Pharmaceutical compositions of obicetrapib

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; and optionally one or more additional pharmaceutically acceptable excipients. Also provided are pharmaceutical dosage forms including the same 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 and other ailments.

Description

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)-l-(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.

[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 disclosure 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; 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. SUMMARY OF THE INVENTION

[0009] One aspect of the disclosure thus relates to a 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: a surfactant, and, optionally, one or more pharmaceutically acceptable excipients.

[0010] The present disclosure 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, obicetrapib calcium which, as used herein, is obicetrapib hemicalcium, and which may, in many embodiments, be amorphous obicetrapib hemicalcium; and a surfactant, and, optionally one or more additional pharmaceutically acceptable excipients.

[0011] One aspect of the disclosure 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; and a surfactant and, optionally, one or more additional pharmaceutically acceptable excipients.

[0012] Yet, a further aspect of the disclosure 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; 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.

[0013] Other aspects of the disclosure 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; 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.

[0014] Other aspects of the disclosure 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 cholesterol and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular 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.

[0015] Other aspects of the disclosure 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.

[0016] Further aspects of the disclosure 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.

[0017] It will be understood that these aspects of the disclosure 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. In many aspects of the disclosure, the presence of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, is excluded. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0019] FIG. 1 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0020] FIG. 2 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0021] FIG. 3 is an x-ray powder diffraction pattern of crystalline obicetrapib hemicalcium.

[0022] FIG. 4 is a polarized light micrograph of amorphous obicetrapib hemicalcium.

[0023] FIG. 5 is a polarized light micrograph of crystalline obicetrapib hemicalcium.

[0024] FIG. 6 is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.

[0025] FIG. 7 is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.

[0026] FIG. 8 is a thermogravimetric analysis plot of amorphous obicetrapib hemicalcium.

[0027] FIG. 9 is a solid-state 13C-NMR spectrum of amorphous and crystalline obicetrapib hemi calcium.

[0028] FIG. 10 is a solid-state 13C-NMR spectrum of crystalline obicetrapib hemicalcium.

[0029] FIG. 11 is a solid-state 13C-NMR spectrum of amorphous obicetrapib hemicalcium.

[0030] FIG. 12 is an x-ray powder diffraction pattern of crystalline HC1 obicetrapib.

[0031] FIG. 13 is an x-ray powder diffraction pattern of crystalline HC1 obicetrapib (pattern 2) and at least partially desolvated crystalline HC1 obicetrapib (pattern 1).

[0032] FIG. 14 Cumulative undersize for small scale FDC1 compositions.

[0033] FIG. 15 Cumulative undersize for small scale FDC2 compositions.

[0034] FIG. 16 Cumulative undersize curve for scale-up batches.

[0035] FIG. 17 Obicetrapib dissolution profile for FDC1 granule from scale up batch.

[0036] FIG. 18 Ezetimibe dissolution profile for FDC1 granule from scale up batch.

[0037] FIG. 19 Ezetimibe dissolution profile for FDC2 final blend from scale up batch.

[0038] FIG. 20 Cumulative undersize curve for technical batches.

[0039] FIG. 21 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches.

[0040] FIG. 22 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches.

[0041] FIG. 23 Particle size distribution (PSD) data of granules from technical batches.

[0042] FIG. 24 Flow diagram for the manufacture of FDC-1.

[0043] FIG. 25 Flow diagram for the manufacture of FDC-2.

[0044] FIG. 26 is a measurement of the impact different concentrations of Tween in the dissolution media make on tablet dissolution.

[0045] FIG. 27 is a dissolution curve of 10 mg amorphous obicetrapib hemicalcium tablets which are film coated in 0.05% Tween 80 and Phosphate buffer at pH 6.8 at 75 rpm.

[0046] FIG. 28 is a dissolution curve of amorphous obicetrapib hemicalcium FCT (film-coated tablets) with different surfactants in 0.2% Tween 80, phosphate pH 6.8, 1000 ml, 75 rpm.

[0047] FIG. 29 is a dissolution curve of amorphous obicetrapib hemicalcium FCT (film-coated tablets) with different surfactants in 0.2% Tween 80, phosphate pH 6.8, 1000 ml, 75 rpm.

[0048] FIG. 30 is a dissolution curve of amorphous obicetrapib hemicalcium FCT (film-coated tablets) with different surfactants in 0.05% Tween 80, phosphate pH 6.8, 1000 ml, 75 rpm. DETAILED DESCRIPTION of the INVENTION

[0049] The present disclosure 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; a surfactant, and optionally one or more additional pharmaceutically acceptable excipients. Also provided are pharmaceutical dosage forms including the same, including tablets.

[0050] 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; and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients thereof.

[0051] 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 obicetrapib hemicalcium; 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.

[0052] In many embodiments, including in many preferred embodiments, of the disclosure, 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 disclosure.

[0053] 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: °          (I)

[0054] In some embodiments, the pharmaceutical compositions comprise 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 disclosure.

[0055] 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 described herein in pharmaceutical composition embodiments containing ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof), 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 or a pharmaceutically acceptable salt, solvate or co-crystal thereof), 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.

[0056] 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.

[0057] 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% 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.

[0058] The amorphous obicetrapib hemicalcium of the present disclosure 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°29, about 7.0°29, and about 9.2°29. 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°29 (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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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 about 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.

[0065] Solid-state 13C-NMR spectroscopy is another technique which may be used to characterize amorphous materials. FIG. 9 shows a solid-state 13C-NMR spectrum of both crystalline and amorphous obicetrapib hemicalcium with FIG. 10 and FIG. 1111 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-state 13C-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-state 13C-NMR spectrum substantially the same as that of FIG. 4 may be used to characterize amorphous obicetrapib hemicalcium.

[0066] In some embodiments of the disclosure, 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.

[0067] In many aspects of the disclosure, 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.

[0068] 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.

[0069] 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 found 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.

[0070] 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).

[0071] 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.

[0072] In many aspects of the disclosure, the disclosure includes methods for preparing obicetrapib calcium salts, such as amorphous obicetrapib hemicalcium. The disclosure further includes obicetrapib calcium salts, including amorphous obicetrapib hemicalcium, so prepared. In one such preparation, an intermediate referred to herein as crystalline HC1 obicetrapib is used in the processes for preparing amorphous obicetrapib hemicalcium.

[0073] In many aspects of the disclosure, amorphous obicetrapib hemicalcium is prepared via a chemical synthesis where an intermediate is used denoted by Formula (IH): • Solvent Where y varies such that the mass percent of HC1 varies from 0.01% to 8% by weight and 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.

[0074] Crystalline HC1 obicetrapib as prepared is crystalline. Thus, unless otherwise stated herein, the term crystalline HC1 obicetrapib means crystalline HC1 obicetrapib. Further, the term crystalline HC1 obicetrapib may include CPME as a solvate when CPME is used in the preparation crystalline HC1 obicetrapib. In Formula (IH), the solvate is of an organic solvent and in many embodiments, that solvent is CPME. In some embodiments, the disclosure provides for compositions comprising crystalline HC1 obicetrapib.

