Fixed dose combination composition of obicetrapib and ezetimibe

Abstract

Provided herein are pharmaceutical compositions comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe; a surfactant; and optionally one or more additional pharmaceutically acceptable excipients. Also provided are pharmaceutical dosage forms, including processes for making such pharmaceutical compositions, and methods for using such pharmaceutical compositions in the treatment of subjects including in treatments requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol.

Description

Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A FIXED DOSE COMBINATION COMPOSITION OF OBICETRAPIB AND EZETIMIBE BACKGROUND OF THE INVENTION

[0001] Despite advances in treatment, cardiovascular disease (CVD) is still a leading cause of death globally, with over 17 million deaths annually. For many years it has been known that abnormal cholesterol levels have been associated with increased risk of cardiovascular disease (CVD), such as cardiomyopathy, atherosclerosis and myocardial infarction. In particular, individuals presenting with high levels of low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol combined with low levels of high-density lipoprotein (HDL) cholesterol were observed to be at the highest risk of developing a cardiovascular disease.

[0002] The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve target blood lipid levels with statin therapy or have partial or complete intolerance to them. To reduce the risk of a recurrent non-fatal or fatal cardiovascular disease, such patients are advised to take combinations of alternative lipid lowering agents.

[0003] One class of alternative therapeutic agents is Cholesterol Absorption Inhibitors (CAIs). CAIs prevent the uptake of cholesterol from the small intestine by blocking the uptake of micellar cholesterol, which reduces the incorporation of cholesterol esters into chylomicrons and chylomicron remnants. CAIs reduce the amount of cholesterol that is circulated back to the liver, which in turn increases the activity of hepatic LDL-receptors and increases the clearance of LDL cholesterol particles from the bloodstream.

[0004] A known example of a CAI is ezetimibe, previously known as compound "Sch- 58235” of Schering-Plough and marketed amongst others under the brand names Ezetrol and Zetia (Merck Sharp & Dohme / Merck). The IUPAC name of ezetimibe is (3R,4S)-1-(4- fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2- one. Ezetimibe is administered frequently either as a mono-therapy, or in an add-on combination therapy. Typically, the ezetimibe dosage form is a tablet comprising 10 mg ezetimibe, for oral administration.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0005] Another therapeutic agent is an inhibitor of the Cholesteryl Ester Transfer Protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles (mainly LDL and VLDL) in exchange for triglycerides (TG), thereby decreasing the cholesterol content in HDL in favor of that in (V)LDL. Hence, CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic ApoB fraction.

[0006] Despite the evidence supporting the potential of CETP inhibition in reducing cardiovascular morbidity, clinical development of CETP inhibitors has not been straightforward, and multiple CETP inhibitors have been dropped at various stages of clinical development. Obicetrapib (also known as TA-8995) is currently under clinical evaluation.

[0007] There remains a need for improved therapies in the treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia, for reducing the risk for cardiovascular events, such as by combination therapy. FIELD OF THE INVENTION

[0008] The present invention relates to pharmaceutical compositions comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof; a surfactant, and, optionally, one or more additional pharmaceutically acceptable excipients, and their use for preparation of medicaments and treatment of subjects in need of such treatment, including such treatments requiring reduction of LDL cholesterol or in patients with heterozygous familial hypercholesterolemia (HeFH) and / or with established atherosclerotic cardiovascular disease (ASCVD). SUMMARY OF THE INVENTION

[0009] In some embodiments, inventors have found that remarkable improvements in blood lipid profiles are attained with obicetrapib and ezetimibe combination treatment and, hence, generally stated, an aspect of the present invention provides methods of treating comprising the concomitant administration of obicetrapib and ezetimibe.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0010] Combination therapy requires co-administration of multiple pills as per the exact instructions of the physician prescribing such therapy to a patient. Since each drug in the combination therapy may have its own set of instructions, it is often cumbersome for the patients to follow such instructions for a long time, and this is further complicated for treatment of chronic diseases such as those requiring lipid lowering, and for the patient or a caregiver of patient. Such difficulties usually result into non-compliance, thereby compromised efficacy, increased risk of adverse reactions, and in many cases, development of resistant or altered sensitivity of target receptors / proteins.

[0011] Preparing a fixed dose combination of different drugs in a single pharmaceutical dosage form is often challenging because of multiple factors such as physicochemical incompatibility of the active pharmaceutical ingredients (APIs), for example API-API- interactions; excipient-excipient interactions and drug-excipient interactions. Physicochemical incompatibility of the active ingredients includes the challenges arising due to differences in the physicochemical properties and behaviour of the APIs, for example, pKa, logP, solubility, hygroscopicity, light sensitivity, particle-size, flowability, compressibility, melting point or any such other parameters of one active ingredient that may not be suitable for the stability of another API in the formulation. As compared to preparing a stable formulation of a single API, the total quantity of excipients that can be used to achieve the desired stability and dissolution of each API from the fixed dose formulation is limited because the size and shape of the dosage form needs to be controlled within the proportions of routinely administered pills. Incompatibility of some excipients for one or more drugs in a fixed dose combination further limits the options for formulation scientists. This is more challenging when one or both APIs have poor water solubility, have differences in their solubility or dissolution pattern, for example one soluble and one insoluble or poorly soluble drug; or one lipophilic and another hydrophilic drug. Interactions of one drug or its impurities with another drug or its impurities in a fixed dose combination can further affect the stability, solubility, efficacy or solubility of one or both the drugs.

[0012] Ezetimibe is a practically insoluble drug and poor solubility across the physiological pH range. Ezetimibe is also incompatible with many commonly used excipients and presents stability problems, for example presence of polyethylene glycol (PEG) in coating layers can cause increase in the tetrahydropyran impurity of ezetimibe. Furthermore, ezetimibe is an inherently non-compressible and poorly flowable API (see for example EPAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 2168573 A1), thereby making preparation of tablet formulations of ezetimibe quite challenging.

[0013] Obicetrapib also has poor water solubility at physiological pH range and exerts a negative effect on the dissolution of ezetimibe (unpublished data). To the best of applicant’s knowledge no fixed dose combination of ezetimibe and obicetrapib is known in the art that (i) can be stabilized over a long period of time without substantial increase in the levels of harmful impurities, (ii) is devoid of any significant API-API, API-excipient or excipient- excipient interactions which can render such composition unsuitable for human use, (iii) can consistently provide desired dissolution profile of each of the two ingredients during its shelf- life which is comparable or better than the formulation of a single drug, (iv) which is easy to formulate and does not pose challenges in terms of processability of the ingredients during formulation and scale-up for manufacturing, (v) that is capable of achieving desired bioavailability upon oral administration to humans and is bioequivalent with the same dose of both active ingredients when co-administered as two separate formulations for each drug, and (vi) which provides an improved patient compliance, thereby demonstrating equivalent or superior therapeutic outcomes in long term without the adverse effects of taking multiple pills of single drug formulations, such as poor patient compliance resulting into development of resistance or hypersensitivity of the receptors / proteins due to chronic and irregular exposure of the receptors / proteins with sub-therapeutic or toxic levels of such drugs and their metabolites.

[0014] The present inventors have found that remarkable improvements in blood lipid profiles are attained with obicetrapib and ezetimibe combination treatment, even in subjects that do not adequately respond to (high intensity) statin treatment, such as HIS (high intensity statin) hypo-responders. More in particular, as described in the experimental part of this document, it has now been shown, in a phase 2b clinical trial (‘ROSE2’; NCT05266586), that an obicetrapib (10 mg) and ezetimibe (10 mg) combination was well tolerated and achieved a median reduction in LDL-C of 59%, which is clearly indicative of a supra-additive effect. In particular, patients treated with Obicetrapib achieved a median reduction of LDL-C of 39%, meaning that ezetimibe, added on top of obicetrapib, resulted in an additional / incremental (median) reduction of LDL-C of about 32%. This (greatly) exceeds LDL-C reductions normally attained with ezetimibe: with ezetimibe mono-therapy LDL-C levels are typically reduced by 15–22% (in hyperlipidemic patients), while in combination with statins, ezetimibe typically provides an incremental reduction in LDL-C levels of 15–20% (see, for instance,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Catapano et al. European Heart Journal (2016) 37, 2999–3058). Significant improvements in ApoB, and Lp(a) levels were also demonstrated in the trial.

[0015] One aspect of the invention thus relates to a fixed dose pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co- crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, such as fixed dose pharmaceutical compositions wherein the composition is a dual component composition, and wherein one of the components comprises ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof and another component comprises obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0016] An embodiment relates to a fixed dose pharmaceutical composition comprising obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may further include amorphous obicetrapib hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, wherein at least about 60%, typically at least about 70% and more typically at least about 80% of ezetimibe is dissolved within about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5ºC.

[0017] An embodiment relates to a fixed dose pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for obicetrapib is within a range of 75%-125%, typically 80%- 125%, and more typically 90%-110% of the area under the curve (AUC0-∞ and / or AUC 0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceuticalAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0018] Another embodiment relates to a fixed-dose pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe is within a range of 75% - 125%, typically 80% - 125%, and more typically 90% - 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax, respectively, for ezetimibe and / or ezetimibe, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co- administration with another pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0019] It has surprisingly been found that the fixed dose pharmaceutical compositions of ezetimibe and obicetrapib can be made to remain stable over a long period of time without substantial increase in the levels of harmful impurities or without formation of new impurities in substantial quantities. It has also been surprisingly found that the fixed dose pharmaceutical compositions of ezetimibe and obicetrapib are devoid of any significant API- API interactions, drug-excipient interactions and / or excipient-excipient interactions which could render the formulation unsuitable for use.

[0020] It has even more surprisingly been found that the said pharmaceutical composition consistently provides a dissolution profile for ezetimibe as well as obicetrapib for the entire period of its shelf life, which is equivalent to the dissolution achieved by a formulation comprising just the single drug. Since, the said stable composition provides desired dissolution profile through a single pill, it surprisingly overcomes the problems associated with co-administration of multiple pills of single drug formulations, such as poor patient compliance, sub-optimal therapeutic outcome and enhanced risk of undesired adverse effects such as development of resistance or hypersensitivity of the receptors. This makes the saidAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A fixed dose composition particularly relevant treatment for chronic treatment of patients requiring lipid lowering therapy having, therefore making such therapy suitable.

[0021] A second aspect relates to a fixed dose pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterol and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular disease (ASCVD).

[0022] The present invention also provides methods of treating a subject in need thereof, said method comprising the concomitant treatment of the subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, typically in the form of the fixed dose pharmaceutical composition as defined herein.

[0023] More in particular, the invention concerns the following aspects.

[0024] One aspect of the invention concerns a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising the concomitant treatment of the subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0025] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, wherein the method comprises the concomitant treatment of the subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof . In a typical embodiment of the invention, said pharmaceutical composition is the fixed dose pharmaceutical composition as defined herein.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0026] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from a disease or disorder selected from the following group: treatment resistant progressive coronary disease, progressive kidney disease, peripheral arterial disease, and complete statin intolerance, wherein the method comprises the concomitant treatment of the subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a calcium salt, thereof. In a typical embodiment of the invention, said pharmaceutical composition is the fixed dose pharmaceutical composition as defined herein.

[0027] A further aspect of the invention concerns a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the concomitant treatment of said subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or co- crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0028] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0029] A further aspect of the invention concerns a method of synergistically slowing the development and / or progression of CVD, more in particular ASCVD, and / or synergistically reducing the risk and / or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or calcium salt thereof . In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0030] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of synergistically slowing the development and / or progression of CVD, more in particular ASCVD, and / or synergistically reducing the risk and / or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the concomitant treatment of the subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0031] A further aspect of the invention concerns a method of enhancement, typically the synergistic enhancement, of the LDL-C lowering effect of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in a subject in need thereof, said method comprising the concomitant treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0032] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of enhancement, typically the synergistic enhancement, of the LDL-C lowering effect of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0033] A further aspect of the invention concerns a method of enhancement, typically the synergistic enhancement, of the therapeutic efficacy of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in particular of the therapeutic efficacy in the treatment and / or prevention of CVD, more in particular ASCVD, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0034] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of enhancement, typically the synergistic enhancement of the therapeutic efficacy of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in particular of the therapeutic efficacy in the treatment and / or prevention of CVD, more in particular ASCVD, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a typical embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0035] Yet, a further aspect of the invention concerns the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in the manufacture of a medicament for use in any one of the afore defined methods. In a typical embodiment of the invention, said medicament is the fixed dose pharmaceutical composition as defined herein.

[0036] Other aspects of the invention concern a kit comprising a package containing a plurality of pharmaceutical unit dosage forms comprising or a pharmaceutically acceptable salt, hydrate or solvate thereof, such as the fixed dose pharmaceutical compositions as defined herein, as well as a leaflet containing printed instructions to repeatedly self- administer said unit dosage forms in order to treat and / or prevent CVD, in particular ASCVD, by combined obicetrapib treatment and ezetimibe therapy.

[0037] In such aspects the obicetrapib may be delivered in a pharmaceutical composition containing said obicetrapib, a surfactant, and optionally, one or more pharmaceutically acceptable excipients.

[0038] Further aspects of the invention relate to pharmaceutical compositions comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; a surfactant, and, optionally, one or more pharmaceutically acceptable excipients.

[0039] The present invention also provides methods of treating a subject in need thereof, said method comprising the concomitant treatment of the subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and a surfactant, and, optionally one or more additional pharmaceutically acceptable excipients.

[0040] One aspect of the invention concerns a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising the concomitant treatment of the subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and a surfactant and, optionally, one or more additional pharmaceutically acceptable excipients.

[0041] Yet, a further aspect of the invention concerns the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; in a composition comprising a surfactant and optionally one or more pharmaceutically acceptable excipients in the manufacture of a medicament for use in the treatment of human disease effected by CETP inhibition.

[0042] Other aspects of the invention concern a kit comprising a package containing a plurality of pharmaceutical unit dosage forms comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; a surfactant, and optionally one or more additional pharmaceutically acceptable excipients, as well as a leaflet containing printed instructions to repeatedly self-administer said unit dosage forms in order to treat and / or prevent a human condition or disease improved or treated by CETP inhibition. Other aspects of the invention concern the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterolAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular disease (ASCVD).

[0043] Other aspects of the invention concern the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium for use in treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia (or mild dyslipidemia) and / or for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with established atherosclerotic cardiovascular disease (ASCVD) and / or use in the treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD). In such aspects the obicetrapib may be delivered in a pharmaceutical composition containing said obicetrapib, a surfactant, and optionally, one or more pharmaceutically acceptable excipients.

[0044] Further aspects of the invention concern the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium for reducing the risk for cardiovascular events. In such aspects the obicetrapib may be delivered in a pharmaceutical composition containing said obicetrapib, a surfactant, and optionally, one or more pharmaceutically acceptable excipients.

[0045] It will be understood that these aspects of the invention all involve the same compositions, the same methods of treatment, the same subjects, etc. unless specifically stated otherwise. Specific details and typical embodiments of the afore-mentioned methods as well as of the compositions and pharmaceutical kits used therein will become evident to those skilled in the art on the basis of the following detailed description and the appended experimental part.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A BRIEF DESCRIPTION OF THE DRAWINGS

[0046] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0047] FIG.1 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0048] FIG.2 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0049] FIG.3 is an x-ray powder diffraction pattern of crystalline obicetrapib hemicalcium.

[0050] FIG.4 is a polarized light micrograph of amorphous obicetrapib hemicalcium.

[0051] FIG.5 is a polarized light micrograph of crystalline obicetrapib hemicalcium.

[0052] FIG.6 is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.

[0053] FIG.7 is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.

[0054] FIG.8 is a thermogravimetric analysis plot of amorphous obicetrapib hemicalcium.

[0055] FIG.9 is a solid-state13C-NMR spectrum of amorphous and crystalline obicetrapib hemicalcium.

[0056] FIG.10 is a solid-state13C-NMR spectrum of crystalline obicetrapib hemicalcium.

[0057] FIG.11 is a solid-state13C-NMR spectrum of amorphous obicetrapib hemicalcium.

[0058] FIG.12 is an x-ray powder diffraction pattern of crystalline HCl obicetrapib.

[0059] FIG.13 is an x-ray powder diffraction pattern of crystalline HCl obicetrapib (pattern 2) and at least partially desolvated crystalline HCl obicetrapib (pattern 1).

[0060] FIG.14 Cumulative undersize for small scale FDC1 compositions.

[0061] FIG.15 Cumulative undersize for small scale FDC2 compositions.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0062] FIG.16 Cumulative undersize curve for scale-up batches.

[0063] FIG.17 Obicetrapib dissolution profile for FDC1 granule from scale up batch.

[0064] FIG.18 Ezetimibe dissolution profile for FDC1 granule from scale up batch.

[0065] FIG.19 Ezetimibe dissolution profile for FDC2 final blend from scale up batch.

[0066] FIG.20 Cumulative undersize curve for technical batches.

[0067] FIG.21 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches.

[0068] FIG.22 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches.

[0069] FIG.23 Particle size distribution (PSD) data of granules from technical batches.

[0070] FIG.24 Flow diagram for the manufacture of FDC-1.

[0071] FIG.25 Flow diagram for the manufacture of FDC-2. DETAILED DESCRIPTION OF THE INVENTION

[0072] The present invention provides a pharmaceutical composition comprising or consisting of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; a surfactant, and optionally one or more additional pharmaceutically acceptable excipients. Also provided are pharmaceutical dosage forms including the same, including tablets.

[0073] Also provided are processes for the preparation of (i) formulations comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients thereof.

[0074] Also provided are methods of use of a pharmaceutical composition comprising formulations of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapibAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients for the treatment of a condition or disease wherein the inhibition of CETP improves such condition or treats such disease or both.

[0075] In some embodiments, the dosage form is a solid dosage form, such as a tablet. Also provided are processes for the preparation of (i) obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof and calcium salts thereof, and fixed dose combination formulations of obicetrapib, or a pharmaceutically acceptable salt, solvate or co- crystal thereof or calcium salt thereof, and (ii) ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. Also provided are (a) methods of use of a pharmaceutical composition of fixed dose combination formulations of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof or calcium salt thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof for treating or preventing hyperlipidemia or mixed dyslipidemia, or preparation of a medicament for the use thereof; (b) methods of use of a pharmaceutical composition of fixed dose combination formulations of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof or calcium salt thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with established atherosclerotic cardiovascular disease (ASCVD), or preparation of a medicament for the use; (c) methods of use of a pharmaceutical composition of fixed dose combination formulations of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof or calcium salt thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with established atherosclerotic cardiovascular disease (ASCVD), or preparation of a medicament for the use thereof; (d) a method of treating a subject requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or subject with established atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering a therapeutically effective dose of the pharmaceutical composition, a fixed dose combination formulation of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof or calcium salt thereof, andAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof to a patient in need thereof; and, (e) a method of treating a subject suffering from hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering a pharmaceutical composition, a fixed dose combination formulation of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof or calcium salt thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof to a patient in need thereof.

[0076] In one of the embodiments, upon oral administration of the said fixed dose pharmaceutical composition to a subject, 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is within a range of about 75%- 125%, typically about 80%-125%, and more typically about 90%-110% of the area under the curve (AUC0-∞ and / or AUC 0-t) and / or Cmax, respectively, of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0077] In another embodiment, upon oral administration of the said fixed pharmaceutical composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of about 75% - 125%, typically about 80% - 125%, and more typically about 90% - 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax, respectively, of and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof orAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A calcium salt thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0078] Ezetimibe is practically insoluble in water and with poor solubility across the physiological pH range. Achieving desired dissolution and thereby bioavailability in in vivo conditions is quite challenging for ezetimibe. This problem is further enhanced as obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof slows down the rate of dissolution and the total amount of ezetimibe that can be dissolved (unpublished data). It has surprisingly been found that from the fixed dose pharmaceutical composition at least about 60%, typically at least about 70% and more typically at least about 80% of ezetimibe is dissolved within about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5ºC. In a typical embodiment, it is surprisingly found that from the fixed dose pharmaceutical composition at least about 60%, typically at least about 70% and more typically at least about 80% of ezetimibe is dissolved within about 20 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5ºC.

[0079] It was further surprisingly found that from the fixed dose pharmaceutical composition at least about 70%, typically at least about 80%, more typically at least about 85%, and even more typically at least about 90% of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is dissolved within about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w / v Polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5ºC. In a typical embodiment, it is surprisingly found that from the fixed dose pharmaceutical composition at least about 70%, typically at least about 80%, and more typically at least about 85% of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is dissolved within about 15 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w / v Polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5ºC.

[0080] Ezetimibe is inherently a poorly / non-compressible API (see for example EP 2168573 A1) along with poor flowability. It is therefore very challenging for the formulation scientists to prepare a tablet formulation that not only satisfies the requirements with respectAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A to hardness, disintegration time, friability, shape and size, but also provides the desired stability and dissolution, of ezetimibe. It has been surprisingly found that the composition not only meets the required specifications for dissolution and stability for being suitable to the claimed uses, but also qualifies the criteria of the processability parameters, namely: flowability, compressibility, disintegration time, friability, hardness, shape and size.

[0081] In many embodiments, including in many preferred embodiments, of the invention, obicetrapib is used in the form of amorphous obicetrapib hemicalcium. Such preferred embodiments herein are used in, for example, pharmaceutical compositions, such as unit dosage forms (which may be in the form of tablets), in methods of treatment, in methods of manufacture, and in kits, of the invention.

[0082] Obicetrapib, or (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2- yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester, is a cholesteryl ester transfer protein (CETP) inhibitor of formula (I), wherein Et represents an ethyl group:

[0083] In some an obicetrapib calcium salt such as amorphous obicetrapib hemicalcium. In particular embodiments, the pharmaceutical composition comprises amorphous obicetrapib hemicalcium. Furthermore, the compositions can comprise obicetrapib or calcium salt thereof in the form of a solvate comprising a pharmaceutically acceptable solvent, such as water (‘hydrate’), ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0084] Obicetrapib or calcium salt thereof, such as amorphous obicetrapib hemicalcium is present in the pharmaceutical composition in a therapeutically effective amount. In some embodiments, a “therapeutically effective amount” of obicetrapib is an amount that, when administered to an individual in one or more doses, in combination therapy (e.g., as describedAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A herein in pharmaceutical composition embodiments containing ezetimibe), is effective to ameliorate or improve a symptom of a metabolic or cardiometabolic disorder. This can include for example, lessening in severity or progression, or to cure. In some embodiments, a “therapeutically effective amount” of obicetrapib is an amount that when administered to an individual in one or more doses, in combination therapy (e.g., as described herein in pharmaceutical composition embodiments containing ezetimibe), is effective to reduce the symptoms in the subject by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 80%, at least about 90%, or at least about 95%, compared to measured levels, assessed, quantified or qualified symptoms in the individual in the absence of, or before, treatment with the combination.

