Fixed-dose combinations comprising ETC1002 and one or more statins for treating or reducing the risk of cardiovascular disease

Abstract

Methods and compositions for treating or reducing the risk of cardiovascular disease are provided. [Solution] Provided are compositions comprising a fixed dose of ETC-1002 and one or more statins. Also provided are methods for using the fixed dose of ETC-1002 and one or more statins. The uses include methods for treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject. The uses also include methods for treating hypercholesterolemia in a subject.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit 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 in its entirety.

[0002] This application relates to methods and compositions useful for treating or reducing the risk of cardiovascular conditions. Statins are the cornerstone of the prevention and treatment of cardiovascular disease, which continues to be 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 disorders. [Background technology]

[0003] Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease. However, many patients, such as those with hypercholesterolemia, fail to reduce their LDL-C to desired levels with conventional therapy. Despite advances in new cholesterol-lowering drugs, residual cardiovascular risk, particularly observed in patients with high cholesterol, has prompted the search for new, non-traditional medications. 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 compounds that have been shown to be effective in inhibiting enzymes in cholesterol biosynthesis are also systemically toxic. Therefore, there is a need for new pharmaceutical formulations that are both effective and safe for lowering cholesterol. Summary of the Invention

[0004] This application relates to methods and compositions 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 oral, once-daily therapy that lowers cholesterol by inhibiting adenosine triphosphate (ATP) citrate lyase (ATPCL), which is further upstream in the cholesterol biosynthetic pathway than HMG-CoA reductase.

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

[0007] The general class of "statins" is compounds that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, concomitantly lowering the body's cholesterol levels by inhibiting the pathway for cholesterol synthesis 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 approximately 2 mg to 80 mg of a statin compound.

[0008] The present inventors have found that inhibiting HMG-CoA reductase increases the activity of LDL receptors. Furthermore, the present inventors have found that combining these two therapies leads to synergistic activity and favorable clinical treatment. Therefore, the present invention is directed to cholesterol-lowering compositions comprising a statin and ETC-1002. These compositions lead to further reductions in total cholesterol, specifically LDL-C, in patients.

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

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

[0011] 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 explanation of the drawings]

[0012] [Figure 1] Figure 1 shows patient disposition. *One patient was randomized but discontinued before receiving study medication. AE = adverse event, mITT = modified intention to treat. [Figure 2] Graph showing the mean percent change in LDL-C from baseline through week 12. These data are from a modified intention-to-treat 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. DETAILED DESCRIPTION OF THE INVENTION

[0013] Benefits and Usefulness Briefly, as described in more detail below, described herein are compositions, methods for making the compositions, and methods for treating cardiovascular disease or reducing the risk of cardiovascular disease using a fixed-dose combination of one or more statins and ETC-1002. The advantages of this approach are numerous, including, but not limited to, increased reductions in cholesterol and low-density lipoprotein levels in patients treated with a fixed-dose combination of one or more statins and ETC-1002 compared to patients treated with either a statin or ETC-1002 alone. As discussed above, statins are the cornerstone of cardiovascular disease prevention and treatment, but can cause undesirable side effects in many patients. These side effects include, but are not limited to, increased liver enzyme levels, muscle problems, and increased risk of diabetes. Statin-associated muscle symptoms are an important clinical issue because discontinuing statins in hypercholesterolemic patients increases cardiovascular risk. Therefore, there is a significant need for cardiovascular therapies for patients who exhibit muscle intolerance to statins.

[0014] definition Terms used in the claims and specification, unless otherwise specified, are defined as set forth below.

[0015] Terms used in the claims and specification are defined as set forth below unless otherwise specified. Furthermore, any term or symbol used herein has its ordinary meaning in the art unless it is defined as set forth below.

[0016] 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. The recitation of ranges of values ​​herein is not intended merely 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; each value is incorporated herein as if 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 further illustrate the examples and does not pose a limitation on the scope of the claims, unless otherwise stated. No language in the specification should be construed as referring specifically to any non-claimed elements.

[0017] 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 35 Compounds containing 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 those of skill in the art based on the disclosure herein.

[0018] The term "amelioration" refers to any therapeutically beneficial result in the treatment of a disease state, e.g., an inflammatory disease state, including a decrease in the severity or progression of, a remission of, or a cure of, the disease state. In some embodiments, "amelioration" includes prevention of the disease state.

[0019] The term "in vitro" refers to processes that occur in living cells grown isolated from an organism, for example, grown in tissue culture.