[0075] 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 HC1 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 HC1 and is thus found in the crystallized material, the resulting crystalline Formula (IH) material is referred to as crystalline HC1 obicetrapib, those x-ray powder diffraction pattern is seen in FIG. 12. It is therefore believed that crystalline HC1 obicetrapib is a solvate of CPME and HC1 together with obicetrapib. Solvates, as opposed to salts, can have a variable composition which help explains the variable amount of HC1 seen in crystalline HC1 obicetrapib. An advantage of using crystalline HC1 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 purity 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 disclosure 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.

[0076] HC1 obicetrapib, as used herein, is not limited to crystalline HC1 obicetrapib. Indeed, upon desolvation, crystalline HC1 obicetrapib may become amorphous.

[0077] Upon stress, crystalline HC1 obicetrapib loses its crystallinity. In FIG. 13, pattern 2 reflects crystalline HC1 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 HC1. 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 HC1 obicetrapib which is not crystalline obicetrapib. It may be obicetrapib, but is believed to have HC1 associated with the obicetrapib as a solvate and thus is HC1 obicetrapib, but with a lower chloride content than typically found in the ranges found for crystalline HC1 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.

[0078] Crystalline HC1 obicetrapib may be characterized by an x-ray powder diffraction pattern comprising a peak at about 9.8°29. In some embodiments, crystalline HC1 obicetrapib may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 8.1°20, about 9.8°29, about 13.8°29, about 16.7°29, or about 19.5°29. Table 1 provides illustrative peaks which may be present in crystalline HC1 obicetrapib. In some embodiments, crystalline HC1 obicetrapib may be characterized by an x-ray powder diffraction pattern substantially the same as that in FIG. 12. Table 1 °20 Intensity 8.1 950 9.8 1650 13.8 2000 16.7 2900 19.5 4100 21.1 3700 21.6 3800 22.4 3600 24.9 1950 26.6 1850

[0079] In some embodiments, the amorphous obicetrapib hemicalcium of the present disclosure is prepared by a method that comprises: i. treating obicetrapib with HC1 to obtain crystalline HC1 obicetrapib; ii. isolating crystalline HC1 obicetrapib; iii. preparing an amorphous calcium salt of obicetrapib from the crystalline HC1 obicetrapib isolated in step (ii); and iv. isolating an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemi calcium.

[0080] 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).

[0081] In some embodiments of the method of preparing amorphous obicetrapib hemicalcium, step (iii) includes the following steps: (iii-1) converting crystalline HC1 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; wherein the compounds in steps (iii-1) and (iii-2) are not isolated.

[0082] 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.

[0083] 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.

[0084] 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); H                                                                  H (IIA) (HIA) (IVA) where X1 is a leaving group and Y1 is a protecting group; (b) preparing a carbamate of Formula (VA) from the compound of Formula (IVA) and isolating as a solid salt form of Formula (VIA): IVA (VA) (VIA) where Y1 is a protecting group, An' is an anion and wherein n is an integer from 1-3; (c) optionally desalting the compound of Formula (VIA) and alkylating with a compound of Formula (VIIA) to provide a compound of Formula (VIIIA): (VIIA)                                         (VIIIA) where, X2 is a leaving group, Y1 is 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.

[0085] 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.

[0086] In some embodiments, the amorphous obicetrapib hemicalcium is prepared by the method set out in Scheme 1. o Ca2+ Scheme 1

[0087] 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 IB), and 3,5-bis(trifluoromethyl)benzyl bromide (compound IE). Compound 1A was coupled with compound IB 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 IC), 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 ID). The crystalline mesylate salt, compound ID was alkylated with 3,5 bis(trifluoromethyl)benzyl bromide (compound IE) under strongly basic conditions to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-t- butoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound IF) 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-l-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-l-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 HC1 obicetrapib and compound 3 is amorphous obicetrapib hemicalcium.

[0088] 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-l-carboxylic acid ethyl ester (compound 1), the intermediate HC1 intermediate (compounds 2), and the corresponding amorphous calcium salt (compound 3) will be described in more detail in Operations 1-9 below.

[0089] 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                                                           (in toluene, <0.1 w% water (in water) not isolated)

[0090] (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 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 M 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 IC) 1A - FREE BASE (in toluene, <0.1 w% water not isolated) 1% Pd(OAc)2, (S)-BINAP, t-BuOH, K3PO4

[0091] Additional toluene (107 L, 1.5 vol.) was added to the reaction vessel (“vessel 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 IB) (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, 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 IM HC1 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 IC) dissolved in acetonitrile. Compound IC 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-l-carboxylic acid ethyl ester, as a crystalline mesylate salt (Compound ID) 1. CICO2Et, pyridine 10 °C - RT 2. aqueous work up 3. MsOH

[0092] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound IC) 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.), IM 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-butoxy carbonylpropoxy )pyrimidin-2-yl)]amino-2-ethyl-6-tri fluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (corresponding free base of compound ID) in isopropyl acetate based on the weight of the solution.

[0093] 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 ID) 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 ID) 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 ID) with a yield of 74 %, based on the number of moles of compound 1A. The purity of the crystalline compound ID obtained was > 99 %. 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 IF) (1) reaction PhMe TBAHS NaOt-Pent (2) work-up AcOH (1 N) (3) distill to traget vol.

[0094] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester, as a crystalline mesylate salt (compound ID) (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 IE) (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 IN 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 IF) in toluene, based on the weight of the solution, 97% yield based on the number of moles of compound ID). 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-l-carboxylic acid ethyl ester (compound 1) 1.HCI, AcOH, 50 °C 2. work - up: heptane, acetonitrile, water 3. Solvent switch to CPME

[0095] A solution of 37 wt.% (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tbutoxy carbonylpropoxy )pyrimidin-2-yl]amino}-2-ethyl-6-tri fluoromethyl-3,4-dihydro-2Hquinoline- 1-carboxylic acid ethyl ester (compound IF) in toluene (128.4 kg of the 37 wt.% solution, equivalent to 47.5 kg compound IF) was diluted to 32wt% with additional toluene and then mixed with acetic acid (253 kg, 5.33 wt.), and 6 M HC1 (109.9 kg, 2.32 wt, prepared in situ with 66.1 kg of cone. HC1 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 / / -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.), / / -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-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester (compound 1, free base form) in cyclopentyl methyl ether (CMPE) having 1 weight percent toluene, less than 1 weight percent / / -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-l-carboxylic acid ethyl ester hydrochloride (compound 2) 1 - in toluene CPME, n-Hept 3M HCI in CPME compound 2 seeds

[0096] The 33.7 weight percent solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimi din-2-yl]amino}-2-ethyl-6-tri fluoromethyl-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.), / / -heptane was then added (54.8 kg, 1.15 wt.) and the internal reaction temperature was increased to 39°C. 3.0 M HCI 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 HCI was complete, the internal temperature was increased to 52°C. Additional / / -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 / / / -heptane (referred to herein as “seed crystal slurry”). A seed crystal slurry of compound 2 (169 g, 0.43 weight percent) in CPME / / / -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 HCI intermediate (compound 2). A mixture of CPME and / / -heptane (56.6 kg CPME, 179 kg / / -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 unloaded from the filter dryer but was further purified by recrystallization according to the following procedure.

