EP3752133A1

EP3752133A1 - Sustained release formulations of bempedoic acid

Info

Publication number: EP3752133A1
Application number: EP19709204.2A
Authority: EP
Inventors: Narendra Dhanraj LALWANI; Mohamed ABDELNASSER; Stephen Lawrence PINKOSKY; Clay Thomas CRAMER
Original assignee: Esperion Therapeutics Inc
Current assignee: Esperion Therapeutics Inc
Priority date: 2018-02-16
Filing date: 2019-02-15
Publication date: 2020-12-23
Also published as: TW202000191A; KR20200123181A; CL2020002101A1; WO2019161307A1; JP2021513987A; CN111971030A; PH12020551263A1; IL276689A; MX2020008527A; SG11202007825XA; RU2020129191A; AU2019221765A1; BR112020016494A2; CA3091259A1

Abstract

Herein disclosed are sustained-release bempedoic acid compositions with improved bioavailability and pharmacokinetic characteristics, kits comprising said compositions, and methods of use thereof. Also described are methods of delivering bempedoic acid.

Description

SUSTAINED RELEASE FORMULATIONS OF BEMPEDOIC ACID

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No.

62/710,417, filed on February 16, 2018 and U.S. Provisional Application No. 62/774,083, filed on November 30, 2018, each of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Bempedoic acid (ETC- 1002) behaves as a prodrug in vivo where it is converted to an active species (ETC-l002-CoA) by endogenous liver acyl-Coenzyme (CoA) synthetase (ACS) activity. A specific ACS isozyme, very long-chain acyl-CoA synthetase (ACSVL1), is required to form the active species. Once activated, ETC-l002-CoA directly inhibits ATP-citrate lyase (ACL) and through that action mediates effects on lipid metabolism. With traditional formulations, a fraction of bempedoic acid within a dosage form becomes activated, with the remaining unactivated fraction of the administered dose being eliminated. In part, this is because many Biopharmaceutics Classification System (“BCS”) Class II active pharmaceutical ingredients (“APIs”)— such as bempedoic acid— have low solubility and high permeability. What is needed, then, is a means for increasing the exposure of the active drug in liver without increasing the dose of bempedoic acid administered to patients.

SUMMARY OF THE INVENTION

[0003] The inventors have found that sustained-release of bempedoic acid affords an increased activation efficiency to the active species and improved exposure of the activated drug in liver.

[0004] Aspects of the disclosure comprise a pharmaceutical formulation comprising the components: (i) 50-70% bempedoic acid, (ii) a filler, (iii) a diluent or solubilizer, and (iv) a binder, wherein the formulation is formulated for the sustained release of bempedoic acid. In some aspects, the filler is selected from the group consisting of, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, and a combination of microcrystalline cellulose and sodium carboxmethylcellulose. In some aspects, the diluent or solubilizer is selected from a group consisting of, e.g., sodium lauryl sulfate and sodium starch glycolate. In some aspects, the binder is, e.g., hydroxylpropyl methylcellulose (HMPC). In some aspects, the formulation is formulated as a solid. In some aspects, the formulation is formulated for oral administration.

[0005] In some aspects, any of the formulation described above comprise bempedoic acid dispersed within a polymeric matrix. In some aspects, any of the formulations described above are formulations which exhibit a drug release profile corresponding to a pattern wherein, e.g., after 2 hours, no more than 30% of the total mass of the bempedoic acid is released into a subject. In some aspects, any of the formulations described above are formulations which exhibit a drug release profile corresponding to a pattern wherein, e.g., after 4 hours, no more than 75% of the total mass of bempedoic acid is released. In some aspects, any of the

formulations described above are formulations which exhibit a drug release profile

corresponding to a pattern wherein, e.g., after 8 hours, no more than 90% of the total mass of bempedoic acid is released. In some aspects, any of the formulations described above are formulations providing a therapeutically effective concentration of bempedoic acid over a period of, e.g., 24 hours when administered to a human subject.

[0006] In some aspects, in any of the formulations described above, the filler component is, e.g., microcrystalline cellulose, or sodium carboxymethylcellulose, or a combination of sodium carboxymethylcellulose and microcrystalline cellulose. In some aspects, the amount of filler component in the formulation is 5-50% w/w. In some aspects, the binder component is about 0.1-1.5% w/w. In some aspects, the formulations described above comprise, e.g., 50-70% w/w bempedoic acid, 30%-45% w/w filler component, 1-5% w/w diluent or solubilizer component, and 0.1-1.5% w/w binder component. In some aspects, the formulations described above comprise, e.g., 55-65% w/w bempedoic acid, 30-45% w/w filler component, 1-5% w/w diluent or solubilizer component, and 0.1-1.5% w/w binder component. In some aspects, the

formulations described above comprise, e.g., 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, or 220 mg of bempedoic acid.

[0007] In some aspects, the formulations described above dissolve at a zero order release rate for at least, e.g., 8, 9, 10, 11, or 12 hours. In some aspects, the formulations described above comprise bempedoic acid and a polymer matrix, and have a hardness of, e.g., 2-30 kg. In some aspects, the formulations described above are either shaped as a sphere or else have a ratio of thickness to diameter that is effective to permit erosion when dissolution is tested. [0008] In some aspects, any of the formulations described above provide a therapeutically effective concentration of bempedoic acid over a period of 24 hours when administered to a human subject. In some aspects, the formulation provides a maximum blood plasma

concentration (Cmax) of bempedoic acid of no more than, e.g., 50 pg/mL, 60 pg/mL, 70 pg/mL, or 80 pg/mL when administered to a human subject. In some aspects, the formulation provides a maximum blood plasma concentration (Cmax) of bempedoic acid in a range from, e.g., 45 pg/mL to 60 pg/mL, for e.g., 20, 21, 22, 23, or 24 hours after administration to a human subject.

[0009] In some aspects, any of the formulations described above are formulated as, e.g., gelatin capsules or tablets. In some aspects, the gelatin capsule comprises, e.g., a powder excipient.

[0010] In some aspects, the disclosure encompasses methods of administering a bempedoic acid formulation to a human subject in need thereof, wherein the formulation comprises bempedoic acid and a polymer matrix, and wherein, the administration results in a maximum blood plasma concentration (Cmax) of bempedoic acid of no more than about, e.g., 60 pg/mL, and wherein the blood plasma concentration is in a range from about 45-57 pg/mL for 24 hours after

administration. In a related aspect, the formulation is one of the formulations described above.

[0011] In some aspects, the disclosure encompasses methods of treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject, the method comprising administering an effective amount of a pharmaceutical formulation to a human subject in need thereof, wherein the formulation comprises the components of bempedoic acid and a polymer, and wherein the dissolution of the formulation exhibits a drug release profile corresponding to a pattern, e.g., after 2 hours, no more than 30% of the bempedoic acid is released; after 4 hours, no more than 75% of the bempedoic acid is released; after 8 hours, no more than 90% of the bempedoic acid is released. In some aspects, the method provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours to treat cardiovascular disease or reduce the risk of cardiovascular disease when administered to the subject. In another related aspect, the administered formulation does not release more than 95% of the bempedoic acid after 8 hours. In a related aspect, the administered formulation is one of the formulations described above.

[0012] In certain aspects of the methods described above, the polymer is hydroxypropyl methylcellulose (HPMC). In certain other aspects, the bempedoic acid in the administered formulation is, e.g., about 30-80% by weight and the polymer is hydroxypropyl methylcellulose (HPMC) and is, e.g., about 15-35% by weight. [0013] In certain aspects of any of the methods described above, the method lowers total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) when administered to a human subject having, e.g., hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease. In certain other aspects of any of the methods described above, the method decreases the level of very low density lipoprotein (VLDL) in the subject below that of a control subject receiving placebo. In certain other aspects of any of the methods described above, the method decreases the size of VLDL particles in the subject below that of a control subject receiving placebo. In certain other aspects of any of the methods described above, the method decreases the ratio of apolipoprotein B (ApoB) to apolipoprotein A- 1 (ApoAl) in the subject below that of a control subject receiving placebo. In certain other aspects of any of the methods described above, the method decreases the level of low-density lipoprotein cholesterol (LDL-C) in the subject. In certain other aspects of any of the methods described above, the method decreases LDL-C levels by at least 5%, 10%, 15%, or 20% relative to an otherwise untreated subject or a placebo-treated subject. In certain other aspects of any of the methods described above, the method decreases LDL-C levels by 5-40% relative to an otherwise untreated subject or a placebo-treated subject. In certain other aspects of any of the methods described above, the method decreases LDL-C levels in a subject at least as effectively as an equal dose of an immediate release bempedoic acid formulation. In certain other aspects of any of the methods described above, the method decreases LDL-C levels in a subject at least as effectively as a higher dose of an immediate release bempedoic acid formulation, wherein the higher dose is 180 mg/day.

[0014] Further, the sustained-release compositions described herein provide an efficient means for systemically delivering bempedoic acid. As a result, a lower dose and/or less frequent administration (relative to known bempedoic acid formulations) is required to produce the same effect. In this manner, unwanted side effects can be reduced, minimized or eliminated.

[0015] In one aspect the disclosure provides for a pharmaceutical composition comprising a solid dosage form, the solid dosage form comprising bempedoic acid and a polymer matrix. In one aspect the disclosure provides for a solid dosage form that is a capsule or a tablet.

[0016] In one aspect, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: bempedoic acid and a polymeric matrix. In one aspect, the bempedoic acid is dispersed within a polymeric matrix.

[0017] In one aspect, the disclosure provides for a zero-order sustained-release composition comprising bempedoic acid and a polymer matrix. In one aspect, the zero-order sustained- release composition comprises bempedoic acid dispersed within a polymeric matrix.

[0018] In one aspect, the disclosure provides for a pharmaceutical composition comprising a solid dosage form, where the solid dosage form has physical properties such that it exhibits a certain dissolution profile when dissolution tested using a United States Pharmacopeia (USP) apparatus.

[0019] In one aspect, the disclosure provides for methods of treating or reducing the risk of cardiovascular disease in a subject by administering the compositions disclosed herein, which may be sustained release formulations in some embodiments or immediate release formulations in other embodiments. In one aspect, the disclosure provides for methods of treating a metabolic syndrome in a subject by administering the compositions disclosed herein. In one aspect, the disclosure provides for methods of treating non-alcoholic fatty liver disease (NAFLD) in a subject by administering the compositions disclosed herein. In one aspect, the disclosure provides for methods of treating non-alcoholic steatohepatitis (NASH) in a subject by administering the compositions disclosed herein.

[0020] In some aspects, the disclosure encompasses a method of inhibiting ATP-citrate lyase (ACL) enzyme in a subject, wherein the method comprises administering to the subject the pharmaceutical dosage form of any of the above formulations.

[0021] In some aspects, the disclosure encompasses a method of treating metabolic syndrome in a subject, wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0022] In some aspects, the disclosure encompasses a method of treating metabolic syndrome in a subject, wherein the subject is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes, or any combination thereof, and wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0023] In some aspects, the disclosure encompasses a method of treating metabolic syndrome in a subject, wherein the subject has hypercholesterolemia, and wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0024] In some aspects, the disclosure encompasses a method of treating metabolic syndrome in a subject, wherein the metabolic syndrome is non-alcoholic fatty liver disease (NAFLD), and wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0025] In some aspects, the disclosure encompasses a method of treating metabolic syndrome in a subject, wherein the metabolic syndrome is non-alcoholic steatohepatitis (NASH), and wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0026] Further, the sustained-release compositions described herein provide an efficient means for systemically delivering bempedoic acid. As a result, a lower dose and/or less frequent administration (relative to known bempedoic acid formulations) is required to produce the same effect. In this manner, unwanted side effects can be reduced, minimized or eliminated.

[0027] In one aspect the disclosure provides for a pharmaceutical composition comprising a solid dosage form, the solid dosage form comprising bempedoic acid and a polymer matrix. In one aspect the disclosure provides for a solid dosage form that is a capsule or a tablet.

[0028] In one aspect, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: bempedoic acid and a polymeric matrix. In one aspect, the bempedoic acid is dispersed within a polymeric matrix.

[0029] In one aspect, the disclosure provides for a zero-order sustained-release composition comprising bempedoic acid and a polymer matrix. In one aspect, the zero-order sustained- release composition comprises bempedoic acid dispersed within a polymeric matrix.

[0030] In one aspect, the disclosure provides for a pharmaceutical composition comprising a solid dosage form, where the solid dosage form has physical properties such that it exhibits a certain dissolution profile when dissolution tested using a United States Pharmacopeia (USP) apparatus.

[0031] In one aspect, the disclosure provides for methods of treating or reducing the risk of cardiovascular disease in a subject by administering the compositions disclosed herein, which may be sustained release formulations in some embodiments or immediate release formulations in other embodiments. In one aspect, the disclosure provides for methods of treating a metabolic syndrome in a subject by administering the compositions disclosed herein. In one aspect, the disclosure provides for methods of treating non-alcoholic fatty liver disease (NAFLD) in a subject by administering the compositions disclosed herein. In one aspect, the disclosure provides for methods of treating non-alcoholic steatohepatitis (NASH) in a subject by

administering the compositions disclosed herein.

[0032] In another aspect, the disclosure provides for methods of administering or methods of delivering bempedoic acid by administering the compositions disclosed above and described in more detail below.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0033] These and other features, aspects, and advantages of the present invention will become better understood with regards to the following description, and accompanying drawings, where:

[0034] Figure 1A is a graph showing the plasma serum concentrations of bempedoic acid (ETC- 1002) in the liver of Male Han Wistar rats after: 1. a single bolus administration of bempedoic acid (circles) and 2. multiple split bolus administrations of bempedoic acid (squares).

[0035] Figure IB is a graph displaying the concentrations of liver Acetyl-CoA in Male Han Wistar rats after: 1. a single bolus administration of bempedoic acid (circles) and 2. multiple split bolus administrations of bempedoic acid (squares).

[0036] Figure 1C is a graph displaying the concentrations of the active species, ETC-l002-CoA in livers of Male Han Wistar rats after: (1) a single bolus administration of bempedoic acid (circles) and (2) multiple split administrations of bempedoic acid (squares).

[0037] Figure 2A is a graph showing the concentration versus times of bempedoic acid released from multiple bempedoic acid formulations upon testing in a ETSP dissolution assay.

[0038] Figure 2B is a graph showing the concentration versus time of bempedoic acid released from bempedoic acid formulations CU07-101 and CU07-118 upon testing in a ETSP dissolution assay.

[0039] Figure 3 is a graph showing the mean plasma concentration of bempedoic acid in human subjects after administration of immediate release tablet comprising 180 mg of bempedoic acid active ingredient. [0040] Figure 4 is a graph showing the mean plasma concentration of bempedoic acid in obese but otherwise healthy subjects after administration of a single dose of sustained release tablets comprising 50 mg, 100 mg, and 200 mg of bempedoic acid.

[0041] Figure 5 is a graph showing the percent change in LDL-C levels from baseline after 14 days of dosing of sustained release tablet comprising 100 mg of bempedoic acid.

