appropriate solutions using isotonic vehicles such as, for example, sodium chloride injection solution, Ringer's injection solution, lactated Ringer's injection solution. If necessary, preservatives, stabilizers, buffers, antioxidants and / or other additives may be included.

[0122] Whether the agent administered to an individual is a small molecule or another pharmaceutically useful compound according to the present disclosure, the administration is preferably made at a "therapeutically effective amount" or "preventively effective amount" (although in some cases prevention can be considered as treatment), which is sufficient to show benefit to the individual. The actual amount administered, as well as the rate and time course of administration, will vary depending on the nature and severity of the protein aggregation disease being treated. The determination of the treatment regimen, such as the dosage, is within the responsibility of the general practitioner and other physicians, and typically takes into account the disorder being treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to the physician. Examples of the techniques and protocols described above can be found in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. (ed.), 1980.

[0123] Kit Kits containing one or more of the compositions disclosed herein are also provided.

[0124] In some embodiments, the kit contains two or more compositions, each of which contains one or more of ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers.

[0125] In some embodiments, the kit contains one composition containing ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers.

Examples

[0126] The following are examples of specific embodiments for carrying out the present disclosure. The examples are given for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. Although efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), some experimental error and deviation should of course be tolerated.

[0127] The practice of the present disclosure will, unless otherwise indicated, employ conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of the art. Such techniques are well explained in the literature. See, for example, T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rd Edition (Plenum Press) Volumes A and B (1992).

[0128] Any terms not directly defined in this specification will be understood to have the meanings customarily associated with them, as understood within the scope of the technology of this disclosure. In describing the compositions, devices, methods, etc. of aspects of this disclosure, and the methods of making or using them, certain terms are set forth herein to provide additional guidance to the practicing physician. It will be understood that the same thing may be described in multiple ways. Accordingly, alternative languages and synonyms may be used for any one or more of the terms set forth herein. Whether a term is detailed or explained in this specification should not be of consequence. Some synonyms or alternative ways, materials, etc. are provided. The listing of one or a few synonyms or equivalent phrases does not exclude the use of other synonyms or equivalent phrases, unless explicitly stated otherwise. The use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the aspects of the disclosure herein.

[0129] It should be noted that when used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0130] <Example 1: Clinical Protocol> Brief Explanation of Clinical Research and Results A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of a triple therapy using 180 mg of bempedoic acid (ETC-1002), 10 mg of ezetimibe, and 20 mg of atorvastatin in patients with elevated LDL-C

[0131] [Table 2] TIFF0007716437000010.tif248167TIFF0007716437000011.tif249166TIFF0007716437000012.tif251165TIFF0007716437000013.tif108166

[0132] In the protocol of this study, the following abbreviations and technical terms are used.

Table 3

[0133] Dose selection In the Phase 2 program, doses of bempedoic acid from 40 to 240 mg / day were evaluated. According to the data from the comprehensive analysis of safety and efficacy, the observed values and percentage changes from baseline in LDL-C, the primary efficacy endpoint, along with a positive safety profile, support the selection of the 180 mg dose for the Phase 3 study. According to the comprehensive analysis of six Phase 2 studies, the placebo-adjusted LS mean for the percentage change from baseline was approximately 32% for bempedoic acid 180 mg monotherapy, 50% for bempedoic acid 180 mg + ezetimibe 10 mg, and 22% for 180 mg in addition to statin therapy. The 180 mg dose was noted to have an excellent safety profile. Overall, considering the balance of efficacy and safety, the 180 mg dose was selected for the Phase 3 program.

[0134] Background of Ezetimibe See the label of ezetimibe.

[0135] Background of Atorvastatin See the label of atorvastatin.

[0136] Summary of Risk-Benefit To date, non-clinical and clinical data have shown that bempedoic acid 180 mg has a favorable risk-benefit profile. The ability of bempedoic acid to demonstrate a favorable tolerance profile in various patient populations while achieving clinically meaningful LDL-C reduction supports the continued development of bempedoic acid in the Phase 3 study.

[0137] The safety and efficacy of bempedoic acid as an adjunct to statins or in combination with ezetimibe have been evaluated in several Phase 2 clinical studies. These studies have shown significant LDL-C reduction and a favorable safety profile. The LDL-C lowering effect and safety of triple therapy using 180 mg of bempedoic acid, 10 mg of ezetimibe, and 20 mg of atorvastatin have not been evaluated to date. That is the objective of this study.

[0138] [Trial Objectives and Purpose] Objective Primary Objective The primary objective was to evaluate the LDL-C lowering effect of triple therapy using 180 mg of bempedoic acid, 10 mg of ezetimibe, and 20 mg of atorvastatin compared to placebo administered daily for 6 weeks in patients with elevated LDL-C. Secondary Objectives · To evaluate the effect of triple therapy compared to placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), high-sensitivity C-reactive protein (hs-CRP), TG, and HDL-C · To evaluate the effect of triple therapy compared to placebo on the percentage of patients achieving an LDL-C level < 70 mg / dL · To evaluate the effect of triple therapy compared to placebo on the percentage of patients achieving an LDL-C reduction of ≥ 50% · To evaluate the safety and tolerability of triple therapy compared to placebo

[0139] Study Endpoints The following endpoints were used to evaluate the objectives of the study. Primary Endpoint · Percentage change in LDL-C from baseline to week 6 Secondary Endpoints: · Percentage change from baseline to week 6 in non-HDL-C, TC, ApoB, hs-CRP, TG, and HDL-C · Percentage of patients with LDL-C < 70 mg / dL at week 6 · Percentage of patients with ≥ 50% reduction in LDL-C from baseline to week 6 Safety endpoints · Incidence of adverse events in the subjects · Results of clinical safety tests (including hematology, blood chemistry, and urine tests) · Findings of vital signs and physical examination (PE)

[0140] [Trial plan] General Study Plan This was a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group study. Patients were first screened at -6 weeks (Visit S1). Eligible patients initiated a washout of all LDL-C lowering medications and nutritional supplements at least 5 weeks prior to randomization. Patients returned for a follow-up visit at -1 week (S2) for lipid and / or other evaluations. Patients who were deemed ineligible for randomization at any point during screening were notified by the clinical site staff and considered screening failures. Approximately 60 patients were randomized at week 0 (Visit T1) in a 2:1 ratio and received triple therapy (180 mg of bempedoic acid + 10 mg of ezetimibe + 20 mg of atorvastatin) or placebo once daily for 6 weeks. Randomized patients returned to the clinic for follow-up visits at week 3 (Visit T2) and week 6 (Visit T3).

[0141] For details of the study evaluations, please refer to the Schedule of Event in Appendix 1.

[0142] Study Hypothesis The clinical hypothesis for this study is that triple therapy with 180 mg of bempedoic acid, 10 mg of ezetimibe, and 20 mg of atorvastatin will significantly reduce LDL-C in patients treated daily for 6 weeks compared to placebo.

[0143] Estimated Study Duration and Period The total treatment duration is 12 weeks (6 weeks of screening and 6 weeks of treatment), with the option to extend screening by an additional 1 week.

[0144] Number of Facilities Up to about 20 sites in the United States participated in this study. Additional sites may be invited to participate to ensure that the study schedule is met.

[0145] Number of Patients Approximately 60 adult male and female patients were enrolled in the study.

[0146] [Patient Selection] Subject Selection Criteria Each patient met the following criteria to be eligible for this study. 1: Provide written informed consent prior to any study-specific procedures; 2: At week -6 (visit S1), 18 years of age or the legal adult age based on local statutes, whichever is greater; 3: Fasting LDL-C calculated value of 130 - 189 mg / dL at week -1 (visit S2) after washout of all LDL-C lowering medications and nutritional supplements; Note: LDL-C may be repeated once by extending the screening period up to 1 week. For patients with repeated LDL-C, the average of the first and repeated values was used to determine eligibility. 4: The patient is sufficiently stable and suitable to undergo a 12-week (which may be extended by 1 week) washout of all LDL-C lowering medications and nutritional supplements based on investigator assessment; 5: Males and non-pregnant, non-lactating females. Females must be one of the following: a. Naturally postmenopausal with amenorrhea defined as being without menses for at least 1 year and i. ≧55 years of age or ii. <55 years of age with follicle-stimulating hormone (FSH) ≧40.0 IU / L or b. Surgically sterile, including hysterectomy, bilateral oophorectomy, and / or tubal ligation or c. Reproductive-age females who intend to use one of the acceptable methods of birth control, including the following, during the study and for 30 days after the end of treatment: i. Birth control pills ii. Use or non-use of an intrauterine device with hormones iii. Barrier methods, including condoms or occlusive caps with spermicidal foam or jelly iv. Vasectomized male partner who is the patient's only partner v. True abstinence (including periodic abstinence such as the calendar, ovulation, symptothermal, and post-ovulation methods, or abstinence from intercourse without interruption); There are no protocol-specific birth control requirements for males with a partner who can become pregnant.