[0097] 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 HC1 in CPME (6.4 kg) was added so that a total of 1.07 equiv. HC1 was achieved based on assay of compound 1 in compound 2 crude and assay of HC1 in compound 2 crude. / / -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 / / / -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 / / -heptane (57.4 kg CPME, 180 kg / / -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 IF) with 99.6 area% purity and residual solvents 0.3%w CPME and < 0.1%w / / -heptane. 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-l-carboxylic acid ethyl ester (compound 3) 2 IPAC, H2O, EtOH O 1 - in EtOH (not isolated) 4M NaOH (not isolated)

[0098] (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-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 base 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-l-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.

[0099] 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.”

[0100] 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

[0101] 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 CaCh solution (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-l-carboxylic acid ethyl ester (compound 3) with <1 weight percent water and a purity of 97.5 % wt. and >99.9 area%. Operation 9 - Milling of Reworked Compound 3

[0102] 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 pm). 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)

[0103] 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)

[0104] XRPD was performed with Panalytical X’Pert3 Powder 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 to 10 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. Table 2 Parameters for XRPD test Parameters Reflection Mode X-Ray wavelength Cu, ka Kal (A): 1.540598, Ka2 (A): 1.544426, Ka2 / Kal intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit Fixed 1 / 8° Scan mode Continuous Scan range (° 2TH) 3-40 Scan step time [s] Step size 18.87 0.0131 (° 2TH) Test Time 4 min 15 s Operation 11A -FIG. 2

[0105] 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 ID 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° (2 Th eta) Rotation      1 Rev / s Operation 1 IB - X-ray Powder diffraction Methodology for Crystalline HC1 Obicetrapib (FIG. 12 and FIG. 13)

[0106] 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 Kal radiation, and a position sensitive gas-ionization detector.

[0107] 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°29 to 120° 29 simultaneously; in the case of HC1 obicetrapib, discernible signals useful for phase identification are seen up to approx. 45°29. The temperature in the diffractometer is typically around 30 °C during measurements.

[0108] The pharmaceutical compositions of the disclosure 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.

[9199] 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.

[9119] The general process of Fig. 24 may also be used to create tablets of obicetrapib wherein there is no additional active pharmaceutical ingredient or wherein there is an additional active pharmaceutical ingredient, but the additional active pharmaceutical ingredient is not ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In such embodiments, either the additional active pharmaceutical ingredient is substituted for where ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, is added in FIG. 24. In other embodiments, there is no additional active pharmaceutical ingredient at all.

[0111] In many embodiments of the disclosure, the pharmaceutical composition comprises amorphous obicetrapib hemicalcium as the only active ingredient. In such embodiments, the pharmaceutical compositions of the disclosure do not contain ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In other embodiments, a second active pharmaceutical ingredient is present, but it is not ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0112] In many of the embodiments of the disclosure, 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 DvlO, Dv50 and Dv90 (also referred as Xio, 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 DvlO means 10% of the particles by volume are below this size and 90% are above.

[0113] In many embodiments, the composition comprises micronized amorphous obicetrapib hemicalcium having a Dv90 not more than 14 pm, in some embodiments, in the range of about 5-14 pm; Dv50 not more than 5 pm, in some embodiments, in the range of about 35gm; and DvlO not more than 3 gm.

[0114] In many embodiments of the disclosure, the pharmaceutical compositions comprise one or more pharmaceutically acceptable excipients. In many of these embodiments, the compositions are tablets. In many of these embodiments, one or more of the excipients is a surfactant.

[0115] 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,

[0116] 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.

[0117] 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.

[0118] Examples of cationic surfactants include quaternary ammonium salts and pyridinium salts.

[0119] 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 monooleate) 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 and polysorbate 80 are also non-ionic surfactants. Further examples of non-ionic surfactants are poloxamers which are synthetic block copolymers of hydrophilic poly(oxy ethylene)

[0120] Examples of zwitterionic and / or amphoteric surfactants include lauryl betaine, lauroyl sarcosinate, lauryl sultaine, lauryl amidopropyl betaine (also known as cocamidoproipylbetaine) and lauryldimethylamine oxide.

[0121] In many embodiments, the surfactant in the compositions of the disclosure is sodium lauryl sulphate.

[0122] 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.

[0123] 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, poly ethoxylated 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.

[0124] 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.

[0125] The pharmaceutical composition may comprise one or more surfactants (which may be the same or different) and comprise one or more additional pharmaceutically acceptable excipients. In other embodiments, the pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients and optionally not comprise a surfactant. Excipients include but are not limited to one or more binders, disintegrants, glidant, lubricant, diluent, chelating agents, desiccants or absorbents. 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’", 9th edition, Rowe et al., Eds., American Pharmaceuticals Association (2020); and “Remington: The Science and Practice of Pharmacy”, 22nd edition, Gennaro, Ed., Lippincott Williams & Wilkins (2013).

[0126] The pharmaceutical compositions of the disclosure may comprise one or more binders. 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.

[0127] 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 such as with tablets made by direct compression, by weight of the total tablet (on an uncoated tablet basis).

[0128] 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.

[0129] The pharmaceutical composition may 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.

[0130] 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 in other embodiment such as with tablets made by direct compression.

[0131] The pharmaceutical composition of the disclosure may comprise one or more diluents. 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 or in tablets not made by wet or dry granulation, such as with direct compression. 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. In some embodiments, the diluents are present between about 80% and 83% by weight. In all such measurements, said weight percentages are calculated on an uncoated tablet basis.

[0132] 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. Examples of Opadry® coatings include Opadry®!! white.

[0133] 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.

[0134] Glidants which may be 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, such as with tablets made by direct compression.

[0135] Lubricants which may be 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, such as with tablets made by direct compression.

[0136] In many embodiments, the pharmaceutical composition is a tablet comprising 10 mg of obicetrapib as free acid in about 10.26 mg of amorphous obicetrapib hemicalcium. In these and other embodiments, the tablets are made by direct compression. The tablets may comprise one or more diluents such as microcrystalline cellulose and mannitol. The tablets may further comprise one or more of a disintegrant, glidant and lubricant. An exemplary disintegrant is sodium starch glycolate. An exemplary glidant is colloidal silicon dioxide. An exemplary lubricant is magnesium stearate.

[0137] In many embodiments, the pharmaceutical composition of the disclosure comprises the tablet set forth in Table 2A. Table 2A Component % w / w mg / tablet Core Tablet Amorphous Obicetrapib hemicalcium 10.26 10.26 Obicetrapib free acid (10.00) Microcrystalline cellulose 59.74 59.74 Mannitol 23.00 23.00 Sodium starch glycolate (type A) 5.00 5.00 Colloidal silicon dioxide 1.00 1.00 Magnesium stearate 1.00 1.00 Total 100.0 100.00 Film Coat Opadry® II white (32K280000) 3.00 3.00 Total Weight 103.00

[0138] In many embodiments of the disclosure, the pharmaceutical compositions of the disclosure comprise another active ingredient. In such embodiments, the additional active ingredient is ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In many embodiments, the pharmaceutical compositions do not contain any active ingredient other than obicetrapib (such as amorphous obicetrapib hemicalcium). In many embodiments, the pharmaceutical compositions of the disclosure do not contain ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0139] In many embodiments of the disclosure, the pharmaceutical compositions comprise amorphous obicetrapib hemicalcium and ezetimibe and one or more pharmaceutically acceptable excipients. In many of these embodiments, such pharmaceutical compositions comprise an intragranular portion and an extragranular portion and is in the form of a tablet which may optionally be film coated ezetimibe is contained within the intragranular portion of the tablet and obicetrapib in the extragranular portion. The non-water intergranular components may be formed by blending followed by wet granulation with water to form granules. The extragranular portion may be made by blending the components and directly compressing them together with the granules made from the intragranular portion. The resulting tablet may then optionally be film coated. Intragranular Components - with mass percents on tablet basis for obicetrapib / ezetimibe tablets

[0140] In these and other embodiments, the intragranular portion comprises ezetimibe and one or pharmaceutically acceptable excipients. Such pharmaceutically acceptable excipients may comprise one or more diluents, binders, disintegrants, and surfactants.