[0020] The term "in vivo" refers to a process that takes place within an organism.

[0021] 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.

[0022] 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.

[0023] The term "therapeutically effective amount" is an amount effective to ameliorate symptoms of a disease. Since prevention can be considered therapy, a therapeutically effective amount can, in some embodiments, be a "prophylactically effective amount."

[0024] 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 hygroscopicity of the compounds. The compounds of the present technology can also exist as organic solvent solvates, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of a person skilled in the art of synthetic organic or medicinal chemistry.

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

[0026] "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 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.

[0027] "Treating" or "treatment" of a disease or disorder in a subject 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 alleviating the cause of the regression of the disease or disorder.

[0028] 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 is at risk of or susceptible to developing the disease, disorder, or condition. Thus, in some embodiments, an agent can be administered prophylactically to prevent the symptoms of the disease, disorder, or condition or to prevent the recurrence of the disease, disorder, or condition.

[0029] For purposes of this specification and the appended claims, unless otherwise indicated, all numerical values ​​expressing quantities, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values ​​used in the specification and claims are to be understood in all instances as being modified by the term "about," even if the term "about" does not explicitly represent a value, amount, or range. Thus, unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are not, and need not be, exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, as well as other factors known to those skilled in the art depending upon the desired properties believed to be obtained by the presently disclosed subject matter. For example, the term "about," when referring to a value, can mean that the variation encompasses variations of in some embodiments ±100%, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the particular amount, as variations are appropriate for practicing the methods or using the compositions of the present disclosure.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0031] wherein 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 for all of the above-defined substituents, polymers arrived at by defining substituents that themselves have further substituents (such as substituted aryls having a substituted aryl group as a substituent that is itself substituted with a substituted aryl group) 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 (in 1 to 3 positions) and that any and all of these substituents may be substituted only once more (in 1 to 3 positions).

[0033] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups), such impermissible substitution patterns being 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 interpreted as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments described herein are merely exemplary and are not intended to limit the scope of the present technology.

[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 high-sensitivity 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 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 combination of ETC-1002 or an analog thereof and one or more statins or analogs thereof to a subject in need thereof, optionally wherein ETC-1002 is administered at a fixed dose of 180 mg or a fixed dose of 120 mg, and the one or more statins are administered at fixed doses of 2 to 80 mg each, optionally reducing the level of low-density lipoprotein cholesterol (LDL-C) in the subject relative to that of a control subject receiving placebo, a fixed dose of 120 mg ETC-1002, a fixed dose of 180 mg ETC-1002, or one or more statins at fixed doses of between 2 and 80 mg each, and optionally treating or reducing the risk of cardiovascular disease in the subject.

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

[0046] In some aspects, the subject has hypercholesterolemia and the method further comprises treating the hypercholesterolemia.

[0047] In some aspects, the methods treat cardiovascular disease or reduce the risk of cardiovascular disease in a subject.

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

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

[0050] In some aspects, 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 LDL particle number by 17% to 21% or more.

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

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

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

[0054] In some embodiments, the subject is dyslipidemia. In some embodiments, the subject has hypercholesterolemia. In some embodiments, the subject is obese, and optionally, the subject has a BMI of 18 to 45 kg / m. 2In some embodiments, the subject is statin resistant. In some embodiments, the subject is statin intolerant. In some embodiments, at the lowest FDA-approved dose of one or more statins, the subject experiences adverse events selected from the group consisting of muscle-related pain, aching, muscle weakness, and cramps. The inventors have discovered that such muscle-related adverse events that begin and increase during statin therapy can be significantly reduced or even resolved when ETC-1002 therapy is added to statin therapy.

[0055] In some embodiments, the subject has a baseline LDL-C level of 115-220 mg / dL.In some embodiments, the subject has a baseline triglyceride level of 400 mg / dL or less.

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

[0057] Also disclosed herein is a method of 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 a fixed dose of ETC-1002 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 120 mg or a fixed dose of 180 mg, and the one or more statins are administered at fixed doses of between 2 and 80 mg each, and optionally wherein the level of low-density lipoprotein cholesterol (LDL-C) in the subject is reduced relative to that of a control subject receiving placebo, a fixed dose of 120 mg ETC-1002, a fixed dose of 180 mg ETC-1002, or a fixed dose of one or more statins each of 2 to 80 mg, and optionally wherein the subject has hypercholesterolemia.

