Methods for reducing risk of diabetes in patients being treated for high cholesterol-related illnesses

Abstract

To provide methods useful for treating diabetes or reducing the risk of diabetic conditions.SOLUTION: The present invention provides methods for decreasing the likelihood of new-onset diabetes in a subject or decreasing the likelihood of worsening existing diabetes in a subject, comprising administering a fixed-dose of ETC-1002 or an analog thereof, a fixed-dose of ezetimibe or an analog thereof, and a fixed-dose of statin, to the subject.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 722,766, filed August 24, 2018, and U.S. Provisional Application No. 62 / 751,404, filed October 26, 2018, the contents of each of which are incorporated herein by reference. [Background technology]

[0002] FIELD OF THEINVENTION This application relates to methods and compositions useful for treating diabetes or reducing the risk of a diabetic condition. Low-density lipoprotein cholesterol (LDL-C) is a well-established indicator of cardiovascular disease and a risk factor for diabetes. Similarly, hemoglobin A1c (HbA 1C ) levels are well-known biomarkers for diabetes and new onset diabetes. A common and basic treatment for managing LDL-C levels for patients who have diabetes, are at risk of developing new onset diabetes, or are at risk for cardiovascular disease is the administration of statins. However, many patients, such as those with hypercholesterolemia, fail to reduce LDL-C to the desired level with conventional statin therapy. New pharmaceuticals have been developed and are effective in reducing cholesterol levels in the human body. Unfortunately, these drugs also induce negative side effects. Many of the compounds that have been shown to be effective in inhibiting enzymes of cholesterol biosynthesis are also systemically toxic. Thus, there is a need for new pharmaceutical formulations that are effective and safe in reducing cholesterol, improving hemoglobin A1c levels, and reducing the risk of developing cardiovascular disease and diabetic conditions. Summary of the Invention

[0003] This application relates to compositions comprising fixed doses of any one of ETC-1002, ezetimibe and a statin, and methods of treating diabetes or reducing the risk of diabetes comprising administration of ETC-1002, or ETC-1002 and ezetimibe, with or without statin treatment.

[0004] ETC-1002 (bempedoic acid) is a typically oral, typically once-daily, treatment that lowers cholesterol by inhibiting adenosine triphosphate (ATP) citrate lyase (ATPCL), which is further upstream in the cholesterol biosynthetic pathway than HMG-CoA reductase.

[0005] ETC-1002 lowers low-density lipoprotein cholesterol (LDL-C) by directly inhibiting hepatic adenosine triphosphate citrate lyase, reducing de novo synthesis of cholesterol and increasing LDL receptor expression. ETC-1002, administered at doses of about 120 mg to about 240 mg daily, reduced LDL-C by about 27% to about 43% in Phase 2a clinical trials in various hypercholesterolemic populations, including patients with type 2 diabetes mellitus and patients with muscle-associated statin intolerance.

[0006] The general class of "statins" are compounds that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and concomitantly, lower the body's cholesterol levels by inhibiting the pathway for synthesizing cholesterol in the liver. Examples of compounds that are part of the "statin" class include, but are not limited to, atorvastatin, simvastatin, rosuvastatin, and pravastatin. Treatment typically involves administering about 2 mg to 80 mg of a statin compound.

[0007] The present inventors have found that the inhibition of HMG-CoA reductase leads to increased LDL receptor activity.Furthermore, the present inventors have found that the combination of these two therapies leads to synergistic activity and favorable clinical treatment.Therefore, the present invention is directed to cholesterol-lowering compositions comprising statins and ETC-1002.These compositions lead to further reduction of total cholesterol, specifically LDL-C, in patients.

[0008] The present application also discloses a method for lowering cholesterol using a fixed-dose combination of ETC-1002 and one or more statins. Based on observations in ongoing studies, combination therapy with ETC-1002 and a fixed high dose of one or more statins has comparable efficacy and safety to combination therapy with ETC-1002 in combination with a fixed low to medium dose of one or more statins. Furthermore, combination therapy with ETC-1002 and a fixed high dose of one or more statins is also significantly superior to statin or ETC-1002 monotherapy (about 120 mg or about 180 mg daily) in patients with or without a history of statin-associated muscle symptoms. The combination therapy also shows a significantly superior efficacy and safety profile in patients with acute hypercholesterolemia.

[0009] In one aspect, the methods and compositions described herein lower cholesterol in patients with persistently elevated LDL-C despite high-dosage statin therapy.

[0010] Chronic use of statin therapy in patients with diabetes mellitus increases HbA 1C It is well known in the art that such an increase in HbA 1C Increased levels often result in a worsening of the pre-existing diabetic condition as well as an increased likelihood of developing new-onset diabetes in patients receiving high-dose statin therapy.

[0011] Thus, the present application also provides methods for evaluating HbA in patients with diabetes or at risk of developing new-onset diabetes. 1C A method for improving the level is disclosed.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS These and other features, aspects, and advantages of the present invention will become better understood in view of the following description and accompanying drawings. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows the current understanding of the mechanism of action of bempedoic acid. [Diagram 2] FIG. 2 shows the change in HbA1C levels observed in patients treated with bempedoic acid or placebo at 12 and 52 weeks when the patients had a history of diabetes and were receiving the maximum tolerated dose of a statin (50% high intensity). [Diagram 3] FIG. 3 shows the change in fasting glucose levels over time for the same patients described in FIG. [Figure 4] FIG. 4 shows the change in HbA1C levels observed in patients treated with bempedoic acid or placebo at 12 and 24 weeks when the patients had a history of diabetes, were statin intolerant, and were being treated with a low dose of statin (8% is a very low dose statin). [Diagram 5] FIG. 5 shows the change in fasting glucose levels over time for the same patients described in FIG. [Figure 6] FIG. 6 shows the change in HbA1C levels observed in statin intolerant patients treated with bempedoic acid or placebo for 12 weeks, when the patients were receiving background levels of ezetimibe, had a history of diabetes, and 31% of the patients were receiving low or very low doses of statins. [Figure 7] FIG. 7 shows the change in fasting glucose levels over time for the same patients described in FIG. [Figure 8]FIG. 8 shows fasting glucose levels in patients with a history of diabetes when they were receiving MTD high-intensity statin (38.6%) or no statin (28%) and when they were treated for 12 weeks with (1) bempedoic acid + ezetimibe (top line; N=48); (2) bempedoic acid alone (middle line; N=57); (3) ezetimibe alone (bottom line; N=57); or (4) placebo (middle line; N=24). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description Benefits and Usefulness Briefly, as described in more detail below, compositions for treating or reducing the risk of diabetes using ETC-1002, ezetimibe, and any one of statins, or a combination of ETC-1002, ezetimibe, and any one of statins, methods for making said compositions, and methods for treating or reducing the risk of diabetes are described herein.The advantages to this approach are numerous, including but not limited to, increased reduction in cholesterol and low-density lipoprotein levels in patients treated with a fixed dose combination of ETC-1002, ezetimibe, and any one or more statins, compared to levels observed when the patient is treated with ETC-1002 or ezetimibe or statins alone.Statins are the cornerstone of cardiovascular disease prevention and treatment, but can cause undesirable side effects in many patients.Such side effects include but are not limited to increased levels of liver enzymes, muscle problems, increased risk of diabetes, and worsening of existing diabetes. Statin-associated muscle symptoms are also an important clinical problem because discontinuing statins in hypercholesterolemic patients increases cardiovascular risk. Thus, there is a significant need for statin therapy for patients who demonstrate muscle-related statin intolerance.

[0015] definition Terms used in the claims and specification are defined as set forth below, unless otherwise specified.

[0016] The terms used in the claims and specification are defined as set forth below, unless otherwise specified. Furthermore, any term or symbol used herein, unless defined as set forth below, is intended to have its ordinary meaning in the art.

