Fixed-dose combinations containing ETC1002 and one or more statins to treat or reduce the risk of cardiovascular disease.

Abstract

Methods and compositions for treating or reducing the risk of cardiovascular conditions are provided. [Solution] A method for treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject, comprising administering to a subject in need thereof a fixed-dose combination of ETC-1002 or an analog thereof and one or more statins or analogs thereof, optionally wherein ETC-1002 is administered at a fixed dose of 120 mg or 180 mg, and the one or more statins are each administered at a fixed dose of between 2 and 80 mg, and optionally wherein the method for treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject comprises administering to the subject a fixed-dose combination of ETC-1002 or an analog thereof and one or more statins or analogs thereof, optionally wherein the fixed dose of ETC-1002 is administered at a fixed dose of 120 mg or 180 mg, and the one or more statins are each administered at a fixed dose of between 2 and 80 mg.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 62 / 133,739 filed March 16, 2015, and U.S. Provisional Patent Application No. 62 / 277,403 filed January 11, 2016, each of which is incorporated herein by reference as a whole.

[0002] This application relates to methods and compositions useful for treating cardiovascular conditions or reducing the risk of cardiovascular conditions. Statins are fundamental to the prevention and treatment of cardiovascular disease, which remains the leading cause of death in the United States and other countries around the world. In the United States alone, millions of people suffer from cardiovascular disease or impairment. [Background technology]

[0003] Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for cardiovascular disease. However, many patients, such as those with hypercholesterolemia, fail to lower their LDL-C levels to the desired level with conventional therapies. Despite advances in new cholesterol-lowering drugs, the persistence of cardiovascular risks, particularly those observed in patients with high cholesterol, is driving the search for new, unconventional medicines. New drugs have been developed that are effective in lowering cholesterol levels in the human body. Unfortunately, these drugs also induce negative side effects. Many compounds that have been shown to be effective in inhibiting enzymes in cholesterol biosynthesis are also systemic toxic. Therefore, there is a need for novel drug formulations that are effective and safe in lowering cholesterol. [Overview of the project]

[0004] This application relates to a method and composition comprising a fixed dose of ETC-1002 and a statin for treating or reducing the risk of cardiovascular disease.

[0005] ETC-1002 (bempedoic acid) is an orally administered once-daily therapy that lowers cholesterol by inhibiting adenosine triphosphate (ATP) citrate triase (ATPCL). ATPCL is located further upstream than HMG-CoA reductase in the cholesterol biosynthesis pathway.

[0006] ETC-1002 lowers low-density lipoprotein cholesterol (LDL-C) by directly inhibiting hepatic adenosine triphosphate citrate triase, thereby reducing de novo cholesterol synthesis and increasing LDL receptor expression. In a Phase 2a clinical trial, ETC-1002 administered at doses of 120 mg to 240 mg per day reduced LDL-C by 27% to 43% in various hypercholesterolemia populations, including patients with type 2 diabetes and muscle-related statin intolerance.

[0007] The general classification of "statins" refers to compounds that lower cholesterol levels in the body by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and consequently inhibiting the pathway for cholesterol synthesis in the liver. Examples of compounds that are part of the "statin" classification, but are not limited to these, include atorvastatin, simvastatin, rosuvastatin, and pravastatin. Treatment typically involves administering approximately 2 mg to 80 mg of a statin compound.

[0008] The inventors have found that inhibition of HMG-CoA reductase increases the activity of the LDL receptor. Furthermore, they have found that combining these two therapies leads to synergistic activity and favorable clinical outcomes. Therefore, the present invention relates to cholesterol-lowering compositions comprising statins and ETC-1002. These compositions lead to a further reduction in the patient's total cholesterol, specifically LDL-C.

[0009] This application also discloses a method of lowering cholesterol using a fixed-dose combination of ETC-1002 and one or more statins. Based on observations from ongoing trials, the combination therapy of ETC-1002 and a fixed high dose of one or more statins is relatively effective and safe compared to the combination therapy of ETC-1002 combined with one or more statins at a fixed low to moderate dose. Naturally, the combination therapy using ETC-1002 and a fixed high dose of one or more statins is also significantly superior to monotherapy with statins or ETC-1002 (120 mg or 180 mg per day) in patients with or without a history of statin-related muscle symptoms. The combination therapy also exhibits a significantly superior efficacy and safety profile in patients with acute hypercholesterolemia.

[0010] In one aspect, the methods and compositions of the invention further lower cholesterol in patients with persistently elevated LDL-C, despite stable statin therapy at this high dose.

[0011] These and other features, aspects, and advantages of the invention will become more understood in view of the following description and the accompanying drawings.

Brief Description of the Drawings

[0012] [Figure 1] It is a diagram showing the arrangement of patients. *One patient was randomized but discontinued before receiving the test drug. AE = adverse event, mITT = modified treatment intention. [Figure 2] It is a graph showing the mean percent change in LDL-C from baseline up to week 12. These data are from the modified treatment intention population. LDL-C = low density lipoprotein cholesterol, LS = least squares. *p = 0.0055 vs placebo, †p < 0.0001 vs placebo. Error bars represent standard error.

Modes for Carrying Out the Invention

[0013] Advantages and Usefulness Briefly stated, as described in more detail below, this specification describes a composition, a method of making the composition, and a method for treating cardiovascular disease or reducing the risk of cardiovascular disease using a fixed-dose combination of one or more statins and ETC-1002. There are numerous advantages to this approach, including, but not limited to, in patients treated with a fixed-dose combination of one or more statins and ETC-1002, an increased reduction in cholesterol and low density lipoprotein levels compared to when the patient is treated with either statin or ETC-1002 alone. As noted above, statins are fundamental to the prevention and treatment of cardiovascular disease, but can cause undesirable side effects in many patients. Such side effects include, but are not limited to, increased concentrations of liver enzymes, muscle problems, and increased risk of diabetes. Since discontinuation of statins in patients with hypercholesterolemia increases cardiovascular risk, muscle symptoms associated with statins are an important clinical problem. Thus, there is a significant need for cardiovascular therapy in patients who exhibit statin intolerance related to muscle.

[0014] Definitions The terms used in the claims and specification are defined as follows, unless otherwise specified.

[0015] The terms used in the claims and specification are defined as follows, unless otherwise specified. Further, any term or symbol used in this specification that is not defined as shown below shall have its ordinary meaning in the art.

[0016] As used herein and in the appended claims, singular articles and similar references such as “a,” “an,” and “the” in the context describing elements (in particular, in the context of the following claims) should be interpreted as encompassing both singular and plural forms unless otherwise shown herein or clearly inconsistent with the context. Descriptions of ranges of values ​​herein, unless otherwise shown herein, are not merely intended as a simplified method of referring individually to the individual values ​​within the range, including upper and lower bounds of the range, but rather the individual values ​​are incorporated herein as they are individually described herein. All methods described herein may be carried out in any appropriate order unless otherwise shown herein or clearly inconsistent with the context. Any and all examples or illustrative language (e.g., “etc.”) given herein, unless otherwise stated, are merely intended to further illustrate the examples and do not impose limitations on the scope of the claims. Language herein should not be interpreted as referring to any unclaimed elements.

[0017] Generally, a reference to a particular element, such as hydrogen or H, implies the inclusion of all isotopes of that element. For example, if the R group is defined as containing hydrogen or H, then deuterium and tritium are also included. Therefore, tritium, C 14 , P 32 and S 35 Compounds containing radioactive isotopes such as those mentioned above fall within the scope of this technology. Procedures for inserting such labels into compounds of this technology will be readily apparent to those skilled in the art based on the disclosures herein.

[0018] The term “remission” refers to any therapeutically beneficial outcome in the treatment of a disease state, such as an inflammatory disease state, including a reduction in the severity or progression of the disease state, remission, or cure. In some embodiments, “remission” includes the prevention of the disease state.