[0085] In some embodiments, the pharmaceutical composition comprises from about 1% to about 25% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In further embodiments, the composition comprises from about 1% to about 20% w / w, or from about 1% to about 15% w / w, or from about 1% to about 10% w / w, or from about 5% to about 15% w / w, or from about 5% to about 12% w / w of obicetrapib or calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w of obicetrapib, or calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 5% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 10% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof.

[0086] In some embodiments, the pharmaceutical composition comprises from 1% to 25% w / w of obicetrapib or calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In further embodiments, the composition comprises from 1% to 20% w / w, or from 1% to 15% w / w, or from 1% to 10% w / w, or from 5% to 15% w / w, or from 5% to 12% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8%Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, or 15% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 5% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 10% w / w of obicetrapib, or a calcium salt, such as amorphous obicetrapib hemicalcium, or a solvate or hydrate thereof.

[0087] The amorphous obicetrapib hemicalcium of the present invention is different from and can be distinguished from the crystalline obicetrapib hemicalcium disclosed in U.S. Patent Number 7,872,126. A common technique used to distinguish crystalline from amorphous materials is x-ray powder diffraction. However, this technique has limitations, especially when the crystalline material is disordered. In the case of amorphous obicetrapib hemicalcium, x-ray powder diffraction patterns of two different lots of amorphous obicetrapib hemicalcium are provided in FIG.1 and FIG.2. These patterns have the familiar “halo” features that are associated with amorphous materials. The x-ray powder diffraction pattern from FIG.2 has peaks at about 3.4°2θ, about 7.0°2θ, and about 9.2°2θ. The x-ray powder diffraction patterns of either FIG.1 or FIG.2 may be used to characterize amorphous obicetrapib hemicalcium, provided, however, that occasionally a sharp higher angle peak is found, such as at about 31.7°2θ (such as in FIG.2), and that peak, when present, is due to sodium chloride. The x-ray powder pattern of crystalline obicetrapib hemicalcium is shown in FIG.3. It too exhibits halo-like behavior which may be indicative of disorder.

[0088] Operations 11 and 11A described below set forth various procedures on how to take x-ray powder diffraction of samples. The procedure of Operation 11 was generally used to collect the data set forth in FIG.1 and FIG.3; Operation 11A was generally used for FIG. 2.

[0089] Another technique that may be used to distinguish crystalline materials from amorphous materials is polarized light microscopy (“PLM”). In PLM, a material is viewed through polarized light, and by viewing the material through cross-polarizers, one can differentiate between materials that are anisotropic (e.g., crystals) or isotropic (e.g., amorphous compounds). Anisotropic materials, when exposed to polarized light through cross polarizers, exhibit birefringence which manifests itself by exhibiting color change through cross polarizers. Isotropic materials, on the other hand, do not show birefringence and exhibit no color change when exposed to polarized light.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0090] In FIG.4, amorphous obicetrapib hemicalcium was analyzed by polarized light microscopy as set forth in Operation 10. As FIG.4 shows, the materials under study do not birefringe, indicating that the material is amorphous. By comparison, FIG.5 is a polarized light micrograph of crystalline obicetrapib hemicalcium. Notably, the compounds shown in FIG.5 are multi-colored which indicates crystallinity. In addition, the crystals in FIG.5 are larger than the particles provided in the amorphous obicetrapib hemicalcium polarized light micrograph of FIG.5. Accordingly, PLM and / or the lack of birefringence can be used to characterize amorphous obicetrapib hemicalcium.

[0091] Other techniques can further be used to distinguish amorphous obicetrapib hemicalcium from crystalline obicetrapib hemicalcium, and therefore can be used to characterize amorphous obicetrapib hemicalcium. One such technique is modulated differential scanning calorimetry also referred to as “mDSC”. In an mDSC thermogram, one can measure a glass transition temperature which can be used to characterize an amorphous material. In FIG.6, the mDSC thermogram of amorphous obicetrapib hemicalcium was measured using a sample holder which is open allowing for volatile gases to escape during a measurement. In this FIG.6, the opening was done by piercing a lid on the pan so as to create a pinhole. A glass transition temperature of about 110°C was recorded for this sample. With respect to thermal measurements, the term “about” generally refers to a variability of plus or minus 1°C. By comparison, crystalline obicetrapib calcium has a higher glass transition temperature under the same conditions, and three measurements in FIG.7 indicate a range between about 118°C and about 125.5°C. The glass transition temperature of amorphous obicetrapib hemicalcium has been measured to be between about 109°C and 112°C when measured with a pinhole.

[0092] For example, the glass transition temperature of amorphous obicetrapib hemicalcium may also be measured using mDSC with a closed pan. The type of sample preparation may affect the measured glass transition temperature. In such cases, the glass transition temperature decreases to temperatures of less than about 100°C and in particular between about 70°C and about 92°C depending on humidity.

[0093] Other thermal techniques may also be used to analyze and characterize amorphous obicetrapib calcium such as thermogravimetric analysis (TGA). FIG.8 is a thermogravimetric analysis thermogram of amorphous obicetrapib hemicalcium showing a weight loss of less than 1% when heated to about 200°C. Such weight losses may be, for example, between about 0.8% and about 0.95% including between about 0.84% and aboutAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 0.92%. In FIG.8, the weight loss was determined to be about 0.85%. This particular material was found to have a water content of about 1.5%. In some embodiments, the water content of may be higher and include a range from about 0% to about 5% water by weight, including up to about 4% by weight, up to about 3% by weight, and between about 0.5% and 1.5% by weight.

[0094] Solid-state13C-NMR spectroscopy is another technique which may be used to characterize amorphous materials. FIG.9 shows a solid-state13C-NMR spectrum of both crystalline and amorphous obicetrapib hemicalcium with FIG.10 and FIG.11 showing the crystalline and amorphous obicetrapib hemicalcium separately. There are at least two differences in the spectra. The crystalline phase has a peak at about 22.1 ppm not present in the amorphous phase. In addition, a peak at about 29.5 ppm in the crystalline phase is pronounced while not nearly so in the amorphous phase. Thus, the absence of a solid-state13C-NMR peak at about 22.1 ppm and / or the absence of a pronounced peak at about 29.5 ppm may be used to characterize amorphous obicetrapib hemicalcium. In addition, a solid-state13C-NMR spectrum substantially the same as that of FIG.4 may be used to characterize amorphous obicetrapib hemicalcium.

[0095] In some embodiments of the invention, there is provided substantially pure amorphous obicetrapib hemicalcium, prior to admixture with an SGLT2i. In these and other embodiments, the chemical purity of substantially pure amorphous obicetrapib hemicalcium is 99.9% or greater.

[0096] In many aspects of the invention, there is provided a method of preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium, wherein the method comprises: treating obicetrapib with an acid to form a salt, solvate, or composition; isolating the resulting salt, solvate or composition; and treating that salt, solvate, or composition with a calcium source to create an amorphous obicetrapib calcium salt, such as amorphous obicetrapib hemicalcium. The resulting salt can then be isolated.

[0097] Examples of calcium sources include calcium salts such as halogenated calcium salts and soluble calcium salts. In many embodiments, the calcium source is calcium chloride.

[0098] The preparation of an amorphous salt of obicetrapib calcium such as amorphous obicetrapib hemicalcium has been found to occur when there is an intermediate salt, solvate or composition (such composition comprising the corresponding acid used to make a salt). Treating obicetrapib directly with a calcium base such as calcium hydroxide has not been foundAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A to be a viable way of making an amorphous salt of obicetrapib calcium due to either low solubility, the weakness of the bases available or both. Rather, it has been found that by deploying an intermediate salt, such as a sodium salt, the preparation of the amorphous calcium is viable. However, even with a sodium salt, it is preferable for purity and yield purposes to utilize an additional salt or salt-type exchange (such as with the use of a composition or solvate rather than an actual salt) in connection with the sodium salt of obicetrapib. In particular, the use of the salt, solvate, or composition enables the production of a highly pure amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium.

[0099] Exemplary salts that may be made as an intermediate include those from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methylsulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, or a teoclate. When the intermediate is a solvate or a composition, then the corresponding acids may be used or present. In addition, when a solvate, the intermediate may further include a solvent such as an organic solvent or water, in which case the solvate would be a hydrate. One such organic solvent is CPME (cyclopentyl methyl ether).

[0100] In some embodiments, the intermediate is a solvate of an acid. In these and other embodiments, the intermediate is a solvate of an acid and an organic solvent. In some particular embodiments, the intermediate is a solvate comprising an acid and a solvent. In some of these embodiments, the acid is hydrochloric acid and a solvent is CPME.

[0101] In many aspects of the invention, the invention includes methods for preparing obicetrapib calcium salts, such as amorphous obicetrapib hemicalcium. The invention further includes obicetrapib calcium salts, including amorphous obicetrapib hemicalcium, so prepared. In one such preparation, an intermediate referred to herein as crystalline HCl obicetrapib is used in the processes for preparing amorphous obicetrapib hemicalcium.

[0102] In many aspects of the invention, amorphous obicetrapib hemicalcium is prepared via a chemical synthesis where an intermediate is used denoted by Formula (IH):Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Where y varies suchand is believed to further include an associated organic solvent such as by way of a solvate. In some embodiments, y varies from 0.002 to 1.5. In some embodiments, y varies from 0.3 to 1. In some embodiments, of Formula (IH), as a solvate, is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents which may form solvates include toluene and heptane.

[0103] Crystalline HCl obicetrapib as prepared is crystalline. Thus, unless otherwise stated herein, the term crystalline HCl obicetrapib means crystalline HCl obicetrapib. Further, the term crystalline HCl obicetrapib may include CPME as a solvate when CPME is used in the preparation crystalline HCl obicetrapib. In Formula (IH), the solvate is of an organic solvent and in many embodiments, that solvent is CPME. In some embodiments, the invention provides for compositions comprising crystalline HCl obicetrapib.

[0104] Without being bound by theory, it is believed that Formula (IH) is a solvate and not a hydrochloride salt of obicetrapib. It has been found that when CPME is used to deliver HCl in the reaction to create Formula (IH), the chloride content of Formula (IH) ranges between about 2.5% and 3.0% by weight which is below what one would expect for a neutral salt – namely about 4.7% by weight. In addition, in many embodiments, when CPME is so used, it is found in the material when crystallized. When CPME is used in the reaction to deliver dry HCl and is thus found in the crystallized material, the resulting crystalline Formula (IH) material is referred to as crystalline HCl obicetrapib, those x-ray powder diffraction pattern is seen in FIG.12. It is therefore believed that crystalline HCl obicetrapib is a solvate of CPME and HCl together with obicetrapib. Solvates, as opposed to salts, can have a variable composition which help explains the variable amount of HCl seen in crystalline HCl obicetrapib. An advantage of using crystalline HCl obicetrapib as an intermediate is that the resulting amorphous obicetrapib hemicalcium has a chemical purity which is routinely 99.9% pure or greater. Chemical purity is the quantitative representation of whether other chemical entities other than the compound being measured are present. For example, a chemical purityAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A of 99.9% amorphous obicetrapib hemicalcium means that not more than 0.1% of the compounds in a sample of amorphous obicetrapib hemicalcium are other entities. Physical purity refers to the amount of other solid forms of the same compound are present which, in the case of amorphous obicetrapib calcium, the other solid form being crystalline obicetrapib hemicalcium. The invention herein provides for amorphous obicetrapib hemicalcium which is physically pure meaning it is free or substantially free of crystalline obicetrapib hemicalcium. Unless otherwise stated herein, the purity measurements provided herein are measurements of chemical purity.

[0105] HCl obicetrapib, as used herein, is not limited to crystalline HCl obicetrapib. Indeed, upon desolvation, crystalline HCl obicetrapib may become amorphous.

[0106] Upon stress, crystalline HCl obicetrapib loses its crystallinity. In FIG.13, pattern 2 reflects crystalline HCl obicetrapib subject to a mild drying treatment whereby surface solvent was removed and it can be seen that this compound is crystalline. By comparison, the sample whose x-ray powder diffraction was measured in pattern 1 was subject to a stronger drying treatment at 48 hours at 55°C at a pressure of 2mbar. As is apparent, this drying changed the material from crystalline to amorphous, likely due to a desolvation of CPME and at least some HCl. NMR spectroscopy, for example, was used to show the presence of CPME in the top pattern, but was substantially absent in the lower, amorphous pattern. The amorphous pattern, therefore, represents HCl obicetrapib which is not crystalline obicetrapib. It may be obicetrapib, but is believed to have HCl associated with the obicetrapib as a solvate and thus is HCl obicetrapib, but with a lower chloride content than typically found in the ranges found for crystalline HCl obicetrapib. In some embodiments, that chloride content is less than 0.1% by weight such as between about 0.01% and 0.1% by weight.

[0107] Crystalline HCl obicetrapib may be characterized by an x-ray powder diffraction pattern comprising a peak at about 9.8°2θ. In some embodiments, crystalline HCl obicetrapib may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 8.1°2θ, about 9.8°2θ, about 13.8°2θ, about 16.7°2θ, or about 19.5°2θ. Table 1 provides illustrative peaks which may be present in crystalline HCl obicetrapib. In some embodiments, crystalline HCl obicetrapib may be characterized by an x-ray powder diffraction pattern substantially the same as that in FIG.12.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 1 °2θ Intensity

[0108] In some embodiments, the amorphous obicetrapib hemicalcium of the present invention is prepared by a method that comprises: i. treating obicetrapib with HCl to obtain crystalline HCl obicetrapib; ii. isolating crystalline HCl obicetrapib; iii. preparing an amorphous calcium salt of obicetrapib from the crystalline HCl obicetrapib isolated in step (ii); and iv. isolating an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium.

[0109] In some embodiments of the method of isolating an amorphous calcium salt of obicetrapib according to step (iv), the amorphous calcium salt of obicetrapib is in the form of amorphous obicetrapib hemicalcium (see, e.g., Scheme 1, Compound 3).

[0110] In some embodiments of the method of preparing amorphous obicetrapib hemicalcium, step (iii) includes the following steps: (iii-1) converting crystalline HCl obicetrapib of step (ii) to provide obicetrapib in an organic solvent; (iii-2) treating obicetrapib in the organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and (iii-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemicalcium;Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A wherein the compounds in steps (iii-1) and (iii-2) are not isolated.

[0111] In some embodiments of step (iv), amorphous obicetrapib hemicalcium is isolated with a purity of 95% or more, such as a purity of 95.5% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98% or more, 98.5% or more, 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.

[0112] In some embodiments, amorphous obicetrapib hemicalcium is subjected to a milling process. In some embodiments, the milling process is adapted (e.g., parameters such as feed rate, venturi pressure and mill pressure are adapted) to allow production of micronized amorphous obicetrapib hemicalcium.

[0113] In some embodiments, obicetrapib (i.e., starting material in step (i) above) is prepared by a method that comprises: (a) preparing a compound of Formula (IVA), by coupling a compound of Formula (IIA) or a salt thereof, with a compound of Formula (IIIA);(b) preparing a carbamate of Formula (VA) from the compound of Formula (IVA) and isolating as a solid salt form of Formula (VIA):Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A (c) optionally desalting the compound of Formula (VIA) and alkylating with a compound of Formula (VIIA) to provide a compound of Formula (VIIIA): Y1O2C O Nwhere, X2is a leaving group, Y1is a protecting group; and (d) converting the compound of Formula (VIIIA) to obicetrapib, wherein the reaction steps (a)-(d) are performed in an organic solvent, compounds (IVA), (VA) and (VIIIA) are optionally not isolated from the organic solvent, and wherein the process does not need to comprise chromatography.

[0114] The reactions in steps (a)-(d) of the subject method are performed in a solvent, and intermediate compounds of Formulae (IVA), (VA) and (VIIIA) do not need to be isolated from their respective solvents if they are to be processed further to end products. This means that any solvent swap between reaction steps (x) and (x+1) takes places by evaporating at least part of the solvent used in step (x) and by gradually adding the solvent of step (x+1), such that the compound remains in solution during the solvent swap. The intermediate compound of Formula (VIA) may be isolated from the solvent as a salt in solid form, such that it can be washed to remove impurities. This isolation step ensures sufficient purity of downstream products. The subject process does not need to comprise purification steps using chromatography, such as column chromatography to achieve the chemical purity levels described herein.

[0115] In some embodiments, the amorphous obicetrapib hemicalcium is prepared by the method set out in Scheme 1.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0116] With reference to Scheme 1, amorphous obicetrapib hemicalcium (compound 3) was prepared in six chemical steps and three isolations from the mesylate salt of (2R,4S)-4- amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A), t-butyl-4-(2- chloropyrimidin-5-yloxy)-butyrate (compound 1B), and 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E). Compound 1A was coupled with compound 1B through a palladium-catalyzed reaction to produce a solution of (2R,4S)-4-[5-(3-t- butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline (compound 1C), which was not isolated but directly reacted with excess ethyl chloroformate in the presence of pyridine to produce (2R,4S)-4-[5-(3-t- butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester, which was isolated as a crystalline mesylate salt (compound 1D). The crystalline mesylate salt, compound 1D was alkylated with 3,5 bis(trifluoromethyl)benzyl bromide (compound 1E) under strongly basic conditions to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-t-Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A butoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester (compound 1F) in toluene. Compound IF was then subjected to an acidic cleavage of the tert-butyl ester to produce a solution of (2R,4S)-4- {[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1). Compound 1 was then converted to compound 2, which is a solvate of (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 2). Finally, compound 2 was converted to the amorphous calcium salt (compound 3) and milled to the target particle size. Compound 2 is crystalline HCl obicetrapib and compound 3 is amorphous obicetrapib hemicalcium.

[0117] Each of the steps in the manufacturing process for (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1), the intermediate HCl intermediate (compounds 2), and the corresponding amorphous calcium salt (compound 3) will be described in more detail in Operations 1-9 below.

[0118] The Operations in this section are offered by way of illustration, and not by way of limitation. The operations represent only some embodiments, and it should be understood that the following operations are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein. Operation 1 – Preparation of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline (Compound 1A Free Base)- 1A) (62 kg, 182 mol, 1.00 equiv.) was added to a reaction vessel fitted with a reflux condenser along with toluene (375 L). The resulting slurry was stirred at 52°C and 1 MAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A aqueous sodium hydroxide solution (322 L, 5.2 vol.) was added. The reaction mixture was stirred until all solid was dissolved and then cooled to 20°C. The stirring was halted and the reaction mixture was allowed to split into two phases. The bottom aqueous phase was drained, and an aqueous solution of sodium chloride (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. The stirring was once again halted and the reaction mixture was allowed to split into two phases. The bottom aqueous phase was drained, and deionized water (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. The stirring was once again halted and the rection mixture was allowed to split into two phases. The bottom aqueous phase was separated. The resulting organic solution was then distilled under vacuum at an internal temperature of 65°C or less. Distillation was continued until a final visual volume of 4.0 volumes (250 L) was reached. The reaction vessel was then cooled to 20°C to provide a solution of (2R,4S)-4-amino-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Compound 1A – FREE BASE) in toluene with a small amount of water present. Compound 1A – FREE BASE was not isolated but used directly in Operation 2. Operation 2 – Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2- yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Compound 1C)A”) containing the (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Compound 1A – FREE BASE) in toluene with <1000 ppm water from the previous step. t- Butyl-4-(2-chloropyrimidin-5-yloxy)-butyrate (compound 1B) (54.6 kg, 200 mol, 1.10 equiv.) was then added to vessel A along with t-BuOH (122 L, 1.55 vol.). The reaction mixture was stirred and sparged with nitrogen. Meanwhile, palladium acetate (410 g, 1.8 mol, 1 mol%) was added under nitrogen to a second reaction vessel (“vessel B”). (S)-BINAP (2.48 kg, 4.0 mol, 2.2 mol%) and toluene (107 L, 1.5 vol.) were further added to vessel B and the resulting mixture was stirred to form a red / orange Pd-BINAP solution. The orange / red Pd-BINAP solution of reaction vessel B was transferred to vessel A. K3PO4 (85 kg, 400 mol,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 2.20 equiv.) was further added to vessel A and the resulting reaction mixture was heated to an internal temperature of 72°C and stirred for at least 2 hours. The mixture was then cooled to 20°C, deionized water was carefully added (124 L) and the mixture was stirred for 30 minutes. Stirring was then halted and layers were allowed to split into two phases. The bottom aqueous phase was separated, and an aqueous solution of 1M HCl was added (123 L) with stirring. After 30 minutes, the stirring was once again stopped and the layers were allowed to split into two phases. The bottom aqueous phase was separated, and an aqueous solution of sodium chloride (326 kg, 5.26 vol.) was added with stirring. After 30 minutes, the stirring was once again stopped and the layers were allowed to split into two phases. The bottom aqueous phase was separated, and deionized water (248 L, 4.0 vol.) was added with stirring. After 30 minutes, the stirring was once again stopped and the layers were allowed to split into two phases. The bottom aqueous phase was separated. The resulting reaction mixture was then treated with ethylenediamine (1.60 kg, 0.15 equiv.) and stirred at 20°C for 80 minutes. The reaction mixture was then filtered over a charcoal cartridge and the filtrate returned to a clean vessel. Mixture was then distilled under a partial vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation in reactor (155 L) remained, then acetonitrile (394 L, 5.0 vol.) was added. The mixture was then distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation in reactor (155 L), then the contents were cooled to 20°C. The reaction vessel was then charged with acetonitrile (394 L, 5.0 vol. vol., to reach 11 volumes by visual observation (approximately 620 L)) to obtain (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) dissolved in acetonitrile. Compound 1C was not isolated but used directly in Operation 3. Operation 3 – Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2- yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, as a crystalline mesylate salt (Compound 1D)Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0121] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) in acetonitrile (approximately 620 L) was cooled to an internal temperature of <10°C and pyridine (72 L, 900 mol, 4.9 equiv.) was added. Ethyl chloroformate (136 L, 1428 mol, 7.84 equiv.) was then added through an addition funnel while keeping the internal temperature of the reactor contents <10°C. The internal temperature of the reaction mixture was then increased linearly to 20°C over the course of 3.5 hours. The mixture was then distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation (155 L). Isopropyl acetate (471 L, 6.6 vol.) was then added to the reaction vessel and distillation was continued under vacuum at an internal temperature of 60°C or less until roughly 2.50 volumes remained by visual observation (155 L). Then isopropyl acetate (471 L, 6.6 vol.), 1M hydrochloric acid (307 L, 5.0 vol.), and 26% aqueous sodium chloride (63 L, 1.2 vol.) were added to the reaction vessel. The resulting mixture was stirred for 30 minutes, then separated into two phases. The bottom aqueous phase was separated, and saturated aqueous sodium bicarbonate solution (132 L, 2.3 vol.) was added. The resulting mixture was stirred for 30 minutes, then separated into two phases. The bottom aqueous phase was separated and the remaining mixture was distilled under vacuum and at 60°C or less to reach a total volume of roughly 4.0 volumes by visual observation (250 L) to obtain (2R,4S)-4-[5- (3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid ethyl ester (corresponding free base of compound 1D) in isopropyl acetate based on the weight of the solution.