[0017] As used herein and in the appended claims, in the context of describing elements (particularly in the context of the claims below), singular articles such as "a," "an," and "the" and similar references should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. References to ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each value within the range, including the upper and lower limits of the range, unless otherwise indicated herein, and each value is incorporated herein as if it were individually set forth herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better describe the embodiments and does not pose a limitation on the scope of the claims, unless otherwise stated. No language in this specification should be construed as indicating any non-claimed element as required.

[0018] In general, a reference to a particular element, such as hydrogen or H, is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, tritium, C 14 , P 32 and S 35Compounds that contain radioisotopes such as are within the scope of the present technology. Procedures for incorporating such labels into the compounds of the present technology will be readily apparent to one of skill in the art based on the disclosure herein.

[0019] The term "amelioration" refers to any therapeutically beneficial outcome in the treatment of a disease state, e.g., an inflammatory disease state, including attenuation of the severity or progression of, remission from, or cure of, the disease state. In some embodiments, "amelioration" includes prevention of the disease state.

[0020] The term "diabetes" refers to diabetes mellitus, including type I diabetes, type 2 diabetes, and the pre-diabetic condition.

[0021] The term "cardiovascular disease" refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemia and / or dyslipidemia. Cardiovascular diseases that the compositions of the present invention are useful for preventing or treating include, but are not limited to, arteriosclerosis; atherosclerosis; stroke; ischemia; endothelial dysfunction, especially dysfunction that affects the elasticity of blood vessels; peripheral vascular disease; coronary heart disease; myocardial infarction; cerebral infarction and restenosis.

[0022] The term "dyslipidemia" refers to disorders that result in or manifest themselves with abnormal levels of circulating lipids. When blood lipid levels are too high, the compositions of the present invention are administered to patients to restore normal levels. Normal levels of lipids are reported in medical literature 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. Currently, the recommended blood HDL cholesterol level is greater than 35 mg / dL; the recommended blood LDL cholesterol level is less than 130 mg / dL; the recommended blood LDL:HDL cholesterol ratio is less than 5:1, ideally 3.5:1; and the recommended blood free triglyceride level is less than 200 mg / dL.

[0023] The term "metabolic syndrome" refers to a group of conditions that occur together and increase the risk of heart disease, stroke and diabetes - elevated blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. These conditions are the co-occurrence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia and hypertension.

[0024] The term "non-alcoholic fatty liver disease (NAFLD)" refers to a condition in which excess fat accumulates in the liver. This fat accumulation is not caused by heavy alcohol intake. Non-alcoholic fatty liver disease (NAFLD) is characterized or diagnosed by the presence of fat in the liver (hepatic steatosis) on either imaging or liver histology after elimination of secondary causes of fat accumulation in the liver (e.g., heavy alcohol consumption, certain medications, and other medical conditions). NAFLD is further classified histologically into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).

[0025] The term "simple fatty liver or nonalcoholic fatty liver (NAFL)" refers to a form of NAFLD in which there is fat in the liver but little or no inflammation or hepatocellular injury. NAFL is characterized by hepatic steatosis without evidence of hepatocellular injury in the form of hepatocellular ballooning.

[0026] The term "nonalcoholic steatohepatitis (NASH)" refers to a form of NAFLD that has hepatitis (inflammation of the liver) and hepatocellular injury in addition to fat in the liver. Inflammation and hepatocellular injury can lead to liver fibrosis or scarring. NASH is characterized by the presence of hepatic steatosis and inflammation accompanied by hepatocellular injury (ballooning), with or without fibrosis.

[0027] The term "statin intolerance" refers to the occurrence of adverse symptoms (e.g., muscle-related symptoms) that are perceived as unacceptable by the patient and / or laboratory abnormalities suggesting undue risk (e.g., serum liver enzyme activity) resulting from statin therapy and leading to its cessation.

[0028] The term "subject" refers to any mammal, including humans, and therefore includes mammals such as animals of veterinary and research importance, including, but not limited to, monkeys, cows, horses, dogs, cats, and rodents. The term "subject" is interchangeable with the term "patient."

[0029] The term "mammal", as used herein, includes both human and non-human mammals, such as non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0030] The term "administering" a drug and / or therapy to a subject or the term "administration" (and grammatical equivalents of this phrase) refers to both direct administration or indirect administration, which may be administration to a subject by a medical professional, self-administration, and / or indirect administration, and which may be the act of prescribing or inducing a subject to prescribe a drug and / or therapy.

[0031] The term "treating" a disorder or disease or "treatment" thereof refers to taking measures to alleviate symptoms of the disorder or disease or otherwise obtain some beneficial or desired result in a subject, including clinical results. Any beneficial or desired clinical result includes, but is not limited to, reduction or amelioration of one or more symptoms of cancer or conditional survival, as well as reduction in tumor burden or tumor volume; reduction in the extent of disease; slowing or halting tumor or disease progression; remission, palliation, or stabilization of the tumor and / or disease state; or other beneficial result.

[0032] The term "in vitro" refers to processes that occur in living cells grown isolated from an organism, for example, in tissue culture.

[0033] The term "in vivo" refers to a process that takes place within an organism.

[0034] The term "mammal", as used herein, includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0035] The term "sufficient amount" means an amount sufficient to produce a desired effect, for example an amount sufficient to modulate protein aggregation in a cell.

[0036] The term "therapeutically effective amount" is an amount effective to ameliorate symptoms of a disease. Since prevention can be considered a therapy, a therapeutically effective amount can, in some embodiments, be a "prophylactically effective amount."

[0037] The compounds of the present technology can exist as solvates, particularly hydrates. Hydrates may form during the preparation of the compounds or compositions containing the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. The compounds of the present technology can also exist as organic solvates, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of one of ordinary skill in the art of synthetic organic or medicinal chemistry.

[0038] "Subject" refers to a mammalian organism that is treated using the compounds of the invention. A "subject" may be a human or non-human mammalian organism.

[0039] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups that contain ring atoms that are bonded to both the ring NH and ring =N moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0040] "Treating" a disease or disorder in a subject or "treatment" thereof refers to 1) preventing the disease or disorder from occurring in a subject who is susceptible to or who does not yet exhibit symptoms of the disease or disorder; 2) inhibiting or arresting the development of the disease or disorder; or 3) ameliorating or reducing the cause of the regression of the disease or disorder.

[0041] As used herein, the terms "prevent," "preventing," "prevention," "prophylactic treatment," and the like 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 who is at risk or susceptible to developing the disease, disorder, or condition. Thus, in some embodiments, an agent can be administered prophylactically to prevent the onset of a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition.

[0042] For purposes of this specification and the appended claims, the term "about," when referring to a value, can mean encompassing variations from the particular amount 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%, as variations are appropriate for practicing the methods or using the compositions of the present disclosure.

[0043] In all of the above defined substituents, it is understood that polymers arrived at by defining the substituents to have further substituents thereon (e.g., substituted aryls having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended to be included herein. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is bounded by the limitations that each functional group is substituted (at 1-3 positions) and that any and all of these substituents may be substituted only once more (at 1-3 positions).

[0044] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with three fluoro groups) as such impermissible substitution patterns are well known to those of skill in the art.

[0045] Throughout this application, the text refers to various embodiments of the compounds, compositions, and methods of the present invention. The various embodiments described are meant to provide various examples and should not be interpreted as descriptions of alternative species. Rather, it should be noted that the descriptions of the various embodiments provided herein may be of overlapping scope. The embodiments described herein are merely.

[0046] List of abbreviations and definitions The following abbreviations and terminology are used in this study protocol:

[0047] [Table 1] TIFF2024081650000003.tif238156TIFF2024081650000004.tif238156TIFF2024081650000005.tif198156

[0048] Therapy Disclosed herein is a method comprising administering to a subject in need thereof a fixed-dose combination of any one of a fixed-dose of ETC-1002 or an analog thereof, a fixed-dose of ezetimibe or an analog thereof, and a fixed-dose of one or more statins or analogs thereof, optionally wherein ETC-1002 is administered at a fixed dose of about 180 mg or a fixed dose of about 120 mg, ezetimibe is administered at a fixed dose of about 10 mg, and each of the one or more statins is administered at a fixed dose of about 2 to about 80 mg.