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

[0059] In some embodiments, the composition further comprises a pharmaceutically acceptable vehicle. In some embodiments, ETC-1002 is present at a fixed dose of 120 mg or 180 mg, and one or more statins are each present at a fixed dose of between 2 and 80 mg. 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 apolipoprotein B (ApoB) levels in the subject relative to those of control subjects receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

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

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

[0063] In some embodiments, the method reduces the ratio of ApoB to ApoA1 in the subject relative to that of control subjects receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at 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% or more. In another embodiment, the method reduces the number of muscle-related AEs by at least 50%, 65%, 75%, or 85% or more.

[0065] In another embodiment, the methods disclosed herein significantly reduce the risk of a cardiovascular event in a subject, in some embodiments, by 35% or more.

[0066] In some aspects, provided herein are methods for treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, comprising administering to a subject a rapidly absorbed, steroid-resistant steroid compound with a T of less than 4 hours. max The method includes administering an amount of a composition comprising ETC-1002 having the formula:

[0067] In some aspects, provided herein are methods for 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.

[0068] In some aspects, provided herein are methods for treating cardiovascular disease 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 15 to 27 hours.

[0069] In some aspects, provided herein are methods for treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, comprising: a) administering to a subject a dose-dependent agonist or antagonist, or b) administering to a subject a dose-dependent agonist or antagonist, or c ... max In one embodiment, the method comprises administering an amount of a composition comprising ETC-1002 as add-on therapy to a statin therapy that provides: 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.

[0070] 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 disclosed herein.

[0071] In one embodiment, the composition comprises one or more statins defined by the fixed dosage amounts 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 the fungi Penicillium (Penecillium) and Aspergillus. In another aspect, one or more or all of the statins are synthetic, meaning they are made by converting petrochemical starting materials to the desired statin compound via organic chemical synthesis.

[0074] Formula I below shows ETC-1002 and analogs of ETC-1002. Formula I:

[0075] [ka] wherein (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 (CH2) or Ph, wherein z is an integer from 0 to 4, and Ph is a 1,2-, 1,3-, or 1,4-substituted phenyl group; and (d) R 1 , R 2 , R 11 , and R 12 is independently at each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, phenyl, or benzyl, where R 1 , R 2 , R 11 , and R 12 are not H at the same time, but (e)Y 1 and Y 2 each occurrence independently represents (C1-C6) alkyl, OH, COOH, COOR 3 , SO3H,

[0076] [ka] (In the formula, (i)Y 1 and Y 2 are not simultaneously (C1-C6) alkyl, and (ii) R3 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, phenyl, or benzyl, unsubstituted or substituted with one or more halo, OH, (C1-C6) alkoxy, or phenyl groups; and (iii) R 4 each occurrence is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl, unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups; and (iv) R 5 is independently at each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl. is].

[0077] ETC-1002 Structure:

[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 substituted ring system (shown below).

[0081] [ka]

[0082] 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 not limiting in any way.

[0083] [ka]

[0084] 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 descriptions can be used in any of the methods and / or compositions or formulations disclosed herein.

[0085] Synthesis of ETC-1002 and statins ETC-1002 and methods for synthesizing 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 at paragraphs

[0247] -

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

[0086] 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), which may include unique or alternative ring systems, are within the skill of one in the art. For example, one skilled in the art can use reference synthetic texts 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, Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd, Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March, Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001), and Larock, Comprehensive Organic Transformations (VCH Publishers Inc., 1989), T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999.

[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 a 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 accompanied by 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, 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 a 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 manifested by abnormal blood levels of lipids. To the extent that blood lipid levels are too high, the compositions of the present invention are administered to the patient until normal levels are restored. 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 Heart, Lung, and Blood Institute's National Cholesterol Education Program website (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 of HDL cholesterol in the blood is greater than 35 mg / dL, the recommended level of LDL cholesterol in the blood is less than 130 mg / dL, the recommended LDL:HDL cholesterol ratio in the blood is less than 5:1, ideally 3.5:1, and the recommended level of free triglycerides in the blood is less than 200 mg / dL.

[0089] Dyslipidemias that the compositions of the present invention are useful for preventing or treating include, but are not limited to, hyperlipidemia and the reduction of blood levels of high-density lipoprotein (HDL) cholesterol. In certain embodiments, the hyperlipidemias to be prevented or treated by the compounds of the present invention are familial hypercholesterolemia, familial combined hyperlipidemia, reduced or deficient lipoprotein lipase levels or activity, including reduced or deficient levels caused by lipoprotein lipase mutations, hypertriglyceridemia, hypercholesterolemia, elevated blood levels of urea bodies (e.g., beta-OH butyrate), elevated blood levels of Lp(a) cholesterol, elevated blood levels of low-density lipoprotein (LDL) cholesterol, elevated blood levels of very-low-density lipoprotein (VLDL) cholesterol, and elevated 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 LDL in the patient's blood, increasing the ratio of HDL to LDL in the patient's blood, and inhibiting saponifiable and / or non-saponifiable 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.