[0042] Figure 6 summarizes the study design of Immediate Release (IR) Study 1.

[0043] Figure 7 summarizes the study design of Immediate Release (IR) Study 2.

[0044] Figure 8 summarizes the study design of Immediate Release (IR) Study 3.

[0045] Figure 9 summarizes the study design of the Sustained Release (SR) Study.

DETAILED DESCRIPTION OF THE INVENTION

Advantages and utility

[0046] In one aspect, the present disclosure provides for compositions and methods for sustained-release formulations of bempedoic acid.

[0047] Included are sustained-release compositions comprising bempedoic acid and a polymer matrix. The present disclosure covers a variety of components to form a sustained-release formulation comprising bempedoic acid and a polymer material. For example, the present disclosure includes formulations for parenteral use such as tablets or caplets that are filled or unfilled. In the case of unfilled caplets, the polymer may be of sufficient porosity so as to allow fluid to enter one or more caplet chambers and drive the release by osmotic pressure. One example of such this technology is the sustained-release caplet pump developed by Alza Corp as described in e.g., U.S. Pat Nos. 3,760,984, 3,845,770, 4,008,719, 4,036,227, 4,093,708, 4,111,202, 4,449,983, 4,455,143, 4,576,604, 4,673,405, 4,732,915, and 4,777,049.

[0048] Sustained release technologies of the present disclosure include delayed-release and extended release formulations. These systems modify the temporal delivery of drug delivery by allowing the active ingredient to be released either by intermittent dosing (an example of delayed-release) or by controlled or maintained dosing (an example of extended release) to a therapeutic level of the active drug for a prolonged period. Delayed-release tablets or caplets can be configured for repeat-action and are enteric-coated so that timed release is achieved by the slow diffusion of the active thru the barrier coating. Such extended release formulations may be a tablet filled with a material, usually a polymer that is a degraded in vivo in a controlled manner.

[0049] These compositions improve the bioavailability of the activated form of bempedoic acid and effectively extend the half-life of the administered drug. Such compositions are useful for treating or reducing the risk of cardiovascular disease and other related co-morbidities.

[0050] Advantages of the disclosed sustained-release bempedoic acid compositions approach are numerous. These bempedoic acid compositions not only maximize conversion to the active moiety and optimize pharmacokinetic properties, e.g., increased amount of the activated form of the drug in the liver, etc., the compositions can be used to reduce the dose per day. The sustained-release bempedoic acid compositions disclosed herein provide a therapeutically- effective amount of bempedoic acid over a longer period of time (as compared to immediate- release formulations) and in concentrations inside the therapeutic window for a longer period of time.

Definitions

[0051] Terms used in the claims and specification are defined as set forth below unless otherwise specified. The practice of the present invention includes the use of conventional techniques of pharmaceutical chemistry that are within the skill of the art.

[0052] The term“cardiovascular diseases” refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemias and/or dyslipidemias.

Cardiovascular diseases which the compositions of the present invention are useful for preventing or treating include but are not limited to arteriosclerosis; atherosclerosis; stroke; ischemia; endothelium dysfunctions, particularly those dysfunctions affecting blood vessel elasticity; peripheral vascular disease; coronary heart disease; myocardial infarction; cerebral infarction and restenosis.

[0053] In general, the term“sustained release” refers to a dosage form designed to release a drug at a predetermined (but not necessarily constant) rate in order to maintain a desired range of drug concentration over a specific period of time, e.g., 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, etc., with minimum side effects. This can be achieved through a variety of formulations, as exemplified by the bempedoic acid sustained release formulations described herein. [0054] The term“dyslipidemias” refers to disorders that lead to or are manifested by aberrant levels of circulating lipids. To the extent that levels of lipids in the blood are too high, the compositions of the invention are administered to a patient to restore normal levels. Normal levels of lipids are reported in medical treatises known to those of skill in the art. For example, recommended blood levels of LDL, HDL, free triglycerides and other parameters relating to lipid metabolism can be found at the web sites of the American Heart Association and that of the National Cholesterol Education Program of the National Heart, Lung and Blood Institute.

Currently, the recommended level of HDL cholesterol in the blood is above 35 mg/dL; the recommended level of LDL cholesterol in the blood is below 130 mg/dL; the recommended LDL: HDL cholesterol ratio in the blood is below 5: 1, ideally 3.5: 1; and the recommended level of free triglycerides in the blood is less than 200 mg/dL.

[0055] The term“metabolic syndrome” refers to a cluster of conditions— increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels— that occur together, increasing your risk of heart disease, stroke and diabetes. These conditions are the co-occurrence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia and hypertension.

[0056] The term“nonalcoholic fatty liver disease (NAFLD)” refers to a condition in which excess fat is stored in your liver. This buildup of fat is not caused by heavy alcohol use.

Nonalcoholic fatty liver disease (NAFLD) is characterized or diagnosed by the presence of fat in the liver (hepatic steatosis) either on imaging or on liver histology after the exclusion of secondary causes of fat accumulation in the liver ( e.g ., significant alcohol consumption, certain medications, and other medical conditions). NAFLD is further categorized histologically into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).

[0057] The term“simple fatty liver or nonalcoholic fatty liver (NAFL)” refers to a form of NAFLD in which you have fat in your liver but little or no inflammation or liver cell damage. NAFL is characterized with hepatic steatosis with no evidence of hepatocellular injury in the form of hepatocyte ballooning.

[0058] The term“nonalcoholic steatohepatitis (NASH)” refers to a form of NAFLD in which you have hepatitis— inflammation of the liver— and liver cell damage, in addition to fat in your liver. Inflammation and liver cell damage can cause fibrosis, or scarring, of the liver. NASH is characterized with the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis.

[0059] The term“subject” refers to any mammal including humans, and so includes mammals such as those animals of veterinary and research interest that are including, but not limited to: simians, cattle, horses, dogs, cats, and rodents. The term“subject” is interchangeable with the term“patient.”

[0060] The term“mammal” as used herein includes both humans and non-human mammals, e.g., non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0061] The term "administering" or "administration” of a drug and/or therapy to a subject (and grammatical equivalents of this phrase) refers to both direct or indirect administration, which may be administration to a subject by a medical professional, self-administration, and/or indirect administration, which may be the act of prescribing or inducing one to prescribe a drug and/or therapy to a subject.

[0062] The term "treating" or "treatment of” a disorder or disease refers to taking steps to alleviate the symptoms of the disorder or disease, or otherwise obtain some beneficial or desired results for a subject, including clinical results. Any beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer or conditional survival and reduction of tumor load or tumor volume; diminishment of the extent of the disease; delay or slowing of the tumor progression or disease progression; amelioration, palliation, or stabilization of the tumor and/or the disease state; or other beneficial results.

[0063] The term“ameliorating” refers to any therapeutically beneficial result in the treatment of a disease state, e.g., a disease state of the cardiovascular system, including prophylaxis, lessening in the severity or progression or remission thereof.

[0064] The term“in situ'’ or“in vitro” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0065] The term“ in vivo” refers to processes that occur in a living organism.

[0066] The term“sufficient amount” means an amount sufficient to produce a desired effect. [0067] The term“bempedoic acid” or“ETC-1002” refers to 8-hydroxy-2,2,l4,l4

tetramethylpentadecanedioic acid:

[0068] The term“activated bempedoic acid” or“activated ETC-1002” refers to (9R)-l- [(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydro-2-furanyl]- 3,5,9,26-tetrahydroxy-8,8,20,20,32,32-hexamethyl-l0,l4,l9-trioxo-2,4,6-trioxa-l8-thia-l 1,15- diaza-3,5-di phosphatritriacontan-33-oic acid 3,5-dioxide:

[0069] The term“zero order release rate” refers to a substantially constant release rate, such that a drug dissolves in the fluid of the environment of use at a substantially constant rate. A zero order release rate can vary by as much as about 25% and preferably by no more than about 10% from its average release rate.

[0070] The term“a therapeutically effective concentration” or“a therapeutically effective amount” means an amount of the drug that is effective to ameliorate a symptom of a disease, e.g. an amount that treats at least one symptom of cardiovascular disease or means an amount of the drug that reduces, in a statistically significant way, the risk of cardiovascular disease in the subject.

[0071] The term“phosphate buffer” means any buffer solution containing disodium hydrogen phosphate and sodium chloride. Some such buffer solutions contain potassium cations in addition to or in place of sodium cations. Regardless, the skilled artisan is well aware of the compatible inorganic compounds and organic compounds that might be added to these solutions (commercially available or otherwise standardly prepared in the laboratory) as small modifications/ additions can be made (such as the addition of relatively small amounts of Ca²⁺,

Fe³⁺, and/or ethylenediaminetetraacetic acid (ETDA) for example) as necessary as long as the capacity of the solution to maintain a reasonably constant pH is not altered. The skilled artisan can refer to, for example, Conover, W. J. Chem. Educ ., 1998, 75 (2), 153, which is herein incorporated by reference in its entirety.

[0072] The term“Cmax” refers to the overall maximum observed plasma concentration of an analyte, such as a drug or a prodrug.

[0073] The pharmacokinetic parameters described herein include: area under the plasma concentration-time curve (AUCo-t and AUCo- , both with units of amount*time/volume);

AUCx,ss; maximum plasma concentration (Cmax); time of maximum plasma concentration (Tmax); and terminal elimination half-life (T1/2). The time of maximum concentration (Tmax) is determined as the time corresponding to Cmax. Area under the plasma concentration-time curve up to the time corresponding to the last measurable concentration (AUCo-t) is calculated by numerical integration using the linear trapezoidal rule as follows:

where Ci is the plasma drug concentrations at the corresponding sampling time point ti and n is the number of time points up to and including the last quantifiable concentration.

The terminal half-life (T1/2) is calculated using the following equation:

where l is the terminal elimination rate constant. The area under the plasma concentration-time curve from time zero to infinity is calculated according to the following equation:

3

where Ciast is the last measurable concentration.

[0074] The term“Tmax” refers to the time at which the plasma concentration of an analyte, such as a drug or a prodrug, attains the maximum plasma concentration.

[0075] The term“AUCx,ss” refers to the area under the concentration-time curve during a dosing interval at steady state wherein the units are defined to be amount*time/volume.

[0076] The term“therapeutic window” is the range of doses of a drug/ API that elicits a therapeutic response without causing any significant adverse effect in patients. Generally, the therapeutic window is a ratio of the minimum effective concentration (MEC) to the minimum toxic concentration (MTC).

[0077] The term“polycellulose’ means a polymer made from cellulose, having a weight average molecular weight from 500 Da to 5,000,000 Da, optionally cross-linked, and including derivatives of cellulose. Such derivatives include“functionalized” cellulose polymers that result from the reaction or cross-linking of cellulose polymers with one or more organic functional groups. The functional group(s) is/are pendent and although they may change the chemo- physical properties of the cellulose polymer, they do not fundamentally change (1) the core structure of the saccharide repeating chemical motif, or (2) where (i.e., carbon numbers on the respective saccharides that the O-glycosidic linkage is attached thru) and how (alpha/beta) the saccharides are covalently attached. The skilled artisan is well aware of such functional groups and methods of preparing these derivatives. The skilled artisan can refer to Handbook of Polymers for Pharmaceutical Technologies: Biodegradable Polymers, Vol. 3, Vijay Kumar Thakur & Manju Kumari Thakur, Wiley, 2015, which is herein incorporated by reference in its entirety.

[0078] The term“weight average molecular weight” refers to Mw or a molecular weight that takes into account the molecular weight of a chain in determining contributions to the molecular weight average. Mw is determined by analytical methods that are sensitive to the molecular size of the polymer chains rather than just the count of chains. Analytical techniques such dynamic light scattering provide Mw. Mw is calculated by:

where Mi is the molecular weight of a chain and Ni is the number of chains of that molecular weight.

[0079] It must be noted that, as used in the specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise.

Pharmaceutical compositions

[0080] Herein disclosed are sustained-release pharmaceutical dosage forms comprising a solid oral dosage form. In some embodiments, the solid oral dosage form comprises bempedoic acid and a polymer matrix. In some embodiments, the solid oral dosage form comprises bempedoic acid dispersed within a polymeric material.

[0081] In some aspects, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral dosage form comprising bempedoic acid and a polymer matrix, wherein the polymer is hydroxypropyl methylcellulose (HPMC). In some aspects, the solid oral dosage form comprises bempedoic acid dispersed within HPMC. In some aspects, the bempedoic acid is not dispersed within the polymer. In some aspects, the bempedoic acid is not dispersed within HPMC.

[0082] In one aspect, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: bempedoic acid and a polymeric matrix, and wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 12 hours, over a period of 14 hours, over a period of 16 hours, over a period of 18 hours, over a period of 20 hours, over a period of 22 hours, over a period of 24 hours, over a period of 36 hours, or over a period of 48 hours when administered to a subject.

[0083] In one aspect, the disclosure provides for a solid oral dosage form that is a gelatin capsule. In one aspect, the solid oral dosage form is a hard-shelled capsule containing spheronized powder particles. In one aspect, the solid oral dosage form that is a soft-shelled capsule. In one aspect, the solid oral dosage form is gelatin capsule further comprising a powder excipient. In one aspect, the solid oral dosage form is gelatin capsule further comprising an excipient in a suspension. In one aspect, the solid oral dosage form is gelatin capsule further comprising one or more plasticizers such as glycerin or sorbitol. In one aspect, the solid oral dosage form is gelatin capsule further comprising one or more of: coloring agents, preservatives, disintegrants, lubricants and surface treatment agents.

[0084] In one aspect, the disclosure provides for a solid oral dosage form that is a tablet. In one aspect, the disclosure provides for a solid oral dosage form that is a lozenge.

[0085] In one aspect, the disclosure provides for a solid oral dosage form that is a gelatin capsule. In one aspect, the disclosure provides for a solid oral dosage form that is a capsule containing a solid composition comprising bempedoic acid and one or more excipients.

Bemyedoic Acid— Structure and Synthesis

[0086] The structure of bempedoic acid (also known as ETC-1002 or 8-hydroxy-2,2,l4,l4- tetramethylpentadecaned-ioic acid) is:

[0087] ETC-1002 and the processes for the synthesis of ETC-1002 are disclosed in issued ET.S. Patent No. 7,335,799. The details of this process can be found in published ET.S. Patent

Publication No. US2005/0043278A1, in paragraphs [0247] - [0343] of the specification, which is herein incorporated by reference in its entirety.

[0088] As used herein the term“bempedoic acid” also encompasses pharmaceutically acceptable salts of the compound. Such pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, citric, tartaric, methanesulfonic, fumaric, malic, maleic and mandelic acids, mucate, N-oxide, sulfate, acetate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bi(heptafluorobutyrate ), bi(methylcarbamate ),

bi(pentafluoropropionate ), bi(pyridine-3-carboxylate ), bi(trifluoroacetate ), bitartrate, chlorhydrate, and sulfate pentahydrate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methyinitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium propionate, and zinc salts and the like.