[0147] Subject Exclusion Criteria Patients who met any of the following criteria were not eligible to participate: 1: Body mass index (BMI) >50 kg / m 2 ; 2: A history of clinically significant cardiovascular disease, including but not limited to the following: a. Myocardial infarction, severe or unstable angina, coronary angioplasty, coronary artery bypass grafting, stroke, transient ischemic attack, cerebrovascular event, symptomatic carotid artery disease, or symptomatic peripheral artery disease b. Poorly controlled hypertension defined as sitting mean systolic blood pressure (SBP) ≥ 160 mmHg and / or diastolic blood pressure (DBP) ≥ 100 mmHg after sitting quietly for 5 minutes. Note: At the investigator's discretion, single repeated sitting mean SBP and DBP may be completed at another visit. For patients with repeated sitting mean SBP and DBP evaluations, the repeated values are used to determine eligibility. c. Arrhythmia requiring medical intervention, d. Abdominal aortic aneurysm, e. New York Heart Association (NYHA) class III and IV heart failure; 3: Fasting TG > 400 mg / dL at week 1 (S2); Note: TG may be repeated once by extending the screening period up to 1 week. For patients with repeated TG, the repeated values are used to determine eligibility. 4: History of type 1 or type 2 diabetes, or fasting glucose > 125 mg / dL at week - 6 (visit S1); 5: Uncontrolled hypothyroidism including thyroid - stimulating hormone (TSH) > 1.5 × upper limit of normal (ULN) at week - 6 (visit S1). 6: Liver disease or disorder including: a. Serology positive for hepatitis B surface antigen (HBsAg) and / or hepatitis C antibody (HCV - ABVivi) at week 1 (visit S2), or b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥ 2 × ULN, and / or total bilirubin (TB) ≥ 2 × ULN at week - 6 (visit S1). When TB ≥ 1.2 × ULN, reflex indirect (unconjugated) bilirubin is obtained, and if it is consistent with Gilbert's disease or the patient has a history of Gilbert's disease, the patient may be enrolled in the study. Note: At the investigator's discretion, a single repeat of ALT, AST, and / or TB may be completed. For patients with repeated ALT, AST, and / or TB, the repeated values were used to determine eligibility. Also, a patient may be enrolled if the test for hepatitis C antibody is positive but the optional reflex test for hepatitis C ribonucleic acid (RNA) is negative. 7: Renal dysfunction or glomerulonephritis including estimated glomerular filtration rate (eGFR; using the Modification of Diet in Renal Disease [MDRD] equation determined by the central laboratory) < 30 mL / min at week - 6 (visit S1); Note: At the investigator's discretion, a single repeat of eGFR may be completed. For patients with repeated eGFR, the repeated values were used to determine eligibility. 8: Gastrointestinal conditions or treatments that can affect drug absorption (including bariatric surgery; e.g., Lap - Band (registered trademark) or gastric bypass); 9: Hematologic or coagulation disorders, or hemoglobin (Hgb) level < 10.0 g / dL at week - 6 (visit S1); 10: Active malignancy including those requiring surgery, chemotherapy, and / or radiation therapy in the past 5 years. Non - metastatic basal or squamous cell carcinoma of the skin, and cervical intraepithelial neoplasia are acceptable; 11: Creatine kinase (CK) > 3 × ULN (i.e., not related to recent trauma or strenuous physical activity) at any time point before randomization. Patients with an explainable CK elevation must have a single repeat CK ≤ 3 × ULN before randomization; 12: History of drug or alcohol abuse within the past 2 years, or reported current consumption of > 14 alcoholic drinks / week or use of any illegal drugs, history of amphetamine and derivative abuse or cocaine abuse. Subjects with amphetamine derivatives prescribed by and under the care of a health care provider may be enrolled after evaluation by the investigator. 13: Donation of blood, participation in multiple blood samplings, clinical research, major trauma, transfusion, or surgery with or without blood loss within 30 days before randomization; 14: Use of any experimental or investigational drug within 30 days before screening; 15: Past enrollment in a bendroic acid clinical study; 16: Use of these prohibited drugs and / or nutritional supplements before randomization or planned use during the study: a. LDL-C lowering drugs and / or nutritional supplements (within 5 weeks before randomization), b. Probenecid or cyclosporine (within 2 weeks before randomization), c. Potent CYP3A4 inhibitors including amiodarone, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), bosentan, clarithromycin, cobicistat, conivaptan, danazol, daptomycin, diltiazem, domperidone, erlotinib, erythromycin, fusidic acid, mibefradil, nefazodone, piperaquine, protease inhibitors (atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir), quinupristin / dalfopristin, telithromycin, verapamil (within 2 weeks before randomization), d. Systemic corticosteroids (topical corticosteroids are allowed; within 5 weeks before randomization); 17: Planned start or change in administration of these allowed drugs before or during the study: a. Hormone replacement (within 5 weeks before randomization), b. Thyroid replacement (within 5 weeks before randomization), c. Anti-obesity drugs (within 3 months before randomization); 18: Medical or situational (i.e., geographical) findings that, in the investigator's opinion, may threaten the patient's safety or ability to complete the study; 19: Employees or contractors of the facility conducting the study, or family members of the study investigator, co-investigator, or any staff of the sponsor of the clinical trial.

[0148] Patient Lifestyle and Diet Guidelines All patients are fasting for at least 10 hours before the collection of all test samples (water and concomitant medications other than IMP are permitted).

[0149] From the start of screening, patients should be advised to follow a heart-healthy diet as per local or regional guidelines and encouraged (if possible) to participate in a stable regular exercise program throughout the study.

[0150] [Treatment of Patients] Administration of Investigational Medicinal Product During the treatment period, patients were randomized and administered 180 mg of bempedoic acid + 10 mg of ezetimibe + 20 mg of atorvastatin or placebo IMP once daily. Each daily allocation of IMP consisted of 1 bempedoic acid tablet, 1 over-encapsulated ezetimibe tablet, and 1 over-encapsulated atorvastatin tablet provided in a blister pack. The placebo blister pack contained the corresponding matching placebo of the three drugs. Patients were instructed to take the IMP orally once daily, with or without food. On the day of clinic visits, patients were instructed to defer taking the IMP until the study procedures were completed.

[0151] If a patient forgot to take the IMP on a non-clinic visit day, it could be taken up to 12 hours maximum on the same day. After that, the patient did not take the IMP on that day and resumed taking the IMP the next morning. Details explaining the reason for the missed dose were recorded in the patient's medical record and the electronic case report form (eCRF). Additional IMP was provided and could be used as needed before the next visit or to replace the allocation of IMP that was lost or damaged and could not be used.

[0152] Other details regarding the IMP, including description, supply and control, accountability, handling, and disposal, were provided in Section 9.

[0153] Prior and Concomitant Medication At each clinic visit, patients were asked about the use of concomitant medications. All concomitant medications taken chronically or intermittently during the study were recorded, along with the indication, total daily dose, and start and stop dates of administration.

[0154] The pre- / concomitant case report form (CRF) was used to record medications, herbal remedies, vitamins, other nutritional supplements, and over-the-counter drugs taken within 6 weeks prior to screening and during the study.

[0155] Prohibited Medications and Dietary Supplements Patients were requested to discontinue taking any prescription or over-the-counter medications or nutritional supplements taken for lipid modification at least 5 weeks (approximately study day -35) prior to randomization. The use of any of the following agents, either alone or in combination therapy, was prohibited during the study: Statins (within 5 weeks prior to randomization): · Atorvastatin (LIPITOR®) (except as provided by the sponsor of the clinical trial) · Fluvastatin (LESCOL®) · Lovastatin (MEVACOR®, ALTOPREV™) · Pravastatin (PRAVACHOL®) · Rosuvastatin calcium (CRESTOR®) · Simvastatin (ZOCOR®) · Pitavastatin (LIVALO®) Selective cholesterol and / or bile acid absorption inhibitors (within 5 weeks prior to randomization): · Ezetimibe (ZETIA®, EZETROL®) · Cholestyramine (QUESTRAN®, QUESTRAN® LIGHT, PREVALITE®, LOCHOLEST®, LOCHOLEST® LIGHT) · Colestipol (COLESTID®) · Colesevelam hydrochloride (WELCHOL®, CHOLESTAGEL®) Fibrate drugs (within 5 weeks before randomization): · Gemfibrozil (LOPID®) · Fenofibrate (ANTARA®, LOFIBRA®, TRICOR®, TRIGLIDE™, LIPANTIL®, SUPRALIP®) · Clofibrate (ATROMID-S®) · Ciprofibrate (MODALIM®) · Bezafibrate (BEZALIP®) PCSK9 inhibitors (within 5 weeks before randomization): · Evolocumab (REPATHA®) · Alirocumab (PRALUENT®) Other lipid-regulating drugs (within 5 weeks before randomization): · Niacin (NIASPAN® Rx and OTC) · Omega-3-acid Ethyl Ester (LOVAZA® and OTC fish oil) · Statin fixed dose combinations (e.g., ATOZET®, VYTORIN®, INEGY®) Lipid-modifying nutritional supplements (within 5 weeks before randomization): · Berberine · Psyllium (Metamucil®) · Green tea extract · Niacin (>500 mg / day crystalline, or any dose of sustained release or extended release) · Phytosterols (found in oral nutritional supplements and some margarines such as Benecol) · β-sitosterol (found in some margarines such as oral nutritional supplements and Promise Activ) · Cholestin (red yeast rice, also known as an extract of Monascus purpureus) · Pantothenic acid (Pantothine) · Polycosanol Other medications: · Probencid or cyclosporine (within 2 weeks before randomization) · Potent CYP3A4 inhibitors including amiodarone, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), bosentan, clarithromycin, cobicistat, conivaptan, danazol, daptomycin, diltiazem, domperidone, erlotinib, erythromycin, fusidic acid, mibefradil, nefazodone, piperazine, protease inhibitors (atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir), quinupristin / dalfopristin, telithromycin, verapamil (within 2 weeks before randomization) · Systemic corticosteroids (topical corticosteroids are permitted) (within 5 weeks before randomization)

[0156] Permitted medications Permitted medications had been stable for at least 2 weeks before visit S1 (-6 weeks) except for the following. · Hormone replacement (within 5 weeks before randomization), · Thyroid replacement (within 5 weeks before randomization), · Anti-obesity medications (within 3 months before randomization);

[0157] Treatment Allocation, Randomization, and Blinding During the treatment period, the double-blind IMP was administered to the patients. On Day 1 (visit T1), the patients were randomized and administered either 180 mg / day of bempedoic acid + 10 mg of ezetimibe + 20 mg of atorvastatin or placebo. At the time of the visit, the investigator or designee obtained the randomization number using the Interactive Web Response System (IWRS) and received the appropriate IMP container via the Medical Identification Number (MED ID). When the randomization number was assigned by the IWRS, the patient was considered randomized.