[0091] Pharmaceutical Composition Methods for treating cardiovascular disease are also encompassed by the present invention. The methods of the present invention comprise administering therapeutically effective amounts of one or more statins and ETC-1002. Fixed-dose combinations of one or more statins and ETC-1002 can be formulated in pharmaceutical compositions. These compositions contain pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art. Such materials should be non-toxic and do not interfere with the efficacy of the active ingredient. The precise nature 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.

[0092] Pharmaceutical compositions 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.

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

[0094] In another aspect, disclosed herein is a method for lowering cholesterol or a related marker 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 containing a fixed dose of 120 mg or 180 mg of ETC-1002 and / or fixed doses of 2-80 mg each of one or more statins.

[0095] For intravenous, cutaneous or subcutaneous injection, or injection into the affected area, the active ingredient is present 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 saline injection, Ringer's solution, lactated Ringer's solution, etc. If necessary, preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included.

[0096] When it is a small molecule or other pharmaceutically useful compound according to the present invention that is given to an individual, it is preferably administered in a "therapeutically effective amount" or a "prophylactically effective amount" (although in the present context, 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, will vary depending on the nature and severity of the protein aggregation disorder being treated. Prescription of treatment, e.g., determining dosage, etc., is within the responsibility of general practitioners and other physicians, and typically takes into account the disorder being treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. (ed.), 1980.

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

[0098] In one aspect, the disclosure provides a method for treating cardiovascular disease and / or reducing the risk of cardiovascular disease in a subject, comprising administering to a subject in need thereof a fixed dose combination of a fixed dose of ETC-1002 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 120 mg or a fixed dose of 180 mg, and wherein the one or more statins are each administered at a fixed dose of between 2 and 80 mg, optionally to treat or reduce the risk of cardiovascular disease in the subject.

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

[0100] 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 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

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

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

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

[0104] In one aspect, the disclosure provides a method in 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 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

[0105] In one aspect, the disclosure provides a method wherein the subject has hypercholesterolemia.

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

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

[0108] In one aspect, the disclosure provides a composition in which the amounts are a 120 or 180 mg dose of ETC-1002 and a fixed dose of 2 to 80 mg of each of one or more statins.

[0109] [Example] Below are examples of specific embodiments for carrying out the present invention. The examples are given 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.

[0110] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and physiology, within the skill of the art. Such techniques are fully explained in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd 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); and Carey and Sundberg Advanced Organic Chemistry, 3rd ed. (Plenum Press), vols. A and B (1992).

[0111] Any term not directly defined herein is understood to have the meaning normally associated with that understood within the art. Certain terms are explained herein to describe the compositions, devices, methods, etc. of embodiments of the present invention and how to make or use them, providing additional guidance to practitioners. It is understood that the same thing may be explained in multiple ways. Consequently, 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 recited or explained herein. Some synonyms or substitute methods, materials, etc. are provided. The recitation of one or a few synonyms or equivalents does not exclude the use of other synonyms or equivalents, unless explicitly stated. The use of examples, including examples of terms, herein is for illustrative purposes only and does not limit the scope and meaning of the embodiments of the present invention.

[0112] 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.

[0113] [Example 1] 1. List of abbreviations and definitions The following abbreviations and terminology are used in this study protocol:

[0114] [Table 2] JPEG2026041848000008.jpg237160JPEG2026041848000009.jpg237160JPEG2026041848000010.jpg208160

[0115] 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 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. Thus, ETC-1002 inhibits ACL via the same pathway as statins inhibit HMG-CoA reductase.

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

[0117] Non-clinical trials The primary pharmacology of ETC-1002 was evaluated in several well-characterized predictive rodent models of dyslipidemia. 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 study did not identify any significant risks to patients within the range of exposures intended for the clinical trial.

[0119] Toxicity studies have completed the evaluation of ETC-1002 in mice, rats, and monkeys in oral studies of up to 12 months duration. No significant central nervous system, respiratory, or cardiac liability was identified. Target organs identified in repeated-dose studies were the liver and kidney in rats and monkeys, and changes were reversible after discontinuation of treatment. Changes in clinical laboratory parameters indicative of liver and kidney function were observed in animals at doses lower than those associated with overt toxicity. Routine clinical laboratory parameters continue to be closely monitored in clinical trials.