Polymer matrix

Hydrophilic & hydrophobic components

[0089] According to the present disclosure, a major component of the matrix for the sustained- release formulations can be a hydrophilic polymer. Hydrophilic polymers are well suited for oral controlled drug delivery because they can reproduce a desirable drug profile and are cost effective. However, bempedoic acid is hydrophobic and the process of absorption in the body relies to some extent on the lipophilic nature of a dosage form. Consequently, a desired release profile can be obtained by including both hydrophilic and hydrophobic components and/or excipients in the dosage form, the exact nature of which is worked out on a case by case basis.

[0090] The matrix of sustained-release pharmaceutical compositions includes a polymer as a major component. Both synthetic and natural polymers, and/or their derivatives, and/or combinations thereof, can be used in compositions within the scope of the present disclosure.

[0091] Polysaccharides can be used as a polymer in the oral sustained-release formulations of the present disclosure. Such formulations can include cellulose (polymer) derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), ethylcellulose, and methylcellulose (MC). Each cellulose derivative possesses different grades and has different properties in terms of molecular weight, viscosity, solubility, hydration, etc. Accordingly, distinct polymers and their respective distinct derivatives can be used to formulate dissolution-controlled and diffusion-controlled release systems of the present disclosure. Polymers following diffusion-control are generally water insoluble, though some are not. Commonly used polymers for diffusion-controlled systems (reservoir and monolithic systems) include cellulose ( e.g ., ethylcellulose), collagen, nylon, poly(alkylcyanoacrylate), polyethylene, poly(ethylene- co -vinylacetate), poly(hydroxyethyl methacrylate), poly(hydroxypropylethyl methacrylate), poly(methyl methacrylate), polyurethane, and silicon rubber.

[0092] Besides dissolution release kinetics, polymer glass transition temperature (Tg) is a very important polymer property. Tg affects properties such as flowability, compactibility, flexibility, permeability, etc.

[0093] Plasticizers can optionally be included into polymer blends of the present disclosure. Examples of plasticizers are glycerin, glyceryl triacetate (triacetin), poly(ethylene glycol) (PEG), and propylene glycol. Plasticizers are also commonly used in film coating to help polymer(s) achieve desired film quality. Since plasticizers reduce the stiffness of polymer molecules, they are useful for increasing the diffusion rate of bempedoic acid through the dosage form.

Synthetic/ natural polymers & derivatives

[0094] So called“natural polymers” are polymeric substances that are found in nature and can be extracted. These are often water-soluble materials. Examples of naturally occurring polymers include polysaccharides such as cellulose, polynucleotides such as RNA or DNA, and polyamides such as proteins.

[0095] Synthetic polymers are derived from petroleum oil, and made by scientists and engineers. Examples of synthetic polymers include (poly)vinyl, acrylates, nylon, polyethylene, polyester, and Teflon.

[0096] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a synthetic polymer and is selected from the group consisting of: poly(vinyl alcohol)s (PVA), poly(acrylic acid)s, poly(ethylene oxide) (PEOs), poloxamers, pluronics, and

polymethacrylates.

[0097] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a combination of two synthetic polymers and the two polymers are selected from the group consisting of: Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611 and Aqualon.

[0098] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropyl cellulose), hydroxyethylcellulose (HEC), EC(ethyl cellulose), MC (methyl cellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose, and Aqualon. In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a combination of two polymers and the two polymers are selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropyl cellulose), hydroxyethylcellulose (HEC), EC(ethyl cellulose),

MC (methyl cellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose, and Aqualon. In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a combination of three polymers and the three polymers are selected from the group consisting of:

hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropyl cellulose), hydroxyethylcellulose (HEC), EC(ethyl cellulose), MC (methyl cellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose, and Aqualon.

[0099] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a combination of four or more synthetic polymers selected from any of the polymers named herein.

[00100] In any of the aspects described herein, the present disclosure provides for a polymer matrix wherein the polymer is a synthetic polymer and the matrix includes a plasticizer. In some aspects, the plasticizer may be one or more of the plasticizers named herein. Plasticizers are well known in the art and, as a result, the skilled artisan may consult a reference text disclosed herein and choose any one of the plasticizers listed within. Examples of plasticizers include, but are not limited to: glycerin, glyceryl triacetate (triacetin), poly(ethylene glycol) (PEG), propylene glycol, and combinations thereof.

[00101] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is selected from the group consisting of: polycellulose, microcrystalline cellulose, polyvinyl acetate, polyvinylpyrrolidone, polyacrylate, a pH-insensitive ammonium polymer, and mixtures thereof.

[00102] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is selected from the group consisting of: (poly)cellulose ( e.g ., ethylcellulose), collagen, nylon, poly(alkylcyanoacrylate), polyethylene, poly (ethylene-co-vinylacetate),

poly(hydroxyethyl methacrylate), poly(hydroxypropylethyl methacrylate), poly(methyl methacrylate), polyurethane, and silicon rubber. [00103] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is microcrystalline cellulose. In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a mixture of microcrystalline cellulose and polycellulose. In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a mixture of microcrystalline cellulose and hydroxypropylmethyl cellulose (HPMC). In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is

hydroxypropylmethyl cellulose (HPMC). In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a polycellulose.

Porosity & permeability

[00104] API tableting and solid granulating has an effect on dosage form density, porosity, and hardness, disintegration and particle size. Increases in solid density and hardness will result in a decrease in permeability and solvent penetrability.

[00105] In some aspects, the present disclosure provides for a polymer matrix that is not porous but rather is amorphous. In some aspects, the present disclosure provides for a polymer matrix that has a relatively low porosity. Porosity can be calculated by:

where e is porosity of the matrix, T is tortuosity, Co is the total amount of drug present per unit volume in the matrix, Ca is the solubility of the drug in the release medium, at time, t, M is the amount of drug release per unit area, and Ds is the diffusion coefficient of drug in the release medium.

[00106] In some aspects, the present disclosure provides for a polymer matrix with a mean particle size from 10-200 pm. In some aspects, the present disclosure provides for a polymer matrix with a mean particle size from 20-180 pm. In some aspects, the present disclosure provides for a polymer matrix with a mean particle size from 20-150 pm. In some aspects, the present disclosure provides for a polymer matrix with a mean particle size from 40-100 pm.

[00107] In some aspects, the present disclosure provides for a polymer matrix with a mean pore size from 10-200 nm, from 20-180 nm, from 20-150 nm, or from 40-100 nm.

Synthesis examples

[00108] In some aspects, the present disclosure provides for a polymer matrix wherein the polymer is a derivative of a synthetic or natural polymer. The skilled artisan can synthesize the monomer compound with organic synthetic techniques so long as the reacting organic functional group of the monomer does not also simultaneously (thermally) polymerize. Another way for the skilled artisan to prepare a derivative of a synthetic polymer is to polymerize (in a controlled polymerization reaction) the desired polymer, z.e., starting material, or in the case of a natural polymer, obtain a desired commercial natural polymer starting material from companies such as Sigma Aldrich, TCI Chemicals, Strem, etc. and then perform one or more organic synthesis reactions to the polymer to functionalize it with the desired pendant groups. The reaction can be initiated with organic functional groups of the polymer that are potentially reactive, i.e. ones that either nucleophilic or electrophilic in nature. The skilled artisan is careful not to react the functional groups that covalently attach each of the monomeric units of the polymer since reacting these groups would degrade the polymer and decrease the average molecular weight of the polymer chains. However, in the case of natural polymers it is often that such chain scission does occur and the skilled artisan will try to mitigate such harsh reaction conditions.

[00109] One example of the first approach employs an acrylate polymer. An acrylate monomer can be functionalized through the carboxylate via esterification or amidation reactions with a desired nucleophilic functional group becoming the pendant group. For example, acrylic acid can be functionalized with a polyethylene glycol of 3000 Da through Steglich esterification reaction conditions. The resulting ethylene glycol acrylate ester can be polymerized under thermal conditions with AIBN“azoisobutylnitrile” (optionally with another monomeric compound like methyl methacrylate to produce a copolymer) in a controlled manner to make a polymer with the desired Tg and other physical properties.

[00110] Another example of synthesizing a polymer derivative applies to natural polymer and includes preparing the derivative by functionalizing the natural polymer with organic functional groups. For example, the natural polymer cellulose can be reacted through hydroxyl functional groups with propylene oxide and methyl chloride with sodium hydroxide reagent. The product formed is a cellulose polymer (polycellulose) having (methyl and isopropyl) ether functional groups at a certain percentage of the former hydroxyl functional groups. In some aspects, the percentage of ether functional groups is from 0.1-50%, preferably from 0.1-45%, preferably from 0.1-30%, preferably from 0.1-15%, preferably from 0.1-10%, preferably from 0.1-9%, preferably from 0.1-8%, preferably from 0.1-7%, preferably from 0.1-6%, preferably from 0.1- 5%, preferably from 0.1-4%, preferably from 0.1-3%, preferably from 0.1-2%, preferably from 0.1-1%, or more preferably from 0.1-0.5%.

[00111] Such derivatization reactions and preparations are well within the purview of the skilled artisan. Textbooks such as Biodegradable Polymers in Pharmacy and Medicine.

Classification, Chemical Structure, Principles of Biodegradation and Use, Jan Gajdziok Roman Gonec David Vetchy, Verlag, 2016; Cellulose and Cellulose Derivatives: Synthesis,

Modification and Applications, Ibrahim H. Mondal, Nova Science Publishers Incorp., 2015 and Biomedical Polymers: Synthesis and Processing, Vinod B. Damodaran, Divya Bhatnagar, N. Sanjeeva Murthy, Springer, 2016 which are herein incorporated by reference in their entirety, are available for the skilled artisan for reference.

Excipients

Components for a solid dosage form

[00112] The dissolution rate of a pure drug can be altered when mixed with various excipients during the manufacturing process of solid dosage forms.

[00113] The skilled artisan can commercially buy certain compounds and materials to use for excipients or rather can derivatize known compounds and starting material. Such methods of synthesis (and of using these excipients in formulating solid dosage forms) are well known in the art and found in the primary texts reference herein as well as in Handbook of Pharmaceutical Excipients, 4th ed. Rowe RC, Sheskey PJ, Weller PJ, ed. London, UK: AphA and the

Pharmaceutical Press, 2003, which is herein incorporated by reference in its entirety.

[00114] In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid and a polymer matrix, wherein the solid dosage form further comprises a surfactant. In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid and a polymer matrix, wherein the solid dosage form further comprises an anionic surfactant. In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid and a polymer matrix, wherein the solid dosage form further comprises an anionic surfactant, wherein the anionic surfactant is sodium lauryl sulfate.

[00115] In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid and a polymer matrix, wherein the solid dosage form further comprises microcrystalline cellulose and sodium lauryl sulfate. [00116] Other suitable compounds to use as excipients for the solid oral dosage forms disclosed herein are also found in the primary textbooks referenced herein such as Remington, The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co. 2l^st Ed.

Classes of excipients

[00117] Excipients can be added to satisfy certain pharmaceutical functions such as diluents (fillers), dyes, binders, granulating agents, disintegrants, and lubricants.

[00118] In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid and a polymer matrix, wherein the solid dosage form further comprises a binder, a filler, a diluent, a dye, a granulating agent, a disintegrant, a lubricant, or any combination thereof.

[00119] In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid, a polymer matrix, and a binder, a filler, a diluent, a dye, a granulating agent, a disintegrant, a lubricant, or any combination thereof. In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid, a polymer matrix, and a binder and a lubricant. In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid, a polymer matrix, and a binder and a lubricant, wherein the lubricant is a surfactant. In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid, a polymer matrix, and a binder and a lubricant, wherein the lubricant is a sodium lauryl sulfate.

Solid dosase forms

[00120] Pharmaceutical dosage forms can include a variety of solid forms, e.g., the pharmaceutical may be a pill, e.g., a tablet, a tablet like buccal dosage form being a tablet or lozenge, e.g. a sub-lingual or orally-disintegrating gum, pill or lozenge, a thin film, etc.

[00121] Genetically, sustained-release solid oral dosage forms may be categorized into three basic categories: matrix-based tablets/ pills, multi-particulate solids, and osmotic solid dosage forms. The present disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises bempedoic acid and a polymer. In some aspects the polymer is in the form of a polymer matrix. In other aspects, the polymer is a neat, dry powder. The presently disclosed solid oral dosage form can be formulated into a dosage form of any one of the categories mentioned above. [00122] In one aspect, the present disclosure provides for a solid oral dosage form comprising bempedoic acid and a polymer matrix.

[00123] In one aspect, the present disclosure provides for a solid oral dosage form, wherein the solid dosage form is a tablet.

[00124] In one aspect, the present disclosure provides for a solid oral dosage form, wherein the solid dosage form is a gelatin capsule. In one aspect, the present disclosure provides for a solid oral dosage form, wherein the solid dosage form is a gelatin capsule further comprising a powder excipient.

[00125] In one aspect, the present disclosure provides for a solid oral dosage form, wherein the dosage form is not diffusion-controlled but rather dissolution controlled.

Formulation properties

[00126] In some aspects, the present disclosure provides for a solid dosage form comprising bempedoic acid, wherein the dosage form provides for a sustained-release of bempedoic acid over a period of at least 2-8 hours following oral administration, or produces a certain release profile for bempedoic acid, e.g ., a Cmax plateau sustained for at least an hour for bempedoic acid (or its metabolite, activated bempedoic acid) following oral administration of bempedoic acid.

Weight ranges & composition amounts

[00127] In one aspect, the disclosure provides for a solid oral dosage form wherein the bempedoic acid is from 30-50% by weight, from 35-55% by weight, from 40-60% by weight, from 45-65% by weight, 50-70% by weight, 55-75% by weight, or 60-80% by weight.

[00128] In some aspects, the present disclosure provides for the administration of a sustained release formulation of bempedoic acid wherein the dosage is 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.

[00129] In some aspects, the present disclosure provides for the administration of a sustained release formulation of bempedoic acid 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.

[00130] In one aspect, the disclosure provides for a solid oral dosage form wherein HMPC is from 0-10% by weight, from 0-5% by weight, from 0-4% by weight, from 0-3% by weight, from 0-2% by weight, or from 0-1% by weight.

[00131] In one aspect, the disclosure provides for a solid oral dosage form comprising:

bempedoic acid from 40-60% by weight and HPMC is from 0-3% by weight, or the bempedoic acid is from 60-80% by weight and HPMC from 0-5% by weight.

[00132] In one aspect, the disclosure provides for a solid oral dosage form wherein the pharmaceutical dosage form comprises:

60.0% w/w bempedoic acid;

37.3% w/w microcrystalline cellulose;

0.7 w/w hydroxypropyl methylcellulose; and

2% w/w sodium lauryl sulfate.

[00133] In one aspect, the disclosure provides for a solid oral dosage form wherein the pharmaceutical dosage form comprises:

60.0% w/w bempedoic acid;

9.3% w/w microcrystalline cellulose;

28.0% w/w microcrystalline cellulose / sodium carboxymethylcellulose;

0.7% w/w hydroxypropyl methylcellulose

2.0% w/w sodium lauryl sulfate.