[0049] In some embodiments, the methods reduce the level of low density lipoprotein cholesterol (LDL-C) in the subject below that of a control subject receiving a placebo.

[0050] In some embodiments, the method includes administering a fixed dose of about 120 mg of ETC-1002, a fixed dose of about 180 mg of ETC-1002, a fixed dose of about 10 mg of ezetimibe, or a combination of any one of one or more statins at fixed doses of about 2 to about 80 mg each, and optionally, the method treats diabetes or reduces the risk of diabetes in the subject.

[0051] In some embodiments, ETC-1002 is administered at a fixed dose of about 120 mg or a fixed dose of about 180 mg, ezetimibe is administered at a fixed dose of about 10 mg, and the statin is administered at a fixed dose of 5-80 mg.

[0052] In some aspects, the subject has hypercholesterolemia and the method further comprises treating the hypercholesterolemia.

[0053] In some aspects, the methods treat cardiovascular disease or reduce the risk of cardiovascular disease in a subject.

[0054] In some aspects, the methods treat or reduce diabetes in a subject.

[0055] In some aspects, the methods treat incipient diabetes or reduce the likelihood of developing incipient diabetes in a subject.

[0056] In some embodiments, the method comprises measuring HbA in patients undergoing chronic statin therapy. 1C Reduce the level.

[0057] In some embodiments, the method comprises measuring HbA in a patient with an existing diabetic condition. 1C Reduce the level.

[0058] In some embodiments, the method comprises measuring HbA in a patient with type 2 diabetes. 1C Reduce the level.

[0059] In some aspects, the methods reduce the level of cholesterol in the subject below that of a control subject receiving a placebo.

[0060] In some embodiments, the method reduces the level of C-reactive protein (hsCRP) in the subject below that of a control subject receiving a placebo.

[0061] In some embodiments, the method reduces the level of apolipoprotein B (ApoB) in the subject below that of a control subject receiving a placebo.

[0062] In some aspects, the methods reduce the level of non-high density lipoprotein cholesterol in the subject below that of a control subject receiving a placebo.

[0063] In some aspects, the methods reduce triglyceride levels in the subject below that of a control subject receiving a placebo.

[0064] In some embodiments, the method reduces the number of LDL particles in the subject below that of a control subject receiving a placebo.

[0065] In some aspects, LDL-C levels are reduced in a subject by at least 30, 35, 40, 43, 45, 48, or 50% relative to baseline.

[0066] In some aspects, non-HDL-C levels are reduced in a subject by at least 30, 35, 37, 40, 42, or 45% relative to baseline.

[0067] In some aspects, hsCRP levels are reduced in a subject by at least 20, 25, 26, 30, 35, 38, or 40% relative to baseline.

[0068] In some aspects, the methods improve glycemic control in a subject.

[0069] In some aspects, the ETC-1002, ezetimibe, and statin are each administered orally.

[0070] In some aspects, the ETC-1002, ezetimibe, and statin are each administered at least once daily.

[0071] In some embodiments, the ETC-1002, ezetimibe, and statin are each administered at least once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0072] In some aspects, the subject has dyslipidemia.

[0073] In some aspects, the subject has hypercholesterolemia.

[0074] In some embodiments, the subject is obese, and optionally, the subject has a BMI of 18-45 kg / m 2 It is.

[0075] In some aspects, the subject is statin resistant.

[0076] In some aspects, the subject is statin intolerant.

[0077] In some aspects, the subject is unable to tolerate at least two statins, including one statin at the lowest FDA approved dose, due to muscle-related symptoms such as pain, aching, weakness or cramps that were initiated or increased during statin therapy and resolved when statin therapy was discontinued.

[0078] In some embodiments, the subject has a baseline LDL-C level of between 130 and 220 mg / dL.

[0079] In some embodiments, the subject has a baseline triglyceride level of less than or equal to 400 mg / dL.

[0080] In some aspects, the ETC-1002, ezetimibe, and statin are administered simultaneously.

[0081] In some aspects, the ETC-1002, ezetimibe, and the statin are administered separately.

[0082] Also disclosed herein is a pharmaceutical composition comprising ETC-1002, ezetimibe, and a statin, optionally wherein ETC-1002 is present at a fixed dose of 120 mg or 180 mg, ezetimibe is present at a fixed dose of 10 mg, and the statin is present at a fixed dose of 5 to 80 mg.

[0083] In some aspects, the composition further comprises a pharma- ceutically acceptable vehicle.

[0084] In some aspects, the composition is formulated for oral delivery.

[0085] In some embodiments, the composition is formulated for once-daily administration.

[0086] In some embodiments, ETC-1002 is administered in an amount of 5-500 mg. In other embodiments, ETC-1002 is administered in an amount of 10-450 mg. In other embodiments, ETC-1002 is administered in an amount of 15-400 mg. In other embodiments, ETC-1002 is administered in an amount of 20-350 mg. In other embodiments, ETC-1002 is administered in an amount of 25-325 mg. In other embodiments, ETC-1002 is administered in an amount of 30-300 mg. In other embodiments, ETC-1002 is administered in an amount of 35-275 mg. In other embodiments, ETC-1002 is administered in an amount of 40-250 mg. In other embodiments, ETC-1002 is administered in an amount of 45-225 mg. In other embodiments, ETC-1002 is administered in an amount of 50-200 mg.

[0087] In some aspects, the disclosure provides for administration of ETC-1002 at dosages of 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, or 250 mg / day.

[0088] In some aspects, the disclosure provides for administration of ETC-1002, wherein the dosage is 45-55 mg / day, 55-65 mg / day, 65-75 mg / day, 75-85 mg / day, 85-95 mg / day, 95-105 mg / day, 105-115 mg / day, 115-125 mg / day, 125-135 mg / day, 135-145 mg / day, 145-155 mg / day, 155-165 mg / day, 165-175 mg / day, 175-185 mg / day, 185-195 mg / day, 195-205 mg / day, 205-215 mg / day, 215-225 mg / day, 225-235 mg / day, 235-245 mg / day, or 245-255 mg / day.

[0089] In some embodiments, ezetimibe is administered in an amount of 1-50 mg; in another embodiment, ezetimibe is administered in an amount of 5-25 mg; in another embodiment, ezetimibe is administered in an amount of 5-15 mg; in another embodiment, ezetimibe is administered in an amount of 1-10 mg; in another embodiment, ezetimibe is administered in an amount of 10-20 mg; in another embodiment, ezetimibe is administered in an amount of 8-12 mg; in another embodiment, ezetimibe is administered in a dose of 10 mg. Dosages are typically administered once daily. In some embodiments, dosages may be administered 2, 3, 4, 5 or more times per day.

[0090] In some aspects, the subject has hypercholesterolemia and the method further comprises treating the hypercholesterolemia.

[0091] In some aspects, the methods treat cardiovascular disease or reduce the risk of cardiovascular disease in a subject.

[0092] In some embodiments, the method reduces cholesterol levels in the subject below that of a control subject receiving a placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, or a fixed dose of one or more statins at doses of about 2 to about 80 mg, each.

[0093] In some aspects, the methods dose-dependently reduce apolipoprotein B by about 10% to about 17% or more, non-high density lipoprotein cholesterol by about 10% to about 17% or more, total cholesterol by about 10% to about 15% or more, and LDL particle number by about 10% to about 21% or more.

[0094] In some embodiments, LDL-C is reduced in a subject by up to about 24% or more relative to baseline. In some embodiments, non-HDL-C is reduced in a subject by at least about 30, about 35, about 37, about 40, about 42, or about 45% or more relative to baseline. In some embodiments, hsCRP is reduced in a subject by at least about 20, about 25, about 26, about 30, about 35, about 38, or about 40% or more relative to baseline.