[0120] In in vitro and in vivo genetic toxicology assays, ETC-1002 is non-mutagenic and non-clastogenic.

[0121] In the pivotal 6-month rat study, the no-observed-adverse-effect level (NOAEL) dose was 30 mg / kg / day in male and female rats, and the corresponding 24-hour area under the curve (AUC 0~24 ) values ​​were up to 528 μg·hr / mL. In the pivotal 12-month monkey study, the NOAEL dose was 60 mg / kg / day, and the corresponding AUC 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, and 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 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 and 6 Phase 2), and the overall data summary is based on the 6 completed Phase 2 trials.

[0124] A pooled analysis of six phase 2 trials showed placebo-adjusted mean percent change from baseline of approximately 32% for ETC-1002 180 mg monotherapy, 50% for ETC-1002 180 mg plus ezetimibe 10 mg, and 22% for stable statin therapy (180 mg). LDL-C reductions with ETC-1002 treatment were consistently accompanied by corresponding reductions in non-HDL-C, total cholesterol, LDL particle number, and apoB. Notably, a pattern of decreasing hsCRP across the study was also observed, with median changes from baseline ranging from 20% to 40%. The effects of ETC-1002 on HDL-C and TG were generally neutral.

[0125] PK data demonstrated that ETC-1002 was rapidly absorbed and max The results show that the C of ETC-1002 and ESP15228 occurs in less than 4 hours and less than 7 hours, respectively. max increases proportionally with increasing dose. However, systemic exposure, AUC tau,ss shows a slightly more than dose-proportional increase with linear dose escalation from 140-220 mg / day up to 120 mg / day. Mean t 1 / 2The mean time to death is approximately 15-27 hours. The metabolite, ESP15228, achieved systemic exposure in 20%-40% of patients, with higher percentages observed at lower doses. 1 / 2 is slightly longer than that of patients, ranging from 20 to 33 hours.

[0126] No drug interactions were demonstrated with ETC-1002 in combination with metformin or Ortho-Novum 1 / 35, a combined oral contraceptive. Food effect / bioequivalence studies demonstrated that ETC-1002 can be taken with or without food. Similar PK results were obtained for the capsule and tablet formulations.

[0127] The effect of ETC-1002 on the PK of atorvastatin was evaluated in Study 1002-007. In this study, all patients received 10 mg / day of atorvastatin during a 28-day run-in period (statin stabilization), followed by a treatment period in which patients received 10 mg / day of atorvastatin and a daily dose of ETC-1002 for 8 weeks. All patients started on ETC-1002 at a dose of 60 mg / day, which was increased every 2 weeks to 120 mg / day, then 180 mg / day, and then 240 mg / day. To determine drug interactions between ETC-1002 and atorvastatin, PK parameters of atorvastatin and ortho-hydroxyatorvastatin on Day 1 (end of statin stabilization period, baseline) were compared with corresponding PK parameters at Week 4 (when ETC-1002 dose reached 120 mg / day, Study 1) and Week 8 (when ETC-1002 dose reached 240 mg / day, Study 2). For atorvastatin and ortho-hydroxyatorvastatin, the ratio of exposure measures (AUC and / or C max ) were between 80% and 125%, suggesting that the two regimens were similar without any drug interactions.

[0128] Results of the drug interaction assessment indicate that a daily regimen of 10 mg atorvastatin and 120 mg ETC-1002 results in approximately 60% higher exposure to atorvastatin and ortho-hydroxyatorvastatin than a daily dose of 10 mg atorvastatin alone. A higher dose of ETC-1002 (240 mg) administered with atorvastatin also resulted in higher exposure to atorvastatin and ortho-hydroxyatorvastatin than administration of atorvastatin alone. The increases for 120 and 240 mg significantly increased the AUC and C for atorvastatin and metabolites. max This study demonstrated a transient increase in atorvastatin exposure (1.4x to 2.0x) when given in combination with ETC-1002. Importantly, ETC-1002 in combination with atorvastatin 10 mg was safe, well tolerated, and reduced LDL-C more effectively than atorvastatin alone.

[0129] The steady-state effect of ETC-1002 on the PK of single doses 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. Starting on the morning of Day 3, serial PK blood samples were collected. Starting on 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 serial PK blood samples were collected.