[00134] In one aspect, the disclosure provides for a solid oral dosage form wherein the pharmaceutical dosage form comprises:

60.0% w/w bempedoic acid;

33.7% w/w microcrystalline cellulose;

3.7% w/w sodium carboxymethylcellulose;

0.7% w/w hydroxypropyl methylcellulose; and 2.0% w/w sodium lauryl sulfate.

[00135] In some aspects, the present disclosure provides for a pharmaceutical composition wherein the composition comprises at least 40% and no more than 80% bempedoic acid w/w, at least 45% and no more than 80% bempedoic acid, at least 50% and no more than 80% bempedoic acid w/w, at least 55% and no more than 80% bempedoic acid w/w, at least 60% and no more than 80% bempedoic acid w/w, at least 65% and no more than 80% bempedoic acid w/w, at least 70% and no more than 80% bempedoic acid w/w, at least 75% and no more than 80% bempedoic acid w/w.

[00136] In some aspects, the present disclosure provides for a pharmaceutical composition wherein the composition comprises at least 5% and no more than 50% of the polymer w/w, at least 10% and no more than 50% of the polymer w/w, at least 15% and no more than 50% of the polymer w/w, at least 20% and no more than 50% of the polymer w/w, at least 25% and no more than 50% of the polymer w/w, at least 30% and no more than 50% of the polymer w/w, at least 35% and no more than 50% of the polymer w/w, at least 40% and no more than 50% of the polymer w/w, at least 45 and no more than 50 of the polymer w/w.

[00137] In some aspects, the present disclosure provides for a pharmaceutical composition wherein the polymer component is hydroxypropyl methylcellulose (HPMC) and is at least 0.1% and no more than 10% of the HPMC w/w, at least 0.5% and no more than 10% of the HPMC w/w, at least 1% and no more than 10% of HPMC w/w, at least 5% and no more than 10% of the HPMC w/w.

[00138] In some aspects, the present disclosure provides for a pharmaceutical composition wherein the polymer is microcrystalline cellulose and is at least 1% and no more than 60% of the microcrystalline cellulose w/w, at least 5% and no more than 60% of the microcrystalline cellulose w/w, at least 10% and no more than 60% of microcrystalline cellulose w/w, at least 15% and no more than 60% of the microcrystalline cellulose w/w, at least 20% and no more than 60% of the microcrystalline cellulose w/w, at least 25% and no more than 60% of the microcrystalline cellulose w/w, at least 30% and no more than 60% of the microcrystalline cellulose w/w, at least 35% and no more than 60% of the microcrystalline cellulose w/w, at least 40% and no more than 60% of the microcrystalline cellulose w/w, at least 45% and no more than 60% of microcrystalline cellulose w/w, at least 50% and no more than 60% of the microcrystalline cellulose w/w, at least 55% and no more than 60% of the microcrystalline cellulose w/w.

[00139] In some aspects, the present disclosure provides for a pharmaceutical composition wherein the polymer is sodium carboxymethylcellulose and is at least 1% and no more than 50% of the sodium carboxymethylcellulose w/w, at least 5% and no more than 50% of the sodium carboxymethylcellulose w/w, at least 10% and no more than 50% of sodium

carboxymethylcellulose w/w, at least 15% and no more than 50% of the sodium

carboxymethylcellulose w/w, at least 20% and no more than 50% of the sodium

carboxymethylcellulose w/w, at least 25% and no more than 50% of the sodium

carboxymethylcellulose w/w, at least 30% and no more than 50% of the sodium

carboxymethylcellulose w/w, at least 35% and no more than 50% of the sodium

carboxymethylcellulose w/w, at least 40% and no more than 50% of the sodium.

[00140] In some aspects, the present disclosure provides for a pharmaceutical composition comprising sodium lauryl sulfate and is at least 0.1% and no more than 10% of the sodium lauryl sulfate w/w, at least 0.5% and no more than 10% of the sodium lauryl sulfate w/w, at least 1% and no more than 10% of sodium lauryl sulfate w/w, at least 5% and no more than 10% of the sodium lauryl sulfate w/w.

[00141] In some aspects, the present disclosure provides for a pharmaceutical composition comprising sodium starch glycolate and is at least 0.1% and no more than 10% of the sodium starch glycolate w/w, at least 0.5% and no more than 10% of the sodium starch glycolate w/w, at least 1% and no more than 10% of sodium starch glycolate w/w, at least 5% and no more than 10% of the sodium starch glycolate w/w.

[00142] In some aspects, the present disclosure provides for a pharmaceutical composition comprising a ratio of bempedoic acid to polymer of about 4 to 1.

[00143] In some aspects, the present disclosure provides for a pharmaceutical composition comprising a ratio of bempedoic acid to polymer of about 3 to 2.

[00144] In some aspects, the present disclosure provides for a pharmaceutical composition comprising a ratio of bempedoic acid to polymer of about 2 to 1.

[00145] In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from l-200pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from 1-150pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from l-l25pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from l0-l00pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from 20-l00pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from 40-l00pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from 50-l00pm. In some aspects, the present disclosure provides for a solid dosage form, wherein the mean particle size is from 80-l00pm.

Threshold & saturation

[00146] Toxicity -related side effects often result post administration when either the rate of rise and/or actual bempedoic acid serum plasma concentrations exceed the threshold maximum tolerable concentration (MTC). At the same time, in order to obtain a therapeutic effect, concentrations need to be sustained above a minimum effective concentration (MEC).

[00147] In some aspects, the present disclosure provides for a solid dosage form wherein, when dosed as recommended, the resulting maximum serum concentration is measured over the dose interval.

[00148] In some aspects, the present disclosure provides for a solid dosage form wherein, when dosed as recommended, the resulting minimum serum concentration (MEC) is measured over the dose interval (i.e., the period between repeated dosings).

[00149] In some aspects, the present disclosure provides for a solid dosage form, wherein bempedoic acid concentration is maintained between MEC and MTC for: at least 8 hours and no more than 48 hours; at least 12 hours and no more than 48 hours; or at least 24 hours and no more than 36 hours after administration.

[00150] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours when administered to a subject. In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 36 hours when administered to a subject. In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 48 hours when administered to a subject.

Unit dose

[00151] A unit dose form is a term that is generally understood by the skilled artisan. A unit dose form is a pharmaceutical drug product that is marketed for a specific use. The drug product includes the active ingredient(s) and any inactive components, most often in the form of polymers and pharmaceutically acceptable carriers or excipients.

[00152] In some aspects, the sustained-release composition is formulated in one (1) unit dose form that is effective for at least twelve (12) hours, eighteen (18), twenty four (24), thirty (30), thirty six (36), or forty eight (48) hours.

[00153] In some aspects, the sustained-release composition is formulated in at least two (2) separately distinct unit dose forms with distinct release profiles.

Pharmacodynamics

[00154] Orally administered API formulations must be absorbed before they become bioavailable, circulating systemically. For most drugs/ APIs, pre-systemic clearance occurs at sites of the GI tract and significantly affects drug/ API absorption. Degradation of orally administered drugs occurs, to some extent, with hydrolysis in the stomach and upper GI or by digestion from enzymes in the gut. Moreover, drugs are metabolized by microorganisms in the gut and by enzymes in the liver (z.e., the first pass effect). These degradation processes can affect variable or poor drug absorption. It is generally observed that the greater the efficiency of the absorption of the drug/ API, the greater the bioavailability of the API. Measures of

bioavailability include values for Cmax, Tmax, and AUC, amongst others. Blood plasma concentrations of bempedoic acid in a subject may be determined by clinical assays, well known to the skilled artisan, to determine pharmacokinetic parameter values and to ascertain the correlation between tolerability and clinical effect and blood plasma concentrations of bempedoic acid.

[00155] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides for bempedoic acid a Cmax of at least 8 pg/L. [00156] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides for bempedoic acid an AUC of at least 0.6 ng*hr/mL per mg of bempedoic acid.

[00157] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides for bempedoic acid a T1/2 of at least 24 hours.

[00158] In some aspects, the present disclosure provides for a solid d osage form, wherein the solid dosage form provides for activated bempedoic acid a Cmax of at least 10 pg/L.

[00159] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides for activated bempedoic acid a Cmax of 60 pg/mL, 57 pg/mL, 55 pg/mL, 53 pg/mL, 50 pg/mL, 47 pg/mL, 45 pg/mL, or 40 pg/mL.

[00160] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides for activated bempedoic acid an AUC of at least 0.8 ng*hr/mL per mg of bempedoic acid .

[00161] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides for activated bempedoic acid at least 28 hours.

[00162] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides an AUC of 1.1 ng*hr/mL per mg of bempedoic acid following oral administration of a single 180 mg bempedoic acid capsule.

[00163] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid dosage form provides an AUC of at least 50 pg*hr/L per mg of activated bempedoic acid following oral administration of a single 180 mg bempedoic acid capsule.

Zero order release

[00164] The ideal release of an API from a given dosage form maintains therapeutic blood and tissue levels of the drug for an extended period of time, usually greater than 8 hours. Such a maintained concentration is typically accomplished by obtaining a zero-order release rate of the API from the dosage form. Zero-order release is an API release from the dosage form that is independent of the amount of drug in the delivery system (z.e., a constant release rate).

[00165] In one aspect, the disclosure provides for a solid oral pharmaceutical dosage form that has a zero order release rate for at least 12 hours when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20°C, the solid oral pharmaceutical dosage form comprising: bempedoic acid and a polymer matrix, wherein the pharmaceutical dosage form has a hardness of 2-30 kg and is either shaped as a sphere or else has a ratio of thickness to diameter effective to permit erosion and penetration control sufficient for controlled surface erosion thereof when dissolution tested.

[00166] In one aspect, the disclosure provides for a solid oral pharmaceutical dosage form that has a zero order release rate for at least 6 hours, for at least 8 hours, for at least 10 hours, for at least 12 hours, for at least 14 hours, for at least 16 hours, for at least 18 hours, for at least 20 hours, for at least 22 hours, for at least 24 hours, or for at least 36 hours. In some aspects, each solid oral pharmaceutical dosage form corresponding to the 6-36 hour period of time for zero- order release when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20°C maintains a zero-order rate of release over that period of time.

Dissolution & pH

[00167] Solid dosage forms may release the API according to erosion (dissolution) and/or diffusion mechanisms depending on the nature of the polymer matrix and API chemo-physical properties.

[00168] Erosion (dissolution) of many API formulations, and of known bempedoic acid formulations in particular, are prone to dose“dumping.” That is, once the dosage form has been solvated beyond a certain threshold, a significant amount of the API leaks out of the

compositions in an uncontrolled matter. The effect of the pH of the local media on the release of the API is largest on those systems that are under erosion control. At relatively high and low pH media, API formulations are susceptible to hydrolysis or degradation such that the dosage form becomes sufficiently solvated so that erosion, and dumping is more likely to occur.

[00169] The sustained-release bempedoic acid solid oral dosage forms herein disclosed are also characterized (at least in part) by their physical characteristics, i.e., the physical properties of the dosage form that provide a certain dissolution profile of bempedoic acid.

[00170] Herein disclosed are sustained-release pharmaceutical dosage forms comprising a solid oral dosage form, wherein the solid oral dosage form comprises bempedoic acid and a polymer matrix and wherein the solid oral dosage form does not dump bempedoic acid for 24 after administration. In one aspect, the disclosure provides for a solid oral dosage form that does not dump more than 10% bempedoic acid in media of pH 8 after 30 minutes.

[00171] Solid dosage form erosion and uptake of the dissolution medium uptake may be determined, amongst other ways, gravimetrically in the same conditions as used for the dissolution testing. Basic calculations are as shown below.

Dissolution Medium i ¾

00 fWet Weight - Remaining

Remaining Dry Weight

Remaining Mass ^~ 100 (Remaining Dry Weight!

Original Dry Weight

[00172] The rotating disk system of USP Wood Apparatus or USP Dissolution Apparatus 2 (United States Pharmacopeia 34/National Formulary 29, 2011, General Chapter <711>

Dissolution, herein incorporated by reference in its entirety, see also Chapter 35, pages 679-687 in Remington, J. P. (1995). Remington, The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co. 2l^st Ed., also herein incorporated by reference in its entirety) is used by skilled artisans to determine the dissolution profile or dissolution rate for sustained-release dosage forms.

Briefly, the apparatus has three parts: the steel punch, a die, and a base plate. The die base is attached to the base plate and the fixed screws on the base plate are inserted onto the die. The punch is inserted into the die cavity thereby compressing the material inside. The pellet and die assembly are then inserted with the pellet side up, into the bottom of the dissolution vessel (1 liter). It is important that the vessel be flat bottomed. The paddles of the USP Apparatus 2 stirs the material and care is taken that no air bubbles are formed on the pellet surface and that no change in the temperature (37 °C) occurs.

[00173] The dissolution apparatus can be USP Type I, II, IV, and VII, that is, rotating basket, rotating paddle, flow-through cell, and reciprocating holder. In the dissolution medium the skilled artisan may select certain parameters based on API stability, sensitivity of assay, sink condition in which the final drug concentration is at least three times lower than a saturated concentration is needed, etc. It is worth noting that current USP dissolution tests exert minimal mechanical force on the solid dosage form.

[00174] In one aspect, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 °C exhibits a drug release profile substantially corresponding to the following pattern: after 2 hours, no more than 30% of the total mass of bempedoic acid is released; after 4 hours, no more than 75% of the total mass of bempedoic acid is released; and after 8 hours, no more than 90% of the total mass of bempedoic acid is released.

[00175] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form comprises:

Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20°C exhibits a drug release profile substantially corresponding to the following pattern: after 1 hour, no more than 8% of the total mass of bempedoic acid is released, or no more than 10% of the total mass of bempedoic acid is released, or no more than 6% of the total mass of bempedoic acid is released, or no more than 4% of the total mass of bempedoic acid is released, or no more than 3% of the total mass of bempedoic acid is released.

[00176] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form comprises:

Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 °C exhibits a drug release profile substantially corresponding to the following pattern: after 2 hours, no more than 30% of the total mass of bempedoic acid is released, or no more than 25% of the total mass of bempedoic acid is released, or no more than 20% of the total mass of bempedoic acid is released, or no more than 15% of the total mass of bempedoic acid is released, or no more than 13% of the total mass of bempedoic acid is released.

[00177] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form comprises:

Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20°C exhibits a drug release profile substantially corresponding to the following pattern: after 3 hours, no more than 50% of the total mass of bempedoic acid is released, or no more than 45% of the total mass of bempedoic acid is released, or no more than 40% of the total mass of bempedoic acid is released, or no more than 35% of the total mass of bempedoic acid is released, or no more than 33% of the total mass of bempedoic acid is released.

[00178] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form comprises:

Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 °C exhibits a drug release profile substantially corresponding to the following pattern: after 4 hours, no more than 75% of the total mass of bempedoic acid is released, or no more than 65% of the total mass of bempedoic acid is released, or no more than 60% of the total mass of bempedoic acid is released, or no more than 55% of the total mass of bempedoic acid is released, or no more than 53% of the total mass of bempedoic acid is released.