[0019] The term "in vitro" refers to the process that occurs in living cells that are isolated from an organism and grown, such as in tissue culture.

[0020] The term "in vivo" refers to processes that occur within living organisms.

[0021] As used herein, the term “mammal” includes, but is not limited to, both humans and non-humans, including humans, non-human primates, dogs, cats, mice, cattle, horses, and pigs.

[0022] The term "sufficient amount" refers to an amount sufficient to produce the desired effect, for example, an amount sufficient to regulate protein aggregation in cells.

[0023] The term "therapeutic dose" refers to the amount effective in alleviating the symptoms of a disease. Since prevention can be considered a form of therapy, the therapeutic dose may, in some embodiments, be the "preventive dose."

[0024] The compounds of this technology may exist as solvates, particularly hydrates. Hydrates may form during the manufacture of the compound or a composition containing the compound, or they may form over time due to the hygroscopic nature of the compound. The compounds of this technology may also exist as organic solvent hydrates, including, in particular, DMF, ethers, and alcohol solvates. The identification and manufacture of any specific solvate is within the scope of the art of those skilled in the field of synthetic organic or medicinal chemistry.

[0025] "Subject" refers to a mammalian organism treated with the compound of the present invention. "Subject" may be a human or a non-human mammalian organism.

[0026] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, or tautomer forms of heteroaryl groups containing ring atoms bonded to both the ring NH moiety and the ring=N moiety, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0027] "Treatment" or "treatment" of a disease or disorder refers to: 1) preventing the onset of the disease or disorder in a subject who is susceptible to its effects or who has not yet exhibited symptoms of the disease or disorder; 2) inhibiting the disease or disorder or preventing its onset; or 3) relieving or mitigating the cause of the regression of the disease or disorder.

[0028] As used herein, the terms “prevent,” “preventing,” “prevention,” and “prophylactic treatment” refer to reducing the likelihood of developing a disease, disorder, or condition in which a person does not currently have the disease, disorder, or condition, but is at risk of developing or is susceptible to developing it. Accordingly, in some embodiments, a drug may be administered prophylactically to prevent the signs of a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition.

[0029] For the purposes of this specification and the attached claims, unless otherwise indicated, all numerical terms used herein to express quantities, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values ​​should be understood in all cases as being modified by the term “about,” even if the term “about” does not explicitly represent a value, quantity, or range. Therefore, unless otherwise indicated, the numerical parameters shown in the following specification and attached claims are not exact, nor do they need to be exact, but may be approximate and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art depending on the desired characteristics that can be obtained by the subject matter of this disclosure. For example, when the term “approximately” refers to a value, the variation may mean that the variation encompasses, in some embodiments, 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 a particular amount, such that it is appropriate for performing the method of the Disclosure or using the composition of the Disclosure.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the meanings that are ordinarily understood by those skilled in the art to which this invention pertains.

[0031] Here, any and all heteroaryl and heterocycloalkyl substituents may contain up to four heteroatoms selected from the group consisting of O, N, and S.

[0032] It should be understood that polymers obtained by defining substituents having further substituents on themselves (such as substituted aryls having substituted aryl groups as substituents that themselves are substituted with substituted aryl groups) are not intended to be included herein. In such cases, the maximum number of such substituents is 3. That is, each of the above definitions is constrained by the limitations that each functional group is substituted (at positions 1 to 3) and any and all of these substituents may be substituted only one more time (at positions 1 to 3).

[0033] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0034] Throughout this application, the text refers to various embodiments of the compounds, compositions, and methods of the present invention. The various embodiments described are intended to provide various examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of the various embodiments provided herein may overlap. The embodiments described herein are merely illustrative and should not be intended to limit the scope of the Art.

[0035] Abbreviation AE is an abbreviation for adverse event.

[0036] CK is an abbreviation for creatine kinase.

[0037] HDL-C is an abbreviation for high-density lipoprotein cholesterol.

[0038] CRP is an abbreviation for highly sensitive C-reactive protein.

[0039] LDL-C is an abbreviation for low-density lipoprotein cholesterol.

[0040] LS is an abbreviation for least squares.

[0041] NCEP ATP-III is an abbreviation for the National Cholesterol Education Program Adult Treatment Panel III.

[0042] non-HDL-C is an abbreviation for non-high-density lipoprotein cholesterol.

[0043] VLDL is an abbreviation for very low-density lipoprotein.

[0044] therapy Disclosed herein is a method comprising administering a fixed dose of ETC-1002 or an analogue thereof and a fixed dose combination of one or more statins or analogues to a subject in need thereof, wherein, optionally, ETC-1002 is administered at a fixed dose of 180 mg or 120 mg, and one or more statins are administered at fixed doses of 2 to 80 mg each, wherein, optionally, the level of low-density lipoprotein cholesterol (LDL-C) in the subject is lower than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins at fixed doses between 2 and 80 mg each, wherein, optionally, the risk of cardiovascular disease in the subject is addressed or reduced.

[0045] In some embodiments, ETC-1002 is administered in a fixed dose of 180 mg or 120 mg, and one or more statins are administered in fixed doses of 2 to 80 mg each.

[0046] In some embodiments, the subject has hypercholesterolemia, and the method further includes treating the hypercholesterolemia.

[0047] In some embodiments, the method treats cardiovascular disease in a subject or reduces the risk of cardiovascular disease.

[0048] In some embodiments, the method lowers cholesterol levels in subjects compared to those in control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0049] In some embodiments, the method reduces LDL-C levels in subjects compared to those of control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. In some embodiments, the method reduces C-reactive protein (hsCRP) levels in subjects compared to those of control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. In some embodiments, the reduction in C-reactive protein is up to 20% or 30% or more compared to baseline. In some embodiments, the method reduces the level of apolipoprotein B (ApoB) in subjects compared to those receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. In some embodiments, the method reduces the level of non-high-density lipoprotein cholesterol in subjects compared to those receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. In some embodiments, the method reduces the number of LDL particles in subjects compared to those receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0050] In some embodiments, the method 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.

[0051] In some embodiments, LDL-C is reduced to 24% or more of baseline in the subjects. In some embodiments, non-HDL-C is reduced to at least 30%, 35%, 37%, 40%, 42%, or 45% of baseline in the subjects. In some embodiments, hsCRP is reduced to at least 20%, 25%, 26%, 30%, 35%, 38%, or 40% of baseline in the subjects.

[0052] In some embodiments, non-HDL-C is reduced by at least 30, 35, 40, 43, 45, 48, or 50% or more compared to baseline in the subjects. In other embodiments, HDL-C is reduced in the subjects compared to baseline.

[0053] In some embodiments, statins and ETC-1002 are administered orally. In some embodiments, one or more statins and ETC-1002 are administered at least once a day. In some embodiments, one or more statins and ETC-1002 are administered at least once a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0054] In some embodiments, the subjects have dyslipidemia. In some embodiments, the subjects have hypercholesterolemia. In some embodiments, the subjects are obese, and participation is random, with a BMI of 18-45 kg / m². 2In some embodiments, the subjects are statin-resistant. In some embodiments, the subjects are statin-intolerant. In some embodiments, with one or more statins at the lowest doses approved by the FDA, the subjects experience adverse events selected from the group consisting of muscle-related pain, throbbing, muscle weakness, and cramps. The inventors have found that such muscle-related adverse events, which initiate and increase during statin therapy, may be significantly reduced or even resolved when treatment is used that adds ETC-1002 therapy to statin therapy.

[0055] In some embodiments, subjects have an LDL-C baseline level of 115–220 mg / dL. In some embodiments, subjects have a triglyceride baseline level of 400 mg / dL or less.

[0056] In some embodiments, one or more statins and ETC-1002 are administered simultaneously. In some embodiments, one or more statins and ETC-1002 are administered separately.