[0141] Examples of diluents in the intragranular portion include microcrystalline cellulose and lactose monohydrate. In many embodiments, the weight percent of the diluents from the intragranular components in an uncoated tablet of the disclosure is between about 40% to about 60% by weight including all values in between including between about 45% and about 55% by weight and including between about 46% and about 50% and between about 48% and about 49% by weight including between about 48.2% by weight and about 48.3% by weight including about 48.26% by weight. In other embodiments, the weight percent of diluents is about 48.0%, about 48.1%, aobut 48.2%, about 18.3%, about 48.4%, or about 48.5%. In many embodiments, both microcrystalline cellulose (such as Avicel PH 101) and lactose monohydrate (such as Pharmatose 200M) are used as diluents in which case the weight percent of microcrystalline cellulose may be between about 10% and about 30 % and that of lactose monohydrate between about 20% and about 40%. For example, the amount of microcrystalline cellulose and lactose monohydrate may each be between about 20% and about 30% by weight, such as between about 22% and about 28% and including between about 23% and about 25% and between about 24% and about 25%. In these and other embodiments, the weight percent of microcrystalline cellulose and lactose monohydrate is approximately equal such as about 24%, about 24.1%, about 24.2% and all values in between.

[0142] Other excipients in the intragranular portion may include binders such as povidone (such as Kollidon 30). In these and other embodiments, the weight percent of povidone from the intragranular portion may be between about 0.5% and about 0.8% by weight including all values in between including about 0.65% by weight. Another excipient may be sodium starch glycolate, a disintegrant (such as Glycolys) and may be present, for example, in an amount between about 1% and about 4% by weight including all values in between including about 2% or about 3%, including about 2.6% by weight. Additionally, a surfactant is often present as a pharmaceutically acceptable excipient. One such surfactant, sodium lauryl sulphate (such as Kolliphor SLS) may be present in an amount between about 0.5% and about 0.8% by weight including all values in between including about 0.65% by weight. Extragranular Components with mass percents on tablet basis for obicetrapib / ezetimibe tablets

[0143] In these and other embodiments, the extragranular portion comprises obicetrapib, often in the form of amorphous obicetrapib hemicalcium and one or pharmaceutically acceptable excipients. Such pharmaceutically acceptable excipients may comprise one or more diluents, binders, disintegrants, glidants, and lubricants.

[0144] Examples of diluents in the extragranular portion include microcrystalline cellulose and mannitol. In many embodiments, the weight percent of the diluents from the extragranular components in an uncoated tablet of the disclosure is between about 25% to about 40% by weight, including all values in between and including between about 28% and about 36%, and between about 30% and about 34% by weight and including between about 31%, about 32%, and about 33%. In these and other embodiments, the diluents are one or more of microcrystalline cellulose (such as Avicel PH 200) and mannitol (such as Pearlitol 200SD). In many embodiments, both microcrystalline cellulose and mannitol are used as diluents in which case the weight percent of microcrystalline cellulose may be between about 20% and about 28% by weight and all values in between, including between about 21% and about 25% and about 22%, about 23%, about 24%, about 25% and 26%. In such embodiments, the weight percent of mannitol in the extragranular portion is between about 5% and about 12% including between about 8% and about 10% including about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about 9.2%, and about 9.3%.

[0145] Other excipients in the extragranular portion may include disintegrants such as sodium starch glycolate (such as Glycolys). In these and other embodiments, the weight percent of sodium starch glycolatee from the extragranular portion may be between about 3% and about 7% by weight including all values in between including about 4%, about 5% and about 6% by weight. Another excipient may be colloidal silicon dioxide, a glidant (such as Aerosil 200) and may be present, for example, in an amount between about 0.5% and about 1.5% by weight including all values in between including about 1% by weight. Additionally, a lubricant may be present. One such lubricant, magnesium stearate (such as Ligamed MF-2- V) may be present in an amount between about 0.5% and about 1.5% by weight including all values in between including about 1% by weight. Film Coating

[0146] The tablets comprising said intragranular and extragranular components may be film coated such as white coat. An exemplary coating is Opadry® AMB II white 88Al 80040. Additional Tablet Embodiments

[0147] In many embodiments, the percent by weight of microcrystalline cellulose in the entire tablet (i.e., intragranular plus extragranular) is greater than about 37.5% by weight including between about 38% and about 48% by weight including between about 40% and about 48% by weight and including between about 46% and about 48% by weight.

[0148] In these and other embodiments, the lactose monohydrate in the tablet is less than about 34.5% by weight including less than 34% by weight and less than 30% by weight and less than 25% by weight, for example, the amount of lactose monohydrate may be between about 20% and 25% including between about 22% and about 24.5% by weight. In these and other embodiments, the weight ratio of microcrystalline cellulose to lactose monohydrate is greater than 1.2:1, and in some embodiments, greater than 1.4:1, greater than 1.5:1, 1.6:1, 1.7:1, 1.8:1, and 1.9:1. In some embodiments, at least 50% of the diluents are microcrystalline cellulose.

[0149] In many embodiments, the tablets comprising ezetimibe in the intragranular portion and obicetrapib in the extragranular portion have components and amounts as set forth in Table 2B. Table 2B Component (mg / Tablet) %w / w Intragranular Components Ezetimibe 10.00 4.348 Microcrystalline cellulose 55.50 24.130 Lactose monohydrate 55.50 24.131 Povidone 1.50 0.652 Sodium starch glycolate 6.00 2.608 Sodium lauryl sulphate 1.50 0.652 Purified water q.s. q.s. Extragranular Components Amorphous Obicetrapib hemicalcium (obicetrapib) 10.26 (10.00) 4.461 Microcrystalline cellulose 53.17 23.118 Mannitol 20.47 8.900 Sodium starch glycolate 11.50 5.000 Colloidal silicon dioxide 2.30 1.000 Magnesium stearate 2.30 1.000 Total core weight (mg) 230.00 100.000 Film-Coating Components Opadry® AMB II white 88Al 80040 containing: Polyvinyl alcohol Talc Titanium dioxide Glyceryl mono and          dicaprylocaprate Sodium lauryl sulphate 6.90[5] 3.0[5] Purified water q.s. q.s. Total tablet weight 236.90 103.0 0150] Stability is an important quality attribute for pharmaceutical formulations that determines the shelflife 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 shelflife 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.

[0151] 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).

[0152] 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, in many embodiments, be amorphous obicetrapib hemicalcium; 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).

[0153] A second aspect relates to the use of a pharmaceutical composition comprising amorphous obicetrapib hemicalcium 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.

[0154] 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).

[0155] In many embodiments, the said subjects are partially or completely intolerant to statins.

[0156] In many embodiments, the use of a pharmaceutical composition of the disclosure 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).