[00179] In some aspects, the present disclosure provides for a solid dosage form, wherein the solid oral dosage form comprises:

Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20°C exhibits a drug release profile substantially corresponding to the following pattern: after 8 hours, no more than 90% of the total mass of bempedoic acid is released, or no more than 85% of the total mass of bempedoic acid is released, or no more than 80% of the total mass of bempedoic acid is released, or no more than 78% of the total mass of bempedoic acid is released, or no more than 75% of the total mass of bempedoic acid is released.

[00180] In some aspects, the sustained-release composition does not release more than 3 mg of bempedoic acid during a given 5 minute period of time up to 8 hours after administration, during a given 15 minute period of time up to 8 hours after administration, during a given 30 minute period of time up to 8 hours after administration, or during a given 1 hour period of time up to 8 hours after administration. Preparation of the formulation

[00181] Numerous references exist that inform the skilled artisan how to make the sustained- release pharmaceutical compositions (and solid oral dosage forms) disclosed herein, for example, see the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association ( current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), (current edition), all of which are hereby incorporated by reference in their entirety. Briefly, in preparing sustained-release formulations in an oral dosage form, many commercially-available excipients and pharmaceutical media are employed. For example, suitable excipient carriers and additives added include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, many of which are disclosed in the above section entitled“Excipients”. Specific excipients may include, for example, sucrose, mannitol, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium lauryl sulphate, chremophor, tweens, spans, pluronics, microcrystalline cellulose, calcium phosphate, talc, fumed silica, hydroxypropyl methyl cellulose, wax, and fatty acids, etc.

[00182] As mentioned above, the solid oral dosage forms fall into: matrix-based tablets/ pills, multi-particulate solids, and osmotic solid categories. Many distinct or separate processes can be used for all of or either one of the three approaches, however there are some preferred or usual processes for each.

[00183] The formulation processes for making matrix-based tablets or pills is based on both diffusion and dissolution (i.e., matrix erosion) controlled systems. The drug release from hydrophilic matrix systems involves both diffusion and dissolution since the size of the matrix decreases as more drug/ API is released, the amount of drug/ API released is then also decreased, that is, resulting in a non-zero-order release. Typical lipophilic matrix systems are often observed to be only under diffusion control. Herein disclosed solid dosage forms may comprise either a hydrophilic matrix or a lipophilic matrix.

[00184] The skilled artisan can use a variety of granulation processes to formulate the matrix- based solid dosage forms disclosed herein. These include dry blend (direct compression), roller compaction, wet granulation, fluid bed granulation, foam granulation and melt extrusion granulation, all of which are useful for making matrix tablets.

[00185] Toward this end, the processes to make solid dosage form include a generic processes such as manufacturing by the wet granulation technique. For example, bempedoic acid and polymer(s) are blended using a solvent, such as methanol, as the granulation fluid. The remaining excipients are dissolved in a portion of granulation fluid and this mixture is wet blended slowly added to the bempedoic acid with continual mixing in the blender. Granulating fluid is added until a wet blend is produced, which wet mass blend is then forced through a predetermined screen onto oven trays. The blend is dried for 18 to 24 hours at 24 C. to 40 C. in a forced-air oven. The dried granules are then sieved. Then a lubricant such as magnesium stearate is granulated into the mixture and then put into milling jars. Milling involves mixing on ajar mill for about 10-30 minutes. Following that, the composition is then co-pressed and perhaps coated with a further excipient.

[00186] Considerations for which process to use include drug loading, flowability, and compactibility. For example, both wet granulation and fluid bed granulation may not be optimal for moisture-sensitive drugs while melt extrusion granulation may not be suitable for thermally unstable drugs.

[00187] On the other hand, multi-particulate solid dosage forms comprise both the drug/ API and layered beads or microspheres. Fluid-bed granulation, extrusion and spheronization, hot- melt extrusion granulation, spray congealing, or roller compaction are a few common methods used for micronizing and coating particles of such dosage forms. Bead formation can be performed by non-covalent alginate layer crosslinking with calcium cations to form alginate beads.

[00188] Finally, solid dose form osmotic tablets, such as the solid dosage forms developed by Alza Corporation, typically contain four components: a drug/ API compartment, the swelling compartment containing an osmotically active salt, a membrane(s), and microscopic hole(s) for release. The drug/ API and swelling compartments are made by the granulation processes described for matrix-based systems above. The osmotic tablet works by forming a“pull-push” osmotic pump of sorts with the drug/ API and swelling compartments. Both compartments are compressed into a bilayer tablet and a membrane(s) containing holes (made with created by laser drilling) is coated (see the processes above for spray drying and the Remington reference) over the tablet. The membrane allows free diffusion of water but not drug. When the tablet is exposed to water or any fluid in the body, water will flow into the tablet because of the osmotic pressure difference. For processes on making osmotic tablets, see, e.g., U.S. Patent Nos. 8,629,179 and 8,163,798, and Remington's Pharmaceutical Sciences (Arthur Osol, editor; current edition).

[00189] The most significant advantage for osmotic systems is that the dosage form to some extent is pH-independent and provides a steady release rate for an extended time period even as the dosage form moves thru the inhomogeneous microenvironments (with respect to pH, salinity, ion concentration, etc) of various sections of the GI tract. Santus and Baker,“Osmotic drug delivery: a review of the patent literature,” Journal of Controlled Release 35 (1995) pp. 1-21, incorporated in its entirety by reference herein, is a nice review of such systems. Moreover, U.S. patents issued to ALZA Corporation, describe how to make and use osmotic dosage forms, each of which are incorporated in their entirety herein: U.S. Pat. Nos. 3,845,770; 3,916,899;

3,995,631; 4,008,719; 4,111,202; 4,160,020; 4,327,725; 4,519,801; 4,578,075; 4,681,583;

5,019,397; and 5,156,850.

[00190] Some exemplary swelling polymers for osmotic systems include, but are not limited to L poly(alkylene oxide) of 1 million to 15 million number-average molecular weight, as represented by poly(ethylene oxide), and poly(alkali carboxymethylcellulose) of 500,000 to 3,500,000 number-average molecular weight (alkali: sodium, potassium or lithium), acidic carboxypolymer, acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol, cross-linked homopolymers and copolymers of acrylic acid including divinyl glycol and/or C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol as the copolymer, a polymer of acrylic cross- linked with a polyallyl sucrose number-average molecular weight- 250,000 to 4,000,000; acrylic acid polymers, polyacrylamides; cross-linked water swellable indenemaleic anhydride polymers; polyacrylic acid number-average molecular weight-80,000 to 200,000; acrylate polymer polysaccharides composed of condensed glucose units e.g., diester cross-linked polygluran; and the like. Some hydrogel forming polymers include those described in U.S. Pat. No. 3,865,108, U.S. Pat. No. 4,002,173, U.S. Pat. No. 4,207,893, and in Handbook of Common Polymers, Scott and Roff, Chemical Rubber Co., Cleveland, OH. Suitable osmotic agent solutes include, but are not limited to: sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, raffmose, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates. Suitable solvents suitable for manufacturing the dosage form components comprise aqueous or inert organic solvents that do not adversely harm the materials used in the system. The solvents include, but are not limited to: aqueous buffer solvents, e.g., phosphate buffer, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride nitroethane, nitropropane tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, l,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts such as sodium chloride, calcium chloride, and the like, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene di chloride and methanol.

[00191] Finally, techniques for drilling the holes in the outer membrane, including mechanical and laser drilling, are disclosed in U.S. Pat. Nos. 3,916,899 and in U.S. Pat. No. 4,088,864, both of which are incorporated in their entirety herein.

[00192] Accordingly, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral osmotic dosage form comprising bempedoic acid and a polymer matrix. In some aspects, the disclosure provides for a sustained-release pharmaceutical dosage form comprising a solid oral osmotic dosage form comprising bempedoic acid and a polymer matrix, wherein the polymer is selected from a group consisting of hydroxypropyl

methylcellulose (HPMC), microcrystalline cellulose, and sodium carboxymethylcellulose.

Methods of use

[00193] Herein disclosed are methods of treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject by administering a sustained-release composition comprising bempedoic acid and a polymer matrix.

[00194] Pharmaceutical compositions useful according to the present invention are given to a subject, administration is preferably in a“therapeutically effective amount”/“therapeutically effective concentration” (meaning the same) or a“prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate- and time-course of administration, will depend on the nature and severity of the disease being treated. The course and prescription of treatment, e.g., decisions on dosage, etc. , is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Exemplary therapeutically effective amounts are 50, 100, 200, 300, 400 or 500 mg per day, more preferably 50, 100 or 200 mg per day, even more preferably 90 or 180 mg per day. Exemplary prophylactically effective amounts are 50, 100, 200, 300, 400 or 500 mg per day, more preferably 50, 100 or 200 mg per day, even more preferably 90 or 180 mg per day.

[00195] In one aspect, the disclosure provides for a method of treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject, the method comprising:

administering an effective amount of a solid oral dosage form to a subject in need thereof, wherein the solid oral dosage form comprises bempedoic acid and a polymer, and wherein the solid oral dosage form when dissolution tested using ETnited States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer exhibits a drug release profile substantially corresponding to the following pattern: after 2 hours, no more than 30% of the bempedoic acid is released; after 4 hours, no more than 75% of the bempedoic acid is released;

after 8 hours, no more than 90% of the bempedoic acid is released; and wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours to treat cardiovascular disease or reduce the risk of cardiovascular disease when administered to the subject.

[00196] In one aspect, the disclosure provides for a method wherein the solid oral dosage form does not release more than 95% of the bempedoic acid after 8 hours when dissolved in 50 mM phosphate buffer having a pH of 8.5 at 20°C. [00197] In one aspect, the disclosure provides for a method of inhibiting ATP-citrate lyase (ACL) enzyme in a subject, the method comprising administering to the subject the

pharmaceutical dosage form of any one disclosed herein.

[00198] In one aspect, the disclosure provides for a method wherein the solid oral dosage form comprises from 5 mg to 500 mg bempedoic acid. In one aspect, the disclosure provides for a method wherein the solid oral dosage form comprises from 5 mg to 100 mg bempedoic acid. In one aspect, the disclosure provides for a method wherein the solid oral dosage form comprises from 5 mg to 50 mg bempedoic acid. In one aspect, the disclosure provides for a method wherein the solid oral dosage form comprises from 180 mg to 240 mg bempedoic acid. In one aspect, the disclosure provides for a method wherein the solid oral dosage form comprises from 200 mg to 240 mg bempedoic acid.

[00199] In one aspect, the disclosure provides for a method wherein the polymer is microcrystalline cellulose. In one aspect, the disclosure provides for a method wherein the polymer is a mixture of microcrystalline cellulose and polycellulose. In one aspect, the disclosure provides for a method wherein the polymer is a mixture of microcrystalline cellulose and hydroxypropylmethyl cellulose (HPMC). In one aspect, the disclosure provides for a method wherein the polymer is hydroxypropylmethyl cellulose (HPMC). In one aspect, the disclosure provides for a method wherein the polymer is a polycellulose.

Cardiovascular disease & bempedoic acid delivery

Clinical endpoints

[00200] In one aspect, the disclosure provides for methods for decreasing the level of a blood lipid, lipoprotein or cholesterol in a subject. In some aspects, lowering is determined by comparing levels of an analyte measured from a sample obtained from the subject before and after administration of the drug. In some aspects, lowering is based on results of clinical trial results comparing matched populations, one receiving drug, and one receiving a placebo. In one aspect, the disclosure provides for methods of lowering low-density lipoprotein cholesterol (LDL-C) in a subject.

[00201] In one aspect, the disclosure provides for methods for lowering total cholesterol (TC) in a subject. In one aspect, the disclosure provides for methods wherein the method lowers total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) in a subject. In one aspect, the disclosure provides for methods for lowering total cholesterol (TC) when administered to a human subject having hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease. In one aspect, the disclosure provides for methods for lowering total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) when administered to a human subject having hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease.

[00202] In one aspect, the disclosure provides for methods for decreasing the level of very low density lipoprotein (VLDL) in a subject.

[00203] In one aspect, the disclosure provides for methods for decreasing the size of VLDL particles in a subject.

[00204] In one aspect, the disclosure provides for methods for decreasing the level of apolipoprotein B (ApoB) in a subject. In one aspect, the disclosure provides for methods for decreasing the level of apolipoprotein A-l (ApoAl) in a subject.

[00205] In one aspect, the disclosure provides for methods for decreasing the ratio of apolipoprotein B (ApoB) to apolipoprotein A-l (ApoAl) in a subject below. In one aspect, the disclosure provides for methods for not changing the ratio of apolipoprotein B (ApoB) to apolipoprotein A-l (ApoAl) in a subject.

[00206] In one aspect, the disclosure provides for methods wherein the subject has hypercholesterolemia. In one aspect, the disclosure provides for methods wherein the subject has mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease, kidney disease, or any combination thereof.

[00207] In one aspect, the disclosure provides for methods wherein the subject is a mammal. In one aspect, the disclosure provides for methods wherein the subject is human.

Therapeutic window

[00208] The therapeutic window can also be generally expressed as a ratio between minimum effective concentrations (MEC, also known as minimum inhibitory concentration (MIC)) to the minimum toxic concentration (MTC) (of the drug/ API). An important goal of drug delivery is to keep the plasma levels of drug between MEC and MTC to provide the most beneficial and most risk-free therapeutic effects. If the drug concentration crosses MTC, then toxic effects will be observed;on the other hand, if drug concentration is unable to surpass MEC, then the treatment suffers therapeutic failure.

[00209] The therapeutic index (TI) describes a relationship between the doses of a drug that causes lethal or toxic effects with the dose that causes therapeutic effects. It can be calculated by:

Therapeutic index (TI)= LD50/ED50

where LD50 is the minimum amount of drug that causes adverse effects in 50% of the population. LD50 could also be replaced with Toxic dose (TD50). ED50 is the quantity of a drug that can produce desired therapeutic effects in 50% of the population.

[00210] In some aspects, the present disclosure provides for methods wherein the

concentration of bempedoic acid is between the MEC and the MTC for a duration of time from 20 minutes to 8 hours after administration. In some aspects, the present disclosure provides for methods wherein the concentration of bempedoic acid is between the MEC and the MTC for a duration of time from: 20 minutes to 9 hours, 20 minutes to 10 hours, 20 minutes to 12 hours, 20 minutes to 14 hours, 20 minutes to 16 hours, 20 minutes to 18 hours, 20 minutes to 20 hours, 20 minutes to 24 hours, 20 minutes to 36 hours, or 20 minutes to 48 hours after administration.

[00211] In some aspects, the present disclosure provides for methods wherein the

pharmaceutical dosage form provides an AETC for bempedoic acid in the rat of 7.5 mg/kg or 30 mg/kg bempedoic acid capsule. In some aspects, the present disclosure provides for methods wherein the pharmaceutical dosage form provides an AUC for activated bempedoic acid in the rat of 661 ng*hr/mL per mg of bempedoic acid following oral administration of a single 7.5 mg/kg or 30 mg/kg bempedoic acid capsule.