[0095] In some embodiments, non-HDL-C is reduced in a subject by at least about 30, about 35, about 40, about 43, about 45, about 48, or about 50% or more relative to baseline. In other embodiments, HDL-C is reduced in a subject relative to baseline.

[0096] In some embodiments, HbA 1CThe levels are reduced in a subject by at least about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%, or 0.6%, or 0.7%, or 0.8%, or 0.9%, or 1.0%, or 1.5%, or 1.7%, or 1.9%, or 2.0%, or 2.5%, or 3.0%, or 3.5%, or 4.0% compared to a subject not receiving the therapy or receiving a placebo.

[0097] In some aspects, the likelihood of incipient diabetes is reduced in a subject by about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 40%, or about 50%, or about 60%, compared to a subject not receiving the therapy or receiving a placebo.

[0098] In some aspects, the ETC-1002, ezetimibe, and statin are each administered orally.

[0099] In some embodiments, the ETC-1002, ezetimibe, and one or more statins are each administered at least once daily.

[0100] In some embodiments, the ETC-1002, ezetimibe, and one or more statins are each administered at least once daily for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks. In some related embodiments, administration of one or more of the ETC-1002, ezetimibe, and the at least one statin occurs at least less than once daily, for example, every other day or once a week.

[0101] In some embodiments, a subject experiences an adverse event while receiving the lowest FDA-approved dose of one or more statins, the adverse event being selected from the group consisting of muscle-related pain, tingling, weakness, and cramps. The inventors have observed that such muscle-related adverse events that begin or increase during statin therapy can be significantly reduced or even eliminated when treatment with add-on ETC-1002 therapy to statin therapy is used.

[0102] In some embodiments, the subject has a baseline LDL-C level of about 115-220 mg / dL.

[0103] In some embodiments, the subject has a baseline triglyceride level of about 400 mg / dL or less.

[0104] In some aspects, administering a combination of bempedoic acid and ezetimibe to patients with both type 2 diabetes and hypercholesterolemia resulted in one or more of the following: a reduction in LDL-C levels of up to 40 percent compared to placebo; a reduction in levels of high sensitivity C-reactive protein (hsCRP) (an important marker of inflammation associated with cardiovascular disease) of up to 25 percent (p<0.001); a mean difference in hemoglobin A1c (HbA1c) of 0.03 percent compared to placebo; no change in overall adverse events (AEs) similar to placebo; no increase in muscle-related AEs, serious adverse events, discontinuations due to AEs, or elevations in liver function tests (LFTs); a reduction in LDL-C levels to <70 mg / dl; a reduction in LDL-C levels of >50 percent.

[0105] Also disclosed herein is a method of treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject, the method comprising administering to a subject in need thereof a fixed dose combination of a fixed dose of ETC-1002 or an analog thereof, a fixed dose of ezetimibe or an analog thereof, and a fixed dose of one or more statins or analogs thereof, optionally wherein ETC-1002 is administered at a fixed dose of about 120 mg or a fixed dose of about 180 mg, ezetimibe is administered at a fixed dose of about 10 mg, and the one or more statins are each administered at a fixed dose of about 2 to about 80 mg, and optionally wherein the method reduces the level of low-density lipoprotein cholesterol (LDL-C) in the subject below that of a control subject receiving a placebo.

[0106] In some aspects, the method reduces the level of apolipoprotein B (ApoB) in the subject relative to that of a control subject receiving a placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or a fixed dose of one or more statins at doses of about 2 to about 80 mg, each.

[0107] In some aspects, the method reduces the level of apolipoprotein A1 (ApoA1) in the subject relative to that of a control subject receiving a placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or a fixed dose of one or more statins at doses of about 2 to about 80 mg, each.

[0108] In some embodiments, the method does not alter the level of ApoA1 in the subject compared to that of a control subject receiving a placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or a fixed dose of one or more statins at doses of about 2 to about 80 mg each.

[0109] In some embodiments, the method reduces the ratio of ApoB to ApoA1 in the subject relative to that of a control subject receiving a placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or a fixed dose of one or more statins at doses of about 2 to about 80 mg, each.

[0110] In some aspects, the methods reduce the number of drug-related AEs by at least about 25%, about 35%, about 45%, or about 50% or more.

[0111] In some aspects, the methods reduce the number of muscle-related AEs by at least about 50%, about 65%, about 75%, or about 85% or more.

[0112] In some aspects, the methods disclosed herein significantly reduce the risk of a cardiovascular event in a subject, hi some aspects, the risk is reduced by up to about 35% or more.

[0113] In some aspects, provided herein are methods of treating and / or reducing the risk of cardiovascular disease in a subject, comprising administering to a subject a composition comprising a medicament for use in treating cardiovascular disease that is rapidly absorbed and has a T of less than about 4 hours. max Methods are provided that include administering an amount of a composition comprising ETC-1002 having the formula:

[0114] In some aspects, provided herein are methods of treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, comprising administering an amount of a composition comprising ETC-1002 that does not prolong QTc or QT / QTc (TQT study). In one aspect, add-on ETC-1002 therapy does not affect the subject's heart rate and PR and QRS intervals.

[0115] In some aspects, provided herein are methods of treating and / or reducing the risk of cardiovascular disease in a subject, comprising measuring systemic exposure, AUC tau,ss But, t 1 / 2 Methods are provided that include administering an amount of a composition comprising ETC-1002 that occurs over approximately about 15 to about 27 hours.

[0116] In some aspects, provided herein are methods of treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, comprising administering to a subject a dose-dependent increase in the exposure measures AUC and / or C that indicate that the two regimens have no apparent drug interactions. max The method includes administering an amount of a composition comprising ETC-1002 as an add-on therapy to a statin therapy to provide a therapeutic effect. In one embodiment, neither the exposure measurements of the one or more statins nor the exposure measurements of ETC-1002 are outside of a range of safety values ​​established by confidence intervals.

[0117] In one embodiment, the compositions include one or more statins defined by fixed dosage amounts 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 methods include one or more statins defined by fixed dosage amounts 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 yet another aspect, 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 or aspect disclosed herein.

[0118] In one embodiment, the composition comprises one or more statins defined by the fixed dosage amounts in Table 2 below:

[0119] [Table 2]

[0120] compound Combinations of one or more statins and ETC-1002 are described herein. In one embodiment, one or more or all of the statins are natural products isolated from natural sources, such as Penicillium and Aspergillus fungi. In another embodiment, one or more or all of the statins are synthetic, meaning that they are produced by processing petrochemical starting materials into the desired statin compound via organic chemical synthesis.

[0121] Formula I below shows ETC-1002 and analogs of ETC-1002. Formula I:

[0122] [ka] (a) each occurrence of m is independently an integer ranging from 0 to 5; (b) each occurrence of n is independently an integer ranging from 3 to 7; (c) X is (CH 2 ), or Ph, z is an integer from 0 to 4, and Ph is a 1,2-, 1,3-, or 1,4-substituted phenyl group; (d) R 1 , R 2 , R 11 , and R 12 Each occurrence of is independently 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, phenyl, or benzyl; R 1 , R 2 , R 11 , and R 12 are not H at the same time; and (e) Y 1 and Y 2 Each occurrence of is independently 1 ~C 6 ) Alkyl, OH, COOH, COOR 3 , S.O. 3 H,

[0123] [ka] TIFF2024081650000009.tif185147, (i) Y 1 and Y 2 are simultaneously (C 1 ~C 6 ) not alkyl; (ii) R 3 is (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, phenyl, or benzyl, which is unsubstituted or substituted with one or more halo, OH, (C 1 ~C 6) is substituted with an alkoxy or phenyl group; and (iii) R 4 Each occurrence of is independently 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, or (C 2 ~C 6 ) alkynyl, unsubstituted or substituted with 1 or 2 halo, OH, C 1 ~C 6 alkoxy, or phenyl; and (iv) R 5 Each occurrence of is independently 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, or (C 2 ~C 6 ) alkynyl.