[0157] 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.

[0158] In many embodiments of the disclosure, 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).

[0159] In many embodiments, the pharmaceutical compositions of the disclosure as orally administered to subjects.

[0160] 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).

[0161] 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.

[0162] As explained herein before, the disclosure provides methods for the curative and / or prophylactic treatment of a subject in need thereof. More particularly, the disclosure 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 disclosure 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 disclosure 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 disclosure 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 compositions as defined herein. The disclosure 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.

[0163] 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.

[0164] 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.

[0165] 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 with 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.

[0166] 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 disclosure 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.

[0167] 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.

[0168] In particularly typical embodiments of the disclosure, the subject is a subject that has been diagnosed with CVD, in particular ASCVD.

[0169] In further typical embodiments of the disclosure, 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.

[0170] In typical embodiments of the disclosure, the subject is a subject suffering from one or more conditions known to bear a causal and / or epidemiological correlation with the occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including, overweight / obesity, metabolic syndrome, etc. In further typical embodiments of the disclosure, the subject is a subject that is genetically predisposed to develop (AS)CVD. In further typical embodiments of the disclosure, 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.

[0171] In one embodiment of the disclosure, the subject is human male. In another embodiment of the disclosure, the subject is human female.

[0172] In further typical embodiments of the disclosure, 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 45 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.

[0173] In accordance with certain embodiments of the disclosure, the subjects to be treated display hypo-responsiveness to statin therapy, in particular HIS therapy.

[0174] The various aspects of the present disclosure 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.

[0175] Hence, in many embodiments of the disclosure, 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, 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.

[0176] In accordance with the various aspects of the disclosure, 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 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.

[0177] In accordance with the various aspects of the disclosure, 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, 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.

[0178] 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.

[0179] 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 disclosure includes dosing such doses as well as the doses themselves.

[0180] 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 a dosage form that 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.

[0181] 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 hemi calcium.

[0182] In particularly typical embodiments of the disclosure, 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 disclosure, 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 disclosure, 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 disclosure, 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.

[0183] 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 disclosure, 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-release dosage forms that remain in the body and keep releasing the active ingredient for a sufficiently long time.

[0184] In embodiments, methods and / or compositions for use according to the disclosure are provided, wherein the methods and / or use comprise the administration, in some embodiments, the repeated administration, of compositions comprising amorphous obicetrapib hemicalcium 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 disclosure, 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.

[0185] Another aspect of the disclosure 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 disclosure 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.

[0186] In accordance with embodiments of the disclosure, 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 disclosure, 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, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In many embodiments of the disclosure, 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 disclosure, 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 and optionally, in some embodiments an equal number, of unit dosage forms that contain another active ingredient, such as, for example, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0187] In accordance with the disclosure, 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 disclosure, 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 disclosure. In particularly typical embodiments of the disclosure, the leaflet contains printed instructions to repeatedly (self-)administer the unit dosage forms in order to treat and / or prevent CVD, in particular ASCVD.

[0188] The methods of treatment of the disclosure, based on compositions comprising amorphous obicetrapib hemicalcium and a surfactant, and optionally, one or more additional pharmaceutically acceptable excipients will be illustrated further by means of the non-limiting examples herein below.

[0189] Obicetrapib, also referred to as “TA-8995”, has the following chemical name and chemical structure: {4-[(2-{[3,5-bis(trifluoromethyl)benzyl] [(2R,4S)-1-(ethoxy carbonyl)-2-ethyl- 6-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid}

[0190] The term “apolipoprotein” as used herein has its conventional meaning and refers to proteins that bind lipids to form lipoproteins.

[0191] The term “apolipoprotein B” (ApoB) as used herein has its conventional meaning and refers to the protein encoded by the ApoB gene.

[0192] The term ‘pharmaceutical composition" as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] The term ‘salt’ as used herein has its conventional meaning and includes the acid addition and base salts of a pharmaceutically active compound.

[0197] 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.

[0198] 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.

[0199] 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 / 1 [100,54 mg / Dl]), such that the subject is at an increased risk of suffering a cardiovascular event, compared to those with lower levels.

[0200] The term ‘treatment’ as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment.

[0201] 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.

[0202] 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, 2017).

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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. Examples

[0210] While the disclosure 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 disclosure.

[0211] 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 Title XRPD Transmission method for phase identification using X-Ray Powder Diffraction PSD Method for particle size distribution by laser diffraction dry powder dispersion TBD standard test method for tapped bulk density analysis using drop height density tester KF determination of water content by indirect (coulometric) karl fischer titration Discriminating Dissolution discriminating dissolution method for obicetrapib at ph 6.8 and 50 rpm paddle speed. Content Uniformity determination of content uniformity of obicetrapib and ezetimibe by hplc-UV. Assay and related substances / impurities for obicetrapib identity, assay and impurities / related substances profile determination of obicetrapib by hplc-UV. Assay and impurities / related substances for ezetimibe identity, assay and impurities / related substances profile determination of ezetimibe by hplc-UV Visual Appearance determination of appearance using the Munsell colour system XRPD

[0212] 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 2-theta range 2-45° Step size [°2-thetal 0.0167 Time per step [seel 59.690 sec Scan Mode Continuous Sample Movement Spinning. 1.0sec rotation time Wavelength [nm] Cu Kai=l.54060 Ka2=l.54443 X-ray Mirror Inc. Beam Cu W / Si focusing MPD. Acceptance Angle 0.8°C. Length 55.3 mm Slits Divergence / Antiscatter / Mask Slit Fixed 1 / 2° / Slit Fixed l / 2° / 10 mm Inc Beam Mask Temperature / RH Room temperature. Lab RH Fixed Slits Soller slits 0.02 rad on Incident and Diffracted beam Detector type X’Celerator ("active length 2.122°) Scanning mode Transmission Sample holder Transmission sample holder. Samples are mounted as a thick film. To minimise typical orientation effects between Mylar film) using a tin plated stainless steel spacer to afford a compact that is 1 mm thick and up to 1 cm in diameter. Configuration Transmission Generator voltage / current 40 Kv / 40 Ma Particle size distribution (PSD)

[0213] 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. Table 5 Instrumental Parameter Value Software Sympatec Windox 5 Version 5.1.2.0 Dispersing Accessory Vibri Optical concentration 2-10% Lens R6 Product details Density: 1.0000 g / cm3 Shape factor 1.000 Calculation mode: HRLD T rigger Condition Reference measurement: duration 10s / single Time base: 100 ms Measurement: standard mode Start 0.000s opt. concentration >1.0% Stop after 5.000s opt. concentration <1.0% Trigger timeout 20 s Disperser Condition RODOS Disperser Type: OASISDRY Injector: 4 mm Primary pressure 0.5 bar Feeder Vibri 70% 0.5 mm gap Vacuum Nilfisk / delay 3 s from start of extraction to start of measurement Discriminating dissolution method Ph 6.8 (obicetrapib) Table 6 Instrumental Parameter Value Apparatus USP apparatus II Dissolution medium Phosphate buffer solution Ph 6.8 + 0.2 %w / v of Polysorbate 80 Dissolution medium volume [Ml] 900 Dissolution medium Temperature [°C] 37 ±0.5 Rotation Speed [rpm] 50 - Infinity point 250 rpm Sampling Time [min] 5; 10; 15; 30; 45; 60 and 70 (70 as Infinity point) Sampling Volume [Ml] 1 Separative technique (*) PVDF 0.45pm membrane Filter Pre-wetting volume [Ml] 9 (sampling 10M1 and discarding the first 9M1 back to the vessel) Detection HPLC-UV