[00212] In some aspects, the present disclosure provides for methods wherein the

pharmaceutical dosage form, when administered at a unit dose of 180 mg of bempedoic acid to a 1 kg male Sprague-Dawley rat results in a maximum blood plasma concentration (Cmax) of bempedoic acid in the rat of no more than 60 pg/mL pg/mL and is in a range from 45 pg/mL - 59 pg/mL for 24 hours after administration.

[00213] In some aspects, the present disclosure provides for methods wherein the

pharmaceutical dosage form provides a Tmax in the rat of greater than 8 hours following oral administration of a single 50, 100, 200, or 180 mg bempedoic acid tablet.

[00214] In some aspects, the present disclosure provides a method of administering bempedoic acid, the method, comprising: administering to a subject an effective amount of a pharmaceutical dosage form comprising a solid oral dosage form to a subject in need thereof, wherein the solid oral dosage form comprises bempedoic acid and a polymer, and wherein, when assayed in a standard pharmacokinetic assay, e.g., rat, said administration results in a maximum blood plasma concentration (Cmax) of no more than 60 pg/mL and, wherein said is in a range from 45 pg/mL-60 pg/mL for 24 hours after administration.

[00215] In some aspects, the present disclosure provides for methods wherein bempedoic acid is delivered at a rate such that it is independent on the amount of bempedoic acid in the dosage form. In such aspects, the method provides for zero-order release of bempedoic acid. In some aspects, the present disclosure provides for methods wherein bempedoic acid is delivered at a near constant rate (meaning deviation from average delivery rate of not more than +/- 10% over the effective delivery lifetime of the dosage form) for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, but no longer than 36 hours (i.e., covering periods from 2-36 hr).

[00216] In some aspects, the described methods can be practiced by administering a pharmaceutical dosage form of bempedoic acid described in this application.

Combination therapy and dosage forms

[00217] In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically- effective amounts of Ezetimibe. In such aspects, the formulations need not provide for sustained- release of Ezetimibe, but do provide sustained-release of bempedoic acid in accordance with this disclosure.

[00218] In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically- effective amounts of a statin. In such aspects, the formulations need not provide a sustained- release of a statin, but do provide sustained-release of bempedoic acid in accordance with this disclosure.

[00219] In some aspects, the present disclosure provides for methods wherein the sustained- release pharmaceutical composition is administered in combination with other lipid-lowering treatments, either simultaneously or sequentially dependent upon the clinical situation of the cardiovascular condition that is being treated.

[00220] In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically- effective amounts of an antibody that lowers proprotein convertase subtilisin-kexin type 9 (PCSK9 inhibitor). In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically-effective amounts of a bile acid sequestrant.

[00221] In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically- effective amounts of a biguanide (e.g., metformin), or adenosine monophosphate activated protein kinase (AMPK) activators, or alpha-glucosidase inhibitors, or amylin analogs, or dipeptidyl peptidase 4 inhibitors, or incretin mimetics, or meglinitides, or sulfonylureas, or non- sulfonylureas, or sodium-glucose transporter-2 (SGLT2) inhibitors, or thiozolidinediones, or glucagon like peptide -1 (GLP-l) and/or combinations thereof.

[00222] In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically- effective amounts of a farnesoid-X-receptor (FXR) and/or bile acid receptor agonists, or peroxisome proliferator activated receptor (PPAR)-alpha agonist, or PPAR-gamma agonists, or PPAR-delta agonists, or PPAR-alpha/gamma agonist, PPAR-alpha/delta agonists, or pan PPAR agonists, or cysteine depleting agents, or phosphodiesterase-4 (PDE-4) inhibitors, or apoptosis signal -regulating kinase l( ASK-l) inhibitors, or chemokine receptor inhibitors, including CCR2/CCR5 inhibitors, or combinations thereof.

[00223] In some aspects, the present disclosure provides for methods and compositions wherein the sustained-release pharmaceutical compositions further comprise therapeutically- effective amounts of a compound that lowers levels of (inhibitor of) alanine aminotransferase, alkaline phosphatase, total bilirubin, or triglycerides or Cytokeratin-l8. Administration schedule

[00224] In some aspects, the present disclosure provides for methods wherein the sustained- release pharmaceutical composition is administered twice daily, once every day, or once every two days.

Metabolic syndrome treatment with bemyedoic acid

Metabolic syndromes / disorders

[00225] Metabolic syndromes and/or metabolic disorders are associated with conditions such as increased adiposity, insulin resistance, dyslipidemia, hepatic steatosis, inflammation and atherosclerosis. These abnormalities are linked to some degree to the process of atherogenesis. Although bempedoic acid may improve metabolic dysregulation pathways related to some of these abnormalities, it unclear whether the therapeutic efficacy is limited by pharmacodynamic parameters.

[00226] Herein the inventors disclose that targeting the enzymes ACL and AMPK with a sustained release formulation of bempedoic acid increases the efficiency of formation, residence lifetime, and therapeutic efficacy of activated bempedoic acid, which in turn provides significantly more therapeutic value in treating metabolic syndrome diseases and disorders such as NAFLD, NASH, hepatic steatosis, inflammation, fibrosis, or any combination thereof.

[00227] In one aspect, the disclosure provides methods of treating a metabolic syndrome and/or a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of any one of the sustained release formulations/dosage forms disclosed herein. In one aspect, the disclosure provides for methods of treating hepatic steatosis in a subject, the method comprising administering to the subject an effective amount of any one of the sustained release formulations/dosage forms disclosed herein. In one aspect, the disclosure provides for methods of treating inflammation or fibrosis in a subject, the method comprising administering to the subject an effective amount of any one of the sustained release formulations/ dosage forms disclosed herein.

[00228] In one aspect, the disclosure provides for methods of treating a metabolic syndrome, metabolic disorder, hepatic steatosis, inflammation, fibrosis or any combination thereof in a subject diagnosed or measured by liver biopsy pathology or imaging methodologies disclosed herein. Nonalcoholic fatty liver disease (NAFLD)

[00229] If the rate of lipid delivery to the liver and de novo lipogenesis within the liver are not matched by the rates of fatty acid b-oxidation and VLDL secretion, then hepatocytes will increase lipid droplet formation and NAFLD will ensue. NAFLD is the hepatic manifestation of the metabolic syndrome due to its tight association with obesity, dyslipidemia, and type 2 diabetes (see, e.g., Asrih, M., and F. R. Jornayvaz. 2015. Molecular and Cellular Endocrinology. 418: 55-65). NAFLD encompasses a spectrum of disorders from simple steatosis to

steatohepatitis.

[00230] NAFLD is largely asymptomatic in the early stages. The standard for diagnosing NAFLD is a liver biopsy. Non-invasive NAFLD diagnosis includes methods using imaging modalities, plasma markers, and scoring algorithms. Imaging is done with ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), transient elastography, or FibroScan®. Plasma markers used to assess liver function include alanine and aspartate transaminases (ALT and AST, respectively), albumen, platelet count, glucose, insulin, TG, and cholesterol (see, e.g, Machado, M. V., and H. Cortez-Pinto. 2013. Journal of Hepatology. 58: 1007-1019; Pacana, T., and A. J. Sanyal. 2015. FlOOOPrime Rep. 7: 28). There are also many scoring algorithms using these plasma measurements in addition to age, gender, body mass index, insulin resistance and glycemia, hypertension, and the results from imaging tools.

[00231] Herein disclosed are sustained release formulation comprising bempedoic acid effective in the treatment of NAFLD, NASH and/or NAFL.

[00232] In one aspect, the disclosure provides for methods of treating NAFLD in a subject, the method comprising administering to the subject an effective amount of any one of the sustained release formulations/ dosage forms disclosed herein.

Nonalcoholic steatohepatitis (NASH)

[00233] NAFLD progresses to a very serious disease termed nonalcoholic steatohepatitis (NASH). This disease is hallmarked by increased inflammation and fibrosis. NASH

histologically presents as simple steatosis with hepatocyte ballooning, monocyte infiltration, and collagen deposition (see, e.g., Yeh, M. M., and E. M. Brunt. 2014. Gastroenterology. 147: 754- 764). The increase in fibrosis and inflammation seen with NASH greatly increases the risk of liver cancer. [00234] In one aspect, the disclosure provides for methods of treating NASH in a subject, the method comprising administering to the subject an effective amount of any one of the sustained release formulations/ dosage forms disclosed herein.

[00235] In one aspect, the disclosure provides for methods of treating NAFLD, NAFL and/or NASH wherein the subject is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes, or any combination thereof.

EXAMPLES

[00236] Below are examples of specific embodiments for carrying out the present invention. The examples are offered 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.

[00237] The practice of the present invention will employ, unless otherwise conventional methods of pharmaceutical chemistry and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Remington's Pharmaceutical Sciences,

18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

Example 1 - Experimental conditions and protocol for pharmacokinetics studies in animals

Animals & administration

[00238] Male Han Wistar [Crl:WI(Han)] rats were purchased from Charles River and were acclimated to study conditions for four days prior to initial dose administration. Certified Rodent Diet #2016C (Envigo RMS, Inc.) was provided ad libitum. Water was provided fresh daily, ad libitum. Animals were assigned to 1 of 3 groups where group 1 received ETC-1002 (30 mg/kg) as a single bolus oral dose, group 2 received ETC- 1002 (30 mg/kg) over 4 separate dosed at 7.5 mg/kg) approximately 4 hours apart, and group three received no dose (Table 1). Animals were identified via individual cage cards and implantable microchip identification devices in the right, dorsal lumbar region.

Dosage, Collection, & Analysis

[00239] Individual doses were calculated based on body weights recorded on the day prior to dose administration and the oral dose was administered via oral gavage. Blood samples were collected at pre-dose and at approximately 2, 4, 6, 8, 10, 12, 14, 20, and 24 hours post dose according to Table 2 schedule via a jugular vein by syringe and needle (approximately 0.3 mL) or by cardiac puncture under appropriate anesthesia. Blood was transferred into tubes containing no anticoagulant (serum separator tubes).

[00240] Blood was allowed to clot at ambient temperature prior to centrifugation to obtain serum. Centrifugation began within 1 hour of collection. Serum was placed into the appropriate tubes and maintained on dry ice prior to storage at approximately -70 °C. Liver samples were collected from three animals/group/time point at approximately 2, 6, 10, 14, 20, and 24 hours post-dose (Table 2). The liver was harvested as quickly as possible using pre-cooled clamps. Afterwards, the tissue and clamp was immediately flash frozen by emersion in liquid nitrogen. Following freezing, the tissues were packaged in foil and maintained on dry ice prior to storage at approximately -70 °C.

[00241] Serum was then analyzed for levels of ETC- 1002 using a validated LC-MS/MS methods, and ETC-l002-CoA (activated bempedoic acid) and acetyl-CoA levels were determined in liver samples following extraction of homogenates in MeOH-formic acid. An acetyl-CoA standard concentration curve was generated in control liver homogenates, and unknown sample concentrations were calculated using a linear curve fit model. ETCl002-CoA levels are expressed as changes in peak area (acetyl-CoA pg equivalents).

Study Design

Table 1.

Target Target

Number Dose Target Dose Dose

of Male Test Dose Level Concentration Volume

Gro Animals Article Route

ETC-

18 Oral 30 3 10

1002

ETC-

2 18 Oral³ 7.5 3 2.5

1002

3 3 NA NA NA NA NA

NA: Not applicable, designated for control collections.

³ : Animals were dosed four times over 12 hours (approximately 4 hours apart) for a

total of 30 mg/kg (3 mg/mL and 10 mL/kg).

Table 2. Animals/ Time Points (Hours Post-dose)

Jugular³ _ Cardiac Puncture

1-3 Pre-dose 2

4-6 4^b 6

7-9 8^C 10

10-12 l2^d 14

13-15 20

16-18 24

a: All collections were based on the first daily dose for Group 2.

b: For Group 2, samples were collected prior to the second dose.

c: For Group 2, samples were collected prior to the third dose.

d: For Group 2, samples were collected prior to the fourth dose.

Formulation

[00242] ETC-1002 formulations were prepared in the appropriate volume of 0.5% CMC (pH

7-8) and were stirred throughout the course of dosing. Specific information regarding dose preparation is in Table 3.

Table 3.

Total Target Dose

Test Article Vehicle Concentration Calculated Dose Weight Volume (mg/mL) Concentration

Groups (mg) (mL) (mg/mL)

1 and 2 390.025 130 3 3.00

Example 2: Single bolus PK study in animals - exemplary immediate release bempedoic acid formulation

[00243] Existing orally-administered formulations are rapidly absorbed in the small intestine (see, e.g., Bilen et al., Curr Atheroscler Rep., 2016; 18(10): 61). The purpose of this Example is to establish a baseline pharmacodynamic profile for an exemplary immediate release bempedoic acid formulation. The experimental procedures employed are described in the“Example 1 - Experimental conditions and protocol for pharmacokinetics (PK) studies in animals”, above.

Results

[00244] The single bolus PK measurements were: Tmax = 2 hours, Cmax = 97.1 pg/mL, and AETCo-24hr = 1244.0 pg hr/mL. Bempedoic acid serum levels provided a peak maximum concentration near 100,000 ng/mL (100 pg/ml) within 1 hour after administration. Further, single bolus administration provided liver ETC-l002-CoA concentrations below 250 ng/gm over a 20 hour period. Example 3: Multiple split administration PK study in animals to simulate the sustained release of bempedoic acid formulation

[00245] Multiple split administrations were employed to simulate the sustained-release of bempedoic acid in vivo. The effect of bempedoic acid absorption on PK properties is tested here in light of biological metabolism. The purpose of this study is to determine the

pharmacodynamic profile for a representative sustained-release bempedoic acid formulation.

The following procedures are described in the“Example 1 - Experimental conditions and protocol for pharmacokinetics (PK) studies in animals,” described above.

Results

[00246] Multiple split PK measurements were: Tmax = 10 hours, Cmax = 55.5 pg/mL, and an AETCo-24hr = 661 pg hr/mL. Multiple split administration provided bempedoic acid serum levels at a maximum concentration around 60,000 ng/mL over 10 hours post-administration. Further, multiple split bolus administration demonstrated an approximately 28% increase in AETCo-24,ss and an approximately 24% increase AETCo-24hrin liver ETC-l002-CoA.

Example 4: Sustained-release vs. immediate release bempedoic acid formulation PK study comparison in rats

[00247] The purpose of this example is to provide support for the proof of concept of bempedoic acid (ETC- 1002) sustained-release formulations possessing increased PK activities by showing that a reduced absorption rate provides an improved pharmacokinetic profile in liver and plasma. An improved PK profile is defined as having either a higher ETC-l002-CoA AETCo-24hr in liver with equal or reduced serum ETC- 1002 Cmax or AETCo-24hr, or an equal amount of ETC-l002-CoA AETCo-24hr in liver with reduced serum ETC- 1002 Cmax or AETCo-24hr for any given dosage level.