[0057] Also disclosed herein are methods for treating cardiovascular disease or reducing the risk of cardiovascular disease in subjects, comprising administering a fixed dose of ETC-1002 or an analogue thereof and a fixed dose combination of one or more statins or analogues to subjects in need thereof, optionally administering ETC-1002 at a fixed dose of 120 mg or 180 mg, and one or more statins at a fixed dose between 2 and 80 mg each, optionally lowering the level of low-density lipoprotein cholesterol (LDL-C) in the subject compared to that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins at a fixed dose between 2 and 80 mg each, optionally in subjects having hypercholesterolemia.

[0058] Also disclosed herein are pharmaceutical compositions comprising ETC-1002 and one or more statins, wherein, optionally, ETC-1002 is present in a fixed dose of 120 mg or 180 mg, and one or more statins are present in a fixed dose between 2 and 80 mg each.

[0059] In some embodiments, the composition further comprises a pharmaceutically acceptable vehicle. In some embodiments, ETC-1002 is present in a fixed dose of 120 mg or 180 mg, and one or more statins are present in a fixed dose between 2 and 80 mg each. In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is formulated for once-daily administration.

[0060] In some embodiments, the method reduces the level of apolipoprotein B (ApoB) in a subject compared to that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0061] In some embodiments, the method reduces the level of apolipoprotein A1 (ApoA1) in a subject compared to that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0062] In some embodiments, the method does not alter the ApoA1 levels in the subjects compared to those in control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0063] In some embodiments, the method reduces the ApoB to ApoA1 ratio in the subjects compared to those in the control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0064] In another embodiment, the method reduces the number of drug-related AEs by at least 25%, 35%, 45%, or 50%. In another embodiment, the method reduces the number of muscle-related AEs by at least 50%, 65%, 75%, or 85%.

[0065] In other embodiments, the methods disclosed herein significantly reduce the risk of cardiovascular events in subjects. In some embodiments, this risk is reduced by 35% or more.

[0066] In some embodiments, this specification provides for methods for treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, which are rapidly absorbed and take less than 4 hours to treat. max A method is provided which involves administering an amount of a composition containing ETC-1002 having the following properties.

[0067] In some embodiments, this specification provides a method for treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, comprising administering an amount of a composition containing ETC-1002 that does not prolong QTc or QT / QTc (TQT trial). In one embodiment, the add-on ETC-1002 therapy does not affect the subject's heart rate, PR, and QRS intervals.

[0068] In some embodiments, this specification provides for methods for treating and / or reducing the risk of cardiovascular disease in a subject, including systemic exposure and AUC. tau,ss However, t 1 / 2 A method is provided which involves administering an amount of a composition containing ETC-1002 that occurs over approximately 15 to 27 hours.

[0069] In some embodiments, this specification provides for methods for treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, wherein the two regimens demonstrate no apparent drug interaction between exposure measurements AUC and / or C. max A method is provided which includes administering an amount of a composition containing ETC-1002 as an add-on therapy to a statin therapy that provides [the necessary treatment]. In one embodiment, neither the exposure measurements of one or more statins nor the exposure measurements of ETC-1002 are outside the range of safety values ​​established by confidence intervals.

[0070] In one embodiment, the composition comprises one or more statins defined by fixed doses 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 another embodiment, the method comprises one or more statins defined by fixed doses 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 another embodiment, any combination 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) may be used in any embodiment disclosed herein.

[0071] In one embodiment, the composition comprises one or more statins as defined by the fixed dosages in Table 1 below.

[0072] [Table 1]

[0073] compound Combinations of one or more statins and ETC-1002 are described herein. In one aspect, one or more or all of the statins are natural products isolated from natural sources such as Penicillium and Aspergillus fungi. In another aspect, one or more or all of the statins are synthetic substances, meaning that they are made by converting petrochemical starting materials into the desired statin compounds via organic chemical synthesis.

[0074] The following formula I shows ETC-1002 and analogs of ETC-1002. Formula I:

[0075]

Chemical formula

[0076]

Chemical formula

[0077] Structure of ETC-1002:

[0078] [ka]

[0079] ETC-1002 is sometimes referred to as 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.

[0080] Statin compounds inhibit HMGR enzyme activity in the liver. Structurally, all statin compounds have a dihydroxyheptanoic acid group or its lactone and a substituted ring system (as shown below).

[0081] [ka]

[0082] However, statins differ in their substituted ring structure. Some statins have a substituted decalin ring structure, while others have substituted aryl and heteroaryl ring systems. The structures of representative statin compounds are shown below, but this list is not limited in any way.

[0083] [ka]

[0084] Any and all analogues of ETC-1002 according to Formula I may be used in any of the methods and / or compositions or formulations disclosed herein. Furthermore, any and all analogues of the statins described above may be used in any of the methods and / or compositions or formulations disclosed herein.

[0085] Synthesis of ETC-1002 and statins ETC-1002 and the method for synthesizing ETC-1002 are disclosed in U.S. Patent No. 7,335,799. 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.

[0086] The synthesis of statins is known in the art. In strategic and general disclosure, the synthesis of statins is disclosed in WO2005047276A2, which is incorporated herein by reference. Any other modification of the synthesis of statins (or, in this regard, modification of the synthesis of analogs of ETC-1002), which may include specific or alternative ring systems, are within the scope of the art. For example, a person skilled in the art can use the reference text on synthesis to incorporate specific or desired substituted aryl, heteroaryl, and decalin ring systems into the final statin compound. Such references include, but are not limited to, Fieser and Fieser's *Reagents for Organic Synthesis*, vols. 1–15 (John Wiley, and Sons, 1991), Rodd's *Chemistry of Carbon Compounds*, vols. 1–5, and *Supplementals* (Elsevier Science Publishers, 1989), *Organic Reactions*, vols. 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), and TW Greene and PGM Wuts' *Protecting Groups in Organic Synthesis*, 3rd edition, Wiley, New York, 1999.

[0087] How to use The present invention provides a method for treating or preventing cardiovascular disease, comprising administering to a subject a fixed dose of a compound or a composition comprising the compound of the present invention and a pharmaceutically acceptable vehicle. 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 invention are useful for prevention or treatment include, but are not limited to, arteriosclerosis, atherosclerosis, heart attack, ischemia, endothelial dysfunction, particularly dysfunction affecting vascular elasticity, peripheral vascular disease, coronary heart disease, myocardial infarction, cerebral infarction, and restenosis.

[0088] The present invention provides a method for treating or preventing dyslipidemia, comprising administering to a subject a fixed dose of a compound or a composition comprising the compound of the present invention and a pharmaceutically acceptable vehicle. As used herein, the term “dyslipidemia” refers to a disorder that leads to or is caused by abnormal blood levels of lipids. For a degree of excessively high blood lipid levels, the composition of the present invention is administered to the patient until normal levels are restored. Normal lipid levels are reported in medical papers known to those skilled in the art. For example, recommended blood levels of LDL, HDL, free triglycerides, and other parameters related to lipid metabolism can be found on the American Heart Association website and the National Cholesterol Education Program website of the National Heart, Lung and Blood Institute (http: / / www.americanheart.org / cholesterol- / about_level.html and http: / / www.nhlbi.nih.gov / health / public / heart / chol / hb-c_what.html, respectively). Currently, the recommended level for blood HDL cholesterol is above 35 mg / dL, the recommended level for blood LDL cholesterol is below 130 mg / dL, the recommended blood LDL:HDL cholesterol ratio is less than 5:1, ideally 3.5:1, and the recommended level for blood free triglycerides is less than 200 mg / dL.

[0089] Lipid abnormalities for which the compositions of the present invention are useful for prevention or treatment include, but are not limited to, hyperlipidemia and decreased blood levels of high-density lipoprotein (HDL) cholesterol. In certain embodiments, hyperlipidemia for prevention or treatment by the compounds of the present invention includes familial hypercholesterolemia, familial combined hyperlipidemia, decreased or deficient lipoprotein lipase levels or activity, including reduction or deficiency resulting from lipoprotein lipase mutations, hypertriglyceridemia, hypercholesterolemia, high blood levels of ureas (e.g., beta-OH butyrate), 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.