[0214] In Examples 8-10 some of the dissolution media were modified as set forth therein. Discriminating Dissolution method Ph 4.5 (ezetimibe) Table 7 Instrumental Parameter Value Apparatus USP apparatus II Dissolution medium Acetate buffer solution Ph 4.5 + 0.45 %w / v of SLS Dissolution medium volume [Ml] 500 Dissolution medium Temperature [°C] 37 ±0.5 Rotation Speed [rpm] 50 - Infinity point 250 rpm Sampling Time [min] 15; 30; 45; 60 and 70 (70' as Infinity point). Sampling Volume [Ml] 1 Separative technique (*) ww / PTFE 0.45 um membrane Filter Pre-wetting volume [Ml] 9 (sampling 10M1 and discarding the first 9M1 back to the vessel) Detection HPLC-UV QC Dissolution method Ph 6.8 (obicetrapib) Table 8 Instrumental Parameter Value Apparatus USP apparatus II Dissolution medium Phosphate buffer solution Ph 6.8 + 0.2 %w / v of Polysorbate 80 Dissolution medium volume [Ml] 1000 Dissolution medium Temperature [°C] 37 ±0.5 Rotation Speed [rpm] 75 - Infinity point 250 rpm Sampling Time [min] 15; 30; 45; 60 and 70 (70' as Infinity point at 250 rpm) Sampling Volume [Ml] 1 Separative technique (*) PVDF 0.45pm membrane Filter Pre-wetting volume [Ml] 9 (sampling 10M1 and discarding the first 9M1 back to the vessel) Detection HPLC-UV QC Dissolution method Ph 4.5 (ezetimibe) Table 9 Instrumental Parameter Value Apparatus USP apparatus II Dissolution medium Acetate buffer solution Ph 4.5 ± 0.45 %w / v of SLS Dissolution medium volume [Ml] 500 Dissolution medium Temperature [°C] 37 ±0.5 Rotation Speed [rpm] 75 - Infinity point 250 rpm Sampling Time [min] 15; 30; 45; 60 and 70 (70' as Infinity point). Sampling Volume [Ml] 1 Separative technique (*) ww / PTFE 0.45 Filter Pre-wetting volume [Ml] 9 (sampling 10M1 and discarding the first 9M1 back to the vessel) Detection HPLC-UV Assay and Impurities / Related Substances (obicetrapib) Table 10 Intrumental Parameters Value Column Kinetex PFP, 100mm x 4.6mm (particle size: 2.6pm) Mobile Phase A): 70 / 30 % v / v Water / Methanol + TFA 0.025% B): 30 / 70 % v / v Methanol / Acetonitrile + TFA 0.025% Gradient Program Time (min) Flow Rate [Ml / min] Mobile Phase (A) Mobile Phase (B) 0.0 1.0 70 30 5.0 50 50 8.0 50 50 30.0 3 97 30.1 70 30 35.0 70 30 Column Temperature [°C] 35 Auto Sampler Temperature [°C1 R.T. Detector UV, MWD or DAD (DAD for release ID) Detector Wavelength [nm] 245 Injection Volume [pL] 10 Diluent (Standard, sensitivity and resolution check solutions) Water / Acetonitrile, 50 / 50 %v / v Diluent (Sample solutions) Diluent A: Water 100% Diluent B: Acetonitrile 100 % Run Time [min] 30 (5 minutes next injection delay) Typical Retention Time [min] 16.7 Example 1: Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by cogranulation of drug substances / active ingredients (FDC1) (small scale batch ~ 500 g) High shear granulation, drying, preparation of final blend and tableting

[0215] 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 at 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 composition Component Composition #1 Composition #2 Composition #3 A4459 / 20 / 02 A4459 / 23 / 02 A4459 / 20 / 03 A4459 / 23 / 03 A4459 / 20 / 04 A4459 / 23 / 04 Granule (%, w / w) Tablet (%, w / w) Granule (%, w / w) Tablet (%, w / w) Granule (%, w / w) T ablet (%, w / w) Intra-granular Ezetimibe 6.981 6.667 6.981 6.667 6.981 6.667 Table 11: Composition (% w / w) of granule and tablet for the FDC1 composition Component Composition #1 Composition #2 Composition #3 A4459 / 20 / 02 A4459 / 23 / 02 A4459 / 20 / 03 A4459 / 23 / 03 A4459 / 20 / 04 A4459 / 23 / 04 Granule (%, w / w) Tablet (%, w / w) Granule (%, w / w) Tablet (%, w / w) Granule (%, w / w) T ablet (%, w / w) Obicetrapib 7.162 6.840 7.162 6.840 7.162 6.840 Avicel PH 101 21.982 20.993 21.982 20.993 21.982 20.993 Phannatose 200 M 57.592 55.000 57.592 55.000 57.592 55.000 KoUidon 30 1.047 1.000 1.047 1.000 1.047 1.000 Glycolys 4.189 4.000 4.189 4.000 4.189 4.000 KoUiphor SLS 1.047 1.000 1.047 1.000 1.047 1.000 MilllQ water* 20.000 + 5.000 N / A 20.000 + 5.000 N / A up to visual (30.000) N / A Total Granule 100.000 95.500 100.000 95.500 100.000 95.500 Extra-granular Glycolys N / A 4.000 N / A 4.000 N / A 4.000 Ligamed MF-2-V N / A 0.500 N / A 0.500 N / A 0.500 Total tablet N / A 100.000 N / A 100.000 N / A 100.000 * Water does not appear in the final product. All excipients for granulation added as a dry powder Results

[0216] 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

[0217] The granules were tested for homogeneity, and obicetrapib and ezetimibe were found to be homogeneously dispersed. Physical properties characterization