[0122] Additional isopropyl acetate (86 L, 1.4 vol.) and methyl t-butylether (MTBE, 593 L, 9.6 vol) were added to (corresponding free base of compound 1D) in isopropyl acetate and the jacket temperature was set to 20°C. Methanesulfonic acid (MsOH, 17.6 kg, 1.0 equiv. based on mmol of compound (corresponding free base of compound 1D) was then added to the reaction mixture over 60 minutes. The resulting slurry was then agitated for 8 hours. The slurry was then filtered under vacuum at 20°C. The solid cake was then washed with 75 / 25 v / v isopropyl acetate (78 L, 1.1 vol.) and methyl t-butyl ether solution (236 L, 2.8 vol.) then dried under vacuum and at 20°C to obtain isolated (2R,4S)-4-[5-(3-t- butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester, as a crystalline mesylate salt (compound 1D) with a yield of 74 %, based on the number of moles of compound 1A. The purity of the crystalline compound 1D obtained was > 99 %.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Operation 4 – Preparation of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- tbutoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline- 1-carboxylic acid ethyl ester (compound 1F) (1) reaction t-BuO2C O t-BuO2C O N PhMe N- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, as a crystalline mesylate salt (compound 1D) (42kg) and toluene (465 kg, 12.7 vol.) was added to a reaction vessel at a temperature of 5°C. Tetrabutylammonium hydrogensulfate (3.5 kg, 0.16 equiv.) and sodium tert-pentoxide (34.5 kg, 4.8 equiv.) were then added and the resulting reaction mixture was stirred for 10 minutes and degassed with nitrogen. 3,5- bis(trifluoromethyl)benzyl bromide (Compound 1E) (28 kg, 1.41 equiv.) was then added to the reaction mixture and stirring was continued for 6.5 hours at 5°C. The reaction mixture was then treated with 1N acetic acid solution (320 kg) and allowed to stir for approximately 30 minutes at 20°C. After which time, the stirring was stopped and the mixture was allowed to separate into two phases. The lower aqueous phase was discarded and the reaction mixture was concentrated under vacuum at an internal temperature 60°C or less until approximately 3.3 volumes (137 L) remained, to obtain a solution of 36.8 weight percent (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-tbutoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl- 6-trifluoromethyl-3,4-dihydro-2Hquinoline- 1-carboxylic acid ethyl ester (compound 1F) in toluene, based on the weight of the solution, 97% yield based on the number of moles of compound 1D). Operation 5 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin- 2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1)Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A-[5-(3- tbutoxycarbonylpropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline- 1-carboxylic acid ethyl ester (compound 1F) in toluene (128.4 kg of the 37 wt.% solution, equivalent to 47.5 kg compound 1F) was diluted to 32wt% with additional toluene and then mixed with acetic acid (253 kg, 5.33 wt.), and 6 M HCl (109.9 kg, 2.32 wt, prepared in situ with 66.1 kg of conc. HCl and 43.8 kg of water). The resulting reaction mixture was vigorously agitated and warmed to 48°C for 3 hours. The reaction mixture was then cooled to 21°C, then n-heptane (159.8 kg, 3.36 wt.), acetonitrile (73.8 kg, 1.55 wt.) and water (170 kg, 3.58 wt.) were added. The resulting mixture was agitated for 34 minutes and then allowed to separate into two phases. The lower aqueous phase was then further treated with water (90 kg, 1.89 wt.), n-heptane (95 kg, 2.00 wt.), acetonitrile (38 kg, 0.80 wt.) and toluene (42 kg, 0.88 wt.) and once again agitated for 20 minutes before separating the organic phase and discharging the lower aqueous phase. The combined organic phases were then treated with water (240 kg, 5.05 wt.) and agitated for an additional 30 minutes before separating into two phases. The lower aqueous phase was discarded and the upper organic phase was treated with 5% w / w sodium citrate tribasic dihydrate (34 kg, 0.72 wt.) and water (205 kg, 4.32 wt.). The resulting mixture was vigorously agitated for 30 minutes and then allowed to separate into two phases before discarding the lower aqueous phase. The remaining organic phase was treated once again with water (240 kg, 5.05 wt.) and agitated for 30 minutes before allowing to separate into two phases and discharging the lower aqueous phase. The organic phase was then concentrated to approximately 3 volumes (approximately 149 L) in-vacuo maintaining an internal temperature of 50°C or less. The reaction mixture was diluted with cyclopentyl methyl ether (CPME, 250 kg, 5.26 wt.) and agitated. The solution was then concentrated to approximately 3 volumes (approximately 165 L) in-vacuo maintaining an internal temperature of 50°C or less. CPME (250 kg, 5.26 wt.) was then added and the mixture concentrated to approximately 2.5 volumes (approximately 124 L) in- vacuo, maintaining an internal temperature of 50°C or less to obtain a solution of 33.7 weight percent of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1, free base form) in cyclopentyl methyl ether (CMPE) having 1 weight percent toluene, less than 1 weight percent n-heptane, based on the weight of the solution. Operation 6 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin- 2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hydrochloride (compound 2)- - [5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester (compound 1, free base form, 115.6 kg, 59.2 mol) in cyclopentyl methyl ether (CPME) from the previous step was added to a clean reaction vessel under nitrogen with a jacket temperature of 22°C. After dilution with CPME (27.8 kg / 0.58 wt.) , n-heptane was then added (54.8 kg, 1.15 wt.) and the internal reaction temperature was increased to 39°C. 3.0 M HCl in CPME (17.6 kg, 0.37 wt.) was then added at a constant rate while maintaining an internal reaction temperature of 39°C. After the addition of HCl was complete, the internal temperature was increased to 52°C. Additional n-heptane was then added (133.2 kg, 2.80 wt.) at a constant rate while maintaining an internal reaction temperature of 51°C. The reaction mixture was heated to 55°C and then it was cooled to 49°C. An aliquot of the reaction mixture was removed, cooled to 11°C at a linear cooling rate until a slurry formed containing crystals of compound 2 in CPME / n-heptane (referred to herein as “seed crystal slurry”). A seed crystal slurry of compound 2 (169 g, 0.43 weight percent) in CPME / n-heptane was then added at 49°C and this temperature was held for 105 minutes. The opaque reaction mixture was then cooled to 11°C over the course of 12 hours at a linear cooling rate. The reaction mixture was then filtered under vacuum at 11°C to collect the solid wet HCl intermediate (compound 2). A mixture of CPME and n-heptane (56.6 kg CPME, 179 kg n-heptane) was then added to the reaction vessel and cooled to 11°C. Half the mixture was then poured through the filter dryer as a chromatography wash. The second half was passed through the filter as a slurry wash. Compound 2 was not unloadedAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A from the filter dryer but was further purified by recrystallization according to the following procedure.

[0126] Compound 2 in cyclopentyl methyl ether (CPME) (77.6 kg) was added into a filter dryer containing compound 2 and heated to 25°C. The dissolved compound 2 was then transferred to a reaction vessel with a reactor jacket temperature set at 25°C under nitrogen, and the internal temperature was increased to 38°C. 3.1 M HCl in CPME (6.4 kg) was added so that a total of 1.07 equiv. HCl was achieved based on assay of compound 1 in compound 2 crude and assay of HCl in compound 2 crude. n-Heptane was then added (139.4 kg and the internal reaction temperature was increased to 51°C. A seed crystal slurry of compound 2 (291 g, 0.87 weight percent) in CPME / n-heptane was then added at 50°C and this temperature was held for 105 minutes. The opaque reaction slurry was then cooled to 11°C over 12 hours at a linear cooling rate. The slurry was then filtered under vacuum at 9°C using a filter dryer. 20 vol.% of CPME in n-heptane (57.4 kg CPME, 180 kg n-heptane) was then added to the reaction vessel and cooled to 11°C. Half the mixture was then poured through the filter dryer as a chromatography wash. The second half was passed through the filter dryer as a slurry wash. The wet filter cake was then dried in vacuo in steps of jacket temperature 25, 35, 46, 54°C to provide compound 2 in 64% yield (from compound 1F) with 99.6 area% purity and residual solvents 0.3%w CPME and < 0.1%w n-heptane.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Operation 7 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin- 2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 3)yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hydrochloride (compound 2, 35.0 kg, 48.4 mol) was added to isopropyl acetate (IPAC, 214 kg, 6.11 wt.) to an inert reactor and stirred at 22°C to achieve dissolution. Deionized water (245 kg, 7.00 wt.) was added, the reaction mixture was stirred at 23°C for 35 minutes, then the stirring was stopped, the phases were separated, and the lower aqueous phase was removed. The process of adding deionized water (245 kg, 7 wt.), stirring, and removing the lower aqueous phase was repeated further 3 times. The organic phase was then concentrated under reduced pressure to approximately 71 L (approximately 2 vol.) maintaining an internal temperature of 55°C or less. Ethanol (115 kg, 3.29 wt.) was then added, and the reaction mixture was concentrated under reduced pressure to approximately 78 L (approximately 2 vol.) maintaining an internal temperature of 55°C or less. The process of adding ethanol (115 kg, 3.29 wt.) and concentrating was repeated twice more. The reaction mixture was then cooled to 25°C and subjected to a charcoal treatment via a cartridge. The cartridge was then rinsed with ethanol (100 kg, 2.86 wt.) and concentrated to 147 L (approximately 3.8 vol.) at 55°C or less in vacuo followed by addition of 35 L of EtOH (1.0 vol.) to provide the free baseAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A form of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2- yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1) in ethanol. The 14% wt. NaOH solution (15.8 kg, 1.13 eq.) was then added to the reaction vessel containing compound 1 in ethanol maintaining a reaction temperature of 20°C. The reaction mixture was stirred at 20°C for 5 hours to achieve full conversion.

[0128] 34 % wt. Calcium chloride (aq.) (10.8 kg) was added to an inert reactor. Deionized water (336 L, 9.61 wt. relative to compound 1) and ethyl acetate (15 kg, 0.43 wt. relative to compound 1) was then added and the mixture was stirred for 30 minutes to provide “Solution B.”

[0129] Solution B was then cooled to 9°C with agitation. Solution A (see above) was then added via a filter to Solution B over 90 minutes, maintaining a temperature of 10°C. The Solution A vessel was then rinsed forward to solution B with additional ethanol (50 kg, 1.43 wt. relative to compound 1). The resulting slurry was stirred for 1 hour at 9°C. The solids were then collected by filtration and rinsed with deionized water (2 x 175 kg, 5 wt. relative to compound 1). The solids were then dried in vacuo at 50°C for 21 hours to obtain 27.6 kg of amorphous obicetrapib hemicalcium (compound 3) with <1 weight percent water (77% yield, based the number of moles of compound 2). The compound 3 was reworked as described below in Operation 8. Operation 8 – Rework of Compound 3

[0130] Compound 3 (27.6 kg) was dissolved in ethanol (55.2 kg 2 wt. relative to compound 3) at 45 - 48°C and subsequently cooled to 11°C. The solution was filtered into a pre-cooled (approximately 10°C) mixture of an aqueous CaCl2solution (8.2 kg of 33-35 weight percent, 0.3 wt.), water (262 kg, 9.5 wt.) and ethyl acetate (12.6 kg, 0.46 wt.). The resulting suspension was filtered off and washed with water (2 x 5 wt., 138 kg per washing step) and the solid was dried in vacuo maintaining an internal temperature of 45°C or less for 23 hours to obtain 24.8 kg (91% yield) of the amorphous calcium salt of (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 3) with <1 weight percent water and a purity of 97.5 % wt. and >99.9 area%.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Operation 9 – Milling of Reworked Compound 3

[0131] Compound 3 was jet-milled using an 8-inch spiral mill. Feed rate, venturi pressure, and mill pressure were adjusted within the ranges listed below to allow the production of micronized compound 3 in compliance with particle size acceptance criteria (D90 = 6-15 µm). Feed rate: 17 – 20 kg / h Mill pressure: 20 PSI / 1.4 bar Venturi pressure: 100 PSI / 6.9 bar Process gas: Nitrogen Analytics: Mastersizer 3000. Operation 10 - Polarized light microscopy (PLM)

[0132] Polarized light microscopic pictures were captured using a Nikon DS-Fi2 upright microscope at room temperature. Samples (2 mg) were mounted on a glass slide and covered with a drop of silicone oil with a cover slip on top of the sample for analysis. Samples were not protected from light. Operation 11 - Powder X-ray Diffraction (XRPD)

[0133] XRPD was performed with Panalytical X’Pert3Powder diffractometer using an incident beam of Cu radiation produced using an Empyran tube, fine focused source, on a silicon zero-background holder. Prior to the analysis, a silicon standard (NIST SRM 640d) was analyzed to verify that the Si 111 peak position is consistent with the NIST-certified position. Approximately 5 to10 mg of sample was placed on a silicon zero-background holder and flattened manually using an aluminum spatula to minimize difference in the overall sample height. The holder was then loaded on the instrument for analysis. The XRPD parameters used are listed immediately in Table 2 below.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 2 Parameters for XRPD test Parameters Reflection Mode Cu, kα Kα1 (Å): 1.540598, X-Ray wavelength Kα2 (Å): 1.544426, Kα2 / Kα1 intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit Fixed 1 / 8º Scan mode Continuous Scan range 3-40 (º 2TH) Scan step time [s] 18.87 Step size 0.0131 (º 2TH) Test Time 4 min 15 s Operation 11A -FIG.2

[0134] A PANalytical x-ray powder diffractometer was used with the following measurement conditions, with data acquisition by DataViewer and data evaluation by X’Pert High Score Plus: X-ray tube Cu LFF HR Geometry Transmission X-ray mirror Focusing X-ray mirror W / Si Soller slit 0.02 rad Detector Pixel 1D Detector active length 1.69° Divergence slit Fixed Divergence slit size 1 / 2° X-ray tube excitation 40mA, 40kV 2Theta range 2° to 40° Measurement mode Continuous Time per Step 300 s Step size 0.013° (2Theta) Rotation 1 Rev / sAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Operation 11B – X-ray Powder diffraction Methodology for Crystalline HCl Obicetrapib (FIG.12 and FIG.13)

[0135] Diffraction patterns were measured using a Thermo Fisher Scientific ARL Equinox 1000 powder diffractometer. The diffractometer is equipped with a copper source and a germanium (111) monochromator providing monochromatic Cu Kα1 radiation, and a position sensitive gas-ionization detector.

[0136] Samples were measured in reflection mode using an Al sample holder without any further preparation (i.e., grinding). The detector measures over the entire angle range from approx. 2°2θ to 120° 2θ simultaneously; in the case of HCl obicetrapib, discernible signals useful for phase identification are seen up to approx. 45°2θ. The temperature in the diffractometer is typically around 30 °C during measurements.

[0137] The fixed dose pharmaceutical composition may comprise a combination of 1 to 10 mg obicetrapib, or the calcium salt, solvate or hydrate thereof, and 5 to 20 mg ezetimibe. In a typical embodiment, the composition comprises 5 mg obicetrapib, or the calcium salt, solvate or hydrate thereof, and 10 mg ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a further typical embodiment, the composition comprises obicetrapib, or the calcium salt, solvate or hydrate thereof, and 10 mg ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0138] In a typical embodiment, the pharmaceutical composition is provided as a unit dosage form comprising 5 mg obicetrapib and 10 mg ezetimibe. In a more typical embodiment, the composition is provided as a unit dosage form comprising 10 mg obicetrapib and 10 mg ezetimibe.

[0139] Wherever the dose of either obicetrapib or ezetimibe is mentioned in this invention as mg and / or in relative amounts (by weight), it means obicetrapib, or ezetimibe in its free form. Whenever a salt, solvate or co-crystal of ezetimibe, or obicetrapib calcium salt is used, for the purpose the said dose shall mean a dose equivalent to the weight of ezetimibe or obicetrapib in its free form, respectively.

[0140] In certain embodiments, the pharmaceutical composition is provided in the form of a solid oral dosage selected form caplets, minitablets, lozenges, granules, beads, pellets, tablets, capsules, pill, and the like, or liquid oral dosage forms which may be used for the pharmaceutical preparation include, but are not limited to drinks, solutions, suspensions, syrups, beverages and emulsions.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0141] In one embodiment, the solid oral dosage form is provided as a dual component pharmaceutical composition. In a typical embodiment, one of the components of the dual component pharmaceutical composition comprises ezetimibe and another component comprises obicetrapib. In another typical embodiment, only one of the components of the dual component pharmaceutical composition comprises both ezetimibe and obicetrapib.

[0142] In certain embodiments, the two-component composition is a bilayer tablet formulation. In a typical embodiment, ezetimibe is present in one of the two layers and obicetrapib in the other layer of bilayer tablet.

[0143] In another embodiment, the two-component system is capsule formulation. In a typical embodiment, the capsule may have two types of granules wherein one granule type comprises ezetimibe and another granule type comprises obicetrapib. In yet another typical embodiment, the capsule may comprise two different type of blends or minitablets each comprising ezetimibe or obicetrapib, and optionally, such blends or minitablets may be filled in two components of a capsule which are segregated from each other. In a certain embodiments, each blend or minitablet is filled in a smaller capsule or such blend is compressed into a tablet / caplet / minitablet and then the tablets / caplets / minitablets are filled in a capsule formulation.

[0144] In another embodiment, the fixed dose pharmaceutical composition is a compressed tablet formulation comprising an extragranular component and an intragranular component. In a typical embodiment, the intragranular component comprises ezetimibe and extragranular component comprises obicetrapib. In a more typical embodiment, the intragranular component comprises both ezetimibe and obicetrapib. In another embodiment, the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe. In yet another embodiment, the extragranular component comprises both ezetimibe and obicetrapib.

[0145] In many of these and other embodiments, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0146] The intragranular components and extragranular components are present in a ratio from about 1:99 to about 99:1, typically about 3: 97 to about 97:3, and more typically from about 5:95 to about 95:5. In another embodiment, intragranular components and extragranular components are present in a ratio from about 10:90 to about 90:10, typicallyAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A about 20:80 to about 80:20 or about 30:70 to about 70:30, and even more typically about 40:60 to about 60:40 or about 50:50.

[0147] The term “Intragranular” refers to being or occurring within granules of the composition i.e. granules comprising a first set of pharmaceutically acceptable excipients including but not limited to a binder, a disintegrant, a diluent, a glidant and a solvent, and optionally one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and / or obicetrapib.

[0148] The term “Extra granular” refers to addition of pharmaceutically acceptable component to a material following granulation i.e. an extra-granular fraction comprising a second set of pharmaceutically acceptable excipients including but not limited to a disintegrant, a diluent, a lubricant, a glidant or the like. Optionally, the extra-granular component may comprise one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and / or obicetrapib.

[0149] The pharmaceutical composition can be obtained by a known conventional method like dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion or the like. In a typical embodiment, the composition is obtained by wet granulation followed by compression of the granules in a tablet formulation or filling such granules in a capsule.

[0150] In one embodiment, the pharmaceutical composition comprises ezetimibe as anhydrous ezetimibe. In another embodiment, the pharmaceutical composition comprises ezetimibe as ezetimibe hydrate, in some embodiments, ezetimibe monohydrate. In yet another embodiment, the pharmaceutical composition comprises a mixture of ezetimibe anhydrous and ezetimibe hydrate, in some embodiments, ezetimibe monohydrate. The molar ratio of anhydrous ezetimibe: ezetimibe hydrate, in some embodiments, ezetimibe monohydrate, in the pharmaceutical composition could be in the range of 100:0 to 0:100, 99.09:0.01 to 0.01:99.09, 99.08:0.02 to 0.02:99.08, 99.07:0.03 to 0.03:99.07, 99.06:0.04 to 0.04:99.06, 99.05:0.05 to 0.05:99.05, 99.04:0.06 to 0.06:99.04, 99.03:0.07 to 0.07:99.03, 99.02:0.08 to 0.02:99.02, 99.01:0.09 to 0.09:99.01, 99:1 to 1:99, 98:2 to 2:98, 90:10 to 10:90, 70:30 to 30:70 or 50:50. In a typical embodiment, the composition is substantially free of the ezetimibe hydrate and about 100% of ezetimibe is in the form of ezetimibe anhydrous. In another typical embodiment, about 99.5% ezetimibe is present in the form of ezetimibe anhydrous and about 0.5% of ezetimibe is present in the form of ezetimibe hydrate, in someAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A embodiments, ezetimibe monohydrate. In a more typical embodiment, the composition is substantially free of the ezetimibe anhydrous and about 100% of ezetimibe is in the form of ezetimibe hydrate, in some embodiments, ezetimibe monohydrate.

[0151] Ezetimibe could be present in the form of a pharmaceutically acceptable salt, solvate, or a co-crystal thereof. obicetrapib could be present in the form of a calcium salt or solvate. Solvates include but are not limited to hydrates. Further, “salt” refers to a compound prepared by the reaction of an organic acid or base drug with a pharmaceutically acceptable mineral or organic acid or base; as used herein, “salt” includes hydrates and solvates of the salts. Exemplary pharmaceutically acceptable mineral or organic acids or bases are as listed in Tables 1-8 in Handbook of Pharmaceutical Salts, P. H. Stahl and C. G. Wermuth (eds.), VHCA, Zurich 2002, pp.334-345. A pharmaceutically acceptable salt of obicetrapib or ezetimibe may be readily prepared by mixing together solutions of such compounds and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. In one embodiment, salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate and besylate salt forms. In one of the typical embodiments, the composition comprises obicetrapib as an alkali metal or alkali earth metal salt of obicetrapib, in some embodiments, obicetrapib sodium, obicetrapib potassium or obicetrapib calcium, and in some embodiments, obicetrapib calcium salt. The term "co-crystal" as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion, with the exception that, if specifically stated, the active pharmaceutical ingredient may be a liquid at room temperature. The co-crystals may comprise a co-crystal former H-bonded to ezetimibe. The co-crystal former may be H-bonded directly to the active pharmaceutical ingredient or may be H-bonded to an additional molecule which is bound to ezetimibe. Solvates of active compounds that do not further comprise a co-crystal former are not co-crystals. The co- crystals may also be a co-crystal between a co-crystal former and a salt of ezetimibe. Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions. Of the interactions listed above, hydrogen- bonding is the dominant interaction in the formation of the co-crystal, whereby a non- covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other. In another embodiment the co-crystal comprises two co- crystal formers. Co-crystal formers include, but are not limited to a free acid, free base, orAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A zwitter ion; a salt, an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminum salts or organic base addition salts, or an inorganic acid addition salts such as HBr, HCl, sulfuric, nitric, or phosphoric acid addition salts or an organic acid addition salt such as acetic, proprionic, pyruvic, malanic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulforic, stearic or lactic acid addition salt; an anhydrate or hydrate of a free form or salt, or more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate, pentahydrate; or a solvate of a free form or salt. The ratio of active ingredient to co-crystal former may be stoichiometric or non-stoichiometric for the purposes . For example, 1:1, 1:1.5, 1:2 and 2:1 ratios of active ingredient (including their salts or solvates).