[0090] The present invention further provides a method for altering lipid metabolism in a patient, for example, reducing the patient's blood LDL, increasing the ratio of HDL to LDL in the patient's blood, and inhibiting saponified fatty acid synthesis and / or unsaponified fatty acid synthesis, the method comprising administering to the patient an amount effective in altering lipid metabolism of the compound of the present invention or a composition containing the compound of the present invention.

[0091] Pharmaceutical composition Methods for treating cardiovascular diseases are also included in the present invention. The aforementioned methods of the present invention involve administering one or more therapeutically effective doses of statins and ETC-1002. Fixed-dose combinations of one or more statins and ETC-1002 can be formulated in pharmaceutical compositions. These compositions include pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art. Such materials should be non-toxic and not interfere with the efficacy of the active ingredients. The exact properties of the carrier or other materials may vary depending on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal routes.

[0092] Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, pills, powders, or liquids. Tablets or pills may contain a solid carrier such as gelatin or an adjuvant. Generally, liquid pharmaceutical compositions contain a liquid carrier such as water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. They may also contain physiological saline, glucose or other sugar solutions, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol.

[0093] In one embodiment, the pharmaceutical composition of the present invention is prepared from one or more compounds disclosed herein and is in the form of a pill.

[0094] In another embodiment, disclosed herein are methods for reducing cholesterol or related markers disclosed herein (such as HDL-C, ApoA1), or for treating or preventing cardiovascular disease or abnormal lipoproteinemia and / or dyslipidemia, comprising administering to a subject a pharmaceutical composition in the form of pills containing a fixed dose of 120 mg or 180 mg of ETC-1002 and / or one or more statins in fixed doses of 2 to 80 mg each.

[0095] For intravenous, cutaneous, or subcutaneous injection, or injection into the affected area, the active ingredient is present in the form of a pyrogen-free, parenterally acceptable aqueous solution with appropriate pH, isotonicity, and stability. Those skilled in the art can adequately prepare a suitable solution using an isotonic vehicle such as, for example, saline injection, Ringer's solution, or lactated Ringer's solution. If necessary, preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included.

[0096] When the substance administered to an individual is a small molecule or another pharmaceutically useful compound according to the present invention, the administration is preferably a "therapeutic effective dose" or a "preventive effective dose" (although prevention can currently be considered therapy), which is sufficient to provide 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 disorder being treated. The prescription of the treatment, such as the determination of the dosage, is the responsibility of the general practitioner and other physicians, and typically takes into account the disorder being treated, the individual patient's condition, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the techniques and protocols described above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.), 1980.

[0097] The compositions can be administered simultaneously or consecutively, alone or in combination with other treatments, depending on the condition being treated.

[0098] In one embodiment, the present disclosure provides a method for treating and / or reducing the risk of cardiovascular disease in a subject, comprising administering a fixed dose of ETC-1002 or an analogue thereof and a fixed dose combination of one or more statins or analogues to a subject in need thereof, optionally administering ETC-1002 at a fixed dose of 120 mg or 180 mg, and administering one or more statins at fixed doses between 2 and 80 mg each, optionally providing a method for treating or reducing the risk of cardiovascular disease in a subject.

[0099] In one embodiment, the disclosure provides a method for lower levels of total cholesterol and non-HDL-C in a subject than in a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0100] In one embodiment, the disclosure provides a method for lowering the level of low-density lipoprotein (LDL) in a subject compared to that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0101] In one embodiment, the present disclosure provides a method for which the number of LDL particles in a subject is lower than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0102] In one embodiment, the disclosure provides a method in which the level of apolipoprotein B (ApoB) in a subject is less than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0103] In one embodiment, the disclosure provides a method in which the level of apolipoprotein A-1 (ApoA1) in a subject is less than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0104] In one embodiment, the present disclosure provides a method for which the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in a subject is lower than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each.

[0105] In one embodiment, the present disclosure provides a method for treating hypercholesterolemia in a subject.

[0106] In one aspect, the disclosure provides a method in which the subject is a human being.

[0107] In one embodiment, the present disclosure provides a therapeutic composition comprising a fixed therapeutic dose of ETC-1002 and one or more statins, each in a fixed dose.

[0108] In one embodiment, the present disclosure provides a composition in which the amount is a fixed dose of 120 or 180 mg for ETC-1002 and 2 to 80 mg for each of one or more statins.

[0109] [Examples] The following are examples of specific embodiments for carrying out the present invention. These examples are given for illustrative purposes only and are not intended to limit the scope of the invention in any sense. While efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantity, temperature, etc.), some experimental errors and deviations should naturally be accepted.

[0110] The implementation of this invention will employ conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and physiology within the scope of the art, unless otherwise specified. Such techniques are well described in the literature. See, for example, T.E. Creighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); AL 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); and Carey and Sundberg, Advanced Organic Chemistry, 3rd edition (Plenum Press), Volumes A and B (1992).

[0111] Any term not directly defined herein is understood to have the meaning commonly associated with that understood within the scope of the art of the present invention. Certain terms are described herein to provide additional guidance to practitioners, describing compositions, devices, methods, etc., of embodiments of the present invention, and methods of making or using them. It should be understood that the same thing may be described in multiple ways. In conclusion, alternative languages ​​and synonyms may be used for any one or more terms described herein. It should not be emphasized whether a term is detailed or described herein. Several synonyms or substitute methods, materials, etc. are provided. Details of one or more synonyms or equivalents do not preclude the use of other synonyms or equivalents unless expressly stated otherwise. The use of examples, including examples of terms, is for illustrative purposes only and is not intended to limit the scope and meaning of embodiments of the present invention.

[0112] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple subjects unless otherwise explicitly specified in the context.

[0113] [Example 1] 1. List of Abbreviations and Definitions The following abbreviations and technical terms are used in this test protocol.

[0114] [Table 2] TIFF0007862336000008.tif237160TIFF0007862336000009.tif237160TIFF0007862336000010.tif208160

[0115] ETC-1002 background Mechanism of action ETC-1002 is a small molecule inhibitor of adenosine triphosphate (ATP) citrateriase (ACL), an enzyme upstream of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (a molecular target of statins) in the cholesterol biosynthesis pathway. ETC-1002 mediates competitive inhibition of ACL. Inhibition of ACL reduces cholesterol synthesis in the liver and increases LDLR expression and clearance of LDL particles from the blood. Therefore, inhibition of ACL by ETC-1002 is via the same pathway as HMG-CoA reductase inhibition by statins.

[0116] A key distinguishing feature of ETC-1002 is that, unlike statins, it does not inhibit cholesterol synthesis in skeletal muscle. Therefore, ETC-1002 is not expected to cause adverse events associated with the inhibition of the cholesterol biosynthesis pathway in skeletal muscle.

[0117] Non-clinical trials The primary pharmacological effects of ETC-1002 were evaluated in predictive models of well-characterized dyslipidemia rodents. In these studies, ETC-1002 lowered LDL-C and triglycerides (TG) and increased high-density lipoprotein cholesterol (HDL-C).

[0118] The results of the safety pharmacology studies did not identify any significant risks to patients within the scope of exposure intended for clinical trials.

[0119] In toxicity studies, ETC-1002 was evaluated in mice, rats, and monkeys in oral studies with a duration of up to 12 months. No significant central nervous system, respiratory, or cardiac susceptibility was identified. The target organs identified in repeated-dose studies were the liver and kidneys in rats and monkeys, and the changes were reversible after discontinuation of treatment. Changes in clinical laboratory parameters indicating liver and kidney function were observed in animals at doses lower than those associated with apparent toxicity. Routine clinical laboratory parameters will continue to be carefully monitored in clinical trials.