[0124] ETC-1002 Structure:

[0125] [ka]

[0126] ETC-1002 can be referred to as 8-hydroxy-2,2,14,14 tetramethylpentadecanedioic acid.

[0127] Statin compounds inhibit HMGR enzyme activity in the liver. In terms of structure, all statin compounds have a dihydroxyheptanoic acid group or its lactone and substituted ring system (shown below).

[0128] [ka]

[0129] However, statins differ with respect to substituted ring structures. Some statins have a substituted decalin ring structure, while others have substituted aryl and heteroaryl ring systems. Structures of representative statin compounds are shown below, although this list is by no means limiting.

[0130] [ka]

[0131] It is recognized that any and all analogs 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 statins according to the above description can be used in any of the methods and / or compositions or formulations disclosed herein. The following formula (II) shows ezetimibe and analogs of ezetimibe:

[0132] [ka]

[0133] In the above formula (II) or a salt thereof, Ar 1 and Ar 2 are independently aryl and R 4 substituted aryl; Ar 3 is aryl or R 5 substituted aryl; X, Y and Z are independently -CH 2 -, -CH(lower alkyl)-, and -C(di-lower alkyl)-; R and R 2 are independently -OR 6 , -O(CO)R 6 , -O(CO)OR 9 and -O(CO)NR 6 R 7 R 1 and R 3are 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; with the proviso 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; and with the proviso that when p is 0 and r is 1, then 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(CH 2 ) 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 SO 2 R 9 , -COOR 6 , -CONR 6 R 7 , -COR 6 , -SO 2 NR 6 R 7 , S(O) 0-2 R 9 , -O(CH 2 ) 1-10 -COOR 6 , -O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6 , -CH=CH-COOR 6 , -CF 3 , -CN, -NO 2 and 1 to 5 substituents independently selected from the group consisting of halogen; R 5 -OR 6 , -O(CO)R 6, -O(CO)OR 9 , -O(CH 2 ) 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 SO 2 R 9 , -COOR 6 , -CONR 6 R 7 , -COR 6 , -SO 2 NR 6 R 7 , S(O) 0-2 R 9 , -O(CH 2 ) 1-10 -COOR 6 , -O(CH 2 ) 1-10 CONR 6 R 7 , -(lower alkylene)COOR 6 and -CH=CH-COOR 6 R 6 , R 7 and R 8 is 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.

[0134] Ezetimibe can be 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.

[0135] The structure of ezetimibe is:

[0136] [ka]

[0137] It is recognized that any and all analogs 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 ETC-1002 according to Formula II can be used in any of the methods and / or compositions or formulations disclosed herein.

[0138] Synthesis of ETC-1002, Ezetimibe and Statins ETC-1002 and methods of synthesis of ETC-1002 are disclosed in issued U.S. Patent No. 7,335,799. Details of this method can be found in published U.S. Patent Application Publication No. 2005-0043278 A1 at paragraphs

[0247] to

[0343] , each of which is incorporated herein by reference.

[0139] Ezetimibe and methods for the synthesis of ezetimibe are disclosed in issued U.S. Patent No. 5,631,365, details of which can be found therein, starting at page 4, right column, line 43, to page 11, right column, line 65, each of which is incorporated herein by reference.

[0140] The synthesis of statins is known in the art. In a strategic and general disclosure, the synthesis of statins is disclosed in WO2005047276A2, which is incorporated herein by reference. Any other synthetic modifications to statins (or, for that matter, to analogs of ETC-1002) that may include unique or alternative ring systems are within the scope of one skilled in the art. For example, one skilled in the art can use reference texts on synthesis to incorporate unique 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, 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), TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999.

[0141] 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 a compound of the present invention and a pharma- ceutically acceptable vehicle.As used herein, the term "cardiovascular disease" refers to diseases of the heart and circulatory system.These diseases are often associated with dyslipoproteinemia and / or dyslipidemia.Cardiovascular diseases that the compositions of the present invention are useful for preventing or treating include, but are not limited to, arteriosclerosis; atherosclerosis; stroke; ischemia; endothelial dysfunction, particularly dysfunction affecting the elasticity of blood vessels; peripheral vascular disease; coronary heart disease; myocardial infarction; cerebral infarction and restenosis.

[0142] 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 a compound of the present invention and a pharma- ceutically acceptable vehicle. As used herein, the term "dyslipidemia" refers to a disorder that results in or manifests as abnormal levels of circulating lipids. When blood lipid levels are too high, the composition of the present invention is administered to the patient to restore normal levels. Normal levels of lipids are reported in medical literature 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, recommended levels of HDL cholesterol in the blood are greater than about 35 mg / dL; recommended levels of LDL cholesterol in the blood are less than about 130 mg / dL; the recommended LDL:HDL cholesterol ratio in the blood is less than about 5:1, ideally about 3.5:1; and recommended levels of free triglycerides in the blood are less than about 200 mg / dL.

[0143] Dyslipidemia that the compositions of the present invention are useful for preventing or treating includes, but is not limited to, hyperlipidemia and low blood levels of high density lipoprotein (HDL) cholesterol.In certain embodiments, the hyperlipidemia that the compounds of the present invention are used to prevent or treat are familial hypercholesterolemia; familial combined hyperlipidemia; reduced or deficient lipoprotein lipase level or activity, including reduced or deficient lipoprotein lipase mutations; hypertriglyceridemia; hypercholesterolemia; high blood levels of urea bodies (e.g., beta-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.

[0144] The present invention provides a method for altering lipid metabolism in a patient, for example reducing LDL in the patient's blood, increasing the ratio of HDL to LDL in the patient's blood, and inhibiting saponified fatty acid synthesis and / or non-saponified fatty acid synthesis, comprising administering to the patient a compound of the present invention or a composition comprising a compound of the present invention in an amount effective to alter lipid metabolism.

[0145] The present invention provides a method for determining whether HbA 1C A method for reducing the level of

[0146] The present invention relates to a method for determining whether HbA 1C A method for reducing the level of

[0147] The present invention relates to a method for measuring HbA 1C Further provided is a method for reducing

[0148] In some embodiments, HbA 1CThe levels are reduced in a subject by at least about 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%, or 0.6%, or 0.7%, or 0.8%, or 0.9%, or 1.0%, or 1.5%, or 1.7%, or 1.9%, or 2.0%, or 2.5%, or 3.0%, or 3.5%, or 4.0% compared to a subject not receiving the therapy or receiving a placebo.

[0149] In some aspects, the likelihood of incipient diabetes is reduced in a subject by about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 40%, or about 50%, or about 60%, compared to a subject not receiving the therapy or receiving a placebo.

[0150] Pharmaceutical Compositions The present invention also encompasses a method for treating cardiovascular disease. The method of the present invention comprises administering a therapeutically effective amount of one or more statins, ETC-1002 and ezetimibe. The fixed dose combination of any one of the one or more statins, ETC-1002 and ezetimibe can be formulated in a pharmaceutical composition. The fixed dose combination of ETC-1002 and ezetimibe can also be formulated in a pharmaceutical composition. These compositions include pharma-ceutically acceptable excipients, carriers, buffers, stabilizers or other materials 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 depend on the route of administration, for example, oral, intravenous, cutaneous or subcutaneous, intranasal, intramuscular, intraperitoneal routes.

[0151] The pharmaceutical composition for oral administration may be in tablet, capsule, pill, powder or liquid form. Tablets or pills may contain a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline, glucose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

[0152] In one embodiment, a pharmaceutical composition of the present invention is made from one or more compounds disclosed herein and is in the form of a pill.