[0158] In accordance with the patient's sequential participation in the study, the randomization number was determined by a computer-generated random code. The randomization number corresponded to the treatment group. The randomization plan for blinding the treatment assignment was created by the Contract Research Organization (CRO), provided to the IWRS, and published only after the study was completed and the database was frozen.

[0159] During the treatment period, all sponsors, site staff, CROs, and patients were unaware / not informed of the patient's treatment assignment.

[0160] Blinding of treatment was maintained for all patients, except when, in the opinion of the investigator, the patient's safety might be at risk. Only under the most exceptional circumstances should the investigator consider unblinding, and only if they are unable to provide medical / supportive therapy without determining whether the patient is receiving active drug treatment. If it becomes necessary to unblind the study before completion, the investigator should contact the appropriate medical monitor by telephone. If unblinding is necessary before consulting the medical monitor, contact must be made within 24 hours of unblinding.

[0161] At the start of the study, the clinical sites were instructed on the unblinding procedures via the IWRS. In all cases of unblinding, the investigator recorded in the patient's medical record the date, time, and reason for unblinding, as well as the names of the staff involved.

[0162] The randomized values of the individual test measurements for LDL-C, non-HDL-C, TC, TG, and HDL-C, which may suggest inadvertent treatment assignment, are not available to the clinical site staff, patients, study sponsors, or CROs. While knowing these values does not truly result in an “open label” situation, the collection of these test evaluations by local (other than study visit) investigators, all collaborating physicians, or patients was strongly discouraged. Investigators did not perform tests for these analytes in local laboratories during the conduct of the study.

[0163] [Investigational Medicinal Product] Description of Investigational Medicinal Product

Table 4

[0164] For detailed storage conditions and usage instructions, please refer to the pharmaceutical manual.

[0165] Supply and Management of Investigational Medicinal Product The study sponsor supplied the IMP for this study as described above. The IMP was distributed and released according to regional and local requirements during the conduct of the study.

[0166] The MED ID number (identifier on the IMP package) was obtained via the IWRS and used to select the double-blind IMP from among the clinical supplies available at the clinical site.

[0167] The IMP was dispensed only to eligible patients who provided informed consent by the investigator or other qualified site staff.

[0168] Packaging and Labeling The double-blind IMP was packaged in blister packs. Each blister pack contained a 9-day supply, and three blister packs were provided in a drug kit.

[0169] The IMP label included warnings, as well as standard language regarding product regulation, administration, and storage, in addition to protocol number, MED ID number, patient identification number, lot number, facility number, and investigator name.

[0170] Investigational Medicinal Product Compliance During each clinic visit during the treatment period, the staff at the designated clinical facility evaluated the patient's compliance with IMP intake by counting the number of doses returned as unused and questioning the patient about daily intake. If the patient was not taking multiple doses as instructed, the patient was asked for a reason, the findings were recorded, and the patient was counseled on the importance of following all dosing instructions carefully. Factors contributing to low compliance were determined and, if possible, improved. Patients showing low compliance during the treatment period were continuously counseled on the importance of following all dosing instructions carefully, but were not excluded from the study.

[0171] Investigational Medicinal Product Usage Record (Accountability) Patients were instructed to return all packaging and unused IMP at each visit for compliance assessment and drug use record-keeping.

[0172] Accurate records of the receipt and disposition of all IMP shipped by the sponsor (or designee) of the clinical trial were maintained.

[0173] IMP records or logs must comply with applicable regulations, local laws, and guidelines and should include the following: · Quantity received / quantity on hand at storage location · Quantity currently at storage location · MED ID number for all IMP · Date of IMP inventory (including receipt / transfer / disposition) and initials of the responsible person · Date and quantity of IMP assigned to each patient, including unique patient identifiers · Date IMP was returned by the patient, compliance assessment, and associated records of discrepancies · Disposition outside the study (e.g., loss, damage, disposal) · After the usage record by the facility monitor, the quantity returned to / discarded by the clinical trial requester (or the nominee), or the quantity discarded in accordance with the local standard operating procedure (SOP).

[0174] Handling, Storage, and Disposal of Investigational Medicinal Product The investigator is to ensure that all IMPs are stored in a safe place under the recommended storage conditions (at room temperature [15°C / 59°F to 30°C / 86°F] protected from extreme conditions of temperature, light, or humidity) in accordance with the regulatory requirements applicable to the investigational medicinal product. The access to IMPs is limited to (restricted to) the clinical facility staff authorized by the investigator. Unless otherwise authorized by the clinical trial requester, upon completion or termination of the study, all IMPs, as well as used and unused IMP packaging, must be returned to the clinical trial requester (or the nominee) for final disposal. All IMP returns must be accompanied by appropriate documentation.

[0175] [Study Procedures and Evaluation Schedule] Informed Consent Patients are fully informed of the nature and risks of the study and understand the informed consent document (ICD). It is the responsibility of the investigator not to perform procedures related to the study until each patient is fully informed about the study, freely agrees to participate in the study, and signs and dates the ICD approved by the clinical trial requester (or the nominee) and the institutional review board (IRB). The written ICD should be created in the local language of the potential patient population.

[0176] Web Automated Response System and eCRF Data was obtained on the eCRF. Randomization, IMP (re)ordering, IMP distribution, and patient status tracking were performed via the IWRS. Descriptions of these systems and additional inquiry points regarding the IWRS were provided separately.

[0177] Patient Identification Number To identify each patient in the study, a unique patient identification number was assigned to each patient. The patient identification number was continuously assigned by the IWRS at the time of informed consent during the screening module transaction and consisted of a protocol, facility, and patient-specific number.

[0178] Re-Screening For patients who are ineligible for screening due to stability requirements of the condition, concomitant medications, or other reasons, rescreening may be considered after consultation with the sponsor (or designee). If rescreened, these patients must also be consented again and the screening procedure repeated. If a patient is ineligible for screening or if a patient withdraws from the study, the patient ID number will not be assigned to another patient.

[0179] Evaluation Procedures and Schedule This study consists of two different periods: screening and double-blind treatment.

[0180] The study event schedule is given in Appendix 1. However, patients can be examined at any time for safety reasons.

[0181] Screening - Week 6 (Visit S1; Day - 42 to Day - 37) The screening period began with the screening visit, which was conducted 6 weeks prior to randomization. At Visit S1, the investigator was able to assess the patient's preliminary eligibility. After the patient submitted written informed consent (see Section 10.1), the patient received the following evaluations and procedures at Visit S1: · Assessment of adverse events (AE) and serious adverse events (SAE) (starting from the signature on the informed consent document) · Demographics · Clinically relevant medical history · Confirmation of previous medications and concomitant medications · Confirmation of all selection / exclusion criteria that are evaluable at the current time · Height (cm) and weight (kg) · Vital sign · Evaluation by the central clinical laboratory: - Thyroid-stimulating hormone (TSH) - Hematology, blood chemistry, and urine tests - Basic fasting lipids (calculated values of TC, LDL-C, HDL-C, non-HDL-C, and TG) - Serum pregnancy test (for female patients capable of childbirth) or follicle-stimulating hormone (FSH) (for postmenopausal women < 55 years old) · Diet and lifestyle counseling · Inquiry to the IWRS for patient registration

[0182] After confirmation of the results of the central clinical laboratory at the first visit S1 (available several days after the first visit S1), for patients who met all the registration criteria that could be evaluated, washout of all lipid-regulating drugs and nutritional supplements was performed, and they were instructed to maintain a consistent diet and exercise pattern during the study. Patients who did not meet any of the participation criteria that could be evaluated at the first visit S1 were considered screening-ineligible, and (although patients could visit the hospital at any time for safety reasons) they were not required to return for additional visits.

[0183] Screening - Week 1 (Second visit S2; -10 to -7 days) Patients received the following evaluations and treatments at the second visit S2: · Confirmation of concomitant medications (ongoing) · Evaluation of AEs and SAEs · Evaluation by the central clinical laboratory: - Basic fasting lipids (calculated values of TC, LDL-C, HDL-C, non-HDL-C, and TG) - Serology (including hepatitis B surface antigen [HBsAg], hepatitis C virus [HCV] antibody) · Diet and lifestyle counseling Note: · If the patient does not meet the inclusion criteria for LDL-C and / or TG, the screening period can be extended by an additional week, and additional visits may be completed before visit T1. If this optional visit is completed, eligibility is determined using the average of the values from visit S2 and the additional visit. · If the patient does not meet the inclusion criteria for diastolic blood pressure (DBP), systolic blood pressure (SBP), TSH, estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serology, and / or creatine kinase (CK), additional visits and / or evaluations may be completed between visit S1 and visit T1. The patient can become eligible for randomization after any relevant medications are adjusted and stabilized and repeated evaluations meet the inclusion criteria.