[0152] In one of the embodiments, the said fixed dose pharmaceutical composition comprises either ezetimibe or obicetrapib, or both as a micronized API. Particle size distribution for such micronized API can be determined by a skilled person using the methods commonly known in the art. These methods include but are not limited to laser diffraction (LD), dynamic light scattering (DLS), dynamic image analysis (DIA) or sieve analysis. Typically, the method employed is laser diffraction dry powder dispersion which provides the particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating a cumulative undersize discrete distribution curve that gives particle size distribution by volume. The particle size from this method is usually reported as a volume equivalent sphere diameter (Dv). The most common percentiles reported are the Dv10, Dv50 and Dv90 (also referred as X10, X50 and X90). Dv90 means 90% of the particles by volume are below a particular size and 10% are above, Dv50 means 50% of the particles by volume are below a particular size and 50% are above, and Dv10 means 10% of the particles by volume are below this size and 90% are above. In many of these and other embodiments, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0153] In one of the typical embodiments, the composition comprises micronized ezetimibe having a Dv90 not more than 10µm, in some embodiments, in the range of 4- 10µm, in some embodiments, not more than 8.5 µm; Dv50 not more than 4 µm, in some embodiments, in the range of about 1-4 µm, in some embodiments, not more than 3.8µm, andAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Dv10 not more than 1µm. In many of these typical embodiments, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0154] FIG.24 illustrates the process for making coated tablets of obicetrapib and ezetimibe using the FDC1, and FIG.25 illustrates the process for making coated tablets of obicetrapib and ezetimibe using the FDC2 process. In each, tablet granules are made via wet granulation which are then compressed into tablets with extra-granular components. The figures provide examples of excipients used for both the granules and the extragranular processes as we as the coating. In both processes, the surfactant sodium lauryl sulphate is present in the granules. In FDC1, the obicetrapib (which is in the tablets is obicetrapib calcium) is in the granules with sodium lauryl sulphate whereas in FDC2, the obicetrapib (which is in the tablets as obicetrapib calcium ) is present in the extragranular portion. Applicants have observed that, as set forth in Example 6, when combined with a surfactant, granules of obicetrapib have increased bioavailability, as seen from measurements in Table 45 and Table 46, then when no surfactant is present such as in FDC2 where there is no surfactant in the extragranular portion of the tablet containing obicetrapib.

[0155] The general process of Fig.24 may also be used to create tablets of obicetrapib and ezetimibe other than the FDC-1 formulation.

[0156] In many of the embodiments of the invention, the pharmaceutical compositions comprise micronized amorphous obicetrapib hemicalcium. The particle size distribution of the micronized amorphous obicetrapib hemicalcium can be determined by a skilled person using the methods commonly known in the art. These methods include but are not limited to laser diffraction (LD), dynamic light scattering (DLS), dynamic image analysis (DIA) or sieve analysis. Typically, the method employed is laser diffraction dry powder dispersion which provides the particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating a cumulative undersize discrete distribution curve that gives particle size distribution by volume. The particle size from this method is usually reported as a volume equivalent sphere diameter (Dv). The most common percentiles reported are the Dv10, Dv50 and Dv90 (also referred as X10, X50 and X90). Dv90 means 90% of the particles by volume are below a particular size and 10% are above, Dv50 means 50%Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A of the particles by volume are below a particular size and 50% are above, and Dv10 means 10% of the particles by volume are below this size and 90% are above.

[0157] In many embodiments, the composition comprises micronized amorphous obicetrapib hemicalcium having a Dv90 not more than 14 µm, in some embodiments, in the range of about 5-14 µm; Dv50 not more than 5µm, in some embodiments, in the range of about 3-5µm; and Dv10 not more than 3µm.

[0158] The term “surfactant” as used herein is a compound that contains a lipophilic segment and a hydrophilic segment, which when added to water or solvents, reduces the surface tension of the system. Surfactants may be anionic, cationic, neutral, or zwiterrionic or amphoteric,

[0159] The term “hydrophilic / lipophilic balance index” or “HLB” is a numerical index for a given surfactant structure, indicating its balance of hydrophilic and lipophilic properties. A surfactant with a high HLB is more hydrophilic and less lipophilic in character than a surfactant with a low HLB.

[0160] Examples of anionic surfactants include carboxylates such as alkyl carboxylates- fatty acid salts; carboxylate fluoro surfactants; sulfates such as alkyl sulfates (e.g., sodium lauryl sulfate), alkyl ether sulfates (e.g., sodium laureth sulfate); branched alkyl sulphates, sulfonates such as docusates (e.g., dioctyl sodium sulfosuccinate) alkyl benzene sulfonates, phosphate esters such as alkyl aryl ether phosphates and alkyl ether phosphates.

[0161] Examples of cationic surfactants include quaternary ammonium salts and pyridinium salts.

[0162] Examples of non-ionic surfactants include ethers of fatty alcohols, and polyol esters such as polyoxyethylene esters, poloxamers, glycol and glycerol esters and sorbitan derivatives. Fatty acid esters of sorbitan (often referred to as Spans) and their ethoxylated derivatives (often referred to as Tweens) are also included. Specific examples include Span 8 (sorbitan trioleate), Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan monostearate), Span 65 (sorbitan tristearate) and Span 80 (sorbitan mono-oleate) and Tween 20 (Polyoxyethylene (20) sorbitan monolaurate, Tween 40 (Polyoxyethylene (20) sorbitan monopalmitate), Tween 60 (Polyoxyethylene (20) sorbitan monostearate), Tween 65 (Polyoxyethylene (20) sorbitan tristearate), Tween 80 (Polyoxyethylene (20) sorbitan mono- oleate), and Tween 85 Polyoxyethylene (20) sorbitan tri-oleate. Polysorbate 20 andAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A polysorbate 80 are also non-ionic surfactants. Further examples of non-ionic surfactants are poloxamers which are synthetic block copolymers of hydrophilic poly(oxyethylene)

[0163] Examples of zwitterionic and / or amphoteric surfactants include lauryl betaine, lauroyl sarcosinate, lauryl sultaine, laurylamidopropyl betaine (also known as cocamidoproipylbetaine) and lauryldimethylamine oxide.

[0164] In many embodiments, the surfactant in the compositions of the invention is sodium lauryl sulphate.

[0165] In many embodiments, the surfactant is a salt, an organosulfur compound, or both. In these and other embodiments, the surfactant contains an alkyl chain and may be monosubstituted such as with a sulfur moiety. That sulfur moiety in many embodiments is a sulphate ion.

[0166] In many embodiments, surfactants are selected from lauric, palmitic, stearic and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oils, polyethylene glycol having molecular weight in the range of about 2000 to 10000, propylene glycol caprylates, glycerol oleates and caprylates, esters of glycerol and fatty acids. In many embodiments, one or more surfactants are selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, Polysorbate 40 or polysorbate 80 or sodium lauryl sulphate. In many embodiments, the surfactant is sodium lauryl sulphate such as Kolliphor SLS. The surfactants used in the composition typically are the surfactants having an HLB value selected from at least about 15, at least about 20, at least about 30 or at least about 40. In many embodiments the HLB is between, and including, 15 and 50, or between, and including, 30 and 45, or between and including 35 and 45, or between, and including, 40 and 45. In many embodiments, the HLB is 40, which is the HLB of sodium lauryl sulphate. In many embodiments, the HBL value is higher than 40.

[0167] The surfactants typically may be present in an amount from about 0.2% to 10%, from about 0.5% to about 5%, from about 0.5% to about 2% or from about 0.5% to about 1%, typically about 1.0 + 0.5% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0168] The pharmaceutical composition further optionally comprises one or more additional pharmaceutically acceptable excipients. Excipients include but are not limited toAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A one or more binders, surfactants, disintegrants, glidant, lubricant, diluent, chelating agents, desiccants or absorbents. When another surfactant is used, it may be a different surfactant than used previously. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See “The Handbook of Pharmaceutical Excipients”, 9thedition, Rowe et al., Eds., American Pharmaceuticals Association (2020); and “Remington: The Science and Practice of Pharmacy”, 22ndedition, Gennaro, Ed., Lippincott Williams & Wilkins (2013).

[0169] The one or more binders used in the pharmaceutical composition are in some embodiments, selected from cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, glucose, sucrose, lactose dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites. In some embodiments, the binder is polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone, such as copovidone or Kollidon 30.

[0170] The binders may typically be present in an amount from about 0.2% to about 10%, from about 0.5% to about 5%, from about 0.5% to about 2% or from about 0.5% to about 1%, and in some embodiments, about 1.0+0.5% by weight of the granule composition, and in other embodiments, by weight of the total tablet.

[0171] In one of the embodiments, the composition comprises a binder : surfactant ratio in the range of about 0.05:5.0 to about 5.0: 0.05, in some embodiments, from about 0.5:4.5 to about 4.5: 0.5, in some embodiments, from about 1:4 to about 4:1, from about 1:2 to about 2:1 and in some embodiments, about 1:1. Such ratios of binder: surfactants may be for the granule composition such as intragranular composition or the extragranular composition or for the total composition of the tablet.

[0172] The pharmaceutical composition may further comprise one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate or pregelatinized starch. In many embodiments, the disintegrant is croscarmellose sodium or sodium starch glycolate.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0173] The disintegrants may be present in an amount from about 0.5% to about 10%, from about 1% to about 8%, from about 2% to about 5%, in some embodiments, 2% to about 3%, from about 4% to about 5%, or from about 7% to about 8% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0174] The one or more diluents used in the pharmaceutical composition may be selected from the group consisting of: an inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomaltose, or celluloses like microcrystalline cellulose or powdered celluloses or the like. In a typical embodiment, the diluent selected from Lactose such as lactose monohydrate, microcrystalline cellulose and mannitol, or a mixture thereof. In a more typical embodiment, intragranular component comprises microcrystalline cellulose and lactose monohydrate as diluent. In another typical embodiment, microcrystalline cellulose and mannitol are present as diluent in the extragranular component. The diluents may present in an amount from about 10% to about 95%, typically from about 40% to about 90%, more typically from about 60% to about 85%, even more typically from about 70% to about 85% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0175] The pharmaceutical composition may optionally be film-coated using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using the hot melt technique. The film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents. Examples of film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; polyvinyl alcohol, waxes; fat substances; or mixtures thereof. Alternatively, commercially available coating compositions comprising film forming polymers marketed under various trade names, such as Opadry®, may be used for coating.

[0176] Examples of solvents used for preparing the coating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof. In a typical embodiment , the film coating is a primary alcohol-free coating. In some embodiments, the primary alcohol- free coating is a coating made using water.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0177] Glidants present in the pharmaceutical dosage form in some embodiments, are selected from silicon dioxide, talc, magnesium stearate and the like. A typical glidant is silicon dioxide such as Aerosil® or magnesium stearate such as Ligamed MF 2V or a mixture thereof. Glidants may typically be present in an amount from about 0.1% to 10%, from about 0.1% to about 5%, or from about 1% to about 2% by weight of the granule composition in some embodiments and by weight of the total tablet in another embodiment.

[0178] Lubricants present in the pharmaceutical composition are in some embodiments, selected from fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and / or palmitic acid and the like. A typical lubricant is magnesium stearate and may typically be present in amount from about 0.1% to 10%, from about 0.1% to about 5% or from about 1% to about 2% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0179] Stability is an essential quality attribute for pharmaceutical formulations that determines the shelf life of the composition during which the composition is suitable for its intended use both from an efficacy and a safety point of view. The term stability of a pharmaceutical composition of a stable pharmaceutical composition means that one or more parameters governing the physical and chemical integrity of the active pharmaceutical ingredients (APIs) remain within a pharmaceutically acceptable criteria during the shelf life of the product. Typically one or more such parameters are selected from identification of the active ingredient(s) in the composition by methods, for example, HPLC and / or UV spectroscopy; visual appearance of the composition, assay percentage of the active ingredient(s) in the composition, individual and / or total percentage of the related substances and / or impurities in the composition, content uniformity of the composition with respect to the active ingredient(s), dissolution rate, microbial limits, and the like.

[0180] Pharmaceutical compositions often lose their efficacy and / or safety over time because of the loss or degradation or conversion of the active ingredient(s) into impurities commonly known as related substance(s). A stable fixed dose pharmaceutical composition retains at least up to about 90%(w / w) of the claimed potency for ezetimibe as well as obicetrapib.

[0181] Ezetimibe is known to give rise to stability problems associated with its formulations because of interactions with excipients and / or the combination drug partner. It has been surprisingly found that the fixed dose pharmaceutical composition effectivelyAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A controls the levels of individual and total related substances of ezetimibe during the preparation as well as storage of the fixed dose composition. In an embodiment , the stable fixed dose pharmaceutical composition has not more than about 5% (w / w), typically, not more than about 2%(w / w), more typically not more than about 1% (w / w) and even more typically not more than about 0.2% (w / w) of an individual related substance of ezetimibe; and not more than about 5% (w / w), typically, not more than about 2%(w / w), more typically not more than about 1%(w / w), and even more typically not more than about 0.5%(w / w) of total related substances of ezetimibe. In a typical embodiment, the fixed dose pharmaceutical composition comprising ezetimibe and obicetrapib wherein the ezetimibe tetrahydropyran analog impurity is not more than about 2% (w / w), typically, not more than about 0.5% (w / w), more typically not more than about 0.3% (w / w), even more typically not more than about 0.2% (w / w).

[0182] In another embodiment , the stable fixed dose pharmaceutical composition has not more than about 5% (w / w), typically, not more than about 2%(w / w), more typically not more than about 0.5% (w / w), even more typically not more than about 0.3%(w / w), and most typically not more than about 0.2%(w / w) of any unspecified individual obicetrapib related substance; and not more than about 5%(w / w), typically, not more than about 2%(w / w), more typically not more than about 1%(w / w), and even more typically not more than about 0.5%(w / w) of total related substances of obicetrapib.

[0183] It has surprisingly been found the pharmaceutical composition remains stable for at least up to 1 month, typically, at least up to 3 months, more typically at least up to 6 months under stability conditions of 40ºC temperature and 75% relative humidity. In a typical embodiment, the composition remains stable at least up to 3 months, in some embodiments, at least up to 6 months under stability conditions of 40ºC temperature and 75% relative humidity. In another typical embodiment, the composition remains stable for at least up to 3 months, 6 months, or 12 months under stability conditions of 25ºC temperature and 60% relative humidity. In yet another typical embodiment, the composition remains stable for at least up to 6 months, 12 months, 18 months, or 24 months at room temperature.

[0184] In one of the typical embodiments, the pharmaceutical composition is a tablet formulation comprising or consisting of: an intragranular component comprising: obicetrapib calcium salt equivalent to 10 mg obicetrapib free acid;Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe monohydrate equivalent to ezetimibe 10 mg; a binder and a surfactant in a ratio of 1:1, typically, the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; typically, the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more typically sodium starch glycolate; typically the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more typically about 4.5+0.5% w / w;

[0185] One or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; sugar alcohols, typically sorbitol, xylitol or mannitol.

[0186] In such compositions, they further comprise an extragranular component comprising: a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more typically sodium starch glycolate, even more typically about 4%-6% w / w sodium starch glycolate; optionally, a lubricant, typically magnesium stearate, more typically about 1%-2% w / w magnesium stearate; optionally, a glidant, typically colloidal silicon dioxide or talk or both, more typically about 1%-2% w / w colloidal silicon dioxide or talk or both; optionally, one or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; sugar alcohols, typically sorbitol, xylitol or mannitol; more typically mannitol or microcrystalline cellulose, even more typically about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.

[0187] Optionally, the composition comprises a film coating, typically the film coating is free from a primary alcohol, more typically the film coating is free from polyethylene glycol. In yet another typical embodiment, the pharmaceutical composition is a tablet formulation comprising or consisting of: an intragranular component comprising: Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; a binder and a surfactant in a ratio of 1:1, typically the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more typically the binder isAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more typically sodium starch glycolate; typically the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more typically about 4.5+0.5% w / w; and one or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; sugar alcohols, typically sorbitol, xylitol or mannitol.

[0188] In such compositions, they further comprise an extra-granular component comprising: Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more typically sodium starch glycolate; even more typically about 4%-6% w / w sodium starch glycollate; optionally, a lubricant, typically magnesium stearate, more typically about 1-2% w / w magnesium stearate; optionally, a glidant, typically colloidal silicon dioxide or talc or both, more typically about 1-2% colloidal silicon dioxide or talc or both; and optionally, one or more diluents selected from disaccharides, typically lactose or sucrose, more typically anhydrous lactose or lactose monohydrate, even more typically lactose monohydrate; polysaccharides, typically cellulose, more typically microcrystalline cellulose; sugar alcohols, typically sorbitol, xylitol or mannitol; more typically mannitol or microcrystalline cellulose, even more typically about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.

[0189] Optionally, the compositions comprise a film coating, typically the film coating is free from a primary alcohol, more typically the film coating is free from polyethylene glycol.

[0190] Another aspect relates to a pharmaceutical compositions comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, inAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A many embodiments, be amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients for use in the treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0191] A second aspect relates to the use of a pharmaceutical composition comprising amorphous obicetrapib hemicalcium, ezetimibe, and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients for preparation of a medicament for treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol.

[0192] In many embodiments, the said subjects are suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).

[0193] In many embodiments, the said subjects are partially or completely intolerant to statins.

[0194] In many embodiments, the use of a pharmaceutical composition of the invention is for treatment of subjects requiring lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0195] A third aspect relates to a method of treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, wherein the method comprises administering to the said subject a therapeutically effective dose of a pharmaceutical composition comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients.

[0196] In many embodiments of the invention, the said method is for the treatment of subjects suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0197] In many embodiments, the pharmaceutical compositions of the invention are orally administered to subjects. In one embodiment, the subject requires additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0198] In one embodiment, the said are partially or completely intolerant to statins.

[0199] A fourth aspect relates to a fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the said pharmaceutical composition is suitable for the said use according to the second aspect or said method of treatment according to the third aspect, when:

[0200] a. the fixed dose pharmaceutical composition is orally administered to a subject;

[0201] b. the concentration of obicetrapib in the subject’s blood is determined at one or more time points after administration to provide a set of obicetrapib concentration / time data points to provide an area-under the curve (AUC); and

[0202] c. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for obicetrapib is within a range of 75%-125%, typically 80%-125%, and more typically 90%-110% of the area under the curve (AUC0-∞ and / or AUC 0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In many of these and other embodiments in this fourth aspect, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0203] A fifth aspect relates to a fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the said pharmaceutical composition is suitable for the said use according to the second aspect or said method of treatment according to the third aspect, when:Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0204] the said fixed dose pharmaceutical composition is orally administered to a subject, ezetimibe and / or ezetimibe glucoronide in the subject’s blood is determined at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucoronide concentration / time data points, respectively, to provide an area-under the curve (AUC) for ezetimibe and / or ezetimibe glucoronide, respectively; and,

[0205] if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of 75% - 125%, typically 80% - 125%, and more typically 90% - 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference composition comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or calcium salt thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0206] In one of the embodiments for the use according to the above aspects, t for AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0- 336) or AUC0-∞, typically 48 hours (AUC 0-48), and more typically 72 hours (AUC0-72) or AUC0-∞.

[0207] In some embodiments, the subject is a healthy human subject, typically a non- tobacco, non-nicotine using adult male or female human, more typically of 18-65 years of age, and optionally, the said human has a body mass index of 18.5 to 29.9 Kg / m2.

[0208] In many of these and other embodiments of this fifth aspect, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0209] In these and other embodiments, the subjects are humans requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol. Many such embodiments, the human subjects are suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0210] In some embodiments, the human subjects have LDL-cholesterol levels >70 mg / Dl, and optionally the said human subjects are not adequately controlled by their current lipid-modifying therapies. For the use of a pharmaceutical composition or a method of treatment according to the other aspects , the subject in need thereof may be administered with the said composition to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, in some embodiments, the subject is administered with the said composition to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.

[0211] It has been surprisingly found that the dissolution profile of ezetimibe from the fixed dose combination was found to be non-inferior or sometime superior as compared to the commercial formulation of ezetimibe (Zetia®) which is discussed in detail in the examples section. It was also surprisingly found that the fixed dose combination composition disclosed herein is bioequivalent to a combination of monotherapy drugs co-administered to human subjects. The confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo-∞ and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide from two of the representative compositions - FDC1 and FDC2 were found to be within a range of 75%- 125%, in some embodiments, 80%-125%, and in some embodiments, 90%-110% of AUCo-t, AUCo-∞ and Cmax of obicetrapib, ezetimibe and ezetimibe glucoronide, respectively as obtained from co-administration of single drug formulations of same dose of ezetimibe and obicetrapib. In many of these and other embodiments, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0212] As explained herein before, the invention provides methods for the curative and / or prophylactic treatment of a subject in need thereof. More particularly, the invention provides methods for the treatment and / or prevention of cardiovascular disease, in particular Atherosclerotic cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and / or prevention of one or more symptoms associated with (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and / or prevention of one or more pathologies associated with and / or caused by (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and / or prevention of one or more aetiological factors associated with (atherosclerotic) cardiovascular disease, such as elevated LDL-C levels and / or elevated ApoB levels, in such subjects, using the compositionsAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A as defined herein. The invention further provides methods for mitigating and / or ameliorating resistance or hypo-responsiveness to statin therapy, in particular high intensity statin therapy, in such subjects, using the compositions as defined herein.

[0213] The terms "treat", "treating" or "treatment", when used in conjunction with a specific disease or symptom (for example: “method of treating disease …”) refers to curing, alleviating or abrogating said disease and / or accompanying symptoms, diminishing extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, ameliorating the disease state, prolonging survival (as compared to expected survival without treatment), etc. The terms "prevent", "preventing" or "prevention", as used herein, refer to reducing the risk for a subject to acquire a disease and / or accompanying symptoms, delaying the moment a subject acquires disease, etc. The terms “treat”, “treating” or “treatment”, when used in relation to a patient or subject (for example: “method of treating a subject”), typically refers to the act of administering a therapeutic compound to said patient or subject for whatever therapeutic and / or prophylactic purpose.

[0214] The term “cardiovascular disease” as used herein has its conventional meaning as referring to a disease or condition in which the function of a subject's cardiovascular system becomes impaired. Examples of cardiovascular diseases include thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart); atherosclerosis; hypertensive heart disease; coronary artery disease; carotid artery disease; stroke; peripheral artery disease involving atherosclerosis; restenosis; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction (AMI); myocardial infarction; ischemic heart disease; cardiac ischemia; ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary arterial thrombosis; cerebral arterial thrombosis, cerebral embolism; kidney embolism; pulmonary embolism; etc.