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

[0131] Simvastatin and simvastatin exposure (AUC 0-inf ) were increased by 29% and 91%, respectively, in the presence of ETC-1002 at steady state compared to simvastatin alone. max appears to be unaffected by co-administration with ETC-1002, but simvastatin C max was increased by 43% for simvastatin in combination with daily ETC-1002 versus simvastatin alone. The magnitude of the geometric mean ratio of observed test (ETC-1002 and simvastatin) AUC to reference (simvastatin alone) AUC for the active metabolite, simvastatin, was consistent with a less than two-fold increase, and the magnitude of the interaction was low relative to the prodrug parent compound (simvastatin).

[0132] Pravastatin exposure (AUC inf and C max ) were increased by 99% and approximately 2-fold, respectively, in the presence of ETC-1002 at steady state compared with pravastatin alone. The magnitude of the geometric mean ratio of the observed test (ETC-1002 and pravastatin) AUC to the reference (pravastatin alone) AUC was consistent with an increase of less than approximately 2-fold.

[0133] Rosuvastatin exposure (AUC inf and C max) increased by 69% and 208%, respectively, in the presence of steady-state ETC-1002 compared with rosuvastatin alone. The magnitude of the geometric mean ratio of observed test (ETC-1002 and rosuvastatin) AUC to reference (rosuvastatin alone) AUC was consistent with a less than two-fold increase. As in Study 1002-007, the combination of ETC-1002 and statin therapy was safe and well tolerated.

[0134] Results of a comprehensive thorough QT / QTc (TQT) study (1002-022) showed no significant changes in QTc. After 9 days of daily ETC-1002 at 240 mg, ETC-1002 did not prolong the QT interval duration and had no clinically significant effects on heart rate or PR and QRS intervals.

[0135] When examining the incidence of TEAEs occurring in three or more patients 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. Among ETC-1002 treatment groups, the greatest number of patients experiencing at least one TEAE occurred in the ETC-1002 40 mg dose group (75.6%), a frequency similar to the frequency of patients experiencing at least one TEAE in the placebo group (74.2%).

[0136] The system organ classes (SOCs) with the highest percentage of patients experiencing at least one TEAE in the ETC-1002 treatment group were infections and infestations, and musculoskeletal and connective tissue disorders, and gastrointestinal disorders.

[0137] In the Infections and Infestations SOC, the percentage of patients experiencing at least one TEAE was highest in the ETC-1002 80 mg group (25.0%). Treatment groups containing ETC-1002 had a TEAE frequency ranging from 11.6% to 25% in this SOC, compared with 23.2% for ezetimibe 10 mg, 14.8% for baseline statins, and 11.8% for placebo. The most frequent TEAEs (those occurring in three or more patients in any treatment group) by preferred term in this SOC were bronchitis, nasopharyngitis, sinusitis, upper respiratory tract infection (URTI), and urinary tract infection (UTI). All TEAEs by preferred term in the Infections and Infestations SOC occurred in 8% or fewer patients in any treatment group.

[0138] In the Musculoskeletal and Connective Tissue Disorders SOC, the percentage of patients experiencing at least one TEAE in almost all ETC-1002 treatment groups was equal to or less than the frequency in the placebo group (23.7%), with the exception of the ETC-1002 240 mg group (32.4%). The most frequent TEAEs (i.e., occurring in three or more patients in any treatment group) in this SOC preferred term were arthralgia, back pain, muscle spasms, muscle weakness, myalgia, and pain in extremity. There was no dose-related trend in the frequency of myalgia in the ETC-1002 treatment groups. Myalgia was most frequently reported in the ETC-1002 120 mg + ezetimibe group (7.7%) and the ezetimibe 10 mg group (6.1%). No rhabdomyolysis was reported. Nearly all TEAEs by SOC preferred term for musculoskeletal and connective tissue disorders occurred in less than 8% of patients in any treatment group, except for 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 statin, and three (3 / 93, 3.2%) in patients receiving placebo alone. Preferred-term SAEs occurred in only one patient reporting an event. There were no muscle-related SAEs.

[0140] One patient died of unknown causes. 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 study day 98. He was found unresponsive and pulseless outside the pool. No cause of death was listed on the death certificate. The investigator considered the sudden death event (cause unknown) to be possibly related to the study drug, as a temporal relationship could not be ruled out.