[0184] Week 0 of treatment (visit T1; day 1) Before the scheduled visit T1, the screening results were confirmed to determine whether the patient continued to meet the eligibility criteria. At visit T1, a physical examination and a urine pregnancy test were also completed before randomization. Patients who did not meet all inclusion criteria at any point before randomization were considered ineligible for screening.

[0185] If the patient met all selection criteria and did not meet any exclusion criteria, the patient was randomized and entered the double-blind treatment period.

[0186] Once all eligibility criteria are confirmed and a randomization number is obtained by the IWRS on the first dosing day, the patient is considered randomized.

[0187] The patient received the following evaluations and procedures on day 1 (visit T1): · Confirmation of concomitant medications (ongoing) · Evaluation of AEs and SAEs · PE · Confirmation of selection / exclusion criteria to establish patient eligibility · Body weight · Vital signs · Evaluation by the central clinical laboratory: - Hematology, blood chemistry, and urine tests - Basic fasting lipids (calculated values of TC, LDL-C, HDL-C, non-HDL-C, and TG) - ApoB and hs-CRP · Urine pregnancy test (in female patients with potential for pregnancy) · Inquiry to the IWRS to obtain the patient's randomization number and MED ID number for double-blind IMP · Double-blind IMP assignment and provision of dosing and storage instructions · Diet and lifestyle counseling

[0188] Week 3 of treatment (Visit T2; 22 ± 3 days) Patients received the following evaluations and procedures at Week 3 (Visit T2): · Confirmation of concomitant medications (ongoing) · Evaluation of AEs and SAEs · Body weight · Vital signs · Central clinical laboratory evaluation: - Hematology, blood chemistry, and urine tests - Basic fasting lipids (calculated values of TC, LDL-C, HDL-C, non-HDL-C, and TG) · Return of IMP; evaluation and recording of IMP medication compliance · Inquiry to the IWRS to obtain a new MED ID number for double-blind IMP · Double-blind IMP assignment and provision of dosing and storage instructions · Diet and lifestyle counseling

[0189] Week 6 of treatment (Visit T3; 43 ± 3 days) / End of study or early termination Patients received the following evaluations and evaluations at Week 6 and / or end of study / early termination: · Confirmation of concomitant medications (ongoing) · Evaluation of AEs and SAEs · PE · Body weight · Vital signs · Central clinical laboratory evaluation: - Hematology, blood chemistry, and urine tests - Basic fasting lipids (calculated TC, LDL-C, HDL-C, non-HDL-C, and TG) - ApoB and hs-CRP · Return of IMP; evaluation and recording of IMP compliance

[0190] Withdrawal of Patients from the Study Patients remained in the study until the scheduled last visit on Day 43 of the study (Visit T3) and were considered to have completed their participation in the study.

[0191] Patients' decisions to participate in the clinical study were made voluntarily. Patients could decline to continue and / or withdraw from participation in the study at any time for any reason, specified or unspecified, without penalty or loss of benefits to which the patient would otherwise be entitled.

[0192] It was the right and obligation of the investigator to discontinue the treatment of any patient whose health or well-being might be endangered by continuing the study. Such patients were withdrawn from the study and did not continue under the modified regimen.

[0193] Patients who withdrew from the study could not re-participate. Reasons for withdrawal from the present study could include the following: · AE · Withdrawal of patient consent · Protocol non-compliance · Loss to follow-up · Diseases, conditions, or treatment complications that affect the patient's ability to participate or require prohibited medications · Sponsor or investigator terminates the study · In the investigator's judgment, it is determined to be in the best interest of the patient to discontinue participation in the study · Any other reason

[0194] If a patient becomes lost to follow-up, the staff at the clinical facility must attempt to contact the patient and make every reasonable effort to determine the reason for discontinuation / withdrawal. The means used to attempt follow-up must be recorded.

[0195] [Evaluation of Efficacy] Evaluation of Lipids and hs-CRP Samples from the central clinical laboratory were collected and analyzed for the parameters detailed in Table 3. LDL-C was calculated or directly measured if TG was > 400 mg / dL or LDL-C was < 50 mg / dL.

[0196] (Not for safety but for) Blood sampling for lipids must meet the following criteria. If these criteria are not met, these blood samples are not collected. By changing the scheduled clinic visit to be within 3 days so that these criteria are met / will be met, these blood samples are collected / will be collected only at the clinic visit after the schedule change. · Blood samples were taken after at least 10 hours of fasting (water and concomitant medications (not IMP) are permitted). · Blood samples were taken only if the patient had ingested IMP the previous day.

[0197] The patient was seated during blood collection. The collection schedule and instructions are provided in the central clinical laboratory manual. Instructions for sample collection, storage, and shipment, as well as monitoring and management of abnormal test values, are described in Section 12.1.5.

[0198] When collecting vital signs and test samples at the same time point, vital sign measurements were taken before test sample collection.

[0199]

Table 5

[0200] [Safety evaluation] Safety Parameters At every clinic visit, the investigator checked safety information including vital signs, AEs, SAEs, and concomitant medications, and confirmed that the data collected was recorded in the appropriate eCRF. Additionally, samples from the central clinical laboratory were collected, sent for analysis, and the investigator checked the results during the study participation to ensure patient safety was maintained.

[0201] The investigator is responsible for monitoring the safety of the patients participating in this study and for appropriately alerting the sponsor or its designee as necessary.

[0202] The investigator is responsible for the appropriate medical care of the patients during the study.

[0203] The investigator was responsible for following up on AEs that were severe or that caused the patient to discontinue until the event resolved or stabilized prior to study completion. The frequency of follow-up evaluations was left to the investigator's discretion.

[0204] Demographics / Medical History Demographic data and a complete medical history were obtained from the patients. For the medical history, relevant and / or clinically significant conditions were recorded, including at least the start date (month and year) and whether the condition was ongoing or had resolved. All surgeries were reported regardless of date.

[0205] Vital Signs Vital signs included DBP, SBP, and heart rate.

[0206] Vital values were collected prior to blood collection. Blood pressure (BP) and heart rate were measured using a calibrated, fully automated machine with a cuff appropriate for the size of the upper arm. If a fully automated machine was not available, BP was measured manually. The same method (automated or manual) and the same arm (right or left) were used throughout the study. The patient was seated with feet on the floor. The patient sat quietly in the chair for at least 5 minutes with the back supported, feet flat on the floor, and the arm supported at heart level. At each clinic visit, two BP measurements were collected at 1- to 2-minute intervals.

[0207] Weight and Height Weight was measured on a calibrated scale in the morning after fasting and voiding.

[0208] Height was measured using standard clinical procedures.

[0209] The body mass index (BMI) was systematically calculated using the formula: BMI (kg / m 2 ) = weight in kg / (height in meters) 2 .

[0210] Physical examination The physical examination included the following assessments: · Overall appearance · Skin · Eyes, ears, nose, and throat · Head and neck · Limbs · Musculoskeletal examination · Respiratory examination · Cardiovascular assessment, including rhythm and the presence of heart abnormalities · Abdominal examination · Neurological examination, including recording of mental status and the presence of abnormalities in motor and sensory functions · Any additional assessments necessary to establish a baseline and evaluate symptoms or adverse experiences

[0211] The records of PE findings were included in the source documentation of the clinical facility. Significant findings before the start of IMP were recorded on the medical history / current medical status page of the eCRF. Only changes from baseline physical examination findings that met the definition of AE were recorded on the AE page of the eCRF.

[0212] Central laboratory tests Central Clinical Laboratory Parameters (Safety) Patients were seated during blood collection. Clinical test parameters and tests included those listed in Table 4. Collection schedules, scheduled test parameters by visit, and instructions were in the clinical laboratory manual provided by the central laboratory.

[0213]

Table 6

[0214] Collection, Storage, and Shipment of Samples Central clinical laboratory samples were collected by appropriate clinical facility staff and then shipped according to a separate laboratory manual provided by the central laboratory. Samples were processed / processed by the central laboratory.

[0215] General Monitoring and Management of Abnormal Clinical Test Values It is the investigator's responsibility to review and sign and date all laboratory test results when they become available. For each laboratory test outside the normal range, the investigator must determine whether this represents a clinically significant change from baseline as defined by the last value or observation before the first dose of double-blind IMP for each patient. The investigator may repeat the laboratory test or request additional tests to verify the results of the original laboratory test.

[0216] If the test value is abnormal and is determined to be a clinically significant change from baseline for that patient, the investigator determines whether it should be considered an AE and, if so, enters it in the appropriate eCRF. All clinically significant laboratory abnormalities occurring during the study that were not present at baseline were followed until the underlying cause or resolution was diagnosed and evaluated using additional tests as necessary. The following section outlines specific monitoring and management guidelines for laboratory values of particular interest.