[0215] As used herein, the term “atherosclerotic cardiovascular disease” refers to a specific subset of cardiovascular diseases that include atherosclerosis as a component or precursor to the particular type of cardiovascular disease. Atherosclerosis is a chronic inflammatory response that occurs in the walls of arterial blood vessels associated withAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A retained LDL-C. It involves the formation of atheromatous plaques that can lead to narrowing ("stenosis") of the artery, and can eventually lead to partial or complete closure of the arterial opening and / or plaque ruptures. Thus, atherosclerotic diseases or disorders include the consequences of atheromatous plaque formation and rupture including, without limitation, stenosis or narrowing of arteries, heart failure, aneurysm formation including aortic aneurysm, aortic dissection, and ischemic events such as myocardial infarction and stroke.

[0216] In particularly typical embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is selected from the group consisting of arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia betalipoproteinemia, hypoalphalipoproteinemia, hypercholesteremia, hypertriglyceridemia, familial-hypercholesteremia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and cerebral stroke.

[0217] As will be apparent from the present teachings, the methods of the present invention are effective in and / or intended for reducing and / or normalizing LDL-C plasma levels. In particular, the methods are effective in and / or intended for reducing LDL-C plasma levels, with at least 5 %, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more typically at least 10 %, at least 15 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 % or at least 50 %. In further embodiments, the methods are effective in and / or intended for reducing LDL-C plasma levels, with at least 5 mg / dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more typically at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, at least 30 mg / dL, at least 35 mg / dL or at least 40 mg / dL. In further embodiments, the methods are effective in and / or intended for reducing LDL-C plasma levels, to a level below 85 mg / dL, in some embodiments, below 80 mg / dL, below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 55 mg / dL or below 50 mg / dL.

[0218] As will be apparent from the present teachings, the administration of ezetimibe (or a pharmaceutically acceptable salt, solvate or co-crystal thereof) in addition to obicetrapib (or a calcium salt or solvate thereof) results in remarkable enhancement, notably supra- additive or synergistic enhancement, of LDL-C reduction. More in particular, the present methods of administering ezetimibe (or a pharmaceutically acceptable salt, solvate or co-Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A crystal thereof), in order to enhance the LDL-C lowering effect of obicetrapib as defined herein, are effective in and / or intended for further reducing LDL-C plasma levels, with at least 20 %, as compared to methods based on therapy with obicetrapib, or a calcium salt or solvate thereof, alone (or, at least, without ezetimibe), more typically at least 22.5 %, at least 25 %, at least 26 %, at least 27 %, at least 28 %, at least 29 % or at least 30 %. In further embodiments, these methods are effective in and / or intended for further reducing LDL-C plasma levels, with at least 20 mg / dL as compared to methods based on therapy with obicetrapib, or the calcium salt thereof, alone (or, at least, without ezetimibe), more typically at least 22.5 mg / dL, at least 25 mg / dL, at least 27.5 mg / dL, at least 30 mg / dL, at least 32.5 mg / dL or at least 35 mg / dL.

[0219] In typical embodiments of the invention, the methods are effective in and / or intended for reducing and / or normalizing ApoB plasma levels. More in particular, the methods are effective in and / or intended for reducing ApoB plasma levels, with at least 5 %, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more typically at least 10 %, at least 15 %, at least 20 %, at least 22.5 %, at least 25 % or at least 27.5 %. In further embodiments, the methods are effective in and / or intended for reducing ApoB plasma levels, with at least 5 mg / dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more typically at least 5 mg / dL, at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 22.5 mg / dL, at least 25 mg / dL or at least 27.5 mg / dL. In further embodiments, the methods are effective in and / or intended for reducing ApoB plasma levels, to a level below 80 mg / dL, in some embodiments, below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 57.5 mg / dL or below 55 mg / dL.

[0220] In typical embodiments of the invention, the methods are effective in and / or intended for reducing and / or normalizing Lp(a) plasma levels. More in particular, the methods are effective in and / or intended for reducing Lp(a) plasma levels, with at least 5 %, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more typically at least 7.5 %, at least 10 %, at least 12.5 %, at least 15 %, at least 17.5 % or at least 20 %. In further embodiments, the methods are effective in and / or intended for reducing Lp(a) plasma levels, with at least 5 nmol / L, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more typically at least 10 nmol / L, at least 15 nmol / L, at least 20 nmol / L, at least 25 nmol / L, at least 30 nmol / L, at least 35 nmol / L or at least 40 nmol / L. In further embodiments, the methods are effective in and / orAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A intended for reducing Lp(a) plasma levels, to a level below 110 nmol / L, in some embodiments, below 105 nmol / L, below 100 nmol / L, below 95 nmol / L, below 90 nmol / L, below 85 nmol / L or below 80 nmol / L.

[0221] In some embodiments of the invention, the methods are effective in and / or intended for mitigating and / or ameliorating resistance or hypo-responsiveness to statin therapy, in particular high intensity statin therapy. High intensity statin therapy is a term conventionally used in the art to denote the regimens based on the highest allowed dosages of the statins having the highest efficacy in reducing LDL-C, notably regimens that typically display a LDL-C reduction ≥ 50 % in normally responsive subjects. Of the statins currently used in clinical practice, only 20 mg (daily) or 40 mg (daily) of rosuvastatin and 40 mg (daily) or 80 mg (daily) of atorvastatin meet the criteria. In the context of the present invention hypo-responsiveness to HIS therapy means that a subject receiving HIS therapy fails to reach a 35 % LDL-C reduction, in some embodiments, it means that a subject receiving HIS therapy fails to reach a 30 % LDL-C reduction, a 25 % LDL-C reduction, a 20 % LDL-C reduction, a 15 % LDL-C reduction, or a 10 % LDL-C reduction. Mitigating and / or ameliorating hypo-responsiveness to HIS therapy, means that the difference between the subject’s response (LDL-C reduction) and the (average) response of normo-responsive subjects is reduced. In further embodiments of the invention, the methods are effective in and / or intended for normalizing the responsiveness to statin therapy.

[0222] As explained herein before, the methods of the invention are directed at the treatment and / or prevention of a subject suffering from or at risk of suffering from CVD, in particular ASCVD.

[0223] The term “a subject " refers to a living organism, typically a mammal, in particular a human subject, suffering from or prone to a disease or condition that can be treated by using the composition provided herein.

[0224] In particularly typical embodiments of the invention, the subject is a subject that has been diagnosed with CVD, in particular ASCVD.

[0225] In further typical embodiments of the invention, the subject is a subject that is considered to be at risk, typically at above-average risk, of developing CVD, in particular ASCVD, as can for example, be judged by healthcare professionals.

[0226] In typical embodiments of the invention, the subject is a subject suffering from one or more conditions known to bear a causal and / or epidemiological correlation with theAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including, overweight / obesity, metabolic syndrome, etc. In further typical embodiments of the invention, the subject is a subject that is genetically predisposed to develop (AS)CVD. In further typical embodiments of the invention, the subject is a subject prone to develop (AS)CVD as a consequence of life-style / habitual factors, such as unhealthy diet, lack of exercise, alcohol consumption, smoking.

[0227] In accordance with a typical embodiment of the invention, the subject to be treated has elevated plasma levels of LDL-C, typically an LDL-C plasma level of at least 70 mg / dL, more typically at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Furthermore, in accordance with typical embodiments of the invention, the subject has an LDL-C plasma level that is at least 125 % of the average LDL-C plasma level in healthy subjects, for example, at least 150 %, at least 175 %, or at least 200 %. Normal LDL-C (reference) values typically depend on gender and age.

[0228] In accordance with a typical embodiment of the invention, the subject to be treated has elevated plasma levels of ApoB, typically an ApoB plasma level of at least 70 mg / dL, more typically at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Furthermore, in accordance with typical embodiments of the invention, the subject has an ApoB plasma level that is at least 125 % of the average ApoB plasma level in healthy subjects, for example, at least 150 %, at least 175 %, or at least 200 %. Normal ApoB (reference) values typically depend on gender and age.

[0229] In accordance with a typical embodiment of the invention, the subject to be treated has elevated plasma levels of non-HDL-C, typically a non-HDL-C plasma level of at least 100 mg / dL, more typically at least 105 mg / dL, at least 110 mg / dL, at least 115 mg / dL, at least 120 mg / dL, at least 125 mg / dL or at least 130 mg / dL. Furthermore, in accordance with typical embodiments of the invention, the subject has a non-HDL-C plasma level that is at least 125 % of the average non-HDL-C plasma level in healthy subjects, for example, at least 150 %, at least 175 %, or at least 200 %. Normal non-HDL-C (reference) values typically depend on gender and age.

[0230] In one embodiment of the invention, the subject is human male. In another embodiment of the invention, the subject is human female.

[0231] In further typical embodiments of the invention, the subject is at increased risk based on age, such as a subject being over 35 years of age, over 40 years of age, over 45Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age or over 70 years of age; typically, in combination with one or more other risk factors as defined herein.

[0232] In accordance with certain embodiments of the invention, the subjects to be treated display hypo-responsiveness to statin therapy, in particular HIS therapy. High intensity statin therapy is a term conventionally used in the art, to denote the regimens based on the highest allowed dosages of statins having the highest efficacy in reducing LDL-C, notably regimens that typically display an LDL-C reduction ≥ 50 % in normally responsive subjects. In current clinical practice, only rosuvastatin 20 mg / day or 40 mg / day and atorvastatin 40 mg / day or 80 mg / day are considered HIS therapy. In typical embodiments of the invention, the subject is a subject that is receiving HIS therapy and fails to reach a 35 % LDL-C reduction, in some embodiments, a subject receiving HIS therapy that fails to reach a 30 % LDL-C reduction, a 25 % LDL-C reduction, a 20 % LDL-C reduction, a 15 % LDL-C reduction, or a 10 % LDL-C reduction. In typical embodiments of the invention, the subject’s hypo-responsiveness to statin therapy, in particular HIS therapy, is established after at least 1 month of (continuous) HIS therapy, more typically at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months.

[0233] The various aspects of the present invention as defined herein, all relate to methods of treatment involving the administration, typically the repeated administration, of a composition comprising obicetrapib or a salt or solvate / hydrate thereof, in some embodiments, any composition as defined herein before.

[0234] Hence, in many embodiments of the invention, the method comprises the administration of pharmaceutical compositions comprising obicetrapib and ezetimibe, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium such that the dose of obicetrapib is at least 1 mg, in some embodiments, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 11 mg, at least 12 mg, at least 13 mg, at least 14 mg, or at least 15 mg.

[0235] In accordance with the various aspects of the invention, the method comprises the administration of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystalAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium, in a dose of 100 mg or less, more typically 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg of obicetrapib.

[0236] In accordance with the various aspects of the invention, the method comprises the administration of pharmaceutical compositions comprising obicetrapib and ezetimibe wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous such that the obicetrapib in a dose is within the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg or 5-10 mg.

[0237] In certain typical embodiments, the method comprises the administration of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium, in a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of obicetrapib.

[0238] In certain particularly typical embodiments, the method comprises the administration obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, including, for example, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium, in a dose of 5, 7.5, 10, 12.5 or 15 mg of obicetrapib. The invention includes dosing such doses as well as the doses themselves.

[0239] As will be apparent to those skilled in the art, based on the present teachings, the methods of the invention further comprises the concurrent treatment with ezetimibe. To this end, ezetimibe and obicetrapib (or a therapeutically acceptable calcium salt or solvate of thereof) may be administered at or around the same time, sequentially or concurrently, or they may be administered at different time points. In typical embodiments of the invention, the frequency and administration intervals of obicetrapib and ezetimibe are equal, more typically each is administered once daily, still more typically at the same time of the day, sequentially or concurrently as two separate unit dosage forms, in some embodiments, in the form of the fixed dose combination product as defined herein. In typical embodiments, the methods of the invention comprise the administration of ezetimibe at a daily dosage of 1-30Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A mg, 2-25 mg, 3-20 mg, 4-17.5 mg, or 5-15 mg e.g.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg, most typically about 10 mg; or a salt, solvate or co-crystal of ezetimibe, in the equipotent dosage. In many of these and other embodiments, the obicetrapib of the embodiments is amorphous obicetrapib hemicalcium.

[0240] In a pharmaceutical composition, such as a tablet, which is loaded with a salt of obicetrapib, such as obicetrapib hemicalcium, the amount of the salt is adjusted so as to meet the dose desired of obicetrapib. For example, in embodiments where the dosage form contains 10 mg of obicetrapib, such a dosage form would, when using obicetrapib calcium, as obicetrapib hemicalcium, contain 10.26 mg of obicetrapib calcium (to 2 significant figures). As used herein, obicetrapib calcium contains one calcium cation for two obicetrapib anion. The term “obicetrapib hemicalcium” means there is one obicetrapib anion for each half calcium cation. The two terms are equivalent, for example, when calculating the amount of obicetrapib in a dosage form. In many of these and other embodiments, the obicetrapib calcium of the embodiments is amorphous obicetrapib hemicalcium.

[0241] In other embodiments, pharmaceutical compositions, including tablets, are provided wherein the dosage of obicetrapib is about 8 mg, including 8 mg. In such embodiments, when the material in the tablet is obicetrapib calcium, and the dosage is 8 mg, the amount of obicetrapib calcium would be 8.21 mg (to 2 significant figures). In many of these and other embodiments, the obicetrapib calcium of the embodiments is amorphous obicetrapib hemicalcium.

[0242] As will be apparent to those skilled in the art, based on the present teachings, the methods of the invention, in some embodiments, further comprises the concurrent treatment with a HMG CoA reductase inhibitor, in some embodiments, concurrent HIS therapy. To this end, the HMG CoA reductase inhibitor and obicetrapib (or a therapeutically acceptable calcium salt or solvate thereof) may be administered at or around the same time, sequentially or concurrently, or they may be administered at different time points. In typical embodiments of the invention, the frequency and administration intervals of obicetrapib and the HMG CoA reductase inhibitor are equal, more typically each is administered once daily, still more typically at the same time of the day, sequentially or concurrently as two separate unit dosage forms, or in the form of a fixed dose combination product. In typical embodiments, the methods of the invention comprise the administration of rosuvastatin at a daily dosage of 10- 50 mg, 15-45 mg, 17.5-42.5 mg, or 20-40 mg, e.g.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mg, most typically about 20 mg or 40 mg; or aAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A salt, solvate or co-crystal of rosuvastatin in the equipotent dosage. In typical embodiments, the methods of the invention comprise the administration of atorvastatin at a daily dosage of 30-90 mg, 35-85 mg, 37.5-82.5 mg, or 40-80 mg, e.g.35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85 mg, most typically about 40 mg or 80 mg; or a salt, solvate or co-crystal of atorvastatin in the equipotent dosage. In certain typical embodiments, the methods of the invention do not comprise the concomitant treatment with an HMG CoA reductase inhibitor.

[0243] In particularly typical embodiments of the invention, the treatment comprises the repeated administration of the composition containing amorphous obicetrapib hemicalcium, including within a dose range as set forth herein. In particularly typical embodiments of the invention, the treatment comprises the repeated administration of the composition, in some embodiments, in a dose within the ranges defined herein before, at a frequency of at least once every two days or at least once every day. In particularly typical embodiments of the invention, the treatment comprises the repeated administration of the composition, in some embodiments, in the dose as defined herein before, at a frequency of once to four times every day. In particularly typical embodiments of the invention, the method comprises the once or twice daily administration of the composition containing amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients.

[0244] As will be apparent to the skilled person, on the basis of the present teachings, the daily doses indicated herein may be contained in a single unit dosage form as well as in a plurality of unit dosage forms. In a most typical embodiment of the invention, the method comprises the administration of a composition comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients in the dosages recited herein once daily. However, methods are also envisaged comprising the administration of 2-unit dose forms, each comprising approximately half of the daily dosage as indicated above, at certain pre-determined moments during the day, e.g., one in the morning, such as shortly after the subject wakes up, and one in the evening, such as around the time the subject has his evening meal or goes to sleep. Embodiments wherein unit dosage forms are used comprising higher amounts of compositions comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients than the daily dose indicated herein are also contemplated. This may e.g., involve the use of extended-releaseAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A dosage forms that remain in the body and keep releasing the active ingredient for a sufficiently long time.

[0245] In embodiments, methods and / or compositions for use according to the invention are provided, wherein the methods and / or use comprise the administration, in some embodiments, the repeated administration, of compositions comprising amorphous obicetrapib hemicalcium; ezetimibe, or a pharmaceutically acceptable salt, solvate or co- crystal thereof and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients, to the subject, at a dose and frequency effective to reduce the subject’s LDL-C plasma levels, the subject’s ApoB plasma levels and / or the subjects Lp(a) plasma levels, more typically to accomplish a reduction in one or more of the subject’s LDL-C plasma levels, the subject’s ApoB plasma levels and / or the subjects Lp(a) plasma levels within the ranges recited herein elsewhere. In particularly typical embodiments of the invention, these treatments comprise the repeated administration of compositions comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients, in accordance with the above-defined regimens, during a period of at least one month, at least three months, at least four months, at least six months, at least nine months, at least one year, at least two year, at least three year, at least 5 year, at least 10 year, at least 20 year, at least 30 year. There is no particular upper limit; treatment may be continued for as long as it is deemed beneficial to the subject’s overall health and well-being (as determined by appropriately qualified healthcare professional), e.g., for the rest of the subject’s life.

[0246] Another aspect of the invention is directed to a pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a leaflet, wherein said unit dosage forms contain the pharmaceutical composition according to the invention and wherein said leaflet contains printed instructions to repeatedly self-administer said unit dosage forms in order to accomplish any of the therapeutic objectives as defined herein, such as to treat and / or prevent any cardiac disease or dysfunction as defined herein.

[0247] In accordance with embodiments of the invention, the pharmaceutical kit comprises a container, such as a cardboard box, holding one or more blister packs, said one or more blister packs containing a plurality of solid unit dosage forms as defined herein before, in some embodiments, a plurality of tablets as defined herein before. In particularly typical embodiments of the invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit dosage forms, e.g.4, 5, 6, 7, 8, 9, 10, 11, 12,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In many embodiments of the invention, the pharmaceutical kit only comprises unit dosage forms as defined herein that contain compositions comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients. In some embodiments of the invention, the pharmaceutical kit only comprises a plurality of unit dosage forms as defined herein that contain compositions comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients as the sole active ingredient. In some embodiments of the invention, the pharmaceutical kit only comprises a plurality of unit dosage forms as defined herein that contain obicetrapib as the sole active ingredient and a plurality, in some embodiments an equal number, of unit dosage forms that contain ezetimibe as the sole active, typically in the dose amounts recited herein elsewhere. In one embodiment of the invention, the pharmaceutical kit only comprises a plurality of unit dosage forms as defined, wherein each unit dosage form comprises obicetrapib and ezetimibe, more typically a plurality of the fixed dose pharmaceutical composition as defined herein. In some embodiments, pharmaceutical kits as defined herein may further comprise a plurality of unit dosage forms that contain a HMG CoA reductase inhibitor as the sole active, in some embodiments atorvastatin or rosuvastatin, typically in the dose amounts recited herein elsewhere.