Results

[00248] Significant differences in serum pharmacokinetics were observed between single bolus and multiple split bempedoic acid administrations. Surprisingly, simulating sustained- release with multiple split bolus administration provided a slow climb in bempedoic acid serum concentration irrespective of rapid absorption. This in contrast to the single bolus

administration, which provided a characteristic short Tmax in bempedoic acid serum levels almost immediately followed by a precipitous fall over the following 22 hours (Figure 1A). [00249] Hepatic acetyl-CoA was suppressed in both groups for the entire 24 hour duration of the study (Figure IB). However, multiple split administration, z.e., simulated sustained-release, showed a more significant decrease in liver acetyl-CoA activity despite achieving a lower maximum serum exposure (47%, Figure IB).

[00250] Moreover, simulated sustained-release achieved greater hepatic ETC-l002-CoA exposure in comparison to the single bolus. Interestingly, the ratio of liver ETC-l002-CoA exposure to serum ETC- 1002 exposure was greater for the simulated sustained-release by more than 2-fold (Figure 1C). These findings support the conclusion that prodrug conversion efficiency was increased by the altered rate of bempedoic acid absorption in the gut.

Example 5: Sustained release formulations of bempedoic acid and their respective

dissolution data

Formulations

[00251] Several formulations comprising bempedoic acid and a hydrophilic cellulosic polymer matrix, hydroxypropyl methylcellulose (HPMC), were prepared and tested in USP dissolution assays. Formulations were constructed as solid microparticle spheres. Each formulation was sieved.

[00252] The individual batches were distinctly formulated to include the compounds described in Tables 4-13 below.

Table 4.

Table 5.

Table 6.

Table 7.

Table 8.

Table 9.

Table 10.

Table 11.

Table 12. Table 13.

Dissolution Assay

[00253] A USP dissolution experiment evaluates the rate and extent that a compound forms a solution under carefully controlled conditions. The dissolution test helps evaluate the performance of a drug product. For detailed description of apparatus set-ups and experimental procedures, please see United States Pharmacopeial Convention, USP 35 NF30, 2012: U S. Pharmacopoeia National Formulary, The United States pharmacopeia , 2011, Chapter 711, 5642-5648.

[00254] Physical properties of the dosage form such as: unit dose wettability, permeability, swelling, disintegration and de-aggregation affect the dissolution of pharmaceutical dosage forms.

[00255] The results of the dissolution assay are described below in Table 14 and presented in Figures 2A and Figure 2B respectively.

Table 14 - Dissolution Assay Results

Time (minutes)

- Numerical values are expressed as the percentage released into solution from the starting total amount of Bempedoic acid in the formulation. *Batches CU07-105 and CU07-107 have relatively low yields in the desired 16/30 sieve cut range. Batches CU07-117 and CU07-115 exhibited sticking behavior during the manufacturing process and also have relatively low overall yields. The 720 min time point is the infinity time-point.

Example 6: Compositions of drug products for immediate release and sustained release (SR) formulations of bempedoic acid

[00256] This example describes the compositions of products and formulations of both immediate release and sustained release of bempedoic acid.

[00257] Table 15 describes the composition of immediately release (IR) formulation of bempedoic acid.

COMPOSITION OF IMMEDIATE RELEASE FORMULATION OF BEMPEDOIC ACID

Table 15 - Composition of Bempedoic Acid 180 mg Tablets

a Removed during processing.

[00258] Table 16 describes the drug product of IR formulation of bempedoic acid and placebo tablets.

Table 16 - Investigational Medicinal Products (IMP) of Immediate Release Formulation of

Bempedoic Acid and Placebo Tablets

[00259] Table 17 describes the composition of the SR formulation of bempedoic acid.

COMPOSITION OF SUSTAINED RELEASE FORMULATION OF BEMPEDOIC ACID

Table 17 - Composition for Sustained Release Formulation of Bempedoic Acid Capsule

a Values have been rounded to the nearest decimal shown. The total sums are determined from exact values and may not be representative of the rounded individual values shown.

b Water and HPMC 606 will be added as a premixed solution.

c Water is processing aid and is not included in the final formulation. Therefore,“Total” does not include water.

d The capsule shell is comprised of titanium dioxide (El 71) (2.9079%) as an opacifer and gelatin (quantity sufficient for 100%). DESCRIPTION OF THE CAPSULES SPHERES FOR

SUSTAINED RELEASE FORMULATION OF BEMPEDOIC ACID

[00260] The sustained release (SR) bempedoic acid capsules are white opaque hard gelatin capsules filled with spheres made of bempedoic acid and excipients. Two capsule sizes and doses are available for the NASH study:

• "Size 3" for 50 mg bempedoic acid SR capsule

• "Size 0" for 200 mg bempedoic acid SR capsule

Example 7 - Administration of representative sustained release bempedoic acid

formulation to humans

[00261] The primary objective is to assess the LDL-C lowering efficacy of a representative bempedoic acid sustained-release solid oral dosage form (tablet) versus placebo administered daily for 6 weeks in patients with elevated LDL-C.

[00262] Secondary objectives are to assess:

1. The effect of a bempedoic acid sustained-release formulation versus placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), high-sensitivity C-reactive protein (hs-CRP), TG, and HDL-C.

2. The effect of bempedoic acid (180 mg) sustained-release solid oral dosage form (tablet) on percent of patients achieving LDL-C level <70 mg/dL.

3. The effect of bempedoic acid (180 mg) sustained-release solid oral dosage form (tablet) versus placebo on percent of patients achieving LDL-C reduction >50%

4. The safety and tolerability of bempedoic acid (180 mg) sustained-release solid oral dosage form (tablet) versus placebo.

[00263] The primary endpoint being used to evaluate the objectives of this study is the percent change from baseline to Week 6 in LDL-C levels. Secondary endpoints also include percent changes from baseline to Week 6 in non-HDL-C, TC, ApoB, hs-CRP, TG, and HDL-C levels, percent change from baseline to Week 6 in Percent of patients with LDL-C <70 mg/dL at Week 6, and percent of patients with LDL-C reduction of >50% from baseline to Week 6.

Administration of the Drug - Treatment of Patients [00264] During the Treatment Period, patients are randomized to receive IMP of either sustained-release bempedoic acid solid dosage forms or placebo once daily. Each daily allotment of IMP was comprised of one bempedoic acid tablet in a blister package. The placebo blister pack contains the corresponding matching placebo of the bempedoic acid solid dosage forms. Patients are instructed to ingest IMP orally once daily with or without food. On clinic visit days, patientsare instructed to delay ingestion of IMP until all study procedures were completed.

Example 8: Single-dose study of immediate release formulation of bempedoic acid in healthy subjects (IR Study 1)

[00265] This example describes a single-dose study that evaluated the safety, tolerability and pharmacokinetics of bempedoic acid in healthy subjects. Figure 6 summarizes the design of this study.

[00266] A key objective of this study was to evaluate and characterize the pharmacokinetic (PK) profile of bempedoic acid and its metabolite after administration of single, escalating, oral doses to healthy subjects.

[00267] This was a single-center, randomized, double-blind, placebo-controlled, escalating, single-dose, cross-over study. The cross-over design involved 2 cohorts of 9 subjects each. Each cohort escalated cautiously through 3 single-dose groups. Each dose group comprised 6 subjects randomized and received bempedoic acid and 3 subjects randomized and received placebo. The randomization scheme ensured that subjects received a total of 2 separate doses of active drug and a single administration of placebo. Dose groups were separated by a washout period no less than 10 days between administration of study medication. Dose escalation was contingent upon acceptable safety, tolerance and pharmacokinetic data and followed clearly defined stopping rules including an exposure limit. The bempedoic acid AUC0-24 exposure limit of 200 pg hr/mL in this study was higher than the estimated therapeutic exposure of 36 to 72 pg hr/mL, provided an opportunity to fully explore the high end of the dose range in the most controlled phase of drug development.

Results

[00268] Table 18 shows measured and dose-corrected pharmacokinetic (PK) parameters after single dose of immediate release (IR) formulation of bempedoic acid in healthy subjects. Table 18 - Measured and Dose-Corrected PK Parameters after A Single Dose of Immediate Release Formulation of Bempedoic Acid from IR Study 1.

a Parameters were dose-corrected to a 50, 100, or 200 mg dose, respectively.

Example 9: Multiple ascending dose study of immediate release formulation of bempedoic acid in subjects with mild dvslipidemia (IR Study 21

[00269] This example describes a multiple ascending dose study of bempedoic acid in subjects with mild dyslipidemia. Figure 7 summarizes the design of this study.

[00270] Key objectives of this study evaluated and characterized the pharmacokinetic (PK) profile and pharmacodynamic (PD) endpoints, such as low-density lipoprotein-cholesterol (LDL- C) level, of bempedoic acid and its metabolite after administration of multiple ascending doses of bempedoic acid to subjects with mild dyslipidemia.

[00271] This was a single-center, randomized, double-blind (sponsor-open), placebo- controlled, ascending, multiple-dose study with 4 ascending cohorts followed by an optional 5^th cohort. The first 4 cohorts included 8 male and female subjects each (6 active/2 placebo) with mildly elevated LDL-C level treated for 14 days duration in the Clinical Unit. Dose escalation in the first 4 cohorts were contingent upon acceptable safety, tolerance, and PK data and will follow clearly defined stopping rules including a predefined exposure limit for AUC0-24 of 200 pg h/mL for the sum of bempedoic acid and its metabolite ESP 15228. Provided that the safety profile from the first 4 cohorts was acceptable, an optional 5^th cohort of 24 free living male and female subjects (18 active/6 placebo) with mildly elevated LDL-C and triglycerides levels treated for 28 days was completed.

[00272] Bempedoic acid capsules (20 mg) or placebo capsules were used for this study.

Multiple oral doses of 20, 60, 100, and 120 mg were administered to subjects in the fasting state in Cohorts 1 to 4 and did not exceed the predefined exposure limit for AUC0-24 of 200 pg h/mL for the sum of bempedoic acid and its metabolite ESP 15228.

Results

[00273] Table 19 shows measured and dose-corrected pharmacokinetic (PK) parameters after single dose of immediate release (IR) formulation of bempedoic acid in healthy subjects.

Table 19 - LS Mean Percent Change from Baseline in LDL-C After Single Dose of

Immediate Release Formulation of Bempedoic Acid from IR Study 2

Example 10: Multiple ascending dose of immeidate release formulation

acid in healthy subjects !IR Study 3)

[00274] This example describes a multiple ascending dose study of bempedoic acid at doses above 120 mg/day in health subjects. Figure 8 summarizes the design of this study.

[00275] Key objectives of this study evaluated and characterized the pharmacokinetic (PK) profile and pharmacodynamic (PD) endpoints, such as low density lipoprotein-cholesterol (LDL- C) level, of bempedoic acid and its metabolite after administration of multiple ascending doses of bempedoic acid to healthy subjects.

[00276] This was a single-center, randomized, double-blind (sponsor-open), placebo- controlled, ascending, multiple-dose study with approximately 4 ascending cohorts, each with 8 healthy male or female subjects (6 active/2 placebo) treated for 14 days duration in the Clinical Unit. Dose escalation in the next cohort was contingent upon acceptable safety, tolerance, and PK data and followed clearly defined stopping rules including a predefined exposure limit for mean AUC0-24 of 400 pg h/mL for the sum of bempedoic acid and its metabolite ESP 15228.

[00277] Bempedoic acid 20 mg capsules or placebo capsules were used for this study.

Multiple oral doses of 140, 180, 220 and 260 mg/day were administered to subjects in the fasting state and did not exceed the predefined exposure limit for mean AUC0-24 of 400 pg h/mL for the sum of bempedoic acid and its metabolite ESP 15228.

Results

[00278] Table 20 shows the mean steady-state PK parameters of immediate release formulation of bempedoic acid.

Table 20 - Mean Steady-State PK Parameters of Immediate Release Formulation of

Bempedoic Acid From IR Study 3^a

a Predicated from 180 mg dose data assuming linear kinetics. ^b Median.

[00279] Table 21 shows the Least Square Mean percent change from baseline in LDL-C after single dose of immediate release formulation of bempedoic acid from IR Study 3.

Table 21 - LS Mean Percent Change from Baseline in LDL-C After a Single Dose of

Immediate Release Formulation From IR Study 3

Example 11: Single- and repeat-dose study of sustained release formulation of bempedoic acid in overweight/obese otherwise healthy subjects (SR Study)

[00280] This example describes a single- and repeat-dose study of sustained release formulation of bempedoic acid carried out on overweight/obese but otherwise healthy subjects.

Figure 9 summarizes the design of this study.

[00281] The formulations of the bempedoic acid sustained release tablets used in this study can be found in Tables 13 and 17.

[00282] The key objectives of this study were to evaluate the pharmacokinetics, safety, tolerability, and pharmacodynamics endpoints, such as LDL-C, of bempedoic acid sustained release therapy in overweight/obese but otherwise healthy subjects.

[00283] Period 1 assessed single-dose PK, safety, and tolerability. Period 1 was randomized, but was not blinded or placebo-controlled. Screening occured up to 21 Days prior to

randomization. Subjects admitted to the Clinical Research Unit (CRU) on the evening of day -1 until the morning of Day 2. On the morning of Day 1, subjects were randomized to receive a single dose of bempedoic acid sustained-release formulation of 50 mg (n = 6), 100 mg (n = 6), or 200 mg (n = 6). The sustained-release formulation of bempedoic acid was outlined in Tables 13 and 17. These treatments were administered in parallel (not sequentially). Serial testing of PK occured on Day 1. On the morning of Day 2, additional blood samples were collected, a meal was provided, and if appropriate, subjects were released from the CRU. Subjects returned to the CRU for outpatient morning clinic visits to collect additional blood samples on Days 3, 5, 7, 9, and 11. Preliminary PK, safety, and tolerability data from Period 1 were assessed prior to initiation of Period 2.

[00284] Period 2 assessed repeat-dose PK, safety, and tolerability during the 14-day treatment phase. De novo lipogenesis was assessed on Day -7 and Day 1, and PD biomarkers were assessed on Day 13. Period 2 was randomized, placebo-controlled, and double-blind. Screening occurred up to 28 days prior to randomization. Subjects were admitted to the CRU on 3 separate occasions. The first occasion was in the afternoon of Day -8 followed on Day -7 with testing of de novo lipogenesis and discharge from the CRU. The second occasion the subjects were admitted to the CRU was on the afternoon of Day -1, followed on Day 1 by the first dose of bempedoic acid SR, testing of de novo lipogenesis, and discharge from the CRU. Eligible subjects were randomized on Day 1 and received bempedoic acid sustained-release formulation of 50 mg (n = 10), 100 mg (n = 10), or 200 mg (n = 10), or placebo (n = 10) for 14 days. The sustained-release formulation of bempedoic acid is outlined in Tables 13 and 17. These treatments were administered in parallel (not sequentially). The third occasion that the subjects were admitted to the CRU was on the evening of Day 13 to the morning of Day 15 for serial PK sampling. On Days 3 to 13, subjects were reported to the CRU in the morning for dosing and, if required, PK sample collection. Subjects returned to the clinic for PK sampling and safety monitoring the morning of Days 17 and 22. De novo lipogenesis was assessed during Period 2 at baseline (Day -7) and with a single dose of study drug (Day 1). The stable isotope tracer (²H₂0) was primed for 2 days prior to each de novo lipogenesis assessment, with 3 small doses of ²H₂0 taken throughout each day. Beginning in the morning of the de novo lipogenesis assessment for 10 hours, hepatic fatty acid synthesis was stimulated with oral fructose feeding every 30 minutes and hourly blood samples were collected to assess incorporation of label into circulating very low density lipoprotein (VLDL) triglycerides.