[0120] In genotoxicology assays using in vitro and in vivo therapies, ETC-1002 is non-mutagenic and does not induce chromosomal aberrations.

[0121] In a key 6-month rat study, the no-observed-adverse-effect level (NOAEL) was 30 mg / kg / day in male and female rats, corresponding to the area under the curve (AUC) of ETC-1002 and ESP15228 combined over 24 hours. 0~24 The maximum value was 528 μg·hr / mL. In a key 12-month monkey study, the NOAEL dose was 60 mg / kg / day, and the total corresponding AUC of ETC-1002 and ESP15228 was... 0~24 The maximum value was 4478 μg·hr / mL.

[0122] In vitro studies have shown that ETC-1002 is neither an inhibitor nor an inducer of major cytochrome P450 (CYP) enzymes at clinically relevant plasma concentrations. Furthermore, ETC-1002 does not appear to inhibit major drug transporters.

[0123] Previous human experiments The entire clinical program for ETC-1002 (conducted between 2009 and 2015) included approximately 1,000 subjects and patients, with approximately 700 receiving ETC-1002 at doses ranging from 2.5 to 240 mg / day (multiple doses) for up to 12 weeks. There are 15 completed clinical trials (9 Phase 1 trials and 6 Phase 2 trials), and the summary of overall data is based on the 6 completed Phase 2 trials.

[0124] A pooled analysis of six phase 2 trials showed that the placebo-adjusted mean LDL-C percentage change from baseline was approximately 32% with ETC-1002 180 mg monotherapy, 50% with ETC-1002 180 mg + ezetimibe 10 mg, and 22% with stable statin therapy at 180 mg. The reduction in LDL-C with ETC-1002 treatment was consistently accompanied by corresponding reductions in non-HDL-C, TC, LDL particle count, and apoB. Notably, a pattern of decreasing hsCRP throughout the trials was also observed, with a median change ranging from 20% to 40% from baseline. The effects of ETC-1002 on HDL-C and TG were generally neutral.

[0125] PK data shows that ETC-1002 was rapidly absorbed, T max This indicates that it occurs in less than 4 hours for ETC-1002 and less than 7 hours for ESP15228. C max It increases proportionally with increasing dose. However, systemic exposure and AUC tau,ss Up to 120 mg per day, and from 140-220 mg per day, the increase in dose is linear, but the increase is slightly greater than the dose-proportional increase. 1 / 2The exposure period is approximately 15-27 hours. The metabolite, ESP15228, achieves systemic exposure in 20-40% of patients, with higher percentages observed at lower doses, and the average exposure time is 15-27 hours. 1 / 2 This is slightly longer than that of the patient, with values ​​ranging from 20 to 33 hours.

[0126] Drug interactions were not demonstrated with ETC-1002 in combination with metformin or Ortho-Novum 1 / 35, or with concomitant oral contraceptives. Food efficacy / bioequivalence studies demonstrated that ETC-1002 can be taken independently of food. Similar PK results were obtained for capsule and tablet formulations.

[0127] The efficacy of ETC-1002 in relation to atorvastatin pharmacokinetics was evaluated in trials 1002-1007. In these trials, all patients received 10 mg / day of atorvastatin for a 28-day induction period (statin stabilization), followed by an 8-week treatment period during which patients received 10 mg / day of atorvastatin and a daily dose of ETC-1002. All patients started with a dose of 60 mg / day of ETC-1002, which was increased every two weeks to 120 mg / day, then 180 mg / day, and then up to 240 mg / day. To determine the drug interaction between ETC-1002 and atorvastatin, the PK parameters of atorvastatin and ortho-hydroxyatorvastatin on day 1 (final, baseline during the statin stabilization period) were compared to the corresponding PK parameters at week 4 (when the ETC-1002 dose reached 120 mg / day, Study 1) and week 8 (when the ETC-1002 dose reached 240 mg / day, Study 2). For atorvastatin and ortho-hydroxyatorvastatin, the ratio of exposure measurements (AUC and / or C) was determined. max The 90% confidence interval (CI) for the two regimens is between 80% and 125%, suggesting that the two regimens are comparable to those without drug interactions.

[0128] Drug interaction evaluations showed that a daily regimen of 10 mg atorvastatin and 120 mg ETC-1002 resulted in approximately 60% higher exposure to atorvastatin and ortho-hydroxyatorvastatin compared to a daily dose of 10 mg atorvastatin alone. Higher doses of ETC-1002 (240 mg) administered with atorvastatin also resulted in higher exposure to atorvastatin and ortho-hydroxyatorvastatin compared to atorvastatin alone. The increases in 120 and 240 mg doses were observed for AUC and C12 for atorvastatin and its metabolites. max The same applies to the increase in atorvastatin. This study showed a transient increase in atorvastatin (1.4×~2.0×) exposure when administered in combination with ETC-1002. Importantly, ETC-1002 combined with atorvastatin 10 mg is safe, well-tolerated, and lowers LDL-C more effectively than atorvastatin alone.

[0129] The steady-state efficacy of ETC-1002 on single-dose pharmacokinetics (PK) of simvastatin, pravastatin, and rosuvastatin was evaluated in study 1002-012. In this study, healthy subjects were assigned to one of three cohorts and received a single oral dose of either simvastatin 20 mg (cohort 1), pravastatin 40 mg (cohort 2), or rosuvastatin 10 mg (cohort 3) on the morning of day 5. PK blood samples were collected continuously from the morning of day 3. Starting from day 1, all subjects received 240 mg of oral ETC-1002 once daily for 16 days. On the morning of day 12, in addition to ETC-1002, subjects received a single dose of a statin drug based on their cohort assignment, and continuous PK blood samples were collected.

[0130] The results of this study showed that the plasma concentrations and PK parameters of ETC-1002 and its metabolite ESP15228 after 12 doses of ETC-1002 at a daily dose of 240 mg in combination with a single dose of simvastatin 20 mg, pravastatin 40 mg, or rosuvastatin 10 mg were consistent with those of previous monotherapy studies and multi-dose studies of ETC-1002 in combination with atorvastatin.

[0131] Simvastatin and simvastatin exposure (AUC 0-inf Compared to simvastatin alone, the C of simvastatin increased by 29% and 91%, respectively, in the presence of steady-state ETC-1002. max It appears that co-administration with ETC-1002 does not affect simvastatin C max The interaction was increased by 43% compared to simvastatin alone compared to simvastatin combined with ETC-1002 daily. The geometric mean ratio of the measured AUC of the test (ETC-1002 and simvastatin) to the baseline (simvastatin alone) for the active metabolite simvastatin was consistent with an increase of less than twofold, indicating that the magnitude of the interaction was lower than that of the prodrug parent compound (simvastatin).

[0132] Pravastatin exposure (AUC inf and C max The AUCs increased by 99% and approximately 2 times, respectively, in the presence of steady-state ETC-1002 compared to pravastatin alone. The geometric mean ratio of the measured AUCs of the study (ETC-1002 and pravastatin) to the baseline (pravastatin alone) was consistent with an increase of less than approximately 2 times.

[0133] Rosuvastatin exposure (AUC inf and C maxThe AUCs increased by 69% and 208% respectively in the presence of steady-state ETC-1002 compared to rosuvastatin alone. The geometric mean ratio of the observed AUCs in the trial (ETC-1002 and rosuvastatin) to the baseline (rosuvastatin alone) was consistent with an increase of less than twofold. As in trial 1002-007, the combination of ETC-1002 and statin therapy was safe and well-tolerated.

[0134] Results from the comprehensive QT / QTc (TQT) trial (1002-022) showed no significant change in QTc. After administering ETC-1002 at a dose of 240 mg daily for 9 days, ETC-1002 did not prolong the QT interval and had no clinically significant effect on heart rate, PR, or QRS interval.