[0153] In another aspect, disclosed herein is a method of lowering cholesterol or related markers disclosed herein (e.g., HDL-C, ApoA1) or treating or preventing cardiovascular disease or dyslipoproteinemia and / or dyslipidemia, comprising administering to a subject a pharmaceutical composition in the form of a pill comprising a fixed dose of about 120 mg or about 180 mg of ETC-1002, a fixed dose of one or more statins, each at a dose of about 2 to about 80 mg, and a fixed dose of about 10 mg of ezetimibe.

[0154] For intravenous, cutaneous or subcutaneous injection, or injection into the affected area, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity and stability.Those skilled in the art can fully prepare appropriate solutions using isotonic vehicles such as sodium chloride injection, Ringer's solution, lactated Ringer's solution, etc.If necessary, preservatives, stabilizers, buffers, antioxidants and / or other additives can be included.

[0155] When it is a small molecule or other pharma- ceutical useful compound according to the invention that is given to an individual, it is preferred that the administration is a "therapeutically effective amount" or a "prophylactically effective amount" (although in some cases prophylaxis can be considered therapy), which is sufficient to show benefit to the individual. The actual amount administered, and the rate and time course of administration, may depend on the nature and severity of the protein aggregation disorder being treated. Prescription of treatment is within the responsibility of general practitioners and other physicians, and typically takes into account the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. (ed.), 1980.

[0156] The compositions may be administered simultaneously or sequentially, alone or in combination with other treatments, depending on the condition to be treated.

[0157] In one aspect, the disclosure provides a method of treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject, the method comprising administering a fixed dose of ETC-1002 or an analog thereof, a fixed dose of one or more statins or analogs thereof, and a fixed dose of ezetimibe to a subject in need thereof, optionally, wherein ETC-1002 is administered at a fixed dose of about 120 mg or a fixed dose of about 180 mg, each of the one or more statins is administered at a fixed dose of about 2 to about 80 mg, and ezetimibe is administered at a fixed dose of about 10 mg, and optionally, the method treats diabetes or reduces the risk of diabetes in the subject.

[0158] In one aspect, the disclosure provides a method, wherein the levels of total cholesterol and non-HDL-C in the subject are lower than those of a control subject receiving placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or a fixed dose of one or more statins at doses of about 2 to about 80 mg, each.

[0159] In one aspect, the disclosure provides a method, wherein the level of low density lipoprotein (LDL) in the subject is lower than that of a control subject receiving placebo, a fixed dose of ETC-1002 at about 120 mg, a fixed dose of ETC-1002 at about 180 mg, a fixed dose of ezetimibe at about 10 mg, or a fixed dose of one or more statins at doses of about 2 to about 80 mg, each.

[0160] In one aspect, the disclosure provides a method, wherein the number of LDL particles in the subject is lower than that of a control subject receiving a placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or a fixed dose of one or more statins at a dose of about 2 to about 80 mg, each.

[0161] In one aspect, the disclosure provides a method, wherein the level of apolipoprotein B (ApoB) in the subject is lower than that of a control subject receiving placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or one or more statins at fixed doses of about 2 to about 80 mg, respectively.

[0162] In one aspect, the disclosure provides a method, wherein the level of apolipoprotein A-1 (ApoA1) in the subject is lower than that of a control subject receiving placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or one or more statins at fixed doses of about 2 to about 80 mg, respectively.

[0163] In one aspect, the disclosure provides a method, wherein the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the subject is lower than that of a control subject receiving placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or one or more statins at fixed doses of about 2 to about 80 mg, each.

[0164] In one aspect, the present disclosure provides a method for determining whether HbA 1C The levels are lower than those of control subjects receiving placebo, a fixed dose of about 120 mg ETC-1002, a fixed dose of about 180 mg ETC-1002, a fixed dose of about 10 mg ezetimibe, or one or more statins at fixed doses of about 2 to about 80 mg, respectively.

[0165] In one aspect, the disclosure provides a method, wherein the subject has hypercholesterolemia.

[0166] In one aspect, the disclosure provides a method, wherein the subject has diabetes.

[0167] In one aspect, the disclosure provides a method, wherein the subject has type 2 diabetes.

[0168] In one aspect, the disclosure provides a method, wherein the subject has risk factors for developing new-onset diabetes.

[0169] In one aspect, the disclosure provides a method, wherein the subject is a human.

[0170] In one aspect, the disclosure provides a therapeutic composition comprising fixed therapeutic doses of ETC-1002, ezetimibe, and one or more statins, each in a fixed dose.

[0171] ETC-1002 Background Mechanism of action ETC-1002 is a small molecule inhibitor of adenosine triphosphate (ATP)-citrate lyase (ACL), an enzyme upstream of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (the molecular target of statins) in the cholesterol biosynthesis pathway. ETC-1002 can mediate competitive inhibition of ACL. Inhibition of ACL reduces cholesterol synthesis in the liver, leading to increased LDLR expression and clearance of LDL particles from the blood. Thus, inhibition of ACL by ETC-1002 is via the same pathway as HMG-CoA reductase inhibition by statins.

[0172] A key distinguishing feature of ETC-1002 is that, unlike statins, it does not inhibit cholesterol synthesis in skeletal muscle, and therefore is not expected to cause the adverse effects associated with inhibition of the cholesterol biosynthetic pathway in skeletal muscle.

[0173] In the examples described herein, unless otherwise stated, the daily doses of bempedoic acid (180 mg or 120 mg) are taken in combination with EZE as individual tablets or in fixed dose combination (FDC) tablets, which represent the doses being evaluated in Phase 3 monotherapy and combination therapy studies of bempedoic acid in subjects with hypercholesterolemia. The daily doses of EZE (10 mg) taken in combination with BA as individual tablets or in FDC tablets represent the recommended therapeutic dose of this drug. Additional details regarding these studies are provided below.

[0174] Inclusion criteria Subjects must be willing to provide informed consent prior to undergoing any study-specific procedures.

[0175] Subjects must be between 18 and 75 years of age, or the legal age of majority (or older) under local law.

[0176] Subjects must have a history of T2D for ≥6 months; must also be currently taking stable antidiabetic medication for ≥3 months, and have an HbA1C between 7% and 10% at Visit S1.

[0177] Subjects must have a fasting calculated LDL-C level >70 mg / dL at Visit S1.

[0178] Subjects must have a fasting calculated LDL-C level of 100-220 mg / dL at visit S3 after washout of all LMT.

[0179] Subjects must be clinically stable and, based on investigator assessment, suitable to undergo a 17-week washout of all LDL-C lowering medications and nutritional supplements (with a potential extension of 1 week if repeat evaluations are required as described in the protocol).

[0180] Subjects may be male or female. Women must not be pregnant (or planning to become pregnant within 30 days after the last dose of IMP) or lactating, and must: a. Postmenopausal (defined as absence of menses for ≥ 1 year) and either: i. ≥ 55 years of age; or ii. Age <55 years and FSH level ≥40.0 IU / L; b. Surgical sterilization by hysterectomy, bilateral oophorectomy, and / or tubal ligation; or c. Willing to use one acceptable method of contraception if of childbearing potential, unless the subject agrees to adhere to the definition of true abstinence. The minimum requirement for use of an acceptable method of contraception is from the time the Informed Consent Form (ICF) is signed, for the duration of the study, and for at least 30 days after the last dose of IMP. Acceptable methods of contraception include: i. Intrauterine device (IUD) placement (hormonal or non-hormonal); ii. Established use of oral, implant, topical, or injectable or hormonal contraceptive methods involving the inhibition of ovulation; iii. Barrier methods, including condoms or occlusive caps with spermicidal foam or spermicidal jelly; iv. A vasectomized male partner who is the subject's only partner; or v. True abstinence if this is consistent with the subject's preferred and usual lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptom-thermometric, postovulatory methods), declared abstinence for the duration of the study, and withdrawal are not acceptable methods of contraception.