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

[0142] Dose selection Doses of ETC-1002 ranging from 40 to 240 mg / day were evaluated in phase 2 trials. Based on data from a pooled analysis of safety and efficacy, the primary efficacy endpoint, observed and percent change in LDL-C, along with a positive safety profile, supported the selection of the 180 mg dose for phase 3 trials. A pooled analysis of six phase 2 trials yielded placebo-adjusted least squares means (LSMs) for percent change from baseline of approximately 32% for ETC-1002 180 mg monotherapy, 50% for ETC-1002 180 mg plus ezetimibe 10 mg, and 22% for 180 mg on stable statin therapy. It is noted that the 180 mg dose had a superior safety profile. Overall, balancing efficacy and safety, the 180 mg dose was selected for clinical development.

[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 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.

[0145] [Example 2] ETC-1002 / high-dose statin fixed-dose combination To evaluate the LDL-C lowering efficacy of ETC-1002 180 mg versus placebo in statin-treated patients given a stable atorvastatin 80 mg background therapy for 28 days.

[0146] The plasma PK of multiple doses of atorvastatin 80 mg and its active metabolites, ortho-hydroxy atorvastatin and para-hydroxy atorvastatin, alone and in combination with ETC-1002 180 mg at steady state will be evaluated.

[0147] We contemplate that this add-on therapy will be at least as effective as the previous study and will result in the same or better safety profile / tolerability.

[0148] Without wishing to be bound by theory, the inventors believe that ETC-1002 180 mg tablets administered in addition to a stable high-dose statin (atorvastatin 80 mg) provide additional LDL-C lowering efficacy and safety relative to atorvastatin alone and are well tolerated in statin-treated adult patients. ETC-1002 in combination provides up to 1.4- to 2.0-fold higher AUC and C values ​​relative to the statin, regardless of the structure, physicochemical properties, or dose of the statin and / or its metabolites when given. max would show an increase in

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

[0150] Patients will 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 muscle toxicity and must have a history of tolerating simvastatin 80 mg for a minimum of the last 12 months.

[0153] Administration Patients take either an active tablet or a placebo tablet orally once daily.

[0154] Patients will keep a diary to record the time and date of each dose taken, whether they fasted, and the times of meals.

[0155] Pharmacokinetic evaluation Whole blood samples are collected for measurement of plasma concentrations of statin and active metabolite, and ETC-1002 and active metabolite.

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

[0157] [Table 4]

[0158] Evaluation of safety parameters Safety information will include recording of vital signs, AEs, concomitant medications, and ECG reports.

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

[0160] electro-cardiogram Electrocardiogram collection will be performed at the indicated sampling points and evaluated using machine readings.

[0161] Adverse events An AE is any untoward medical occurrence when a patient receives a medicinal product, including a control, and does not necessarily have a causal relationship to the treatment.

[0162] An AE may be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the drug, any new disease or worsening of an existing disease, any decline in a laboratory value or other clinical test (e.g., ECG or X-ray) that produces a symptom but does not require a protocol, a change in treatment, or discontinuation from the study drug, whether or not considered related to the drug.

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

[0164] adverse drug reactions All adverse, unintended reactions to a drug for any administration are considered adverse drug reactions (ADRs). A "reaction" to a drug means that a causal relationship between the drug and the AE is at least reasonably possible (i.e., a relationship cannot be excluded).

[0165] An unexpected ADR is defined as an adverse reaction the nature or severity of which is inconsistent with the applicable product information (e.g., IB for an unapproved investigational medicinal product or package insert or summary of product characteristics for an approved product).

[0166] The severity of an AE 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: Causes low level of inconvenience or concern to 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 incapacitates them, and has a significant impact on their clinical status and warrants intervention and / or detailed follow-up study.

[0170] Note: A severe AE does not have to be severe, and an SAE, by definition, does not have to be severe.

[0171] Definition of serious adverse events An SAE is defined as any AE occurring at any dose that results in any of the following outcomes:

[0172] Causes death

[0173] Life-threatening

[0174] Requires hospitalization of the patient or extension of current hospitalization

[0175] Continuing or significant impairment / incapacity or substantial disruption of the ability to perform normal life functions

[0176] Have a birth defect / congenital abnormality

[0177] Important Medical Events

[0178] Any significant medical event that does not result in death, is life-threatening, or may require hospitalization may be considered an SAE if, based on sound medical judgment, it endangers the patient and may require medical or surgical intervention to prevent one of the outcomes enumerated in this definition. Examples of such medical events include allergic bronchospasm requiring intensive care in an emergency room, a blood disorder, a seizure that does not result in inpatient hospitalization, or the development of drug dependence or abuse.