[0135] In a comprehensive review of the incidence of TEAEs (Tetraumatic Epileptic Examinations) in any treatment group across six integrated phase 2 trials, no dose-related trends in the frequency of TEAEs were observed in the ETC-1002 treatment groups. The highest number of patients experiencing at least one TEAE within the ETC-1002 treatment groups occurred in the ETC-1002 40 mg dose group (75.6%), a frequency similar to that of patients experiencing at least one TEAE in the placebo group (74.2%).

[0136] In the ETC-1002 treatment group, the organ-specific major categories (SOCs) with the highest percentage of patients experiencing at least one TEAE were infectious and parasitic diseases, musculoskeletal and connective tissue disorders, and gastrointestinal disorders.

[0137] In the SOC for infectious diseases and parasitic infections, the percentage of patients experiencing at least one TEAE was highest in the ETC-1002 80 mg group (25.0%). Treatment groups including ETC-1002 had a TEAE frequency ranging from 11.6% to 25% in this SOC, compared to 23.2% in the ezetimibe 10 mg group, 14.8% in the baseline statin group, and 11.8% in the placebo group. The most frequent TEAEs (occurring in 3 or more patients in any treatment group) based on the basic terms of this SOC were bronchitis, nasopharyngitis, sinusitis, upper respiratory tract infection (URTI), and urinary tract infection (UTI). All TEAEs based on the basic terms of infectious diseases and parasitic infections in this SOC occurred in 8% or less of patients in any treatment group.

[0138] In the musculoskeletal and connective tissue disorder (SOC), the percentage of patients experiencing at least one TEAE in almost all ETC-1002 treatment groups was less than or equal to the placebo group (23.7%), except in the ETC-1002 240 mg group (32.4%). The most frequent TEAEs (i.e., occurring in 3 or more patients in any treatment group) in this SOC were arthralgia, back pain, muscle spasms, muscle weakness, myalgia, and limb pain. There was no dose-related trend in the frequency of myalgia in the ETC-1002 treatment groups. The most frequent reports of myalgia were in the ETC-1002 120 mg + ezetimibe group (7.7%) and the ezetimibe 10 mg group (6.1%). There were no reports of rhabdomyolysis. Almost all TEAEs, defined by the basic terminology of SOC for musculoskeletal and connective tissue disorders, occurred in less than 8% of patients in any treatment group, with the exception of arthralgia (9.7% in the placebo group), back pain (8.1% in the ezetimibe 10 mg group), and muscle spasms (13.5% in the ETC-1002 240 mg group).

[0139] A total of 11 SAEs were reported across six integrated phase 2 trials: five (5 / 579, 0.9%) in patients receiving ETC-1002, one (1 / 99, 1%) in patients receiving ezetimibe 10 mg, two (2 / 61, 3.3%) in patients receiving placebo plus baseline statins, and three (3 / 93, 3.2%) in patients receiving placebo alone. Only one SAE reported an event. No muscle-related SAEs were observed.

[0140] One patient died of unknown cause. A 55-year-old Caucasian male with hyperlipidemia and statin intolerance in the ETC-1002 120 mg treatment group (Study 1002-008) died suddenly on day 98 of the study. He was found outside the pool unresponsive and without a pulse. The death certificate did not specify a cause of death. The principal investigator considered the possibility of a link between the sudden death event (of unknown cause) and the study drug, as a temporal relationship could not be ruled out.

[0141] Other general safety measures, including laboratory results, did not show any clinically significant trends associated with ETC-1002 compared to placebo or other comparator drugs.

[0142] Dosage selection ETC-1002 doses ranging from 40 to 240 mg / day were evaluated in a Phase 2 trial. Based on data from a pooled safety and efficacy analysis, the primary efficacy endpoint—measured and percentage changes in LDL-C with a positive safety profile—supported the selection of the 180 mg dose for the Phase 3 trial. A pooled analysis of six Phase 2 trials yielded placebo-adjusted least squares mean (LSM) percentage changes from baseline of approximately 32% for ETC-1002 180 mg monotherapy, 50% for ETC-1002 180 mg + ezetimibe 10 mg, and 22% for stable statin therapy at 180 mg. Note that the 180 mg dose had a superior safety profile. Overall, the 180 mg dose was selected for clinical development due to its balance of efficacy and safety.

[0143] Basic therapy In this trial, ETC-1002 is currently being evaluated as an add-on to high-dose statin (atorvastatin 80 mg) therapy.

[0144] Risk-Benefit Overview To date, nonclinical and clinical data have shown that ETC-1002 has a favorable risk-benefit profile. ETC-1002's ability to achieve a clinically significant LDL-C reduction response while demonstrating a favorable tolerability profile across various patient populations supports the continued development of ETC-1002, an oral ACL inhibitor.

[0145] [Example 2] ETC-1002 / Fixed-dose combination of high-dose statins This study evaluates the LDL-C reduction efficacy of ETC-1002 180 mg compared to placebo in statin-treated patients who received stable atorvastatin 80 mg as basal therapy for 28 days.

[0146] We will evaluate the plasma pharmacokinetics (PK) of high-dose atorvastatin 80 mg and its active metabolites, ortho-hydroxyatorvastatin and para-hydroxyatorvastatin, both alone and in combination with steady-state ETC-1002 180 mg.

[0147] The inventors expect this add-on therapy to be at least as effective as the previous trials and to produce the same or better safety profile / tolerance.

[0148] Without being bound by theory, the inventors believe that a 180 mg tablet of ETC-1002, administered in addition to a stable high-dose statin (atorvastatin 80 mg), provides further efficacy and safety in lowering LDL-C compared to atorvastatin alone, and is tolerable in adult patients treated with statins. In combination, ETC-1002 exhibits 1.4 to 2.0 times the AUC and C of the statin compared to the statin and / or its metabolites, regardless of the structure, physicochemical properties, or dose given. max This will likely show an increase.

[0149] Patients will be randomized in a double-blind, 2:1 ratio to receive either an ETC-1002 180 mg tablet or a suitable placebo tablet as an add-on to statin therapy.

[0150] Patients receive ETC-1002 as an add-on to high-intensity statin therapy, as shown in Table 3.

[0151] [Table 3]

[0152] Patients taking simvastatin 80 mg must have no evidence of myotoxicity and must have a history of developing tolerance to simvastatin 80 mg for at least the last 12 months.

[0153] Administration The patient takes either an active tablet or a placebo tablet orally once a day.

[0154] The patient should record the time and date of each dose taken, whether or not they were fasting, and the time of meals in a diary.

[0155] Pharmacokinetic evaluation Collect whole blood samples to measure the plasma concentrations of statins and their active metabolites, as well as ETC-1002 and its active metabolites.

[0156] Samples are collected and analyzed for basic fasting lipids, including calculated values ​​of LDL-C, TC, HDL-C, non-HDL-C, TG, apoB, apoA1, and hsCRP.

[0157] [Table 4]

[0158] Evaluation of safety parameters Safety information includes vital signs, adverse events (AEs), concomitant medications, and ECG reports.

[0159] Vital signs Vital signs include systolic and laxary blood pressure and heart rate.

[0160] electro-cardiogram Electrocardiograms are collected at the designated sampling points and evaluated using machine reading.

[0161] Adverse events An adverse event (AE) is any undesirable medical event that occurs when a patient is administered a drug, including a control drug, and is not necessarily causally related to the treatment.

[0162] An adverse event (AE) may be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease, any new disease or worsening of an existing disease, any decrease in laboratory values ​​or any measurement of other clinical tests (e.g., ECG or X-ray) that produce symptoms, a change in treatment, or discontinuation of the study drug, whether or not it is considered to be related to the drug.

[0163] TEAE is defined as an adverse event that begins or worsens after the first dose of IMP.

[0164] Harmful drug reaction All adverse unintended reactions to a drug in connection with any administration are considered adverse drug reactions (ADRs). A “reaction” to a drug means that there is at least a reasonable possibility (i.e., the relationship cannot be ruled out) that there is a causal relationship between the drug and the adverse event (AE).