[0181] Criteria for excluding targets The target is >40kg / m 2 have a body mass index (BMI) of

[0182] Subjects have a history of documented clinically significant cardiovascular disease, including, but not limited to, myocardial infarction, severe or unstable angina, coronary angioplasty, coronary artery bypass graft, stroke, transient ischemic attack, cerebrovascular event, symptomatic carotid artery disease, or symptomatic peripheral arterial disease, uncontrolled hypertension (defined as mean systolic blood pressure ≧160 mmHg and / or diastolic blood pressure ≧100 mmHg after sitting quietly for 5 minutes), arrhythmia requiring medical intervention, or abdominal or thoracic aortic aneurysm.

[0183] Subjects have a history of type 1 diabetes.

[0184] Subjects will have fasting TG levels >400 mg / dL at visit S3.

[0185] The subject has uncontrolled hypothyroidism, eg, a thyroid stimulating hormone (TSH) level >1.5 times the upper limit of normal.

[0186] Subjects have liver disease or dysfunction, e.g., positive serology for Hepatitis B virus surface antigen (HBsAg) and / or Hepatitis C virus antibody (HCV-AB) at week -1 (visit S2 / day 7), or serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values ​​of > 2xULN, and / or serum total bilirubin (TB) values ​​of > 2xULN. Subjects may be enrolled in the study if serum TB values ​​are > 1.2xULN, if reflex indirect (unconjugated) bilirubin is obtained consistent with Gilbert's disease, or if the subject has a history of Gilbert's disease.

[0187] Subjects have renal insufficiency or glomerulonephritis, eg, estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2 (as determined by a central laboratory using the Modification of Diet in Renal Disease [MDRD] formula).

[0188] The subject has a gastrointestinal condition or has undergone a procedure that may affect drug absorption (eg, weight loss surgery; eg, lap-band, gastric bypass).

[0189] Subjects have a hematological or coagulation disorder, or a hemoglobin (Hgb) level <10.0 g / dL.

[0190] Subjects had an active malignancy within the past 5 years, e.g., requiring surgery, chemotherapy, and / or radiation therapy. Nonmetastatic basal or squamous cell carcinoma of the skin and cervical intraepithelial neoplasia are permitted.

[0191] Subjects will have an unexplained (i.e., not related to recent trauma or physically strenuous activity) serum creatine kinase (CK) value >3xULN at any time prior to randomization. Subjects with an explained elevation in serum CK must have a single repeat serum CK value ≤3xULN prior to randomization.

[0192] Subjects must have a history of drug or alcohol abuse within the past two years or report current consumption of >14 alcoholic drinks per week, use any illicit drug, or have a history of amphetamine or derivative abuse or cocaine abuse. Subjects using amphetamine derivatives prescribed by and under the care of a health care professional may be enrolled after evaluation by the investigator.

[0193] Subjects were required to have donated blood, had multiple blood draws for clinical studies, experienced significant trauma, received a blood transfusion, or undergone surgery (with or without blood loss) within 30 days prior to randomization.

[0194] Subjects have been using any experimental or investigational drug within 30 days prior to screening and throughout the study.

[0195] Subjects had previously participated in a clinical study of BA.

[0196] The subject has a history of intolerance to EZE.

[0197] Subjects were either using prohibited substances and / or nutritional supplements within 5 weeks prior to Visit T1 (unless otherwise specified) or intending to use any of the prohibited substances and / or nutritional supplements during the study, including, but not limited to, statins, fibrates (including fenofibrate), niacin and derivatives, bile acid sequestrants, ezetimibe (if provided in the study is permitted), apheresis, mipomersen or lomitapide (6 months prior to Visit S1), proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors (4 months prior to Visit S1, except PCSK9 small interfering RNA (siRNA), which is prohibited if used any time in the past), cholesteryl ester transfer protein (CETP) inhibitors (12 months prior to Visit S1), red yeast rice extract-containing products, omega-3 fatty acids and derivatives, e.g., Lovaza® and over-the-counter (OTC) fish oils.

[0198] Risk-benefit summary To date, preclinical and clinical data indicate that ETC-1002 has a favorable risk-benefit profile. The ability of ETC-1002 to achieve clinically meaningful LDL-C lowering responses while demonstrating a favorable tolerability profile in various patient populations supports the continued development of ETC-1002, an oral ACL inhibitor. EXAMPLES

[0199] Below are examples of specific embodiments for carrying out the present invention. The examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0200] Patients with diabetes were identified primarily through medical history and / or baseline laboratory results. There were no entry restrictions for these patients, except for having an HbA1c of <10% during screening. Background concomitant medication use related to diabetes treatment was recorded at the start of the study. Changes in all concomitant medications were tracked during the treatment phase. There were no restrictions on changing (stopping, starting, or dose modification) diabetes medications during the study.

[0201] Example 1: Bempedoic acid reduces diabetes risk in patients receiving high-intensity statin therapy A total of 2230 patients received background MTD statins (50% high intensity) for 52 weeks. Of these, 637 patients (28.6%) had a history of diabetes. Patients were treated with bempedoic acid or placebo. The baseline HbA1c level for patients receiving bempedoic acid was 6.85% and for patients receiving placebo was 6.89%. The baseline fasting glucose level for patients receiving bempedoic acid was 131.4 mg / dl. The baseline fasting glucose level for patients receiving placebo was 130.6 mg / dl. Changes in HbA1c levels were measured at 12 and 52 weeks, and changes in fasting glucose levels were measured at 4, 8, 12, 24, and 36 and 52 weeks. The data are presented in Figures 2 and 3 and demonstrate that bempedoic acid reduces the occurrence of diabetes-related phenotypes, worsening of diabetes, and new onset of diabetes compared to placebo in patients receiving statin therapy.

[0202] Example 2: Bempedoic acid reduces diabetes risk in statin-intolerant patients A total of 345 patients with statin intolerance (8% were on very low doses of statins) were treated for 24 weeks. Of these, 89 patients (25.8%) had a history of diabetes. Patients were treated with bempedoic acid or placebo. The baseline HbA1c level for patients receiving bempedoic acid was 6.91% and for patients receiving placebo was 7.12%. The baseline fasting glucose level for patients receiving bempedoic acid was 130.7 mg / dl. The baseline fasting glucose level for patients receiving placebo was 139.8 mg / dl. Changes in HbA1c levels were measured at 12 and 24 weeks, and changes in fasting glucose levels were measured at 4, 12, and 24 weeks. The data are presented in Figures 4 and 5 and demonstrate that bempedoic acid reduces the occurrence of diabetes-related phenotypes, worsening of diabetes, and new onset of diabetes compared to placebo in statin-intolerant patients.

[0203] Example 3: Bempedoic acid reduces diabetes risk in statin-intolerant patients receiving background ezetimibe therapy A total of 269 patients with statin intolerance (31% low / very low dose statin) were treated for 12 weeks; all patients were on background ezetimibe therapy. Of these, 52 patients (19.3%) had a history of diabetes. Patients were treated with bempedoic acid or placebo. The baseline HbA1c level for patients receiving bempedoic acid was 6.66% and for patients receiving placebo was 6.76%. The baseline fasting glucose level for patients receiving bempedoic acid was 133.7 mg / dl. The baseline fasting glucose level for patients receiving placebo was 133.4 mg / dl. Changes in HbA1c levels were measured at 12 weeks and changes in fasting glucose levels were measured at 4, 8, and 12 weeks. The data are presented in Figures 6 and 7 and demonstrate that bempedoic acid reduces the incidence of diabetes-related phenotypes, worsening of diabetes, and new onset of diabetes compared to placebo in statin-intolerant patients receiving background ezetimibe therapy.