[0218] 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

[0219] 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

[0220] XRPD data of the Tablets from FDC1 compositions are summarized in Table 14. There is no presence of ezetimibe hydrate in all samples. Table 12: XRPD data summary of granules from FDC1 compositions Sample Batch ID XRPD Prototype 1 Blend before granulation A4459 / 20 / 02 OBI + EZE Anhydrous Prototype 1 Wet Granules OBI + EZE Anhydrous +small EZE Hydrate Prototype 1 Final dry Granules OBI + EZE Anhydrous Prototype 2 Blend before granulation A4459 / 20 / 03 OBI + EZE Anhydrous Prototype 2 Wet Granules OBI + EZE Anhydrous +small EZE Hydrate Prototype 2 Final dry Granules OBI + EZE Anhydrous Prototype 3 Blend before granulation A4459 / 20 / 04 OBI + EZE Anhydrous Prototype 3 Wet Granules OBI + EZE Anhydrous +small EZE Hydrate Prototype 3 Final dry Granules OBI + EZE Anhydrous Table 13: Results of the chemical characterization of FDC 1 compositions Manufacturing lot number A4459 / 23 / 02 A4459 / 23 / 03 A4459 / 23 / 04 Prototype Composition #1: prototype C, Composition #2: prototype C, Composition #3: prototype C, Test Method Result Result Result Assay Obicetrapib (%claim) Ezetimibe (%claim) HPLC 2730 2731 100.1 99.9 97.6 99.7 99.2 99.7 Impurities IMPRRT0.94 (% claim) FROL(% claim) MONO-BN FREE(% claim) Total impurities of Obicetrapib > 0.05% EzetimibeKetone (% a / a) Ezetimibe tetrahydropyran analog (%a / a) Total impurities of Ezetimbe > 0.05% HPLC 2730 2730 2730 2730 2731 2731 2731 0.06 0.05 0.17 0.28 < QL (0.05%) N.D. < QL (0.05%) 0.06 0.06 0.16 0.28 < QL (0.05%) N.D. < QL (0.05%) 0.06 0.05 0.17 0.28 < QL (0.05%) N.D. < QL (0.05%) Uniformity of dosage units Obicetrapib USP <905> Ph.Eur. 2.9.40 or JP 6.02 by UNIC / 1190 Average % Claim: 99.7 Range % Claim: (94.0-102.4) AV = 5.5 Average % Claim: 98.5 Range % Claim: (97.1 -99.2) AV = 1.8 Average % Claim: 99.3 Range % Claim: (97.6-100.5) AV = 2.3 Ezetimibe Average % Claim: 102.6 Range % Claim: (96.8- 105.6) AV = 7.0 Average % Claim: 101.5 Range % Claim: (100.3 - 102.2) AV = 1.5 Average % Claim: 101.6 Range % Claim: (100.0 -103.1) AV = 2.5 Dissolution Obicetrapib Discriminating method at Ph 6.80.2 %w / v of Tween 80, 50 rpm paddle speed 5 min Average (Min Max) 10 min Average (Min Max) 74 (72 - 76) 77 (74 - 79) 80 (77 - 83) 94 (90 - 97) 95 (92 - 97) 95 (94 - 96) Table 13: Results of the chemical characterization of FDC1 compositions Manufacturing lot number 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 min Average (Min Max) 70 min Average (Min Max) and 900 Ml vessel volume A4459 / 23 / 02 98 (95 - 102) 103 (99 - 106) 103 (100- 105) 103 (101 - 107) 104 (102- 108) ..A4459 / 23 / 03.......... 99 .........(98-101)....... 104 ........(103.-.106)....... 104 ........(1.03-..10.7)....... 103 ........(1.Q2..-1.Q5)....... 103 (102- 104) A4459 / 23 / 04 99 (98 - 99) 100 (102- 106) 100 (102-101) 100 (100- 100) 100 (99-101) Dissolution Ezetimibe 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 min Average (Min Max) 70 min Average (Min Max) Dissolution method based on USP method conditions at Ph 4.5, 75 rpm paddle speed and 500 Ml vessel volume 86 (83 - 88) 100 (97- 102) 105 (102- 107) 107 (105- 109) 109 (107-111) 88 .........33.-321........ 100 ........(98-..102)........ 104 (102- 105) 106 ........(1.05.-.107)....... 108 (107- 108) 90 (86 - 92) 102 (99 - 104) 106 (104-107) 107 (106- 109) 108 (107- 109) Water content KF 4.6 % w / w 4.6 % w / w 4.6 % w / w Table 14: XRPD data summary of granules of FDC1 compositions Sample Batch ID XRPD Composition 1 Tablet A4459 / 23 / 02 OBI + EZE Anhydrous Composition 2 Tablet A4459 / 23 / 03 OBI + EZE Anhydrous Composition 3 Tablet A4459 / 23 / 04 OBI + EZE Anhydrous 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

[0221] 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

[0222] 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)

[0223] 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.

[0224] 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=l 1) 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.

[0225] The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.

[0226] 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 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, content uniformity and water content by KF.

[0227] 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 ta )let of FDC2 compositions Component Prototype 1 Prototype 2 Prototype 3 A4459 / 20 / 01 A4459 / 23 / 01 A4459 / 27 / 01 A4459 / 25 / 01 A4459 / 26 / 01 A4459 / 27 / 02 A4459 / 25 / 02 A4459 / 26 / 02 A4459 / 27 / 03 Granule (%, w / w) Tablet (%, w / w) Tablet coated (%, w / w) Granule (%, w / w) Tablet (%, w / w) Table t coate d (%, w / w) Granule (%, w / w) Tablet (%, w / w) Table t coate d (%, w / w) Intra-granule Ezetimibe 7.692 4.348 4.348 7.692 4.348 4.348 7.692 4.348 4.348 Avicel PH 101 23.614 13.347 13.347 23.614 13.347 13.347 23.614 13.347 13.347 Pharmatose 200 M 61.771 34.914 34.914 61.771 34.914 34.914 61.771 34.914 34.914 Table 15: Composition (% w / w) of granule, tablet and coated ta )let of FDC2 compositions Component Prototype 1 Prototype 2 Prototype 3 A4459 / 20 / 01 A4459 / 23 / 01 A4459 / 27 / 01 A4459 / 25 / 01 A4459 / 26 / 01 A4459 / 27 / 02 A4459 / 25 / 02 A4459 / 26 / 02 2 tn Granule (%, w / w) Tablet (%, w / w) Tablet coated (%, w / w) Granule (%, w / w) Tablet (%, w / w) Table t coate d (%, w / w) Granule (%, w / w) Tablet (%, w / w) Table t coate d (%, w / w) Kollidon 30 1.154 0.652 0.652 1.154 0.652 0.652 1.154 0.652 0.652 Glycolys 4.615 2.608 2.608 4.615 2.608 2.608 4.615 2.608 2.608 Kolliphor SLS 1.154 0.652 0.652 1.154 0.652 0.652 1.154 0.652 0.652 MilliQ water* 20+5 N / A N / A 20+5 N / A N / A 20+5 N / A N / A Total Granule 100.000 56.521 56.521 100.000 56.521 56.521 100.000 56.521 56.521 Extra-granule Obicetrapib N / A 4.461 4.461 N / A 4.461 4.461 N / A 4.461 4.461 Avicel PH 200 N / A 25.974 25.974 N / A 23.118 23.118 N / A 22.757 22.757 Pearlitol 200 SD N / A 10.000 10.000 N / A 8.900 8.900 N / A 8.761 8.761 Glycolys N / A 2.174 2.174 N / A 5.000 5.000 N / A 5.000 5.000 Aerosil 200 N / A 0.435 0.435 N / A 1.000 1.000 N / A 1.000 1.000 Ligamed MF-2-V N / A 0.435 0.435 N / A 1.000 1.000 N / A 1.500 1.500 Opadry AMB II N / A N / A 3.000 N / A N / A 3.000 N / A N / A 3.000 Total tablet N / A 100.000 103.00 0 N / A 100.000 103.00 N / A 100.000 103.00 *Water does not appear in the final product. All excipients for granulation added as a dry powder Results