[0165] An unexpected ADR is defined as an adverse reaction, and its nature or severity is inconsistent with the applicable product information (e.g., the IB for an unapproved clinical trial product or the product characteristics document or summary for an approved product).

[0166] The severity of adverse events (AEs) is characterized as mild, moderate, or severe according to the following definitions.

[0167] Mild: The event is usually temporary and does not interfere with the patient's daily activities.

[0168] Moderate: May cause a low level of inconvenience or concern to the patient and may interfere with daily activities.

[0169] Severe: The event disrupts the patient's normal daily activities, renders them unable to perform normal activities, and significantly impacts their clinical condition and the appropriate intervention and / or detailed follow-up studies.

[0170] Note: Severe AEs do not need to be severe, and SAEs do not need to be severe according to the definition.

[0171] Definition of serious adverse events A SAE is defined as any AE that occurs at any dose resulting in any of the following outcomes:

[0172] Causes death

[0173] life-threatening

[0174] The patient requires hospitalization or extension of the current hospitalization.

[0175] Persistent or serious disability / incapacity, or substantial breakdown of the ability to perform normal daily living activities.

[0176] It is a congenital anomaly / congenital defect.

[0177] Important medical events

[0178] A serious medical event (SAE) may be considered a non-fatal, life-threatening, or hospitalization-related medical event that, based on appropriate medical judgment, puts the patient at risk and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive care in the emergency room, blood disorders, non-hospitalization-related seizures in hospitalized patients, or the onset of drug dependence or abuse.

[0179] Determination of sample size For the LDL-C reduction trial, the sample size of 40 patients in the atorvastatin 80 mg / day + ETC 1002 treatment group and 20 patients in the atorvastatin 80 mg / day + placebo group (60 patients in total) is expected to yield an 80% ability to detect a 15% difference in the percentage change in LDL C from baseline to day 29 between atorvastatin 80 mg / day + ETC 1002 and atorvastatin 80 mg / day + placebo. This calculation is based on a two-sided t-test with a significance level of 5%, a normal standard deviation of 18%, and a dropout rate of 10%. Sample size calculations were performed using nQuery Advisor®, version 7.0 (Statistical Solutions).

[0180] For the objectives of the PK drug interaction study, the sample size of 36 patients in the treatment group of atorvastatin 80 mg / day + ETC 1002 (assuming data from 4 patients are not included) is expected to yield 79% or greater capability for each parameter / analyte, given that the predicted value of the test / reference ratio of exposure measurements is 100% (no difference between atorvastatin alone and atorvastatin + ETC 1002) and the acceptance criteria are 80% to 125% for a 90% confidence interval (CI). Therefore, the 36 patients planned for 1002 035 will participate to adequately characterize the effect of ETC 1002 on PK in relation to atorvastatin.

[0181] A Protocol-Adapted Analysis Set (PPAS) is defined as a set of patients in a FAS that further includes all pre-administration PK samples > BLQ (atorvastatin PK sample > BLQ for placebo patients, and pre-administration atorvastatin and pre-administration ETC samples > BLQ for ETC 1002 patients) and has lipid assessments at day 29. The PPAS is used to select sensitivity analyses for lipid parameters.

[0182] Pharmacokinetic analysis An overview of lipids (LDL-C, TC, HDL-C, non-HDL-C, TG, apoB, apoA1, and hsCRP) over time is provided. For each parameter, the overview includes the value and the percentage change from baseline (relative to a point in time after baseline).

[0183] The percentage change from baseline is calculated for LDL-C and other parameters.

[0184] Analysis of pharmacokinetics and drug interactions The pharmacokinetic parameters for atorvastatin, ortho-hydroxyatorvastatin, para-hydroxyatorvastatin, ETC 1002, and ESP15228 after multiple administrations are derived from the following plasma concentration-time profiles.

[0185] Cmax: maximum plasma concentration

[0186] tmax: The time relative to Cmax measured at the first occurrence within the profile.

[0187] AUClast: Area under the plasma concentration-time profile curve from time 0 to the last quantifiable concentration (Clast) time, calculated using a linear / logarithmic trapezoidal method.

[0188] AUC24: Area under the plasma concentration-time profile curve from time 0 to 24 hours, calculated using the linear / logarithmic trapezoidal method.

[0189] CL / F: Apparent oral clearance calculated from dose / AUC24 for atorvastatin and ETC 1002 only.

[0190] Cmin: Minimum plasma concentration measured prior to drug administration.

[0191] Cavg: Mean plasma concentration calculated from AUC24 (Amount divided by dosing interval and 24 hours).

[0192] C24: Concentration in a sample taken 24 hours after administration or before the next administration.

[0193] Standard non-compartmental PK analysis is used to calculate Cmax, tmax, AUClast, AUC24, Cmin, Cavg, and C24. Pharmacokinetic parameters are summarized using descriptive statistics based on the sampling date and the administration of ETC 1002 using the PK parameter population. Different PK parameter populations may be used for each analyte.

[0194] Drug interaction evaluation from PK analytes

[0195] Safety evaluation Safety assessments include AEs, clinical safety laboratory tests, PEs, vital signs, and ECGs.

[0196] While the present invention has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the art that various modifications in form and detail can be made without departing from the spirit and scope of the invention.

[0197] All references, published patents, and patent applications cited in the main body of this Specified Specification are incorporated in their entirety by reference for all purposes. (Note) (Note 1) A method for treating cardiovascular disease in a subject or reducing the risk of cardiovascular disease, comprising administering a fixed dose of ETC-1002 or its analogue and a fixed dose combination of one or more statins or their analogues to a subject in need thereof, wherein, optionally, ETC-1002 is administered at a fixed dose of 120 mg or 180 mg, and one or more statins are administered at fixed doses between 2 and 80 mg each, and optionally, the method is used to treat cardiovascular disease in a subject or reduce the risk of cardiovascular disease. (Note 2) The method according to Appendix 1, wherein the levels of total cholesterol and non-HDL-C in the subjects are lower than those in the control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. (Note 3) The method according to Appendix 1, wherein the level of low-density lipoprotein (LDL) in the subjects is lower than that of the control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. (Note 4) The method according to Appendix 1, wherein the number of LDL particles in the subjects is lower than that of the control subjects receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. (Note 5) The method according to Appendix 1, wherein the apolipoprotein B (ApoB) level in the subject is less than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. (Note 6) The method according to Appendix 1, wherein the level of apolipoprotein A-1 (ApoA1) in the subject is less than that of a control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. (Note 7) The method according to Appendix 1, wherein the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the subject is lower than that of the control subject receiving placebo, a fixed dose of 120 mg of ETC-1002, a fixed dose of 180 mg of ETC-1002, or one or more statins in fixed doses of 2 to 80 mg each. (Note 8) The method according to Appendix 1, wherein one or more statins are selected from the group consisting of rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, fluvastatin, and pitavastatin. (Note 9) The method described in Appendix 1, for subjects with hypercholesterolemia. (Note 10) The method described in Appendix 1, wherein the subject is an animal. (Note 11) The method described in Appendix 1, wherein the subject is a human. (Note 12) A therapeutic composition comprising a fixed therapeutic dose of ETC-1002 and one or more statins, each in a fixed dose. (Note 13) The composition described in Appendix 12, wherein the dose is between 2 and 80 mg of one type of statin. (Note 14) The composition as described in Appendix 12, wherein the quantity is a fixed dose of 120 or 180 mg for ETC-1002 and 2 to 80 mg for each of one or more statins. (Note 15) The composition described in Appendix 12, wherein the dose is between 40 and 80 mg of one type of statin. (Note 16) The composition according to Appendix 12, wherein one or more statins are selected from the group consisting of rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, fluvastatin, and pitavastatin.