[0248] In accordance with the invention, the pharmaceutical kit comprises a leaflet inserted into the container, typically a patient information leaflet containing printed information, which information may include a description of the form and composition of the unit dosage forms contained in the kit, an indication of the therapeutic indications for which the product is intended, instructions as to how the product is to be used and information and warnings concerning adverse effects and contraindications associated with the use. It will be understood by those of ordinary skill in the art, based on the information presented herein, that the leaflet that is part of the kit according to the invention, will typically contain the information concerning the therapeutic indications, uses, treatment regimens, etc. as described here above in relation to the methods of treatment of the present invention. In particularly typical embodiments of the invention, the leaflet contains printed instructions to repeatedly (self-) administer the unit dosage forms in order to treat and / or prevent CVD, in particular ASCVD.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0249] Additional embodiments include: 1. A fixed dose pharmaceutical composition comprising or consisting of: a. Obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, b. Ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, c. a Surfactant, and d. one or more pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to embodiment 1, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for obicetrapib is within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of the area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co- crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. 3. The pharmaceutical composition according to anyone of the preceding embodiments, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of 75% - 125%, preferably 80% - 125%, and more preferably 90% - 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co- crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystalAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments for use in treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, wherein the pharmaceutical composition is considered to be suitable for said use when: a. the said fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of obicetrapib in the subject’s plasma is determined at one or more time points after administration to provide a set of obicetrapib concentration / time data points to provide an area-under the curve (AUC); and c. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for obicetrapib is within a range of 75%- 125%, preferably 80%-125%, and more preferably 90%-110% of the area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments for use in treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, wherein the pharmaceutical composition is considered to be suitable for said use when: a. the said fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of ezetimibe and / or ezetimibe glucoronide in the subject’s plasma is determined at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucoronide concentration / time data points,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A respectively, to provide an area-under the curve (AUC) for ezetimibe and / or ezetimibe glucoronide, respectively; and, c. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of 75% - 125%, preferably 80% - 125%, and more preferably 90% - 110% of the area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference composition comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the use of the said composition is for reduction in LDL cholesterol and / or an increase in HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or having an established atherosclerotic cardiovascular disease (ASCVD). The pharmaceutical composition according to anyone of the preceding embodiments, wherein the t for AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC0-∞, preferably 48 hours (AUC 0-48), and more preferably AUC0-∞. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the subject is a human, preferably a healthy human, more preferably a human requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or having an established atherosclerotic cardiovascular disease (ASCVD).Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to anyone of the preceding embodiments, wherein the subject is an healthy, non-tobacco, non-nicotine using adult male or female human of 18-65 years of age, and optionally, the said human has a body mass index of 18.5 to 29.9 Kg / m2. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the human requiring reduction in LDL cholesterol, and / or the human suffering from heterozygous familial hypercholesterolemia (HeFH), and / or the human having an established atherosclerotic cardiovascular disease (ASCVD) has LDL-cholesterol levels >70 mg / dL, and optionally the said humans are not adequately controlled by their current lipid-modifying therapies. The pharmaceutical composition according to anyone of the preceding embodiments, wherein at least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved in about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5ºC. The pharmaceutical composition according to anyone of the preceding embodiments, wherein at least about 70%, preferably at least about 80% and more preferably at least about 85% of obicetrapib is dissolved in about 15 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w / v of polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5ºC. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises 1 to 20 mg obicetrapib and 5 to 20 mg ezetimibe, preferably said composition comprises 5 mg obicetrapib and 10 mg ezetimibe or 10 mg obicetrapib and 10 mg ezetimibe. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is provided as a unit dosage form comprising 1 to 20 mgAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A obicetrapib and 5 to 20 mg ezetimibe, preferably the unit dosage comprises 5 mg obicetrapib and 10 mg ezetimibe, or 10 mg obicetrapib and 10 mg ezetimibe. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises ezetimibe tetrahydropyran analog as an impurity not more than about 2% (w / w), preferably not more than about 0.5% (w / w), more preferably not more than about 0.3% (w / w), even more preferably not more than about 0.2% (w / w). The pharmaceutical composition according to any one of the preceding embodiments, wherein either ezetimibe or obicetrapib or both are micronized. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises micronized ezetimibe having a Dv90 not more than 10µm, preferably in the range of 4-10µm, more preferably not more than 8.5 µm; Dv50not more than 4 µm, preferably in the range of about 1-4 µm more, more preferably not more than 3.8µm, and Dv10 not more than 1µm. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises micronized obicetrapib having a Dv90 not more than 14 µm, preferably in the range of about 5-14 µm; Dv50 not more than 5µm, preferably in the range of about 3-5µm; and Dv10 not more than 3µm. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises ezetimibe as anhydrous ezetimibe, ezetimibe monohydrate or a mixture thereof. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises obicetrapib as an alkali metal or alkali earth metal salt of obicetrapib, preferably obicetrapib sodium, obicetrapib potassium or obicetrapib calcium, and more preferably obicetrapib calcium salt.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is a dual component composition, and wherein one of the components comprises ezetimibe and another component comprises obicetrapib. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is a dual component composition, and wherein one of the two components comprises both ezetimibe and obicetrapib. The pharmaceutical composition according to anyone of the embodiments 21-22, wherein the two component composition is a bilayer tablet formulation, a capsule formulation comprising or consisting of two types of granules, or a tablet formulation comprising an extragranular component and an intragranular component. The pharmaceutical composition of embodiment 22, wherein: a. the intragranular component comprises ezetimibe and extragranular component comprises obicetrapib; or the intragranular component comprises both ezetimibe and obicetrapib; and the extragranular component comprises only excipients. The pharmaceutical composition according to embodiment 22, wherein: a. the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe; or b. the extragranular component comprises both ezetimibe and obicetrapib and the intragranular component comprises only excipients. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition further comprises one or more binders with a binder : surfactant ratio, preferably the ratio in the intragranular component, in the range of about 0.05:5.0 to about 5.0: 0.05, preferably from about 0.5:4.5 to about 4.5: 0.5, more preferably from about 1:4 to about 4:1, even more preferably from about 1:2 to about 2:1 and most preferably about 1:1. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition further comprises one or more binders selected from celluloseAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, sucrose, sorbitol, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites, preferably the binder is polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone, more preferably copovidone, and even more preferably the binder is Kollidon 30. The pharmaceutical composition according to any one of the preceding embodiments, wherein the surfactant has an HLB value of at least 15, at least 20, at least 30 or at least 40; preferably the surfactant is selected from lauric, palmitic, stearic and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oils, polyethylene glycol having molecular weight in the range of about 2000 to 10000, propylene glycol caprylates, glycerol oleates and caprylates, esters of glycerol and fatty acids; more preferably the surfactant is selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, Polysorbate 40 or polysorbate 80 or sodium lauryl sulphate; and even more preferably the surfactant is sodium lauryl sulphate. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition further comprises one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, preferably the disintegrant is croscarmellose sodium or sodium starch glycolate, and more preferably the disintegrant is sodium starch glycolate. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is stable for at least 1 month, preferably at least 3 months and more preferably at least 6 months at 40ºC / 75% relative humidity, or for at least 3 months, preferably at least 6 months and more preferably at least 12 months at 25ºC / 60% relative humidity.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is a tablet formulation comprising or consisting of: a. an intragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; iii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; iv. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. An extragranular component comprising: i. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; ii. optionally, a lubricant, preferably magnesium stearate, iii. optionally, a glidant, preferably colloidal silicon dioxide or talc or both; iv. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A c. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises tablet formulation comprising or consisting of: a. an intragranular component comprising: i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; ii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. an extragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate, iv. optionally, a glidant, preferably colloidal silicon dioxide or talc or both; v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose orAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. c. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises tablet formulation comprising or consisting of: a. an intragranular component comprising: i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid ii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; b. an extragranular component comprising: i. Ezetimibe anhydrous or a mixture of Ezetimibe anhydrous and Ezetimibe hydrate equivalent to Ezetimibe 10 mg ii. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; iii. optionally, a lubricant, preferably magnesium stearate,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A iv. optionally, a glidant, preferably colloidal silicon dioxide or talc or both, v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. c. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol. The pharmaceutical composition according to anyone of the preceding embodiments for use in the treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, preferably the subjects suffering from hyperlipidaemia or mixed dyslipidaemia. The pharmaceutical composition according to anyone of the preceding embodiments for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterol and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular disease (ASCVD). Use of a pharmaceutical composition according to anyone of the preceding embodiments for preparation of a medicament for treatment of subjects suffering from hyperlipidaemia or mixed dyslipidaemia. Use of a pharmaceutical composition according to anyone of the preceding embodiments for preparation of a medicament for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with established atherosclerotic cardiovascular disease (ASCVD).Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Use of a pharmaceutical composition according to anyone of the preceding embodiments for preparation of a medicament for reducing the risk for cardiovascular events. Use according to anyone of the preceding embodiments, wherein the subject suffers from mild dyslipidemia. A method of treatment of a subject requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or subject with established atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering a therapeutically effective dose of the pharmaceutical composition of anyone of the preceding embodiments to a patient in need thereof. A method of treatment of subjects suffering from hyperlipidaemia or mixed dyslipidaemia, wherein the method comprises administering the pharmaceutical composition of anyone of the preceding embodiments to a patient in need thereof. The use of a pharmaceutical composition for preparation of a medicament or a method of treatment according to anyone of the preceding embodiments, wherein the subject has LDL-cholesterol levels >50 mg / dL, preferably >70 mg / dL, and optionally, the said humans are not adequately controlled by their current lipid-modifying therapies. The use of a pharmaceutical composition or a method of treatment according to anyone one of the preceding embodiments, wherein the subject in need thereof is administered with the said composition to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, preferably the subject is administered with the said composition to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe. The use of a pharmaceutical composition or a method of treatment according to anyone of the preceding embodiments, wherein the subject in need thereof is a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of adults withAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD 45. A pharmaceutical composition comprising obicetrapib and ezetimibe or pharmaceutically acceptable salts, solvates or co-crystals thereof and a pharmaceutically acceptable carrier for use in the treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0250] Still further embodiments include: 1. A fixed dose pharmaceutical composition comprising of: a. amorphous obicetrapib or calcium salt thereof; b. ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof; a c. surfactant; and d. one or more pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to embodiment 1, wherein the amorphous obicetrapib is amorphous obicetrapib hemicalcium. 3. The pharmaceutical composition according to embodiment 1 or embodiment 2, wherein the amorphous obicetrapib calcium salt is substantially free of any crystalline salt of obicetrapib calcium. 4. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has an x-ray powder diffraction pattern substantially the same as either that of FIG.49 or 50. 5. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°2θ, about 7.0°2θ, and about 9.2°2θ.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium does not birefringe. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has a glass transition temperature at a value between about 107°C and about 112°C. The pharmaceutical composition according to embodiment 7, wherein the glass transition temperature is measured with modulated differential scanning calorimetry. The pharmaceutical composition according to embodiment 8, wherein the measurement with modulated differential scanning calorimetry uses a sample pan which is open. The pharmaceutical composition according to embodiment 9, wherein the opening is a pinhole. The pharmaceutical composition according to any one of embodiments 6 to 10, wherein the glass transition temperature is at a value between about 110°C and about 112°C. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan. The pharmaceutical composition according to embodiment 12, wherein the amorphous obicetrapib calcium has a glass transition temperature at a value between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan. The pharmaceutical composition according to embodiment 13, wherein the amorphous obicetrapib calcium has a loss in weight of less than about 1% when heated to about 200°C.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to embodiment 14, wherein the amorphous obicetrapib calcium loss in weight is between about 0.8% and about 0.95%. The pharmaceutical composition according to embodiment 15, wherein the amorphous obicetrapib calcium loss in weight is between about 0.84% and about 0.92%. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has a water content of less than about 5%. The pharmaceutical composition according to embodiment 17, wherein the amorphous obicetrapib calcium water content is less than about 4%. The pharmaceutical composition according to embodiment 18, wherein the amorphous obicetrapib calcium water content is less than about 3%. The pharmaceutical composition according to embodiment 19, wherein the amorphous obicetrapib calcium water content is between about 0.5% and about 1.5%. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium is in bulk form or formulated composition, having a particle size distribution wherein about 90% of the particles have a diameter of about 15 microns or less. The pharmaceutical composition according to embodiment 21, wherein about 90% of the amorphous obicetrapib calcium particles have a diameter of between about 6 microns and about 15 microns. The pharmaceutical composition according to embodiment 22, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 14 microns or less.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to embodiment 23, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 13 microns or less. The pharmaceutical composition according to embodiment 24, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 12 microns or less. The pharmaceutical composition according to embodiment 25, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 11 microns or less. The pharmaceutical composition according to embodiment 26, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 10 microns or less. The pharmaceutical composition according to embodiment 27, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 9 microns or less. The pharmaceutical composition according to embodiment 28, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 8 microns or less. The pharmaceutical composition according to embodiment 29, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 7 microns or less. The pharmaceutical composition according to embodiment 30, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 6 microns or less. The pharmaceutical composition according to embodiment 31, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 5 microns or less.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to embodiment 32, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 4 microns or less. The pharmaceutical composition according to embodiment 33, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 3 microns or less. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium is in bulk form or formulated composition, having a particle size distribution wherein about 50% of the particles have a diameter of about 5 microns or less. The pharmaceutical composition according to embodiment 35, wherein about 50% of the amorphous obicetrapib calcium particles have a diameter of about 4 microns or less. The pharmaceutical composition according to embodiment 36, wherein about 50% of the amorphous obicetrapib calcium particles have a diameter of about 3 microns or less. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium is in bulk form or formulated composition, having a particle size distribution wherein about 10% of the particles have a diameter of about 2 microns or less. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has a chemical purity of at least 98.0%. The pharmaceutical composition according to embodiment 39, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.0%. The pharmaceutical composition according to embodiment 40, wherein the amorphous obicetrapib calcium has a chemical purity of at least 98.0%.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to embodiment 41, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.0%. The pharmaceutical composition according to embodiment 42, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.5%. The pharmaceutical composition according to embodiment 43, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.6%. The pharmaceutical composition according to embodiment 44, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.7%. The pharmaceutical composition according to embodiment 45, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.8%. The pharmaceutical composition according to embodiment 46, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.9%. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has a solid-state 13C-NMR spectrum substantially the same as that of FIG.59. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has having a solid-state 13C-NMR spectrum where no peak is present at about 22.1 ppm. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has having a solid-state 13C-NMR spectrum where no peak is present at about 29.5 ppm. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has been milled. The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has been jet milled.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to any one of the preceding embodiments, wherein the amorphous obicetrapib calcium has been spray dried. The pharmaceutical composition according to any one of the preceding embodiments, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of the area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax for obicetrapib is within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of the area under the curve (AUC0-∞ and / or AUC 0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of amorphous obicetrapib or its calcium salt thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments, wherein upon oral administration of the said composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of 75% - 125%, preferably 80% - 125%, and more preferably 90% - 110% of the area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co- crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising amorphous obicetrapib or calcium salt thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments for use in treatment of subjects requiring reduction in LDL cholesterol and / or anAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A increase in HDL cholesterol, wherein the pharmaceutical composition is considered to be suitable for said use when: a. the said fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of obicetrapib in the subject’s plasma is determined at one or more time points after administration to provide a set of obicetrapib concentration / time data points to provide an area-under the curve (AUC); and c. if 90% confidence interval for the geometric mean of the area under the curve (AUC0-∞and / or AUC0-t) and / or Cmax for obicetrapib is within a range of 75%- 125%, preferably 80%-125%, and more preferably 90%-110% of the area under the curve (AUC0-∞ and / or AUC 0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of amorphous obicetrapib or its calcium salt thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments for use in treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, wherein the pharmaceutical composition is considered to be suitable for said use when: a. the said fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of ezetimibe and / or ezetimibe glucoronide in the subject’s plasma is determined at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucoronide concentration / time data points, respectively, to provide an area-under the curve (AUC) for ezetimibe and / or ezetimibe glucoronide, respectively; and, c. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of 75% - 125%, preferably 80% - 125%, and moreAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A preferably 90% - 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference composition comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising amorphous obicetrapib or calcium salt thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the use of the said composition is for reduction in LDL cholesterol and / or an increase in HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or having an established atherosclerotic cardiovascular disease (ASCVD). The pharmaceutical composition according to anyone of the preceding embodiments, wherein the t for AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC0-∞, preferably 48 hours (AUC 0-48), and more preferably AUC0-∞. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the subject is a human, preferably a healthy human, more preferably a human requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, a human suffering from heterozygous familial hypercholesterolemia (HeFH) and / or having an established atherosclerotic cardiovascular disease (ASCVD). The pharmaceutical composition according to anyone of the preceding embodiments, wherein the subject is an healthy, non-tobacco, non-nicotine using adult male or female human of 18-65 years of age, and optionally, the said human has a body mass index of 18.5 to 29.9 Kg / m2.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to anyone of the preceding embodiments, wherein the human requiring reduction in LDL cholesterol, and / or the human suffering from heterozygous familial hypercholesterolemia (HeFH), and / or the human having an established atherosclerotic cardiovascular disease (ASCVD) has LDL-cholesterol levels >70 mg / dL, and optionally the said humans are not adequately controlled by their current lipid-modifying therapies. The pharmaceutical composition according to anyone of the preceding embodiments, wherein at least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved in about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5ºC. The pharmaceutical composition according to anyone of the preceding embodiments, wherein at least about 70%, preferably at least about 80% and more preferably at least about 85% of amorphous obicetrapib is dissolved in about 15 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w / v of polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5ºC. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises 1 to 20 mg amorphous obicetrapib and 5 to 20 mg ezetimibe, preferably said composition comprises 5 mg amorphous obicetrapib and 10 mg ezetimibe or 10 mg amorphous obicetrapib and 10 mg ezetimibe. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is provided as a unit dosage form comprising 1 to 20 mg amorphous obicetrapib and 5 to 20 mg ezetimibe, preferably the unit dosage comprises 5 mg amorphous obicetrapib and 10 mg ezetimibe, or 10 mg amorphous obicetrapib and 10 mg ezetimibe. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises ezetimibe tetrahydropyran analog as an impurity not more than about 2% (w / w), preferably not more than about 0.5% (w / w), moreAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A preferably not more than about 0.3% (w / w), even more preferably not more than about 0.2% (w / w). The pharmaceutical composition according to any one of the preceding embodiments, wherein either ezetimibe or amorphous obicetrapib or both are micronized. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises micronized ezetimibe having a Dv90 not more than 10µm, preferably in the range of 4-10µm, more preferably not more than 8.5 µm; Dv50not more than 4 µm, preferably in the range of about 1-4 µm more, more preferably not more than 3.8µm, and Dv10 not more than 1µm. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises micronized amorphous obicetrapib having a Dv90 not more than 14 µm, preferably in the range of about 5-14 µm; Dv50not more than 5µm, preferably in the range of about 3-5µm; and Dv10 not more than 3µm. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises ezetimibe as anhydrous ezetimibe, ezetimibe monohydrate or a mixture thereof. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises amorphous obicetrapib as an alkali metal or alkali earth metal salt of amorphous obicetrapib, preferably amorphous obicetrapib sodium, amorphous obicetrapib potassium or amorphous obicetrapib calcium, and more preferably amorphous obicetrapib calcium salt. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is a dual component composition, and wherein one of the components comprises ezetimibe and another component comprises amorphous obicetrapib.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is a dual component composition, and wherein one of the two components comprises both ezetimibe and amorphous obicetrapib. The pharmaceutical composition according to anyone of the embodiments 21-22, wherein the two component composition is a bilayer tablet formulation, a capsule formulation comprising or consisting of two types of granules, or a tablet formulation comprising an extragranular component and an intragranular component. The pharmaceutical composition of embodiment 22, wherein: a. the intragranular component comprises ezetimibe and extragranular component comprises amorphous obicetrapib; or the intragranular component comprises both ezetimibe and amorphous obicetrapib; and the extragranular component comprises only excipients. The pharmaceutical composition according to embodiment 22, wherein: a. the intragranular component comprises amorphous obicetrapib and the extragranular component comprises ezetimibe; or b. the extragranular component comprises both ezetimibe and amorphous obicetrapib and the intragranular component comprises only excipients. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition further comprises one or more binders with a binder : surfactant ratio, preferably the ratio in the intragranular component, in the range of about 0.05:5.0 to about 5.0: 0.05, preferably from about 0.5:4.5 to about 4.5: 0.5, more preferably from about 1:4 to about 4:1, even more preferably from about 1:2 to about 2:1 and most preferably about 1:1. The pharmaceutical composition according to any one of the preceding embodiments, wherein the composition further comprises one or more binders selected from cellulose derivatives, preferably selected from methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, sucrose, sorbitol, pregelatinized starch, gum tragacanth,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites, preferably the binder is polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone, more preferably copovidone, and even more preferably the binder is Kollidon 30. The pharmaceutical composition according to any one of the preceding embodiments, wherein the surfactant has an HLB value of at least 15, at least 20, at least 30 or at least 40; preferably the surfactant is selected from lauric, palmitic, stearic and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oils, polyethylene glycol having molecular weight in the range of about 2000 to 10000, propylene glycol caprylates, glycerol oleates and caprylates, esters of glycerol and fatty acids; more preferably the surfactant is selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, Polysorbate 40 or polysorbate 80 or sodium lauryl sulphate; and even more preferably the surfactant is sodium lauryl sulphate. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition further comprises one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, preferably the disintegrant is croscarmellose sodium or sodium starch glycolate, and more preferably the disintegrant is sodium starch glycolate. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is stable for at least 1 month, preferably at least 3 months and more preferably at least 6 months at 40ºC / 75% relative humidity, or for at least 3 months, preferably at least 6 months and more preferably at least 12 months at 25ºC / 60% relative humidity. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition is a tablet formulation comprising or consisting of:Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A b. an intragranular component comprising: v. Amorphous obicetrapib calcium equivalent to 10 mg obicetrapib free acid; vi. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; vii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; viii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; ix. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; d. An extragranular component comprising: i. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; ii. optionally, a lubricant, preferably magnesium stearate, iii. optionally, a glidant, preferably colloidal silicon dioxide or talc or both; iv. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A e. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises tablet formulation comprising or consisting of: d. an intragranular component comprising: i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; ii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; e. an extragranular component comprising: vi. Amorphous obicetrapib calcium equivalent to 10 mg obicetrapib free acid; vii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; viii. optionally, a lubricant, preferably magnesium stearate, ix. optionally, a glidant, preferably colloidal silicon dioxide or talc or both;Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A x. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. f. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol. The pharmaceutical composition according to anyone of the preceding embodiments, wherein the composition comprises tablet formulation comprising or consisting of: d. an intragranular component comprising: v. Amorphous obicetrapib calcium equivalent to 10 mg obicetrapib free acid vi. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; vii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; viii. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; e. an extragranular component comprising: vi. Ezetimibe anhydrous or a mixture of Ezetimibe anhydrous and Ezetimibe hydrate equivalent to Ezetimibe 10 mgAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A vii. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; viii. optionally, a lubricant, preferably magnesium stearate, ix. optionally, a glidant, preferably colloidal silicon dioxide or talc or both, x. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol and microcrystalline cellulose. f. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol. The pharmaceutical composition according to anyone of the preceding embodiments for use in the treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, preferably the subjects suffering from hyperlipidaemia or mixed dyslipidaemia. The pharmaceutical composition according to anyone of the preceding embodiments for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterol and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular disease (ASCVD). Use of a pharmaceutical composition according to anyone of the preceding embodiments for preparation of a medicament for treatment of subjects suffering from hyperlipidaemia or mixed dyslipidaemia. Use of a pharmaceutical composition according to anyone of the preceding embodiments for preparation of a medicament for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and / or an increase in HDL cholesterol, aAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with established atherosclerotic cardiovascular disease (ASCVD). 90. Use of a pharmaceutical composition according to anyone of the preceding embodiments for preparation of a medicament for reducing the risk for cardiovascular events. 91. Use according to anyone of the preceding embodiments, wherein the subject suffers from mild dyslipidemia. DISCLAIMERS

[0251] In many embodiments of the invention, various pharmaceutical compositions are excluded as set forth below.

[0252] In certain embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of: an intragranular component comprising: obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe monohydrate equivalent to ezetimibe 10 mg; a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A an extragranular component comprising: a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w / w sodium starch glycolate; optionally, a lubricant, preferably magnesium stearate, more preferably about 1%-2% w / w magnesium stearate; optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about 1%-2% w / w colloidal silicon dioxide or talk or both; optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol; optionally, wherein the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.

[0253] In certain embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of: an intragranular component comprising: ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w;Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; an extra-granular component comprising: obicetrapib calcium equivalent to 10 mg obicetrapib free acid; a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w / w sodium starch glycollate; optionally, a lubricant, preferably magnesium stearate, more preferably about 1% w / w magnesium stearate; optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about 1%-2% w / w colloidal silicon dioxide or talk or both; optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol; wherein, optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.

[0254] In certain embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of: an intragranular component comprising: obicetrapib calcium equivalent to 10 mg obicetrapib free acid; a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably theAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; an extra-granular component comprising: ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; even more preferably about 4%-6% w / w sodium starch glycollate optionally, a lubricant, preferably magnesium stearate, more preferably about 1-2% w / w magnesium stearate optionally, a glidant, preferably colloidal silicon dioxide or talc or both, more preferably about 1-2% colloidal silicon dioxide or talc or both ; optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol. wherein, optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0255] In certain embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of: an intragranular component comprising: obicetrapib calcium equivalent to 10 mg obicetrapib free acid; ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe monohydrate equivalent to ezetimibe 10 mg; a binder and a surfactant in a ratio of 1:1; a disintegrant selected from croscarmellose sodium, pregelatinized starch and sodium starch glycolate; one or more diluents selected from disaccharides, polysaccharides and sugar alcohols; and an extragranular component comprising: a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate.