[0217] Monitoring and Management of Elevated Liver Function Tests At any time after randomization, if a patient experiences new ALT and / or AST > 3 × ULN, the patient received a repeat confirmatory liver function test (LFT) evaluation as soon as reasonably possible, preferably within 3 to 7 days after the test results became available.

[0218] Repeated LFT evaluations include the following: 1) measurement of ALT, AST, alkaline phosphatase, total and direct bilirubin, prothrombin time (PT) / international normalized ratio (INR), eosinophil count, CK; 2) history of use of concomitant medications; 3) history of exposure to environmental chemicals including ethanol; and 4) questions about related symptoms. Additionally, further tests such as anti-hepatitis A virus (total), HBsAg (confirmation of screening measurement), HCV (confirmation of screening measurement), and anti-cytomegalovirus / immunoglobulin M. Liver ultrasound or magnetic resonance imaging (MRI) scans for Epstein-Barr may be warranted to rule out additional pathology depending on clinical symptoms and should be discussed with the sponsor staff or authorized medical monitor. Samples are collected, although some repeated LFT parameters may not be measured until an increase is confirmed. · If repeated LFT evaluation confirms that ALT and / or AST are >3×ULN but ≤5×ULN, consideration should be given to not administering further doses of IMP. At the investigator's discretion, IMP may be interrupted and the patient rechallenged with IMP after the LFTs have returned to baseline levels. · If repeated LFT evaluation confirms that ALT and / or AST are >5×ULN and no other reason for the increase is identified, the patient should discontinue IMP. At the investigator's discretion, IMP may be interrupted and the patient rechallenged with IMP after the LFTs have returned to baseline levels. · If repeated LFT evaluation confirms that, in addition to any of the following, ALT and / or AST are >3×ULN and no other reason for the increase is identified, the patient should discontinue IMP and should not receive further IMP treatment: - TB >2×ULN - INR >1.5×ULN (except if the patient is continuing anticoagulant medication) - Appearance or worsening of discomfort in the right upper abdomen, anorexia, fatigue, nausea, vomiting, fever, rash, or eosinophilia.

[0219] Monitoring and Management of Elevated Creatine Kinase At any time after randomization, if a patient experiences a marked CK elevation >5×ULN, the patient should receive a repeat confirmatory evaluation as soon as reasonably possible, preferably within 3 to 7 days after the test results become available. If the initial CK elevation is >10×ULN, instruct the patient to discontinue IMP immediately (rather than continuing IMP until repeat test values are evaluated). It is very important to perform the repeat confirmatory evaluation as soon as possible (within 1 day after discontinuing IMP).

[0220] The repeat CK evaluation includes questions about the nature, duration, and intensity of any muscle symptoms; confirmation of potential factors such as unaccustomed exercise, heavy alcohol intake, viral disease (consider performing serology), concomitant medications, and / or other conditions that can cause muscle disease; physical examination for muscle tenderness, weakness, and rash; measurement of serum creatinine, dipstick urine test ± microscopy if indicated; and basic metabolic panel. · If the repeat CK evaluation confirms a CK abnormality >5×ULN of unknown origin (i.e., not associated with recent trauma or strenuous physical activity) and the patient is asymptomatic, the investigator may consider continuing IMP while repeating the CK evaluation once every 1 to 2 weeks using information from the sponsor of the clinical trial. · If the repeat CK evaluation confirms a CK abnormality of unknown origin (i.e., not associated with recent trauma or strenuous physical activity) listed below, the patient should discontinue IMP: - >5×ULN associated with symptoms of myalgia, muscle weakness, or dark urine; or - >10×ULN even in the absence of symptoms · At the investigator's discretion, IMP may be interrupted and the patient may be rechallenged with IMP after the CK has returned to baseline level.

[0221] Monitoring and Management of Elevated LDL-C After randomization, the results of LDL-C were hidden from the investigators to maintain blinding. The central laboratory informed the investigators if the patient's LDL-C level was ≥ 220 mg / dL. The patient returned to the clinic for repeated fasting lipid samples to confirm that the LDL-C value met the threshold criteria. The patient was advised on healthy dietary guidelines and strongly encouraged to take the IMP. If confirmed, the patient discontinued the IMP.

[0222] Monitoring and Management of Elevated TG After randomization, the results of TG were hidden from the investigators to maintain blinding. The central laboratory informed the investigators if the patient's TG level was > 1000 mg / dL. The patient was advised on healthy dietary guidelines and strongly encouraged to take the IMP. The patient returned to the clinic for repeated fasting lipid samples to confirm that the TG value met the threshold criteria. If confirmed, the patient discontinued the IMP.

[0223] Monitoring and Management of Potential Hypoglycemia and Metabolic Acidosis Educate the patient about the signs and symptoms of hypoglycemia. Advise the patient to report such signs and symptoms to the study facility if experienced (see Section 13.3 for further details).

[0224] Evaluate clinical laboratory values and determine any signs of anion gap metabolic acidosis. If the test values are consistent with metabolic acidosis, perform rapid follow-up of the patient for further medical evaluation of the acidosis (see Section 13.3 for further details). This event should be recorded as an AE.

[0225] Total Blood Volume of Central Clinical Laboratory Samples The total number of venipunctures during the study and the total volume of whole blood collected are limited to the amounts necessary for safety, efficacy, and biomarker evaluation. The total volume of whole blood collected over the study duration should not exceed approximately 250 mL per patient.

[0226] [Adverse and Serious Adverse Events] Adverse Events Definition of Adverse Event An AE is defined as any untoward medical occurrence in a clinical trial patient administered a medicinal product, including the control, which does not necessarily have a causal relationship with the treatment. The investigator is responsible for ensuring that any AE observed by the investigator or reported by the patient is recorded in the patient's medical record.

[0227] An AE can be the following: · Any undesirable and unintended sign / symptom, including abnormal laboratory findings or diseases, temporally related to the use of the medicinal product, whether or not considered related to the medicinal product. · Any new disease or exacerbation of an existing disease · If any of the following occurs, an abnormal laboratory finding or diagnostic test abnormality (e.g., electrocardiogram [ECG] or X-ray) should be reported as an AE: - Treatment required due to the abnormality - Discontinuation of the IMP - At the discretion of the investigator · A TEAE is defined as an AE that starts or worsens after the administration of the first dose of the IMP, as defined in the Statistical Analysis Plan (SAP).

[0228] Drug Adverse Reaction All harmful and unintended reactions to a medicinal product related to any administration should be considered as a drug adverse reaction (ADR). By "reaction" to a medicinal product is meant that there is at least a reasonable possibility of a causal relationship between the medicinal product and the AE (i.e., the relationship cannot be excluded).

[0229] An unexpected ADR is defined as a harmful reaction whose nature or severity does not conform to the applicable product information (e.g., the IB for an unapproved investigational product or the package insert / product characteristics summary for an approved product).

[0230] Reporting of Adverse Events All AEs occurring during the conduct of the study (from signing the informed consent until 30 days after study completion / termination) should be collected on the AE eCRF. Patients should be instructed to report to the investigator any AE they experience. The investigator should evaluate for AEs at each visit and record the event on the appropriate AE eCRF.

[0231] Whenever possible, the investigator should identify and record on the eCRF a specific disease or syndrome rather than individual related signs and symptoms. However, if the investigator does not consider an observed or reported sign or symptom to be an element of a specific disease or syndrome, it should be recorded as a separate AE on the eCRF. Additionally, a condition that resulted in a medical or surgical procedure should be recorded as an AE rather than as the procedure.

[0232] Any medical condition already present at screening or baseline should not be reported as an AE, except if the severity or seriousness of a medical condition or sign or symptom present at baseline worsens at any time during the study. In this case, it should be reported as an AE.

[0233] It is the investigator's responsibility to assess the clinical significance of all outliers as defined by the list of references obtained from the local library. In some cases, a significant change in an in-range test value may require a similar judgment.

[0234] Abnormal test values that are not already associated with an AE should be recorded as an AE only if any one of the following criteria is met: · As a result of the abnormality, an action is taken with respect to the investigational drug · Intervention is required for management of the abnormality · In the investigator's judgment, the abnormality should be considered clinically significant

[0235] Significant abnormal test values that occur during clinical research should be followed up until the repeated test values return to normal, stabilize, or are no longer clinically significant. Any abnormal test results determined to be errors do not need to be reported as AEs.

[0236] Each AE should be evaluated for duration, severity, seriousness, and causal relationship to the IMP. For each AE, the following information was recorded / has been recorded: · Description of the event (e.g., headache) · Date of onset · Date of resolution (or that the event is ongoing) · Actions taken as a result of the event · Seriousness of the event · Severity of the event · Outcome of the event · Investigator's assessment of the relationship to the IMP

[0237] A group of signs and symptoms arising from a single cause should be reported / reported as a single AE (e.g., fever, elevated white blood cell [WBC], cough, abnormal chest X-ray, etc. could all be reported as "pneumonia").

[0238] Investigators should carefully evaluate / evaluate the patient's comments and responses to treatment so as to be able to judge the nature and severity of the AE. Questions regarding the relationship between the AE and IMP administration should be determined by the investigator or study physician after thorough consideration of all available facts.

[0239] Severity It is the responsibility of the investigator to assess the intensity (severity) of the AE.