Claims

1. A pharmaceutical composition comprising bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin, The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A pharmaceutical composition containing atorvastatin in an amount of 40 to 80 mg.

2. A pharmaceutical composition for use in the treatment of cardiovascular disease or reduction of the risk of cardiovascular disease in subjects requiring treatment of cardiovascular disease or reduction of the risk of cardiovascular disease, wherein the pharmaceutical composition comprises bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin. The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A pharmaceutical composition containing atorvastatin in an amount of 40 to 80 mg.

3. A pharmaceutical composition for use in the treatment of hypercholesterolemia in subjects requiring treatment for hypercholesterolemia, wherein the pharmaceutical composition comprises bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin. The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A pharmaceutical composition containing atorvastatin in an amount of 40 to 80 mg.

4. A pharmaceutical composition for use in lowering LDL-C in subjects requiring a reduction in LDL-C, wherein the pharmaceutical composition comprises bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin. The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A pharmaceutical composition containing atorvastatin in an amount of 40 to 80 mg.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the pharmaceutical composition lowers the levels of total cholesterol and non-HDL-C in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

6. The pharmaceutical composition according to any one of claims 2 to 5, wherein the pharmaceutical composition lowers the level of low-density lipoprotein (LDL) in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

7. The pharmaceutical composition according to any one of claims 2 to 6, wherein the pharmaceutical composition reduces the number of LDL particles in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

8. A pharmaceutical composition according to any one of claims 2 to 7, wherein the pharmaceutical composition reduces the level of apolipoprotein B (ApoB) in a subject to a level lower than that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

9. A pharmaceutical composition according to any one of claims 2 to 8, wherein the pharmaceutical composition reduces the level of apolipoprotein A-1 (ApoA1) in a subject to a level lower than that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

10. The pharmaceutical composition according to any one of claims 2 to 9, wherein the pharmaceutical composition reduces the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the amount of bempedoic acid is 120 mg.

12. A pharmaceutical composition according to any one of claims 1 to 10, wherein the amount of bempedoic acid is 180 mg.

13. The pharmaceutical composition according to claim 11, wherein one or more statins are rosuvastatin, and the amount of rosuvastatin is 20 to 40 mg.

14. The pharmaceutical composition according to claim 11, wherein one or more statins are atorvastatin, and the amount of atorvastatin is 40 to 80 mg.

15. The pharmaceutical composition according to claim 12, wherein one or more statins are rosuvastatin, and the amount of rosuvastatin is 20 to 40 mg.

16. The pharmaceutical composition according to claim 12, wherein one or more statins are atorvastatin, and the amount of atorvastatin is 40 to 80 mg.

17. A pharmaceutical composition according to any one of claims 1 to 16, wherein the subject has familial hypercholesterolemia.

18. A pharmaceutical composition according to any one of claims 1 to 17, wherein the subject has atherosclerotic cardiovascular disease.

19. The use of bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin in the manufacture of pharmaceuticals for the treatment of cardiovascular disease or the reduction of the risk of cardiovascular disease in subjects requiring treatment of cardiovascular disease or reduction of the risk of cardiovascular disease, The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. Atorvastatin is used in doses of 40-80 mg.

20. The use of bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin in the manufacture of pharmaceuticals for the treatment of hypercholesterolemia in subjects requiring treatment of hypercholesterolemia, The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. Atorvastatin is used in doses of 40-80 mg.

21. The use of bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin in the manufacture of pharmaceuticals for lowering LDL-C in subjects requiring a reduction in LDL-C, The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. Atorvastatin is used in doses of 40-80 mg.

22. The use according to any one of claims 19 to 21, wherein the pharmaceutical is formulated to lower the levels of total cholesterol and non-HDL-C in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

23. The use according to any one of claims 19 to 22, wherein the pharmaceutical is formulated to lower the level of low-density lipoprotein (LDL) in a subject to a level lower than that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

24. The use according to any one of claims 19 to 23, wherein the pharmaceutical is formulated to lower the number of LDL particles in a subject than in a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

25. The use according to any one of claims 19 to 24, wherein the pharmaceutical is formulated to reduce the level of apolipoprotein B (ApoB) in a subject to a level lower than that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

26. The use according to any one of claims 19 to 25, wherein the pharmaceutical is formulated to reduce the level of apolipoprotein A-1 (ApoA1) in a subject to a level lower than that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

27. The use according to any one of claims 19 to 26, wherein the pharmaceutical is formulated to lower the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in a subject than that in a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

28. The use according to any one of claims 19 to 27, wherein the amount of bempedoic acid is 120 mg.

29. The use according to any one of claims 19 to 27, wherein the amount of bempedoic acid is 180 mg.

30. The use according to claim 28, wherein one or more statins are rosuvastatin, and the amount of rosuvastatin is 20 to 40 mg.

31. The use according to claim 28, wherein one or more statins are atorvastatin, and the amount of atorvastatin is 40 to 80 mg.

32. The use according to claim 29, wherein one or more statins are rosuvastatin, and the amount of rosuvastatin is 20 to 40 mg.

33. The use according to claim 29, wherein one or more statins are atorvastatin, and the amount of atorvastatin is 40 to 80 mg.

34. The use according to any one of claims 19 to 33, wherein the subject has familial hypercholesterolemia.

35. The use according to any one of claims 19 to 34, wherein the subject has atherosclerotic cardiovascular disease.

36. A combination for use in the treatment of cardiovascular disease or reduction of the risk of cardiovascular disease in subjects requiring treatment of cardiovascular disease or reduction of the risk of cardiovascular disease, wherein the combination comprises bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin. The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A combination of atorvastatin containing 40-80 mg.

37. A combination for use in the treatment of hypercholesterolemia in subjects requiring treatment for hypercholesterolemia, wherein the combination comprises bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin. The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A combination of atorvastatin containing 40-80 mg.

38. A combination for use in lowering LDL-C in subjects requiring a reduction in LDL-C, wherein the combination comprises bempedoic acid and one or more statins selected from rosuvastatin and atorvastatin. The amount of bempedoic acid is 120 mg or 180 mg. The dosage of rosuvastatin is 20-40 mg. A combination of atorvastatin containing 40-80 mg.

39. The combination according to any one of claims 36 to 38, wherein the combination lowers the levels of total cholesterol and non-HDL-C in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

40. The combination according to any one of claims 36 to 39, wherein the combination reduces the level of low-density lipoprotein (LDL) in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

41. The combination according to any one of claims 36 to 40, wherein the combination reduces the number of LDL particles in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

42. A combination according to any one of claims 36 to 41, wherein the combination reduces the level of apolipoprotein B (ApoB) in a subject to a level below that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

43. The combination according to any one of claims 36 to 42, wherein the combination reduces the level of apolipoprotein A-1 (ApoA1) in a subject to a level below that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

44. The combination according to any one of claims 36 to 43, wherein the combination reduces the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in a subject compared to that of a control subject receiving placebo, 120 mg or 180 mg of bempedoic acid, or one or more statins.

45. The combination according to any one of claims 36 to 44, wherein the amount of bempedoic acid is 120 mg.

46. The combination according to any one of claims 36 to 44, wherein the amount of bempedoic acid is 180 mg.

47. The combination according to claim 45, wherein one or more statins are rosuvastatin, and the amount of rosuvastatin is 20 to 40 mg.

48. The combination according to claim 45, wherein one or more statins are atorvastatin, and the amount of atorvastatin is 40 to 80 mg.

49. The combination according to claim 46, wherein one or more statins are rosuvastatin, and the amount of rosuvastatin is 20 to 40 mg.

50. The combination according to claim 46, wherein one or more statins are atorvastatin, and the amount of atorvastatin is 40 to 80 mg.

51. The combination according to any one of claims 36 to 50, wherein the subject has familial hypercholesterolemia.

52. A combination according to any one of claims 36 to 51, wherein the subject has atherosclerotic cardiovascular disease.

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