[0256] In certain embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of: an intragranular component comprising: ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; a binder and a surfactant in a ratio of 1:1; a disintegrant selected from croscarmellose sodium, pregelatinized starch and sodium starch glycolate; one or more diluents selected from disaccharides, polysaccharides and sugar alcohols; and an extra-granular component comprising: obicetrapib calcium equivalent to 10 mg obicetrapib free acid; and a disintegrant selected from microcrystalline cellulose, pregelatinized starch and sodium starch glycolate.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0257] In certain embodiments, the pharmaceutical composition is not a tablet formulation comprising or consisting of: an intragranular component comprising: obicetrapib calcium equivalent to 10 mg obicetrapib free acid; a binder and a surfactant in a ratio of 1:1; a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate; and one or more diluents selected from disaccharides, polysaccharides, and sugar alcohols; and an extra-granular component comprising: ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg; and a disintegrant selected from croscarmellose sodium, pregelatinized starch and sodium starch glycolate.

[0258] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 7.168% w / w of ezetimibe; 3.678% w / w of obicetrapib or a salt thereof; 26.826% w / w of microcrystalline cellulose, in particular Avicel PH101; 53.651% w / w of lactose monohydrate, in particular Pharmatose 200M; 5.018% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 3.301% w / w of sodium starch glycolate, in particular Glycolys; and 0.358% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0259] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.666% w / w of ezetimibe; 3.421% w / w of obicetrapib or a salt thereof; 27.948% w / w of microcrystalline cellulose, in particular Avicel PH101; 49.895% w / w of lactose monohydrate, in particular Pharmatose 200M; 4.667% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 5.570% w / w of sodium starch glycolate, in particular Glycolys; 0.333% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 0.750% w / w of fumed sillica, in particular Aerosil 200; and 0.750% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 5 mg.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0260] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 7.168% w / w of ezetimibe; 3.678% w / w of obicetrapib or a salt thereof; 53.651% w / w of microcrystalline cellulose, in particular Avicel PH101; 28.826% w / w of lactose monohydrate, in particular Pharmatose 200M; 5.018% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 3.301% w / w of sodium starch glycolate, in particular Glycolys; and 0.358% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0261] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.666% w / w of ezetimibe; 3.421% w / w of obicetrapib or a salt thereof; 52.895% w / w of microcrystalline cellulose, in particular Avicel PH101; 24.948% w / w of lactose monohydrate, in particular Pharmatose 200M; 4.667% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 5.570% w / w of sodium starch glycolate, in particular Glycolys; 0.333% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 0.750% w / w of fumed sillica, in particular Aerosil 200; and 0.750% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 5 mg.

[0262] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 7.017% w / w of ezetimibe; 3.601% w / w of obicetrapib or a salt thereof; 20.968% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.887% w / w of lactose monohydrate, in particular Pharmatose 200M; 4.211% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.211% w / w of sodium starch glycolate, in particular Glycolys; and 2.105% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0263] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.666% w / w of ezetimibe; 3.421% w / w of obicetrapib or a salt thereof; 19.920% w / w of microcrystalline cellulose, in particular Avicel PH101; 54.993% w / w of lactose monohydrate, in particular Pharmatose 200M; 4.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 2.000 % w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 1.000% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 5 mg.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0264] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 7.073% w / w of ezetimibe; 3.630% w / w of obicetrapib or a salt thereof; 21.775% w / w of microcrystalline cellulose, in particular Avicel PH101; 60.095% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.061% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.244% w / w of sodium starch glycolate, in particular Glycolys; and 2.122% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0265] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.666% w / w of ezetimibe; 3.421% w / w of obicetrapib or a salt thereof; 20.717% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.196% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 2.000 % w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 1.000% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 5 mg.

[0266] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 20.935% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, in particular Glycolys; and 2.094% w / w of sodium lauryl sulphate.

[0267] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.667% w / w of ezetimibe; 6.840% w / w of obicetrapib; 19.993% w / w of microcrystalline cellulose, in particular Avicel PH101; 55.000% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 2.000% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0268] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 21.982% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, in particular Glycolys; and 1.047% w / w of sodium lauryl sulphate.

[0269] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 6.667% w / w of ezetimibe; 6.840% w / w of obicetrapib; 20.993% w / w of microcrystalline cellulose, in particular Avicel PH101; 55.000% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 1.000% w / w of sodium lauryl sulphate, in particular Kollipho r SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0270] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 21.982% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, in particular Glycolys; and 1.047% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0271] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 21.982% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, in particular Glycolys; and 1.047% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0272] In certain embodiments, the pharmaceutical composition is not a tablet comprising 5.000% w / w of ezetimibe; 5.130% w / w of obicetrapib; 25.432% w / w of microcrystallineAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A cellulose, in particular Avicel PH101; 51.688% w / w of lactose monohydrate, in particular Pharmatose 200M; 3.750% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.000% w / w of sodium starch glycolate, in particular Glycolys; 1.500% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0273] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 21.982% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, in particular Glycolys; and 1.047% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0274] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 6.632% w / w of ezetimibe; 6.804% w / w of obicetrapib; 20.883% w / w of microcrystalline cellulose, in particular Avicel PH101; 54.712% w / w of lactose monohydrate, in particular Pharmatose 200M; 0.995% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.980% w / w of sodium starch glycolate, in particular Glycolys; 0.995% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 1.000% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0275] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 20.935% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, in particular Glycolys; and 2.094% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0276] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.667% w / w of ezetimibe; 6.840% w / w of obicetrapib; 19.993% w / w of microcrystalline cellulose, in particular Avicel PH101; 55.000% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 2.000% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0277] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.667% w / w of ezetimibe; 6.840% w / w of obicetrapib; 20.993% w / w of microcrystalline cellulose, in particular Avicel PH101; 55.000% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 1.000% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0278] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 5.000% w / w of ezetimibe; 7.162% w / w of obicetrapib; 26.182% w / w of microcrystalline cellulose, in particular Avicel PH101; 51.688% w / w of lactose monohydrate, in particular Pharmatose 200M; 3.750% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.000% w / w of sodium starch glycolate, in particular Glycolys; 0.750% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0279] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 6.981% w / w of ezetimibe; 7.162% w / w of obicetrapib; 21.982% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.592% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.047% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.189% w / w of sodium starch glycolate, inAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A particular Glycolys; and 1.047% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0280] In certain embodiments, the pharmaceutical composition is not a tablet comprising 6.667% w / w of ezetimibe; 6.840% w / w of obicetrapib; 20.993% w / w of microcrystalline cellulose, in particular Avicel PH101; 55.000% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 1.000% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 0.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0281] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 4.348% w / w of ezetimibe; 4.461% w / w of obicetrapib; 39.321% w / w of microcrystalline cellulose, in particular Avicel PH101; 34.914% w / w of lactose monohydrate, in particular Pharmatose 200M; 0.652% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.782% w / w of sodium starch glycolate, in particular Glycolys; 0.652% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 10.000% (w / w) of mannitol, in particular Pearlitol 200 SD; 0.435% (w / w) of fumed silica, in particular Aerosil 200; and 0.435% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0282] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 4.348% w / w of ezetimibe; 4.461% w / w of obicetrapib; 36.465% w / w of microcrystalline cellulose, in particular Avicel PH101; 34.914% w / w of lactose monohydrate, in particular Pharmatose 200M; 0.652% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.608% w / w of sodium starch glycolate, in particular Glycolys; 0.652% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 8.900% (w / w) of mannitol, in particular Pearlitol 200 SD; 1.000% (w / w) of fumed silica, in particular Aerosil 200; and 1.000% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0283] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 4.348% w / w of ezetimibe; 4.461% w / w of obicetrapib; 36.104% w / w of microcrystalline cellulose, in particular Avicel PH101; 34.914% w / w of lactose monohydrate, in particular Pharmatose 200M; 0.652% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.608% w / w of sodium starch glycolate, in particular Glycolys; 0.652% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 8.761% (w / w) of mannitol, in particular Pearlitol 200 SD; 1.000% (w / w) of fumed silica, in particular Aerosil 200; and 1.500% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0284] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 7.89% w / w of obicetrapib; 23.614% w / w of microcrystalline cellulose, in particular Avicel PH101; 61.573% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.154% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.615% w / w of sodium starch glycolate, in particular Glycolys; and 1.154% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0285] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 4.438% w / w of ezetimibe; 4.46% w / w of obicetrapib; 36.577% w / w of microcrystalline cellulose, in particular Avicel PH101; 34.802% w / w of lactose (monohydrate), in particular Pharmatose 200M; 0.652% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.608% w / w of sodium starch glycolate, in particular Glycolys; 0.652% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 8.9% (w / w) of mannitol, in particular Pearlitol 200 SD; 1% (w / w) of fumed silica, in particular Aerosil 200; and 1% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0286] In certain embodiments, the pharmaceutical composition is not a bi-layer tablet or a coated bi-layer tablet comprising, based on the total weight of the tablet excluding any coating, 10 mg of ezetimibe; 10.26 mg of obicetrapib; 61.4 mg of microcrystalline cellulose, in particular Avicel PH101; 160.34 mg of lactose (monohydrate), in particular Pharmatose 200M; 3 mg of polyvinylpyrrolidone, in particular Kollidon 30; 23 mg of sodium starchAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A glycolate, in particular Glycolys; 3 mg of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 1.4 mg of magnesium stearate, in particular Ligamed MF-2-V.

[0287] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 4.438% w / w of ezetimibe; 4.461% w / w of obicetrapib; 36.465% w / w of microcrystalline cellulose, in particular Avicel PH101; 34.914% w / w of lactose (monohydrate), in particular Pharmatose 200M; 0.652% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 7.608% w / w of sodium starch glycolate, in particular Glycolys; 0.652% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; 8.900% (w / w) of mannitol, in particular Pearlitol 200 SD; 1.000% (w / w) of fumed silica, in particular Aerosil 200; and 1% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.

[0288] In certain embodiments, the pharmaceutical composition is not a granulate comprising, based on the total dry weight of the granulate, 7.018% w / w of ezetimibe; 7.200% w / w of obicetrapib; 21.950% w / w of microcrystalline cellulose, in particular Avicel PH101; 57.516% w / w of lactose monohydrate, in particular Pharmatose 200M; 1.053% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 4.210% w / w of sodium starch glycolate, in particular Glycolys; and 1.053% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine.

[0289] In certain embodiments, the pharmaceutical composition is not a tablet or a coated tablet comprising, based on the total weight of the tablet excluding any coating, 6.667% w / w of ezetimibe; 6.840% w / w of obicetrapib; 20.853% w / w of microcrystalline cellulose, in particular Avicel PH101; 54.640% w / w of lactose (monohydrate), in particular Pharmatose 200M; 1.000% w / w of polyvinylpyrrolidone, in particular Kollidon 30; 8.000% w / w of sodium starch glycolate, in particular Glycolys; 1.000% w / w of sodium lauryl sulphate, in particular Kolliphor SLS fine; and 1.000% w / w of magnesium stearate, in particular Ligamed MF-2-V. More specifically, it is preferred that the pharmaceutical composition is not a (coated) tablet of said composition, wherein ezetimibe is present at an amount of about 10 mg and obicetrapib is present at an amount of about 10 mg.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A TERMS AND DEFINITIONS

[0290] Obicetrapib, also referred to as “TA-8995”, has the following chemical name and chemical structure: OH-1-(ethoxycarbonyl)-2-ethyl- 6- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid}.

[0291] Ezetimibe, also referred to as “Sch-58235”, has the following chemical name and chemical structure: -3-hydroxypropyl]-4-(4-hydroxyphenyl)114zetimibe-2-one.

[0292] Both obicetrapib and ezetimibe may also be used as different salt forms, solvates or co-crystals. They may also be formulated as pro-drugs.

[0293] The term “apolipoprotein” as used herein has its conventional meaning and refers to proteins that bind lipids to form lipoproteins.

[0294] The term “apolipoprotein B” (ApoB) as used herein has its conventional meaning and refers to the protein encoded by the ApoB gene.

[0295] The term ‘pharmaceutical composition’ as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0296] The term ‘pharmaceutically acceptable’ as used herein has its conventional meaning and refers to compounds, material, compositions and / or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0297] The term “carrier” as used herein has its conventional meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient or vehicle with which a pharmaceutically active ingredient is administered.

[0298] The term ‘excipient’ as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.

[0299] The term ‘salt’ as used herein has its conventional meaning and includes the acid addition and base salts of a pharmaceutically active compound.

[0300] The term “solvate” as used herein has its conventional meaning and refers to a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols, nitriles and polar organic solvents.

[0301] The term “subject” as used herein refers to humans suffering from or at risk for a certain disease or disorder. The term “subject” and “patient” herein are used interchangeably.

[0302] The term ‘increased risk’ has its conventional meaning and refers to a situation where a subject, in some embodiments a human subject, either male or female, based on his or her risk profile (including an LDL-cholesterol level above 70 mg / Dl, such as above 2.6 mmol / l [100,54 mg / Dl]), such that the subject is at an increased risk of suffering a cardiovascular event, compared to those with lower levels.

[0303] The term ‘treatment’ as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment.

[0304] The term ‘cardiovascular disease’ as used herein has its conventional meaning and includes clinical manifestations of arteriosclerosis, peripheral vascular disease angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and cerebral stroke.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0305] The term “cardiovascular event” as used herein has its conventional meaning and refers to occurrence of myocardial infarction, stroke, coronary death or the necessity to undergo a coronary revascularization (Ference et al., European Heart J.38(32):2459-2472, 2017).

[0306] The term “hypercholesterolemia” as used herein has its conventional meaning and refers to the condition in which high levels of cholesterol are present in the blood.

[0307] The term “hyperlipidaemia” as used herein has its conventional meaning and refers to the condition in which there are high amounts of lipids found in the blood.

[0308] The term “mixed dyslipidaemia” as used herein has its conventional meaning and refers to the condition in which there are elevations of LDL cholesterol and triglyceride levels that are accompanied by low levels of HDL cholesterol in the blood.

[0309] The term “statin intolerant” as used herein has its conventional meaning and refers to subjects inability to tolerate two or more statins, one at a low dose, due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin was discontinued, reference is in this regard also made to the similar definition approved by the FDA in the bempedoic acid (Esperion) phase III trial.

[0310] The term ‘cholesterol absorption inhibitor’ (CAI) as used herein has its conventional meaning and refers to compounds which are used to lower LDL-C by blocking enteric and biliary absorption of cholesterol. A known cholesterol absorption inhibitor is ezetimibe.

[0311] The term “cholesteryl ester transfer protein inhibitor” (CETP inhibitor) as used herein has its conventional meaning and refers to a class of compounds that inhibits the CETP receptor in mammals. A known CETP inhibitor is obicetrapib.

[0312] The term ‘unit dosage form’ has its conventional meaning and refers to a dosage form which has the capacity of being administered to a subject, in some embodiments a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the therapeutic agent, i.e., obicetrapib or combination of therapeutic agents, such as obicetrapib and ezetimibe.

[0313] The term ‘fixed dose combination’ as used herein has its conventional meaning and refers to a combination of defined doses of two or more drugs or active ingredients presented in a single dosage unit (e.g., a tablet or a capsule) and administered as such.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0314] The term ‘free dose combination’ as used herein has its conventional meaning and refers to a combination of two drugs or active ingredients administered simultaneously but as two distinct dosage units.

[0315] The fixed dose combination pharmaceutical compositions and methods of treatment of the invention of and with obicetrapib, including those containing obicetrapib calcium, and ezetimibe will be illustrated further by means of the non-limiting examples herein below. 1. EXAMPLES

[0316] While the invention has been particularly shown and described with reference to a typical 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. The methods used throughout the study are summarised in Table 3. The specific parameters and conditions for analytical and physical assessments used for each non-limiting example is described in relevant section of such example. Table 3 Test TitleAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A XRPD The XRPD analyses were run in transmission mode on an X'pert Pro / Empyrean X-Ray Diffractometer (PANalytical) equipped with an X’Celerator detector using a standard XRPD Aptuit method. The data were evaluated using the Highscore Plus software. The instrumental parameters used are listed in Table 4 below. Table 4 Instrumental Parameter Value °Particle size distribution (PSD) The PSD analyses were run on a Sympatec Helos laser diffraction instrument equipped with the RODOS / M for dispersion and the ASPIROS or VIBRI for sample delivery. The powder dispersion is achieved by the use of compressed air and through a gun that uses the Venturi effect. PSD method details are listed in Table 5.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 5 Instrumental Parameter Valuescrmna ng ssou on me o . (o cerap ) Table 6 InstrumentalValueAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Discriminating Dissolution method Ph 4.5 (ezetimibe) Table 7 InstrumentalValueQC Dissolution method Ph 6.8 (obicetrapib) Table 8 Instrumental Parameter ValueAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A QC Dissolution method Ph 4.5 (ezetimibe) Table 9 InstrumentalValueAssay and Impurities / Related Substances (obicetrapib)Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 10 Intrumental Parameters ValueExample 1: Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by co- granulation of drug substances / active ingredients (FDC1) (small scale batch ~ 500 g) High shear granulation, drying, preparation of final blend and tableting

[0317] Three compositions (Composition 1 batch A4459 / 20 / 02, Composition 2 batch A4459 / 20 / 03 and Composition 3 batch A4459 / 20 / 04) were prepared as summarized in Table 11. The prototype formulation composition selected for these compositions was that of “prototype C” (e.g. granule batch A4459 / 13 / 03). The preparation and characterization (LOD and XRPD) of the granules are described in the previous sections (small-scale manufactures). The granules were tested for content uniformity, LOD, sieve analysis, TBD and XRPD. The blend for tableting and the compression profile and manufacture of a small batch of tablets atAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 150 mg tablet weight was performed as described in the previous example. The tablets were tested for content uniformity, XRPD, dissolution and water content by KF. All the intermediates of production and the final drug product were stored as described in the previous sections. Table 11: Composition (% w / w) of granule and tablet for the FDC1 compositionpowderAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Results

[0318] The high shear granulation was conducted successfully. The drying step was conducted without any issues and, after 15 minutes drying the LOD of the granules was lower than the initial LOD. In general, the and the granules presented a relatively large quantity of fine particles despite the increase of the impeller speed (composition 1) (FIG.14), the time of wet massing (composition 2) or the quantity of granulating agent (composition 3). The tablet friability, time of disintegration, thickness and hardness were found to be similar among these tablet batches. Granules chemical characterization

[0319] The granules were tested for homogeneity, and obicetrapib and ezetimibe were found to be homogeneously dispersed. Physical properties characterization

[0320] XRPD data of the Blend / granules prototypes FDC1 approach are summarized in Table 12. Ezetimibe hydrate appears only in the wet granule samples. All the three prototypes present similar flowability. Tablets chemical characterization

[0321] Results of the chemical characterization of the FDC 1 tablets are reported in Table 13. The results of the analytical characterization did not show any significant differences between the three compositions. Physical properties characterization

[0322] XRPD data of the Tablets from FDC1 compositions are summarized in Table 14. There is no presence of ezetimibe hydrate in all samples.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 12: XRPD data summary of granules from FDC1 compositionsTable 13: Results of the chemical characterization of FDC1 compositionsAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 13: Results of the chemical characterization of FDC1 compositions Manufacturing lot number A4459 / 23 / 02 A4459 / 23 / 03Table 14: XRPD data summary of granules of FDC1 compositionsAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Example 2: Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by granulation of ezetimibe and addition of obicetrapib in the extra-granule (FDC2) High shear granulation and drying

[0323] Three compositions were prepared as summarised in Table 15. The excipients contained in the granule were the same of those used for the manufacture of the granule for the FDC1 approach. The formulation composition of these granules reflected that of FDC1 granule “prototype C”. The method of high shear granulation, granule drying, and milling was described in the previous sections. The granules were tested for content uniformity (ezetimibe only), sieve analysis, TBD and XRPD. Preparation of final blend, tableting and coating The components of the extra-granular formulation are listed below: - Obicetrapib - Plastic filler (Avicel PH 200) - Brittle filler (Pearlitol 200 SD) - Disintegrant (Glycolys) - Glydant (Aerosil 200) - Lubricant (Ligamed MF-2-V)

[0324] The final blend was prepared by weighing accurately and sieving the extra-granular components (excipients and API). The excipients and the granule were loaded in a bin of suitable volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the bin and mixed.

[0325] For the generation of a compression profile and the manufacture of a small batch of tablets, a single punch compression machine (EK0) equipped with an 9.0 mm round punch (R=11) was used. The target tablet weight was 230 mg and, throughout the process, the tablet friability, disintegration time, hardness, appearance end thickness was monitored as well as the individual tablet weight and the tablet weight of ten tablets.

[0326] The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.

[0327] The tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension at the required target weight increase (target weight increase 3% w / w, limits 2% w / w – 4% w / w). The coating suspension and the method of coating was described in theAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A previous section. The coating parameters as well as the weight gain of the tablets was monitored throughout processing. The coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.

[0328] All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminum bag that was thermosealed. Table 15: Composition (% w / w) of granule, tablet and coated tablet of FDC2 compositions Prototype 1 Prototype 2 Prototype 3 pow er Results

[0329] The high shear granulation of the FDC2 compositions was conducted successfully. The drying step was conducted without any issues and, after ca.16 minutes drying, the LOD of the granules was lower than the initial LOD. The granules showed a relatively large quantity of fine particles (FIG.15). The values of disintegration time and thickness were similar among FDC2 tablet batches. Granules chemical characterizationAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0330] A4459 / 20 / 01 blend was tested for homogeneity of both obicetrapib and ezetimibe, and was found to be homogeneously dispersed. Results for other two granules were not collected. Tablets chemical characterization

[0331] Chemical characterization of the protoype 1 of FDC 2 tablets results are reported in Table 16 and Table 17. The results of the analytical characterization did not show any significant differences between the three prototypes of FDC2. Physical Properties characterization

[0332] XRPD data of the Blend / granules from FDC2 compositions are summarized in Table 18. XRPD data of the tablets from FDC2 approach are summarized in Table 19. There was a presence of small amount of Eze hydrate in prototype 1. Table 16: Results of the analytical characterization of FDC2 - Uncoated Manufacturing lot number A4459 / 23 / 01 A4459 / 26 / 01 Prototype Prototype 1 Prototype 2Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 16: Results of the analytical characterization of FDC2 - Uncoated f i lTable 17: Results of the analytical characterization of FDC2- Coated M f t i l t b A44 27 1 A44 27 2 A44 27Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 17: Results of the analytical characterization of FDC2- Coated f i lTable 18: XRPD data summary of granules from FDC2 compositions l B t h ID XRPDTable 19: XRPD data summary of tablets from FDC2 compositions l B t h ID XRPDStress Stability Prototype 2 coated tablet was selected for the stress stability study with the following design Table 20: Stress stability study design Storage Conditions T / RH T e= ese or appearance, assay reae susances, scrmna ng ssou on, water content by KF, and form check by XRPD (T)= Optional testing Results are reported in Tables 21-23.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 21: Results for assay, water content and visual appearance of prototype 2Table 22: Results for impurities profile of prototype 2 FDC2 stress stability Obicetrapib related impurities Ezetimibe related impurities Time IMP_R FRO MON TotalTable 23: Results of the dissolution characterization of prototype 2 FDC2 stress stability f i lAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 23: Results of the dissolution characterization of prototype 2 FDC2 stress stability f i lExample 3: Scale-up of FDC1 and FDC2 compositions High shear granulation, drying, final blend, tableting and coating

[0333] The API and excipients were dispensed accurately, sieved and added to the granulation bowl according to the approach detailed in the FDC1 and FDC2 formulation approaches above. The parameters of granulation for both the FDC1 and FDC2 approach were identical. The granules were tested for content uniformity (only for the FDC1 approach), LOD, sieve analysis, TBD and XRPD.