[0240] The severity of the AE was characterized / characterized as mild, moderate, or severe according to the following definitions: · Mild: The event is usually transient and does not interfere with the patient's daily activities · Moderate: The event causes a low level of discomfort or concern to the patient or may interfere with daily activities · Severe: The event interrupts the patient's normal daily activities, incapacitates the patient from performing normal activities, or has a significant impact on the clinical condition and requires intervention and / or intensive follow-up. Note: Severe AEs do not have to be serious, and by definition, SAE does not have to be severe.

[0241] relationship It is the investigator's responsibility to assess the relationship between the IMP and the AE. The degree of "relatedness" of the AE to the IMP can be described using the following scale: · Not related: There is no temporal relationship, and another etiology is probably the cause. · Probably not related: It cannot be clearly determined that it is not related to the IMP, but the causal relationship is weak, and another etiology is more likely to be the cause. For reporting and summarization, events evaluated as probably not related to the IMP should be considered not related to the IMP. · Possibly related: There is a temporal relationship, but another etiology is probably the cause. However, the involvement of the IMP cannot be excluded. · Probably related: There is a temporal relationship, and another etiology may exist, but probably does not. If the IMP is discontinued, the event may respond. · Clearly related: There is an established temporal relationship with the administration of the IMP, and there are no other more likely causes. Typically, the event should resolve when the IMP is discontinued and recur upon rechallenge.

[0242] Monitoring and Follow-up of Adverse Events Patients with AEs are monitored / monitored using relevant clinical evaluations and laboratory tests determined by the investigator. All follow-up results are reported / reported to the sponsor staff or authorized medical monitors. Any measures taken and follow-up results must be recorded on the appropriate page of the eCRF or in an appropriate written follow-up communication, as well as in the patient's original records. Follow-up test results should be filed with the patient's original records.

[0243] For all AEs that require the patient to discontinue the study, relevant clinical evaluations and laboratory tests shall be repeated at appropriate intervals until the event has finally resolved or stabilized.

[0244] Patients who have an AE related to the ongoing IMP at the time of study discontinuation or completion, except for those who have reported an SAE, shall be followed up until resolution or for 30 days after study completion, whichever is earlier (see Section 13.2.2).

[0245] Adverse events occurring under treatment TEAE is defined as an AE that starts or worsens after the administration of the first dose of IMP, as defined in the SAP.

[0246] Serious Adverse Events Definition of serious adverse events SAE is defined as any AE occurring at any dose that results in any of the following outcomes: · Results in death · Threatens life · Requires hospitalization or prolongs an existing hospitalization · Results in persistent or significant disability / incapacity or substantial disruption of the ability to perform normal life functions · Is a congenital anomaly / birth defect · Is a significant medical event

[0247] Note: Emergency department visits without hospitalization do not meet the hospitalization criteria, nor do hospitalizations planned or scheduled before the signing of the informed consent for elective or outpatient procedures for foreign patients. However, unexpected complications and / or prolonged hospitalizations occurring during elective surgery or outpatient surgery for foreign patients should be recorded as AEs and evaluated for severity. Hospitalizations for social or situational reasons (e.g., no place to stay, living too far away to come to the hospital for medical treatment) are not considered hospitalizations.

[0248] Important medical events that may not result in death, endanger life, or require hospitalization may be considered SAEs if, based on appropriate medical judgment, they may put the patient at risk and medical or surgical intervention may be required to prevent one of the outcomes listed in this definition. Examples of these medical events include allergic bronchospasm requiring intensive treatment in the emergency room, blood disorders, seizures that do not result in hospitalization, or the occurrence of drug dependence or drug abuse.

[0249] Adverse events of special interest Adverse events of special interest (AESIs) are included in this protocol for reasons related to other lipid-lowering therapies or considered important based on non-clinical data. AESIs for this protocol include metabolic acidosis (clinical laboratory values), hypoglycemia, muscle (AE and CK elevation), liver, and neurocognitive / neurological events.

[0250] Hypoglycemia and metabolic acidosis: These resulted in death of monkeys in preclinical studies. Exposure in these studies was more than 17-fold higher than the exposure associated with the 180 mg dose of bempedoic acid in Phase 1 and Phase 2 clinical studies; the 180 mg dose is the dose to be studied in Phase 3. Subsequent monkey studies demonstrated that hypoglycemia is reversible by discontinuation of dosing and oral glucose administration. Cases of hypoglycemia or metabolic acidosis have not been identified to date in Phase 1 or Phase 2 clinical trials. All patients enrolled in bempedoic acid clinical trials are monitored for any potential risk of metabolic acidosis by standard clinical chemistry, and appropriate follow-up is conducted if detected. Patients in all clinical trials are provided with information (in the ICD) on the signs and symptoms of hypoglycemia, including dizziness, tremor, shaking hands, sweating, tingling, blurred vision, nausea or vomiting, confusion, difficulty concentrating, and drowsiness. Investigational sites are required to specifically record reports of these symptoms.

[0251] Muscle: Muscle events are associated with statins (Thompson 2003) and other lipid-lowering therapies and are mentioned in the product information for these therapies. Closely monitor muscle symptoms, CK elevation, and symptoms of potential muscle disorders through AE confirmation.

[0252] Liver: Liver function is continuously monitored using clinical safety tests. If the safety clinical test results are > 3 × ULN, conduct a more detailed investigation.

[0253] Neurocognitive events: Theoretically, lipid-lowering drugs that disrupt cholesterol homeostasis in the brain may affect neurological function, and cognitive dysfunction (such as memory loss) associated with the use of statins has been reported (FDA 2012). Summarize the events using the terms of the pre-specified medical regulatory terminology set (MedDRA) as outlined in the SAP.

[0254] [Statistics] General Considerations The statistical analysis described in this section will be performed as further outlined in the SAP finalized before the end of this study. If there are any differences between the two documents in the plan for data analysis, prioritize the SAP over the protocol. The SAP will be included as an appendix in the clinical study report for this protocol.

[0255] Generally, summary statistics for continuous variables include the number of subjects, mean, median, standard deviation or standard error, first and third quartiles, minimum and maximum values. For categorical variables, provide frequencies and percentages.

[0256] Determination of sample size A sample size of 40 randomized patients in the triplet therapy group and 20 randomized patients in the placebo group is predicted to provide 90% power to detect a 25% difference in the percent change in calculated LDL-C from baseline to week 6 between the triplet therapy and placebo groups. This calculation is based on a two-sided t-test at a 5% significance level, a common standard deviation of 26%, and a dropout rate of 10%. A conservative but clinically meaningful 25% treatment difference was selected to have a sample size adequate to evaluate other efficacy and safety information.

[0257] Analysis set The modified intention-to-treat (mITT) population used for all efficacy analyses is defined as all randomized patients who received at least one dose of the IMP and had a baseline assessment and at least one post-baseline assessment, excluding any assessments performed more than 2 days after IMP dosing.

[0258] The safety population (SP) used for all safety summaries is defined as all randomized patients who received at least one dose of the study medication. Patients in the SP are included in the treatment group they actually received, regardless of their randomized treatment.

[0259] Trial continuation status, demographics, and baseline characteristics Trial continuation status, including the IMP and reasons for withdrawal from the study, is summarized by treatment group. Demographic information and patient characteristics, including but not limited to gender, race, age, and baseline vital signs, are also summarized by treatment group.

[0260] Primary endpoint analysis The primary efficacy endpoint is the percentage change from baseline to week 6 in LDL-C. Baseline is defined as the mean of the values at week -1 (visit S2) and on the day before dosing / week 0 (visit T1). Using the mITT population, for the primary endpoint, an analysis of covariance (ANCOVA) is performed with treatment group as a factor and baseline LDL-C as a covariate to compare triple therapy to placebo (section 14.3). Missing values at week 6 are imputed using the last observation carried forward (LOCF) method (only values after baseline are carried forward). For both treatment groups, least-squares means (LSM) and standard errors (SE) are given along with the placebo-adjusted LSM, its 95% confidence interval (CI), and the associated p-value.

[0261] Secondary Efficacy Endpoint Analysis The secondary efficacy endpoints, including the percentage change from baseline to week 6 in additional lipid and cardiometabolic biomarkers, are analyzed in the same manner as the primary efficacy endpoint. Baselines for non-HDL-C, HDL-C, TC, and TG are defined as the mean of the values at week -1 (visit S2) and on the day before dosing / week 0 (visit T1), and baselines for ApoB and hs-CRP are defined as the values at the day before dosing / week 0 (visit T1).

[0262] Statistical tests for the primary and secondary efficacy endpoints are two-sided and are performed at a 5% significance level without adjustment for multiple comparisons.

[0263] Safety Endpoints For safety endpoints, a descriptive summary is provided.

[0264] All AEs are coded using MedDRA to the System Organ Class (SOC) and preferred term.

[0265] The summary of AEs includes only TEAEs defined as AEs that start or worsen after the first dose of IMP administration as defined in SAP. All TEAEs, SAEs, AEs that lead to discontinuation of IMP use, fatal AEs, and AEs of particular note are summarized by SOC and preferred terms in descending order of frequency for each treatment group.

[0266] Clinical safety test values including hematology, blood chemistry, glucose, and urine tests; PE findings; vital signs; and body weight are summarized by the values at each time point after each baseline and the change or percent change (where appropriate) from the baseline of those values.

[0267] Ethical Conduct of the Study At the time of signing the protocol, the investigator agrees to conduct the study in accordance with ethical principles having their origin in the latest revision of the Declaration of Helsinki and consistent with GCP, applicable regulatory requirements, and the ethical requirements for IRB review and the guidelines and procedures outlined by the ICD.