[0179] Sample size determination For the LDL-C lowering study objectives, a 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 overall) is expected to provide 80% power to detect a 15% difference in the percent change from baseline to Day 29 in calculated LDL-C between atorvastatin 80 mg / day + ETC 1002 and atorvastatin 80 mg / day + placebo. This calculation is based on a two-tailed t-test with a 5% significance level, a normal standard deviation of 18%, and a 10% dropout rate. Sample size calculations were performed using nQuery Advisor®, version 7.0 (Statistical Solutions).

[0180] For the PK drug interaction study goals, a sample size of 36 patients in the atorvastatin 80 mg / day + ETC 1002 treatment group (assuming data from 4 patients are not included) is expected to provide 79% or greater power for each parameter / analyte if the predictive value of the test / reference ratio for exposure measures 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, a planned 36 patients in 1002 035 will be enrolled to adequately characterize the effect on PK of ETC 1002 with respect to atorvastatin.

[0181] The per-protocol analysis set (PPAS) is defined as the set of patients in the FAS who additionally had all pre-dose PK samples > BLQ (for placebo patients, atorvastatin PK samples > BLQ; for ETC 1002 patients, pre-dose atorvastatin and pre-dose ETC samples > BLQ) and had lipid assessments on Day 29. The PPAS will be used to select sensitivity analyses for lipid parameters.

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

[0183] Percent changes from baseline are calculated for LDL-C and other parameters.

[0184] Pharmacokinetic and drug interaction analysis Pharmacokinetic parameters for atorvastatin, ortho-hydroxy atorvastatin, para-hydroxy atorvastatin, ETC 1002, and ESP15228 after multiple doses were derived from plasma concentration-time profiles as follows:

[0185] Cmax: maximum plasma concentration

[0186] tmax: Time to the first observed Cmax in the profile

[0187] AUClast: Area under the plasma concentration-time profile curve from time 0 to the time of the last quantifiable concentration (Clast), calculated using the 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: The minimum plasma concentration measured before drug administration

[0191] Cavg: average plasma concentration calculated from AUC24 divided by 24 hours during the dosing interval

[0192] C24: Concentration in the 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 by sampling date and ETC 1002 dose using PK parameter populations. Different PK parameter populations may be used for each analyte.

[0194] Drug interaction assessment from PK analyses

[0195] Safety evaluation Safety assessments included AEs, clinical safety laboratories, PEs, vital signs, and ECGs.

[0196] 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.

[0197] All references, issued patents, and patent applications cited in the body of this specification are incorporated by reference in their entirety into the body of this specification for all purposes.

Claims

1. A method of 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 a fixed dose of ETC-1002 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 120 mg or a fixed dose of 180 mg, and wherein the one or more statins are each administered at a fixed dose of between 2 and 80 mg, optionally to treat cardiovascular disease or reduce the risk of cardiovascular disease in the subject.

2. 10. The method of claim 1, wherein the levels of total cholesterol and non-HDL-C in the subject are lower than those of control subjects receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

3. 10. The method of claim 1, wherein the level of low-density lipoprotein (LDL) in the subject is lower than that of a control subject receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

4. 10. The method of claim 1, wherein the number of LDL particles in the subject is lower than that of control subjects receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

5. 10. The method of claim 1, wherein the level of apolipoprotein B (ApoB) in the subject is less than that of a control subject receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

6. 2. The method of claim 1, wherein the level of apolipoprotein A-1 (ApoA1) in the subject is less than that of a control subject receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

7. 2. The method of claim 1, wherein the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the subject is lower than that of control subjects receiving placebo, a 120 mg fixed dose of ETC-1002, a 180 mg fixed dose of ETC-1002, or one or more statins at fixed doses of 2 to 80 mg each.

8. 10. The method of claim 1, wherein the one or more statins are selected from the group consisting of rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin.

9. The method of claim 1, wherein the subject has hypercholesterolemia.

10. The method of claim 1, wherein the subject is an animal.

11. The method of claim 1, wherein the subject is a human.

12. A therapeutic composition comprising a fixed therapeutic dose of ETC-1002 and each fixed dose of one or more statins.

13. 13. The composition of claim 12, wherein the dose is between 2 and 80 mg of one statin.

14. 13. The composition of claim 12, wherein the amounts are a 120 or 180 mg dose of ETC-1002 and a fixed dose of 2 to 80 mg of each of the one or more statins.

15. 13. The composition of claim 12, wherein the dose is between 40 and 80 mg of one statin.

16. 13. The composition of claim 12, wherein the one or more statins are selected from the group consisting of rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin.

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