[0334] The final blend of the FDC1 and FDC2 compositions were prepared to manufacture tablets whose batch number and composition is detailed in Table 24. The components of the extra-granule were manually sieved and loaded in a bin of suitable volume. The granule was mixed with the extra-granular materials using a Pharmatech mixer. Then, the FDC2 blend was tested for content uniformity.

[0335] For the generation of a compression profile and for the tableting exercise the use of rotary press machines was assessed. The friability, disintegration time, hardness, thickness and appearance of the tablets as well as the individual tablet weight and the tablet weight of ten tablets was monitored during the tableting exercise. The tablets were tested for content uniformity (stratified samples: start, middle and end of production), XRPD, dissolution and water content by KF.

[0336] The tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension at the required target weight increase (target weight increase 3% w / w, limits 2%Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A w / w – 4% w / w). The coating suspension and the method of coating was described in the previous section. The coating parameters as well as the weight gain of the tablets was monitored throughout processing. The coated tablets were tested for XRPD, dissolution, appearance, assay and impurities, and water content by KF.

[0337] All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminum bag that was thermosealed. Table 24: Composition (% w / w) of granule, tablet and coated tablet of FDC1 and FDC2 as a ry pow er ResultsAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A

[0338] The high shear granulation of the scale-up batches was conducted successfully. The granules presented similar values of PSD by sieve analysis and a large quantity of fines (FIG.16). These PSD values were comparable to those found in the previous trials (e.g. batch A4459 / 16 / 02 as a reference for the FDC1 scale-up batch and batch A4459 / 25 / 01 as a reference for the FDC2 scale-up batch). Despite this similarity of PSD data, the flowability of the scale-up batches improved in comparison to that of the reference batches according to the value of the Hauser ratio. These tablets presented disintegration time shorter than 5 mins and friability lower than 0.2%. The coating process was performed without any critical issues and the appearance of the coated tablets for both formulation approaches was suitable since the surface of the tablets was smooth. Granules chemical characterization

[0339] The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe and were found to be homogeneously dispersed. Dissolution of both obicetrapib and ezetimibe and impurities profile of ezetimibe, results reported in Table 25, FIG.17, FIG. 18 and FIG.19. Tablets chemical characterization

[0340] Chemical characterization of the scale up batches uncoated tablets results are reported in Table 26. Dissolution results on uncoated tablets at different compression forces are reported in Table 27, Table 28, Table 29 and Table 30. Results for coated tablets are reported in Table 29. Physical properties characterization

[0341] XRPD data of the Granules / Tablets from Scale up batches are summarized in Table 30. All the batches tested showed the absence of EZE hydrate. Table 25: Granule and final blend impurities profile and dissolution result for scale upAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 25: Granule and final blend impurities profile and dissolution result for scale upTable 26: Results of the analytical characterization of scale up batches - Uncoated M f t i l t b A44 2 2 A44 2Table 27: Ezetimibe dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) atAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 70 105.2 105.6 105.1 106.8 105.2 107.7 105.0 1.0Table 28: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) atTable 29: Ezetimibe dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) atAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Tablet at 20 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSDTable 30: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) atTable 31: Results of the analytical characterization of scale up batches 10mg ezetimibe 10Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 31: Results of the analytical characterization of scale up batches 10mg ezetimibe 10Table 32: XRPD data summary of granules / tablets from scale up batch l B t h ID XRPDExample 4: Technical batches of FDC1 and FDC2 compositions

[0342] The batch numbers and compositions of the granules, tablets and coated tablets of the technical manufactures of the FDC1 and FDC2 formulations are detailed in Table 33. High shear granulation and drying

[0343] The components of the FDC1 granule (batch A4459 / 30 / 02) and FDC2 granule (batch A4459 / 30 / 01) were sieved manually and added to the granulation bowl. For both FDC1 and FDC2 compositions, the batch size of the granule was 2 kg, and, identical processing condition of granulation were used. The physical mixture was blended for 5 mins at 220 rpm and a LOD testing was executed. The granulating agent (purified water) was sprayed and, following spraying, 1 min wet massing was conducted. A sample for XRPD and LOD was taken. Then, the granule was dried using a fluid bed drier. The drying step was concluded as the LOD of the granule was equal or lower than the initial LOD or below 3% (w / w). The granules were tested for content uniformity (only for FDC1), PSD, LOD, sieve analysis, TBD and XRPD.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Final Blend and tableting

[0344] The method of preparation of the final blend was described in the previous section (scale-up batches). The FDC2 blend was tested for content uniformity.

[0345] For the generation of a compression profile and for the tableting campaign, a rotary press machine was used. To manufacture FDC1 tablets (150 mg target tablet weight), a 7.0 mm diameter punch was used whereas, for FDC2 tablets (230.0 mg tablet weight) an 8.5 mm diameter punch. The friability, disintegration time, hardness, thickness and appearance of the tablets as well as the individual tablet weight and the tablet weight of ten tablets was monitored during tableting. The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF. Coating

[0346] The coating suspension was prepared at 20% (w / w) solid content by adding the required quantity of Opadry to water under stirring. The suspension was mixed for no less than 45 minutes and its visual homogeneity confirmed. Then, the spray rate of the coating suspension was measured. The coating suspension was kept under stirring all the time. The weight gain of the tablets was monitored throughout the manufacture and spraying was stopped as the required target gain (3% w / w, 2% w / w – 4% w / w limits) was achieved. The coated tablets were visually inspected and tested for XRPD, dissolution, appearance, content uniformity, and water content by KF.

[0347] All the intermediates of production and the final drug product were stored in the stability chambers with following packaging: • 60mL High Density Polyethylene (HDPE) induction sealed and closed with child resistant cap. The fill count for tablets is 20; • 60mL High Density Polyethylene (HDPE) induction sealed with 2g of desiccant canister and closed with child resistant cap. The fill count for tablets is 20. Table 33: Composition (% w / w) of the granule, tablet and coated tablet of the FDC1 andAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 33: Composition (% w / w) of the granule, tablet and coated tablet of the FDC1 andResults: Technical batches of FDC1 and FDC2 compositions

[0348] The high shear granulation of the technical batches was conducted successfully, and no issues occurred during the process. The powder consumption was comparable to that observed in the scale-up batches. The drying process was executed within 45 mins as the LOD of the granule was lower than 3%. The granules showed similar PSD values and the quantity of fine particles was relatively large (e.g. the quantity of particles smaller than 125 µm was ca.70 % - 73 %) (FIG.20). No relevant differences were observed in comparison to the scale-up batches.

[0349] In comparison to the FDC2 scale-up batch (batch A4459 / 29 / 06), the FDC2 technical batch presented harder tablets for similar levels of compression force albeit, theAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A time of disintegration between these batches was very similar for a given value of tablet hardness. Granules chemical characterization

[0350] The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe and were found to be homogeneously dispersed. Tablets chemical characterization

[0351] Chemical characterization of the technical batches coated tablets results are reported in Table 34. The tablets showed a suitable level of quality with the % claims within the typical acceptance criterion for clinical phases (i.e., 90.0 – 110.0 %). The results of the content uniformity test met the pharmacopoeia requirement of AV < 15.0. Dissolution met the proposed specification for Q=75% at 45 minutes (FIG.21 and FIG.22). Physical properties characterization

[0352] XRPD data of the Granules / Tablets from Technical Batches are summarized in Table 35. All the batches tested showed the absence of EZE hydrate with exception of the granules from the FDC2 formulation. However, the hydrate form disappears in the coated tablet. Both batches of Granules show similar flowability. PSD data of granules are reported in Table 36 and in FIG.23. Batches show similar bi-modal curves. Stability studies

[0353] A summary of physicochemical analysis of technical batches after three months of storage for FDC2 composition is provided in Table 37 (without desiccant) and Table 38 (with desiccant), and for FDC1 composition in Table 39 (without desiccant) and Table 40 (with desiccant). Table 34: Results of the analytical characterization of technical batches – Coated M f t i l t b A44 1 2 A44 1 1Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 34: Results of the analytical characterization of technical batches – Coated Manufacturing lot number A4459 / 31 / 02 A4459 / 31 / 01 Obicetrapib Ph.Eur.2.9.40 or Average % Claim: 98.3 Average %Table 35: XRPD data summary of granules / tablets from technical batches l B t h ID XRPDTable 36: PSD data summary of granules from technical batches D 1 1 D DAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 37: Long-term and accelerated storage stability results for FDC2 technical batch no.Condition (Months) Amount Amount degradation Amount CYCLIC KETONECondition (Months) Amount Amount Amount degradation point(min) 15 point(min) 15Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Storage Time Time Time Time Time Time Time Condition (Months point(min) 30 point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60Condition (Months) point(min) 70 point(min) 70 point(min) point(min) point(min) point(min)Condition (Months) point(min) point(min) point(min) point(min) 60 point(min) 70 point(min)(Months) UMID / 1231 RESR / 1001 RESR / 1001 RESR / 1001 RESR / 1001Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 38: Long-term and accelerated storage stability results for FDC1 technical batch no.Condition (Months) Amount Amount degradation Amount CYCLIC KETONECondition (Months) Amount Amount Amount degradation point(min) 15 point(min) 15Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Storage Time Time Time Time Time Time Time Condition (Months point(min) 30 point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60Condition (Months) point(min) 70 point(min) 70 point(min) point(min) point(min) point(min)Condition (Months) point(min) 45 point(min) 45 point(min) 60 point(min) 60 point(min) 70 point(min) 70(Months) UMID / 1231 RESR / 1001 RESR / 1001 RESR / 1001 RESR / 1001Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 39: Long-term and accelerated storage condition results for FDC2 technical batchCondition (Months) Amount Amount degradation Amount CYCLIC KETONECondition (Months 3 Amount 9 Amount degradation point(min) 15 point(min) 15 point(min) 30Condition (Months point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60 point(min) 70Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Storage Time Time Time Time Time Time Time Condition (Months point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60 point(min) 70Condition (Months) point(min) 70 point(min) point(min) point(min) point(min) point(min)Condition (Months) point(min) 45 point(min) 60 point(min) 60 point(min) 70 point(min) 70 contentRESR / 1001 (N) RESR / 1001 (N) RESR / 1001 (Kp) RESR / 1001 (Kp)Table 40: Long-term and accelerated storage condition results for FDC1 technical batchAttorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Table 40: Long-term and accelerated storage condition results for FDC1 technical batchCondition (Months) Amount Amount degradation Amount CYCLIC KETONECondition (Months 3 Amount 9 Amount degradation point(min) 15 point(min) 15 point(min) 30Condition (Months point(min) 30 point(min) 45 point(min) 45 point(min) 60 point(min) 60 point(min) 70Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Storage Time Time Time Time Time Time Time Condition (Months) point(min) 70 point(min) point(min) point(min) point(min) point(min)Condition (Months) point(min) 45 point(min) 60 point(min) 60 point(min) 70 point(min) 70 contentExample 5: Study to evaluate the comparative bioavailability of two fixed-dose combination formulations of obicetrapib / ezetimibe 10 mg / 10 mg (fdc1 and fdc2) with obicetrapib, 10 mg co-administered with ezetimibe, 10 mg in healthy adult subjects under fasted conditions. Study design

[0354] This was an open-label, single-dose, randomized, three-treatment, three-period, six- sequence crossover study comparing the two test products and coadministration of the reference products under fasted conditions. In each of the study periods, the subjects ...

Claims

Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising: obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof; a surfactant; and, optionally, one or more additional pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the surfactant is a salt and the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, is amorphous obicetrapib hemicalcium.

3. The pharmaceutical composition of claims 1 or 2, wherein the surfactant is an organosulfur compound.

4. The pharmaceutical composition of claims 1, 2, or 3, wherein the surfactant is a substituted alkyl.

5. The pharmaceutical composition of claim 4, wherein the surfactant is monosubstituted.

6. The pharmaceutical composition of claim 5, wherein the mono substituent comprises a sulfur atom.

7. The pharmaceutical composition of claim 6, wherein the mono substituent is a sulfate.

8. The pharmaceutical composition of claim 1, wherein the surfactant is an anionic surfactant.

9. The pharmaceutical composition of claim 1, wherein the surfactant is a cationic surfactant.

10. The pharmaceutical composition of claim 1, wherein the surfactant is a non-ionic surfactant.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 11. The pharmaceutical composition of claim 1, wherein the surfactant is a zwitterionic surfactant.

12. The pharmaceutical composition of claims 1 or 8, wherein the surfactant is a carboxylate, a sulfate, a sulfonate, or a phosphate compound.

13. The pharmaceutical composition of claims 1 or 8, wherein the surfactant is a sulfate or sulfonate.

14. The pharmaceutical composition of claims 1 or 8, wherein the surfactant is selected from alkyl carboxylates-fatty acid salts; carboxylate fluoro surfactants; alkyl sulfates alkyl ether sulfates; branched alkyl sulphates; docusates; alkyl benzene sulfonates; phosphate esters; and alkyl ether phosphates.

15. The pharmaceutical composition of claims 1 or 8 wherein the surfactant is sodium lauryl sulfate, or sodium laureth sulfate or dioctyl sodium sulfosuccinate or an alkyl aryl ether phosphates and alkyl ether phosphates.

16. The pharmaceutical composition of claim 1, wherein the surfactant is sodium lauryl sulfate.

17. The pharmaceutical composition of claims 1 or 9, wherein the surfactant is a quaternary ammonium salt.

18. The pharmaceutical composition of claim 17, wherein the surfactant is a pyridinium salt.

19. The pharmaceutical composition of claims 1 or 10, wherein the surfactant is an ether of fatty alcohols and polyol esters, a fatty acid ester of sorbitan or ethoxylated derivatives thereof, or synthetic block copolymers of hydrophilic poly(oxyethylene).

20. The pharmaceutical composition of claims 1 or 10, wherein the surfactant is a polyoxyethylene ester, a polazamer, a glucol, a glycol ester, or a sorbitan derivative.

21. The pharmaceutical composition of claims 1 or 10, wherein the surfactant is sorbitan trioleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and sorbitan mono-oleate and polyoxyethylene (20) sorbitan monolaurate, Polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate,Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A Polyoxyethylene (20) sorbitan tristearate, Polyoxyethylene (20) sorbitan mono-oleate, Polyoxyethylene (20) sorbitan tri-oleate, polysorbate 20, or polysorbate 80.

22. The pharmaceutical composition of claims 1 or 11, wherein the zwitterionic surfactant is lauryl betaine, lauroyl sarcosinate, lauryl sultaine, laurylamidopropyl betaine, or lauryldimethylamine oxide 23. The pharmaceutical composition of any one of claims 1 to 22, wherein the HLB of the surfactant is at least 15.

24. The pharmaceutical composition of claim 23, wherein the HLB of the surfactant is at least 20.

25. The pharmaceutical composition of claim 24, wherein the HLB of the surfactant is at least 30.

26. The pharmaceutical composition of claim 25, wherein the HLB of the surfactant is at least 35.

27. The pharmaceutical composition of claim 23, wherein the surfactant has an HLB of between 15 and 50, including 15 and 50.

28. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB of between 30 and 45, including 30 and 45.

29. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB of between 40 and 45, including 40 and 45.

30. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB of between 38 and 42, including 38 and 42.

31. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB of between 39 and 41, including 39 and 41.

32. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB of 38, 39, 40, 41, or 42.

33. The pharmaceutical composition of claim 27, wherein the surfactant has an HLB of 40.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 34. The pharmaceutical composition of any one of claims 1-33, wherein the surfactant is present in the composition from about 0.2% to about 10% by weight.

35. The pharmaceutical composition of claim 34, wherein the surfactant is present in the composition from about 0.5% to about 5% by weight.

36. The pharmaceutical composition of claim 35, wherein the surfactant is present in the composition from about 0.5% to about 2% by weight.

37. The pharmaceutical composition of claim 35, wherein the surfactant is present in the composition from about 0.5% to about 1% by weight.

38. The pharmaceutical composition of claim 35, wherein the surfactant is present in the composition from about 0.5% to about 1.5% by weight.

39. The pharmaceutical composition of claims 1 to 38, wherein the composition comprises an intragranular portion and an extragranular portion.

40. The pharmaceutical composition of claim 39, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof and the surfactant are in the intragranular portion.

41. The pharmaceutical composition of claims 1-40, wherein the pharmaceutical composition is uncoated.

42. The pharmaceutical composition of claims 1-40, wherein the pharmaceutical composition is coated.

43. The pharmaceutical composition of claims 1-42, further comprising one or more additional pharmaceutically acceptable excipients.

44. The pharmaceutical composition of claim 43, wherein the one or more pharmaceutically acceptable excipients are selected from one or more diluents, binders, disintegrants, a second surfactant, and lubricants.

45. The pharmaceutical composition of claim 44, wherein the one or more diluents is an inorganic phosphates, a sugars, a sugar analogue, or a sugar derivative.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 46. The pharmaceutical composition of claim 44, wherein the one or more diluents is dibasic calcium phosphate, lactose, lactose monohydrate, water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomaltose, a celluloses, microcrystalline cellulose, or a powdered cellulose.

47. The pharmaceutical composition of claim 45 or claim 46, wherein the one or more diluents is in the intragranular component.

48. The pharmaceutical composition of claim 45 or claim 46, wherein the diluent is in the extragranular component.

49. The pharmaceutical composition of any one of claims 44 – 48, wherein the one or more binders is a cellulose derivative.

50. The pharmaceutical composition of claims 44-49, wherein the one or more binders is methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, glucose, sucrose, lactose dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, pregelatinized starch, gum tragacanth, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites.

51. The pharmaceutical composition of any one of claims 44-49, wherein the one or more binders is sodium alginate, polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone.

52. The pharmaceutical composition of any one of claims 44-49, wherein the one or more binders is copovidone or Kollidon 30.

53. The pharmaceutical composition of any one of claims 44-52, wherein the one or more disintegrants is cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate or pregelatinized starch.

54. The pharmaceutical composition of any one of claims 44-52, wherein the one or more disintegrants is croscarmellose sodium or sodium starch glycolate.

55. The pharmaceutical composition of claims 44-54, wherein the one or more lubricants is a fatty acid or fatty acid derivatives.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 56. The pharmaceutical composition of claims 44-54, wherein the one or more lubricants is an alkali or earth alkali salts of stearic, lauric or palmitic acid.

57. The pharmaceutical composition of claims 44-54, wherein the one or more lubricants is magnesium stearate. The pharmaceutical composition according to anyone of the preceding claims for use in the treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, preferably the subjects suffering from hyperlipidemia or mixed dyslipidemia.

58. The pharmaceutical composition according to anyone of claims 1-57 for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterol and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular disease (ASCVD).

59. Use of a pharmaceutical composition according to anyone of claims 1-57 for preparation of a medicament for treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia.

60. Use of a pharmaceutical composition according to anyone of claims 1-57 for preparation of a medicament for reducing LDL cholesterol in a subject requiring a reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or a subject with established atherosclerotic cardiovascular disease (ASCVD).

61. Use of a pharmaceutical composition according to anyone of claims 1-57 for preparation of a medicament for reducing the risk for cardiovascular events.

62. Use according to anyone of claims 1-57, wherein the subject suffers from mild dyslipidemia.

63. A method of treatment of a subject requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, a subject with heterozygous familial hypercholesterolemia (HeFH) and / or subject with established atherosclerotic cardiovascular disease (ASCVD), wherein the method comprises administering a therapeutically effective dose of the pharmaceutical composition of anyone of claims 1-57 to a patient in need thereof.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 64. A method of treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering the pharmaceutical composition of anyone of claims 1-57 to a patient in need 65. The use of a pharmaceutical composition for preparation of a medicament or a method of treatment according to anyone claims 1-57, wherein the subject has LDL- cholesterol levels >50 mg / dL, preferably >70 mg / dL, and optionally, the said humans are not adequately controlled by their current lipid-modifying therapies.

66. The use of a pharmaceutical composition or a method of treatment according to anyone of claims 1-57, wherein the subject in need thereof is a subject requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

67. A pharmaceutical composition comprising an effective dose of any one of the pharmaceutical compositions of claims 1-57 for use in the treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

68. The pharmaceutical composition of any one of claims 1-57 wherein obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, a surfactant, and optionally one or more additional pharmaceutically acceptable excipients are in a granule.

69. The pharmaceutical composition of claim 68, wherein the granule is made through wet granulation.

70. A process for making a pharmaceutical composition granule comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, a surfactant, and optionally one or more additional pharmaceutically acceptable excipients comprising the steps of:Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A (a) combining obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, a surfactant, a binder, and optionally one or more additional pharmaceutical excipients to form a solid mixture; (b) combining the solid mixture with water to form a wet mixture; and (c) granulating the wet mixture into granules.

71. The process of claim 70, further comprising compressing the granules into tablets.

72. The process of claim 71, further comprising mixing the granules with an additional powder and compressing into tablets.

73. The process of claim 72, wherein the additional powder comprises one or more excipients.

74. The process of claim 73, wherein the additional powder comprises obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

75. The process of claim 73, wherein the additional powder comprises an active ingredient other than obicetrapib.

76. The process of any one of claims 70 to 75 wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

77. The process of any one of claims 70 to 76, further comprising coating the tablets.

78. A pharmaceutical composition granule made by the process of claim 70.

79. A pharmaceutical composition tablet made by the process of any one of claims 71 to 78.

80. A pharmaceutical composition of any one of claims 1-57 and 78-70 wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is the only active ingredient in the pharmaceutical composition.

81. The processes or uses of any one of claims 58-67 or 71-77 wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is the only active ingredient in the pharmaceutical composition.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 82. The pharmaceutical composition of claim 82, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

83. The process of claim 81, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

84. The pharmaceutical composition of any one of claims 39 – 58 or 68-69, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

85. The pharmaceutical composition of any one of claim 1-58, 67-69, 78-80, 82, or 84 wherein the amount of obicetrapib in the pharmaceutical composition is between about 5 and 15 mg.

86. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 5 mg.

87. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 6 mg.

88. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 7 mg.

89. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 8 mg.

90. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 9 mg.

91. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 10 mg.

92. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 11 mg.

93. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 12 mg.

94. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 13 mg.Attorney Ref: 37726-58171 / WO-A Client Ref: 036WO-A 95. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 14 mg.

96. The pharmaceutical composition of claim 85, wherein the amount of obicetrapib in the pharmaceutical composition is 15 mg.

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