[0268] The investigator agrees to permit monitoring and auditing of all essential clinical study documents by the sponsor or its authorized representative and inspection by the FDA. Monitoring and audit visits by the sponsor or authorized designee are scheduled at mutually agreeable times and with appropriate staff on a regular basis throughout the study.

[0269] The investigator ensures the proper conduct and implementation of the study, including the performance and implementation of study-related obligations delegated to other appropriately qualified individuals. The investigator ensures that study staff cooperate with monitoring and auditing and exercise due diligence during the recruitment and screening of study patients. The investigator must sign and return to the sponsor the page "Investigator's Signature" (see Appendix 3) and provide a copy of the current curriculum vitae. For this study and all studies conducted under the IND, the investigator must sign and return the completed form FDA 1572 "Statement of Investigator" to the sponsor (or designee).

[0270] Written informed consent The investigator at each facility shall ensure that patients are provided with sufficient and appropriate oral and written information about the nature, purpose, potential risks and benefits of the study. Patients must also clearly understand that they can freely discontinue the study at any time. Opportunities should be given to patients to ask questions and time to consider the information provided.

[0271] The informed consent signed and dated by the patient must be obtained before any study procedures for the ICD approved by the sponsor are conducted. Updates to the ICD during the conduct of the study are communicated by letter from the sponsor to the investigator. The ICD should be provided in the appropriate language of the patient population.

[0272] The investigator must retain the original signed ICD. A copy of the signed ICD must be given to the patient.

[0273] Patient confidentiality The investigator must ensure that the confidentiality of patients is maintained.

[0274] The names and identities of all study patients are kept strictly confidential and do not appear on the eCRF or other records provided to or maintained by the sponsor (or designee). If a patient's name appears on any document, it must be redacted and replaced with an identifier for the patient before a copy of the document is provided to the sponsor (or designee). The ICD must include an appropriate statement explaining that the patient's data is confidential and what measures are taken to ensure patient confidentiality.

[0275] Any other confidentiality requirements specified by the facility, IRB, or local regulations shall be faithfully observed and appropriately detailed in the ICD.

[0276] [Table 7]

[0277] <Example 2: Clinical Data> Brief Explanation of Clinical Research and Results.

Table 8

[0278]

Table 9

[0279]

Table 10

[0280]

Table 11

[0281]

Table 12

[0282]

Table 13

[0283]

Table 14

[0284]

Table 15

[0285]

Table 16

[0286] Summary · By 180 mg of bempedoic acid, 10 mg of ezetimibe, and 20 mg of atorvastatin: · At p < 0.001, LDL-C was significantly reduced by 64% (61% after placebo adjustment) compared to baseline. · At p < 0.001, hsCRP was significantly reduced by 48%. · Total cholesterol, non-HDL-C, and apoB were significantly reduced. · 95% of patients had > 50% reduction in LDL-C. · Had a safety profile comparable to placebo and showed good tolerance.

[0287]

Table 17

[0288] Conclusion · With bempedoic acid + ezetimibe + 20 mg of atorvastatin, both LDL-C and hsCRP were significantly reduced. The effect on LDL-C was consistent across all patients treated. · Data from Study 1002-038 demonstrate that optimal tolerability and safety were achieved with the use of bempedoic acid + ezetimibe + 20 mg of atorvastatin. · Bempedoic acid and ezetimibe complemented the LDL-C-lowering effect of atorvastatin 20 mg, the most frequently prescribed statin and dose. · Oral combination therapies such as the regimen evaluated in this study may be able to meet the needs of the majority of patients with elevated LDL-C, and once-daily oral therapy provides physicians with more oral options and flexibility and provides payers with price determination desired in the current constrained healthcare environment.

[0289] Although the present disclosure has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail may be made therein without departing from the spirit and scope of the present disclosure.

[0290] All references, issued patents, and patent applications cited in the text of this specification are hereby incorporated by reference in their entirety for all purposes. The present invention also provides the following aspects. [1] A method for treating cardiovascular disease or reducing its risk in a subject in need thereof, the method comprising administering to the subject ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, the administration being for treating cardiovascular disease or reducing its risk in the subject. [2] The method according to [1], wherein the dose of ezetimibe administered is constant for at least one week. [3] The method according to [1], wherein the dose of ETC-1002 administered is constant for at least one week. [4] The method according to [1], wherein the dose of statin administered is constant for at least one week. [5] The method according to [1], wherein the doses of statin, ezetimibe, and ETC-1002 administered are each constant for at least one week. [6] The method according to [1], wherein the doses of statin, ezetimibe, and ETC-1002 administered are each constant for at least three weeks. [7] The method according to any one of [1] to [6], wherein the amount of ETC-1002 per dose is 180 mg or 120 mg. [8] The method according to any one of [1] to [6], wherein the amount of ETC-1002 per dose is 40 mg to 90 mg. [9] The method according to any one of [1] to [8], wherein the amount of ezetimibe per dose is 10 mg.

[10] The method according to any one of [1] to [9], wherein the amount of statin per dose is 1 mg to 80 mg.

[11] The method according to any one of [1] to

[10] , wherein the administration comprises administering to the subject a fixed-dose combination formulation of ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers.

[12] The method according to any one of [1] to

[11] , wherein the low density lipoprotein cholesterol (LDL-C) level in the subject is lower than the LDL-C level in a matched control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[13] The method according to

[12] , wherein the low density lipoprotein cholesterol (LDL-C) level in the subject is reduced by 64% compared to the baseline LDL-C level in the subject.

[14] The method according to any one of [1] to

[13] , wherein the very low density lipoprotein (VLDL) level in the subject is lower than the VLDL level in a matched control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[15] The method according to any one of [1] to

[14] , wherein the number of VLDL particles in the subject is lower than the number of VLDL particles in a matched control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[16] The method according to any one of [1] to

[15] , wherein the size of VLDL particles in the subject is lower than the size of VLDL particles in a matched control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[17] The method according to any one of [1] to

[16] , wherein the apolipoprotein A-1 (ApoA1) level in the subject is higher than the ApoA1 level in a matched control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[18] The method according to any one of [1] to

[17] , wherein the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the subject is lower than the said ratio in a matched control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[19] The method according to any one of [1] to

[17] , wherein the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the subject does not significantly change from the ratio in a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[20] The method according to any one of [1] to

[16] , wherein the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the subject increases from the ratio in a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[21] The method according to any one of [1] to

[16] , wherein the apolipoprotein B (ApoB) level in the subject decreases by 54% compared to the baseline ApoB level in the subject.

[22] The method according to any one of [1] to

[21] , wherein the triglyceride (TG) level in the subject is lower than the TG level in a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[23] The method according to any one of [1] to

[22] , wherein the triglyceride (TG) level in the subject decreases by 27% compared to the baseline TG level in the subject.

[24] The method according to any one of [1] to

[23] , wherein the total cholesterol (TC) level in the subject is lower than the TC level in a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[25] The method according to any one of [1] to

[24] , wherein the total cholesterol (TC) level in the subject decreases by 47% compared to the baseline TC level in the subject.

[26] The method according to any one of [1] to

[25] , wherein the high-sensitivity C-reactive protein (hs-CRP) level in the subject is lower than or does not change from the hs-CRP level in a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[27] The method according to any one of [1] to

[26] , wherein the high-sensitivity C-reactive protein (hs-CRP) level in the subject is reduced by 54% compared to the baseline.

[28] The method according to any one of [1] to

[27] , wherein the non-HDL-C level in the subject is lower than the non-HDL-C level of a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

[29] The method according to any one of [1] to

[28] , wherein the non-HDL-C level in the subject is reduced by 60% compared to the baseline non-HDL-C level in the subject.

[30] The method according to any one of [1] to

[29] , wherein the subject is statin-intolerant.

[31] The method according to any one of [1] to

[30] , wherein the subject suffers from muscle-related adverse events associated with the use of statins.

[32] The method according to any one of [1] to

[31] , wherein the subject has hypercholesterolemia.

[33] The method according to any one of [1] to

[32] , wherein the subject has hyperlipidemia.

[34] The method according to any one of [1] to

[33] , wherein the subject has dyslipidemia or mixed dyslipidemia.

[35] The method according to any one of [1] to

[34] , wherein the subject has atherosclerotic cardiovascular disease.

[36] The method according to any one of [1] to

[35] , wherein the subject is human.

[37] The method according to any one of [1] to

[36] , wherein ETC-1002, ezetimibe, and a statin are administered in a single pharmaceutical formulation.

[38] The method according to any one of [1] to

[37] , wherein the statin is atorvastatin.

[39] The method according to any one of [1] to

[38] , wherein the amount of ETC-1002 is 180 mg and the amount of ezetimibe is 10 mg.

[40] The method according to any one of [1] to

[41] , wherein the method reduces the LDL-C level by 50% compared to the baseline LDL-C level in the subject 6 weeks after administration.

[41] A pharmaceutical preparation comprising ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers.

[42] The composition according to

[41] , wherein the amount of ETC-1002 is 180 or 120 mg.

[43] The composition according to

[41] , wherein the amount of ETC-1002 is 40 mg to 90 mg.

[44] The composition according to

[41] , wherein the amount of ezetimibe is 10 mg.

[45] The composition according to

[41] , wherein the amount of the statin is 1 mg to 80 mg.