[0204] Example 4: Bempedoic acid plus ezetimibe treatment reduces diabetes risk in patients receiving ezetimibe A total of 381 patients (38.6% high-intensity statins; 28% no statins) receiving maximum tolerated statin dosage were treated for 12 weeks. Of these, 195 patients (51.2%) had a history of diabetes. Patients were randomized to one of four arms: bempedoic acid + ezetimibe; bempedoic acid; ezetimibe; or placebo (2:2:2:1). Baseline fasting glucose levels for patients receiving bempedoic acid + ezetimibe were 125.8 mg / dl. Baseline fasting glucose levels for patients receiving bempedoic acid were 130.9 mg / dl. Baseline fasting glucose levels for patients receiving ezetimibe were 142.5 mg / dl. Baseline fasting glucose levels for patients receiving placebo were 124.9 mg / dl. Fasting glucose levels were measured at weeks 4, 8, and 12. The data are presented in FIG. 8 and demonstrate that bempedoic acid plus ezetimibe reduces the occurrence of diabetes-related phenotypes, worsening of diabetes, and new onset of diabetes in patients receiving relatively high-intensity statin therapy.

[0205] The cumulative data presented in these Examples demonstrate (among other findings) that new onset or worsening of diabetes and diabetes-related symptoms occurred less frequently in patients receiving a statin and bempedoic acid (4%) compared to patients receiving a statin and placebo (5.6%).

[0206] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, within the skill of the art. Such techniques are fully explained in the literature. See, for example, TE 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 ed., 1989); Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th ed. (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry, 3rd ed. (Plenum Press) Vols. A and B (1992).

[0207] Any term not directly defined herein is understood to have the meaning normally associated with that understood within the art of the present invention. Certain terms are described herein to provide additional guidance to practitioners, describing the compositions, devices, methods, etc. of the present invention aspects and how to make or use them. It is understood that the same thing may be described in more than one way. In conclusion, alternative language and synonyms may be used for any one or more terms described herein. No importance should be placed on whether a term is detailed or described herein. Some synonyms or substitute methods, materials, etc. are provided. The detailed description of one or a few synonyms or equivalents does not exclude the use of other synonyms or equivalents unless expressly stated. 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 present invention herein.

[0208] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0209] While the present invention has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention.

[0210] All references, issued patents, and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A composition for use in a method for reducing the likelihood of new-onset diabetes in a subject or reducing the likelihood of exacerbation of existing diabetes in a subject, comprising ETC-1002, The method includes administering ETC-1002 to a subject; The composition, wherein the subject is undergoing statin therapy.

2. The composition described in claim 1, wherein the method comprises administering ETC-1002 and ezetimibe to a subject.

3. The composition of claim 1 or 2, wherein the subject has diabetes.

4. 4. The composition of claim 3, wherein the diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, type 3 diabetes, gestational diabetes, latent autoimmune diabetes of adults, maturity-onset diabetes of the young, double diabetes, steroid-induced diabetes, brittle diabetes, secondary diabetes, and juvenile diabetes.

5. The composition of claim 4, wherein the subject has a history of type 2 diabetes of 6 months or more.

6. The composition of any one of claims 1 to 4, wherein the subject has been on stable diabetes medication for three months.

7. A composition described in any one of claims 1 to 5, wherein the subject has been washed out of all lipid-modifying therapies (LMT).

8. Subjects had HbA of 5% to 10% or 7% to 10% 1c The composition according to any one of claims 1 to 7, having a level.

9. A composition described in any one of claims 1 to 8, wherein the subject has a calculated fasting LDL-C level of greater than 70 mg / dL, for example 100 to 220 mg / dL.

10. The subjects were divided into the following groups: Not pregnant, 40kg / m 2 not have a body mass index (BMI) greater than no history of documented cardiovascular disease, not have uncontrolled high blood pressure, not have fasting triglycerides greater than 400 mg / dL, No history of type 1 diabetes, not have uncontrolled hypothyroidism, No liver disease or dysfunction, No renal insufficiency or glomerulonephritis, not have any gastrointestinal pathology or undergoing any treatment that affects drug absorption, No hematological disorders, No coagulation disorder, not have a hemoglobin (Hgb) level less than 10.0 g / dL, No active malignant tumors, No unexplained serum creatine kinase (CK) levels greater than 3 times the ULN have no history of drug or alcohol abuse; Do not use amphetamine or its derivatives Have not donated blood or had multiple blood draws within the past 30 days Have not received a blood transfusion or undergone surgery within the past 30 days have not previously participated in a clinical trial study involving administration of ETC-1002; No history of intolerance to ezetimibe Not using prohibited drugs selected from the group consisting of statins, fibrates, niacin, niacin derivatives, bile acid sequestrants, ezetimibe, mipomersen, lomitapide, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, red yeast rice extract-containing products, omega-3 fatty acids and derivatives, over-the-counter (OTC) fish oils, and systemic corticosteroids. The composition according to any one of claims 1 to 9, which falls into one or more of the following categories:

11. the cardiovascular disease is selected from the group consisting of myocardial infarction, severe or unstable angina, coronary angioplasty, coronary artery bypass graft, stroke, transient ischemic attack, cerebrovascular event, symptomatic carotid artery disease, and symptomatic peripheral artery disease; The uncontrolled hypertension is defined as having a mean systolic blood pressure of 160 mmHg or greater and / or a diastolic blood pressure of 100 mmHg or greater. The composition of claim 10.

12. The composition described in claim 10, wherein the uncontrolled hypothyroidism includes a value for thyroid-stimulating hormone (TSH) greater than 1.5 times the upper limit of normal (ULN).

13. The composition described in claim 10, wherein the liver disease or dysfunction is selected from the group consisting of positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (HCV-AB), serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than or equal to two times the ULN, and serum total bilirubin (TB) levels greater than or equal to two times the ULN.

14. The composition of claim 10, wherein the renal dysfunction or glomerulonephritis comprises a glomerular filtration rate (eGFR) of less than 30 mL / min / 1.73 m 2 .

15. The composition of claim 10, wherein the active malignant tumor is selected from the group consisting of those requiring surgery, chemotherapy, and radiation therapy.

16. The composition of any one of claims 1 to 15, wherein the subject has a risk factor for type 2 diabetes.

17. A composition described in any one of claims 1 to 16, wherein the subject is receiving maximally tolerated statin therapy.

18. 17. The composition of claim 16, wherein the risk factors are selected from the group consisting of overweight or obesity, age 45 years or older, a family history of diabetes, high blood pressure, low levels of high density lipoprotein cholesterol, high levels of triglycerides, a history of gestational diabetes, heart disease or stroke, polycystic ovary syndrome, and acanthosis nigricans.

19. 19. The composition of any one of claims 1 to 18, wherein ETC-1002 is administered in an amount of 120 mg or 180 mg.

20. A composition described in any one of claims 2 to 19, wherein ETC-1002 is administered in an amount of 120 mg or 180 mg, and ezetimibe is administered in an amount of 10 mg.

21. 21. The composition of any one of claims 2-20, wherein subjects experience a statistically significant change in LDL-C levels from baseline after 12 weeks of receiving 120 mg or 180 mg of ETC-1002 and 10 mg of ezetimibe.

22. A composition described in any one of claims 2 to 20, wherein the subject experiences a statistically significant change in LDL-C levels from baseline 24 weeks after receiving 120 mg or 180 mg of ETC-1002 and 10 mg of ezetimibe.

23. A composition described in any one of claims 2 to 20, wherein the subject experiences a statistically significant change from baseline in non-LDL-C, total cholesterol, apolipoprotein B, or C-reactive protein levels 12 weeks after receiving 120 mg or 180 mg of ETC-1002 and 10 mg of ezetimibe.

24. The composition of any one of claims 2 to 20, wherein the subject experiences a statistically significant improvement in HbA 1C levels from baseline 12 weeks after receiving 120 mg of ETC-1002 and 10 mg of ezetimibe.

25. The composition of any one of claims 1 to 24, wherein the subject is a human.

26. 26. The composition of any one of claims 1 to 25, wherein the amount of ETC-1002 or ezetimibe or both is effective to reduce LDL-C in the subject.

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