[00285] During both periods 1 and 2, subjects received study drug after fasting for a minimum of 10 hours with up to 8 ounces of water. On days that serial PK blood samples were collected (Period 1 = Day 1; Period 2 = Day 14) dosing was followed by 4 hours of additional fasting and a standardized meal at 4 and 10 hours post dose. Concentrations of bempedoic acid and metabolite ESP 15228 were measured from serial blood samples to assess PK parameters.

Results

[00286] Table 22 shows the measured PK parameters of patients following administrations of a single dose of a sustained release tablet of bempedoic acid.

Table 22 - Measured PK Parameters after A Single Dose of Sustained Release Formulation of SR Study

a The sustained release formulation of bempedoic acid is described in Tables 13 and 17.

[00287] Table 23 shows the mean steady-state PK parameters of bempedoic acid sustained release tablets.

Table 23 - Mean Steady-State PK Parameters of Sustained Release Formulation of

Bempedoic Acid Tablet (SR Study)

a Median

[00288] Table 24 describes the data of percent change from baseline in LDL-C levels in patients treated with sustained release formulation of bempedoic acid during period 2 of this study.

Attorney Ref: 32040-42638/US

Table 24 - Percent Change from Baseline in LDL-C in Patients Treated with Sustained Release Formulation of Bempedoic

Acid During Period 2 of SR Study

[00289] Table 25 shows the Least Square (LS) Mean percent change from baseline in LDL-C of patients following administrations of sustained release formulation tablet of bempedoic acid at day 14 during period 2.

Table 25 - LS Mean Percent Change from Baseline in LDL-C After a Single Dose of

Sustained Release Formulation of Bempedoic Acid from SR Stud ^a

a Statistics are estimated based on an Analysis of Covariance (ANCOVA) model with fixed terms for treatment and baseline of LDL-C level. ANCOVA analysis (LS Mean and p value) was performed post hoc without repeat measures. Baseline is defined as the last value collected prior to the first dose of study drug.

[00290] In addition to the results in Table 31, Figure 5 further demonstrates the change in LDL-C between patients who received placebo versus patients who received 100 mg of sustained release formulation of bempedoic acid tablet, wherein a change of -24.7% in LDL-C level was estimated from baseline in patients who received the sustained release tablet of bempedoic acid.

Example 12: Comparison of PK parameters and PD endpoints from IR studies 1, 2, and 3 with those from the SR study

[00291] This example compares various PK parameters and PD endpoints from IR Study 1 (Example 8), IR Study 2 (Example 9), and IR Study 3 (Example 10) with those from the SR Study (Example 11).

[00292] Table 26 shows the comparison between dose-corrected PK parameters of IR Study 1 and those obtained from the SR study at dosages of 50 mg, 100 mg, and 200 mg respectively.

Table 26 - PK Comparison between IR Study 1 and the SR Study

a Parameters were dose-corrected to a 50, 100, or 200 mg dose, respectively. ^b The sustained release formulation of bempedoic acid is described in Tables 13 and 17.

[00293] Table 27 shows the comparison of the mean steady-state PK parameters of IR study 3 and those obtained from the SR study.

Table 27 - Comparison of Mean Steady-State PK Parameters of IR Study 3 and the SR

Study

a Median

b Sustained release formulation of bempedoic acid is described in Tables 13 and 17. c Predicted from 180 mg dose data assuming linear kinetics [00294] As evident from Table 26 and Table 27, the SR formulation provided delayed delivery of bempedoic acid as compared to the IR formulation since less amount of bempedoic acid was detected in patients who received the SR formulation at similar times and dosages as compared to those who received IR formulation.

[00295] Table 28 shows the comparison of least-square mean percent change in LDL-C levels in patients from IR Study 1, IR Study 2 and the SR Study.

Table 28 - Comparison of Mean Percent Change in LDL-C Levels in Patients from IR

Study 2, IR Study 3 and the SR Study.

[00296] As Table 28 demonstrates, treatment with the SR formulation of bempedoic acid in obese/overweight but otherwise healthy patients provided consistent and dose-related LDL-C lowering from baseline of up to 27%. Furthermore, treatment with the SR formulation of bempedoic acid provided LDL-C lowering across dosages that was consistent with treatments of IR formulation from similar studies, namely IR Studies 1, 2, and 3.

Example 13: Preparation of Bempedoic Acid Sustained Release Formulation

[00297] The following describes the process for making a sustained release formulation of bempedoic acid. The process comprises four general steps: granulation, extrusion,

spheronization and drying. During the granulation step, the raw materials bempedoic acid, microcrystalline cellulose, sodium carboxymethylcellulose, and sodium lauryl are dispensed. Separately, HPMC 606 or hydroxypropyl methylcellulose is added to treated water and mixed until the solution is uniform. Next, a GMX High Shear Granulator is set up with a four-liter bowl equipped with an impeller and a chopper. The remaining raw materials are added to the bowl and the resulting composition is mixed with only the impeller at 560 RPM. After two minutes, the composition inside the GMX bowl is mixed with the addition of the chopper, at a speed of 1800 rpm, while maintaining the impeller at 560 RPM. Simultaneously, the HMPC 606 solution is added to the GMX bowl via a pump at a rate of 30 g/min and the resulting composition is mixed for an additional minute following the complete addition of the HPMC 606 solution. The granulator is then stopped momentarily to ensure that all of the composition inside the GMX bowl is scraped to the center of the bowl. One minute of additional mixing follows. The granulation process is then stopped and the granulated composition is collected.

[00298] Next, a DG-L1 Extruder is set up with a 0.8 mm plate and 5 shims for the extrusion step. The granulated composition comprising ETC- 1002 is then extruded at a speed of 60 RPM with recordation of the exact speed, time and amperage during this process. Next, a QJ-230 Spheronizer with a 2 mm plate is set up for the spheronization step. The ETC-1002 Extrudate from the extrusion step is then spheronized at 1350 RPM. The resulting spheres are collected from the Spheronizer onto a drying tray, which is then placed in an oven preheated to 40 °C.

The wet spheres comprising ETC-1002 are then dried until their moisture content, as measured in terms of loss on drying (LOD), is <2%. The trays containing ETC-1002 spheres are removed from the oven, and the individual ETC- 1002 spheres are placed into a poly bag.

[00299] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[00300] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

1. A pharmaceutical formulation comprising the components: (i) 50-70% bempedoic acid, (ii) a filler, (iii) a diluent or solubilizer, and (iv) a binder, wherein the formulation is formulated for the sustained release of bempedoic acid.

2. The pharmaceutical formulation of claim 1, wherein the filler is selected from a group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, and a combination of microcrystalline cellulose and sodium carboxmethylcellulose.

3. The pharmaceutical formulation of claim 1, wherein the diluent or solubilizer is selected from a group consisting of sodium lauryl sulfate and sodium starch glycolate.

4. The pharmaceutical formulation of claim 1, wherein the binder is hydroxylpropyl methylcellulose (HMPC).

5. The pharmaceutical formulation of any one of claims 1-4, wherein the formulation is formulated as a solid.

6. The pharmaceutical formulation of any one of claims 1-5, wherein the formulation is formulated for oral administration.

7. The pharmaceutical formulation of any one of claims 1-6, wherein the formulation comprises: bempedoic acid dispersed within a polymeric matrix, and wherein the formulation exhibits a drug release profile corresponding to the following pattern: after 2 hours, no more than 30% of the total mass of bempedoic acid is released; after 4 hours, no more than 75% of the total mass of bempedoic acid is released; and after 8 hours, no more than 90% of the total mass of bempedoic acid is released.

8. The pharmaceutical formulation of any one of claims 1-7, wherein the dissolution of the formulation is determined using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 °C.

9. The pharmaceutical formulation of any one of claims 1-8, wherein the formulation provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours when administered to a human subject.

10. The pharmaceutical formulation of any one of claims 1-9, wherein the formulation is a gelatin capsule.

11. The pharmaceutical formulation of claim 10, wherein the gelatin capsule further comprises a powder excipient.

12. The pharmaceutical formulation of any one of claims 1-11, wherein the formulation is a tablet.

13. The pharmaceutical formulation of any one of claims 1-12, wherein the filler component is microcrystalline cellulose and is 5-50% w/w.

14. The pharmaceutical formulation of any one of claims 1-13, wherein the filler component is sodium carboxymethylcellulose and is 5-50% w/w.

15. The pharmaceutical formulation of any one of claims 1-14, wherein the diluent or solubilizer component is sodium lauryl sulfate and is about 1-5% w/w.

16. The pharmaceutical formulation of any one of claims 1-15, wherein the binder component is HPMC and is about 0.1-1.5% w/w.

17. The pharmaceutical formulation of any one of claim 1-16, wherein said formulation comprises: 50-70% w/w bempedoic acid, 30%-45% w/w filler component, 1-5% w/w diluent or solubilizer component, and 0.1-1.5% w/w binder component.

18. The pharmaceutical formulation of any one of claims 1-17, wherein said formulation comprises: 55-65% w/w bempedoic acid, 30-45% w/w filler component, 1-5% w/w diluent or solubilizer component, and 0.1-1.5% w/w binder component.

19. The pharmaceutical formulation of any of claims 1-18, wherein said formulation comprises 60% w/w bempedoic acid, 30-45% w/w filler component, 1-5% w/w diluent or solubilizer component, and 0.1-1.5% w/w binder component.

20. The pharmaceutical formulation of any one of claims 1-19, wherein said formulation comprises 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, or 220 mg of bempedoic acid.

21. The pharmaceutical formulation of any one of claims 1-20, wherein the dissolution of the formulation has a zero order release rate for at least 12 hours.

22. The pharmaceutical formulation of claim 21 comprising bempedoic acid and a polymer matrix, wherein the formulation has a hardness of 2-30 kg and the formulation is either shaped as a sphere or else has a ratio of thickness to diameter effective to permit erosion and penetration control sufficient for controlled surface erosion thereof when dissolution is tested.

23. The pharmaceutical formulation of any one of claims 1-22, wherein the formulation provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours when administered to a human subject.

24. The pharmaceutical formulation of any one of claims 1-23, wherein the formulation provides a maximum blood plasma concentration (Cmax) of bempedoic acid of no more than 60 pg/mL when administered to a human subject.

25. The pharmaceutical formulation of any one of claims 1 -24, wherein the formulation provides a maximum blood plasma concentration (Cmax) of bempedoic acid is in a range from 45 pg/mL to 57 pg/mL for 24 hours after administration to a human subject.

26. A method of administering bempedoic acid comprising: administering an effective amount of a pharmaceutical formulation to a human subject in need thereof, wherein the formulation comprises bempedoic acid and a polymer matrix, and wherein, said administration results in a maximum blood plasma concentration (C max ) of bempedoic acid of no more than about 60 pg/mL, and wherein said blood plasma concentration is in a range from about 45-57 pg/mL for 24 hours after administration.

27. A method of treating cardiovascular disease or reducing the risk of cardiovascular disease in a subject, the method comprising: administering an effective amount of a pharmaceutical formulation to a human subject in need thereof, wherein the formulation comprises the components of bempedoic acid and a polymer, and wherein the dissolution of the formulation exhibits a drug release profile corresponding to the following pattern: after 2 hours, no more than 30% of the bempedoic acid is released; after 4 hours, no more than 75% of the bempedoic acid is released; after 8 hours, no more than 90% of the bempedoic acid is released; and wherein the formulation provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours to treat cardiovascular disease or reduce the risk of cardiovascular disease when administered to the subject.

28. The method of claim 26 or 27, wherein the formulation does not release more than 95% of the bempedoic acid after 8 hours.

29. The method of any one of claims 26-28, wherein the polymer is hydroxypropyl methylcellulose (HPMC).

30. The method of any one of claims 26-29, wherein the bempedoic acid is about 30-80% by weight and the polymer is hydroxypropyl methylcellulose (HPMC) and is 15-35% by weight.

31. The method of any one of claims 26-30, wherein the method lowers total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) when administered to a human subject having hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease.

32. The method of any one of claims 26-31, wherein the method decreases the level of very low density lipoprotein (VLDL) in the subject below that of a control subject receiving placebo.

33. The method of any one of claims 26-32, wherein the method decreases the size of VLDL particles in the subject below that of a control subject receiving placebo.

34. The method of any one of claims 26-33, wherein the method decreases the ratio of apolipoprotein B (ApoB) to apolipoprotein A-l (ApoAl) in the subject below that of a control subject receiving placebo.

35. The method of any one of claims 26-34, wherein the subject has hypercholesterolemia.

36. The method of any one of claims 26-35, wherein the method decreases the level of low- density lipoprotein cholesterol (LDL-C) in the subject.

37. The method of any one of claims 26-36, wherein the method decreases LDL-C levels by at least 5%, 10%, 15%, or 20% relative to an otherwise untreated subject or a placebo-treated subject.

38. The method of any one of claims 26-36, wherein the method decreases LDL-C levels by at least 5%, 10%, 15%, or 30% relative to an otherwise untreated subject or a placebo-treated subject.

39. The method of any one of claims 26-36, wherein the method decreases LDL-C levels by 5-40% relative to an otherwise untreated subject or a placebo-treated subject.

40. The method of any of claims 26-39, wherein the method decreases LDL-C levels in a subject at least as effectively as an equal dose of an immediate release bempedoic acid formulation.

41. The method of claim 40, wherein the method wherein the method decreases LDL-C levels in a subject at least as effectively as a higher dose of an immediate release bempedoic acid formulation, wherein the higher dose is 180 mg/day.

42. A method of inhibiting ATP-citrate lyase (ACL) enzyme in a subject, the method comprising administering to the subject the pharmaceutical dosage form of any one of claims 1- 25.

43. A method of treating metabolic syndrome in a subject, the method comprising administering an effective amount of a pharmaceutical dosage form of any one of claims 1-25.

44. The method of claim 43, wherein the subject is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes, or any combination thereof.

45. The method of claim 43, wherein the subject has hypercholesterolemia.

46. The method of any one of claims 43-45, wherein the metabolic syndrome is non alcoholic fatty liver disease (NAFLD).

47. The method of any one of claims 43-45, wherein the metabolic syndrome is non alcoholic steatohepatitis (NASH).