[46] The composition according to any one of

[41] to

[45] , wherein the statin is selected from the group consisting of atorvastatin, simvastatin, fluvastatin, resuvastatin, and pitavastatin.

[47] The composition according to any one of

[41] to

[45] , wherein the statin is atorvastatin.

[48] The composition according to

[47] , wherein the amount of atorvastatin is 10 to 80 mg.

[49] The composition according to any one of

[41] to

[45] , wherein the statin is simvastatin.

[50] The composition according to

[49] , wherein the amount of simvastatin is 10 to 40 mg.

[51] The composition according to any one of

[41] to

[45] , wherein the statin is fluvastatin.

[52] The composition according to

[51] , wherein the amount of fluvastatin is 20 to 80 mg.

[53] The composition according to any one of

[41] to

[45] , wherein the statin is rosuvastatin.

[54] The composition according to

[53] , wherein the amount of rosuvastatin is 5 to 40 mg.

[55] The composition according to any one of

[41] to

[45] , wherein the statin is pitavastatin.

[56] The composition according to

[55] , wherein the amount of pitavastatin is 1 to 4 mg.

[57] A method for treating cardiovascular disease or reducing its risk in a subject in need thereof, the method comprising administering to the subject ETC-1002, ezetimibe, a statin, PCSK9 inhibitor antibody therapy, and one or more pharmaceutical excipients or carriers, wherein the administration treats cardiovascular disease or reduces its risk in the subject.

[58] The method according to

[57] , wherein the antibody therapy is administered once every two weeks.

[59] The method according to

[57] , wherein the antibody therapy is administered once every four weeks.

[60] A method for treating cardiovascular disease or reducing its risk in a subject in need thereof, the method comprising administering to the subject ETC-1002, ezetimibe, a statin, an approved lipid-lowering therapy other than statin and / or ezetimibe, and one or more pharmaceutical excipients or carriers, wherein the administration treats cardiovascular disease or reduces its risk in the subject.

[61] A kit comprising the composition according to any one of

[41] to

[56] and instructions for use.

[0291] Cited References TIFF0007716437000031.tif217150TIFF0007716437000032.tif230151TIFF0007716437000033.tif84147

Claims

1. A pharmaceutical composition for use in a method of treating cardiovascular disease or reducing the risk thereof in a subject in need thereof, comprising ETC-1002, ezetimibe, a statin, and one or more pharmaceutical excipients or carriers, wherein the statin is selected from atorvastatin in an amount of 10 to 80 mg and rosuvastatin in an amount of 5 to 40 mg, pharmaceutical composition.

2. The pharmaceutical composition for use according to claim 1, wherein the amount of ETC-1002 is 180 mg or 120 mg.

3. The pharmaceutical composition for use according to claim 1, wherein the amount of ETC-1002 is 40 mg to 90 mg.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the amount of ezetimibe is 10 mg.

5. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the low density lipoprotein cholesterol (LDL-C) level in the subject to which the pharmaceutical composition is administered is lower than the LDL-C level in a matched control subject to which the same dose of statin and ezetimibe are administered but ETC-1002 is not administered.

6. The pharmaceutical composition for use according to claim 5, wherein the LDL-C level in the subject to which the pharmaceutical composition is administered is reduced by 64% compared to the baseline LDL-C level in the subject.

7. The pharmaceutical composition for use according to any one of claims 1 to 6, wherein the very low density lipoprotein (VLDL) level in the subject to which the pharmaceutical composition is administered is lower than the VLDL level in a matched control subject to which the same dose of statin and ezetimibe are administered but ETC-1002 is not administered.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the number of VLDL particles in the subject to which the pharmaceutical composition is administered is lower than the number of VLDL particles in a matched control subject to which the same dose of statin and ezetimibe are administered but ETC-1002 is not administered.

9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the size of the VLDL particles in the subject to which the pharmaceutical composition is administered is lower than the size of the VLDL particles in a matched control subject to which the same dose of statin and ezetimibe are administered but ETC-1002 is not administered.

10. The level of apolipoprotein A-1 (ApoA1) in a subject to whom the pharmaceutical composition is administered is higher than the ApoA1 level in a control subject who is administered the same dose of statin and ezetimibe but not administered ETC-1002. A pharmaceutical composition for use according to any one of claims 1 to 9.

11. The ratio of apolipoprotein B (ApoB) to ApoA1 in a subject to whom the pharmaceutical composition is administered is lower than the ratio in a control subject who is administered the same dose of statin and ezetimibe but not administered ETC-1002. A pharmaceutical composition for use according to any one of claims 1 to 10.

12. The ratio of ApoB to ApoA1 in a subject to whom the pharmaceutical composition is administered does not significantly change from the ratio in a control subject who is administered the same dose of statin and ezetimibe but not administered ETC-1002. A pharmaceutical composition for use according to any one of claims 1 to 11.

13. The ratio of ApoB to ApoA1 in a subject to whom the pharmaceutical composition is administered increases from the ratio in a control subject who is administered the same dose of statin and ezetimibe but not administered ETC-1002. A pharmaceutical composition for use according to any one of claims 1 to 12.

14. The ApoB level in a subject to whom the pharmaceutical composition is administered is reduced by 54% compared to the baseline ApoB level in the subject. A pharmaceutical composition for use according to any one of claims 1 to 13.

15. The triglyceride (TG) level in a subject to whom the pharmaceutical composition is administered is lower than the TG level in a control subject who is administered the same dose of statin and ezetimibe but not administered ETC-1002. A pharmaceutical composition for use according to any one of claims 1 to 14.

16. The TG level in a subject to whom the pharmaceutical composition is administered is reduced by 27% compared to the baseline TG level in the subject. A pharmaceutical composition for use according to any one of claims 1 to 15.

17. The total cholesterol (TC) level in a subject to whom the pharmaceutical composition is administered is lower than the TC level in a control subject who is administered the same dose of statin and ezetimibe but not administered ETC-1002. A pharmaceutical composition for use according to any one of claims 1 to 16.

18. The pharmaceutical composition for use according to any one of claims 1 to 17, wherein the TC level in the subject to which the pharmaceutical composition is administered is reduced by 47% compared to the baseline TC level in the subject.

19. The pharmaceutical composition for use according to any one of claims 1 to 18, wherein the high-sensitivity C-reactive protein (hs-CRP) level in the subject to which the pharmaceutical composition is administered is lower than or unchanged from the hs-CRP level of a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

20. The pharmaceutical composition for use according to any one of claims 1 to 19, wherein the hs-CRP level in the subject to which the pharmaceutical composition is administered is reduced by 54% compared to the baseline hs-CRP level in the subject.

21. The pharmaceutical composition for use according to any one of claims 1 to 20, wherein the non-high-density lipoprotein cholesterol (non-HDL-C) level in the subject to which the pharmaceutical composition is administered is lower than the non-HDL-C level of a control subject to whom the same dose of statin and ezetimibe is administered but ETC-1002 is not administered.

22. The pharmaceutical composition for use according to any one of claims 1 to 21, wherein the non-HDL-C level in the subject to which the pharmaceutical composition is administered is reduced by 60% compared to the baseline non-HDL-C level in the subject.

23. The pharmaceutical composition for use according to any one of claims 1 to 22, wherein the subject has hypercholesterolemia.

24. The pharmaceutical composition for use according to claim 23, wherein the hypercholesterolemia is familial hypercholesterolemia.

25. The pharmaceutical composition for use according to any one of claims 1 to 22, wherein the subject has hyperlipidemia.

26. The pharmaceutical composition for use according to any one of claims 1 to 22, wherein the subject has dyslipidemia or mixed dyslipidemia.

27. The pharmaceutical composition for use according to any one of claims 1 to 26, wherein the subject has atherosclerotic cardiovascular disease.

28. The pharmaceutical composition for use according to any one of claims 1 to 27, wherein the subject is human.

29. The pharmaceutical composition for use according to any one of claims 1 to 28, wherein the statin is atorvastatin and the amount of atorvastatin is 10 to 80 mg.

30. A pharmaceutical composition for use according to any one of claims 1 to 28, wherein the statin is rosuvastatin and the amount of rosuvastatin is 5 to 40 mg.

31. A pharmaceutical composition for use according to any one of claims 1 to 30, wherein the amount of ETC-1002 is 180 mg and the amount of ezetimibe is 10 mg.

32. A pharmaceutical composition for use according to any one of claims 1 to 31, wherein the method reduces the LDL-C level by 50% compared to the baseline LDL-C level in the subject to whom the pharmaceutical composition is administered 6 weeks after administration.

33. A pharmaceutical composition for use according to any one of claims 1 to 32, wherein the subject has hypercholesterolemia.

34. A pharmaceutical composition for use according to any one of claims 1 to 33, which is configured to be administered together with a PCSK9 inhibitor antibody therapy.

35. A pharmaceutical composition for use according to claim 34, wherein the antibody therapy is administered once every two weeks.

36. A pharmaceutical composition for use according to claim 34, wherein the antibody therapy is administered once every four weeks.

37. A pharmaceutical composition for use according to any one of claims 1 to 33, which is configured to be administered together with an approved lipid-lowering therapy other than statin and / or ezetimibe.

38. A kit for treating cardiovascular disease or reducing its risk in a subject, comprising the pharmaceutical composition according to any one of claims 1 to 33 and an instruction manual.

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