[0228] 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 characterization

[0229] 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

[0230] 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

[0231] 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 A4459 / 26 / 02 Prototype Prototype 1 Prototype 2 Prototype 3 Test Method Result Result Result Assay HPLC Obicetrapib (%claim) Ezetimibe (%claim) 2730 2731 97.6 102.1 96.8 102.7 95.6 101.0 Impurities IMPRRT0.94 (% claim) FROL(% claim) MONO-BN FREE(% claim) Total impurities of Obicetrapib > 0.05% Ezetimibe □ Ketone (% a / a) Ezetimibe tetrahydropyran analog (%a / a) Total impurities of Ezetimbe > 0.05% HPLC 2730 2730 2730 2730 2731 2731 2731 0.06 0.05 0.19 0.31 0.05 N.D. 0.05 0.06 0.05 0.16 0.27 0.05 N.D. 0.05 0.05 0.05 0.16 0.26 0.05 N.D. 0.05 Uniformity of dosage units Obicetrapib USP <905> Ph.Eur. 2.9.40 or JP 6.02 by UNIC / 1190 Average % Claim: 97.6 Range % Claim: (95.5-100.3) AV = 4.9 Average % Claim: 96.7 Range % Claim: (96.1 -97.4) AV = 2.9 Average % Claim: 96.4 Range % Claim: (95.2 - 98.2) AV = 4.7 Ezetimibe Average % Claim: 101.7 Range % Claim: (100.6- 103.1) AV = 2.2 Average % Claim: 102.3 Range % Claim: (101.0- 103.2) AV = 2.6 Average % Claim: 101.1 Range % Claim: (99.3 -103.1) AV = 2.9 Dissolution Obicetrapib 5 min Average (Min Max) 56 (51-62) 56 (51-61) 55 (50 - 57) 10 min Average (Min Max) 80 (73 - 86) 78 (74 - 79) 77 (76 - 78) 15 min Average (Min Max) Discriminating method at Ph 6.80.2 %w / v of 86 (77 - 92) 86 (84 - 89) 83 (82 - 86) 30 min Average (Min Max) Tween 80, 50 rpm paddle speed and 900 89 (81-97) 91 (89 - 92) 91 (87 - 93) 45 min Average (Min Max) Ml vessel volume 89 (80 - 96) 91 (88 - 92) 91 (88-93) 60 min Average (Min Max) 88 (80-95) 91 (89 - 92) 90 (88 - 92) 70 min Average (Min Max) 98 (95 - 100) 97 (96 - 89) 96 (95 - 97) Dissolution Ezetimibe 15 min Average (Min Max) 68 (61-71) - - 30 min Average (Min Max) Dissolution method based on USP method 76 (70 - 79) - - 45 min Average (Min Max) conditions at Ph 4.5, 50 rpm paddle speed and 79 (74-81) - - 60 min Average (Min Max) 500 Ml vessel volume 80 (75 - 83) - - 70 min Average (Min Max) 101 (100-101) - - Dissolution Ezetimibe 15 min Average (Min Max) Dissolution method based on USP method 88 (85 - 94) 85 (81-88) 82 (76 - 88) 30 min Average (Min Max) conditions at Ph 4.5, 75 rpm paddle speed and 94 (92-101) 94 (90 - 96) 90 (84 - 97) 45 min Average (Min Max) 500 Ml vessel volume 97 (94- 103) 97 (93 - 100) 93 (87-101) Table 16: Results of the analytical characterization of FDC2 - Uncoated Manufacturing lot number A4459 / 23 / 01 A4459 / 26 / 01 A4459 / 26 / 02 60 min Average (Min Max) 70 min Average (Min Max) 98 (95 - 104) 98 (94-101) 94 (88- 102) 103 (102- 105) 102 (101 - 104) 101 (99- 103) Water content KF 4.4 % w / w 4.3 % w / w 4.0 % w / w Table 17: Results of the analytical characterization of FDC2- Coated Manufacturing lot number A4459 / 27 / 01 A4459 / 27 / 02 A4459 / 27 / 03 Prototype Prototype 1 -Coated Prototype 2 Coated Prototype 3 Coated Test Method Result Result Result Assay HPLC Obicetrapib (%claim) Ezetimibe (%claim) 2730 2731 95.9 102.1 96.4 102.6 95.0 101.0 Impurities IMPRRT0.94 (% claim) FROL(% claim) MONO-BN FREE(% claim) Total impurities of Obicetrapib > 0.05% Ezetimibe □ Ketone (% a / a) Ezetimibe tetrahydropyran analog (%a / a) Total impurities of Ezetimbe > 0.05% HPLC 2730 2730 2730 2730 2731 2731 2731 0.06 0.05 0.16 0.27 < QL (0.05 %) N.D. < QL (0.05 %) 0.06 0.05 0.16 0.27 < QL (0.05 %) N.D. < QL (0.05 %) 0.06 0.05 0.16 0.27 < QL (0.05 %) N.D. < QL (0.05 %) Uniformity of dosage units Obicetrapib USP <905> Ph.Eur. 2.9.40 or JP 6.02 by UNIC / 1190 Average % Claim: 97.0 Range % Claim: (94.0-99.1) AV = 6.1 Average % Claim: 96.4 Range % Claim: (95.4 -97.8) AV = 4.0 Average % Claim: 95.2 Range % Claim: (93.2-96.1) AV = 5.5 Ezetimibe Average % Claim: 101.2 Range % Claim: (99.6 - 102.5) AV = 2.2 Average % Claim: 101.9 Range % Claim: (100.7- 102.9) AV = 2.2 Average % Claim: 101.0 Range % Claim: (99.6-102.3) AV = 1.7 Dissolution Obicetrapib 5 min Average (Min Max) 58 (43 - 66) 59 .........£51-631........ 57 (52-61) 10 min Average (Min Max) Discriminating method at Ph 6.8 + 0.2 %w / v of Tween 80, 50 rpm paddle speed and 900 Ml vessel volume 83 (76 - 86) 79 (77 - 83) 85 (82 - 87) 15 min Average (Min Max) 88 (84-91) 84 (82 - 90) 90 (87 - 93) 30 min Average (Min Max) 94 (91-96) 90 (87 - 97) 96 (92-101) 45 min Average (Min Max) 95 (91-99) 90 (88-98) 95 (91 - 102) 60 min Average (Min Max) 95 (91 - 102) 90 (90 - 98) 94 (91 - 100) 70 min Average (Min Max) 103 (100- 104) 97 (95 -98) 98 (97 - 99) Dissolution Obicetrapib 15 min Average (Min Max) Discriminating method at Ph 6.8+ 0.2 %w / v of Tween 80, 75 rpm paddle speed and 1000 Ml vessel volume 89 (87-91) 90 (88-92) 90 (87 - 93) 30 min Average (Min Max) 95 (94 - 96) 95 (94 - 97) 95 (92 - 97) 45 min Average (Min Max) 96 (95 - 98) 96 .........£95-971........ 96 (94 - 97) 60 min Average (Min Max) 97 (96 - 98) 96 .........£95-971........ 96 (94 - 97) 70 min Average (Min Max) 98 (95 - 100) 96 (94 - 98) 96 (95 - 98) Dissolution Ezetimibe Dissolution method based on USP method conditions at Ph 4.5, 75 rpm paddle speed and 500 Ml vessel volume 15 min Average (Min Max) 82 (76 - 89) 84 (78 - 90) 85 (76 - 88) 30 min Average (Min Max) 92 (85-101) 92 (87 - 97) 92 (86-95) 45 min Average (Min Max) 94 (87- 102) 95 (90 - 100) 95 (89 - 98) Table 17: Results of the analytical characterization of FDC2- Coated Manufacturing lot number A4459 / 27 / 01 A4459 / 27 / 02 A4459 / 27 / 03 60 min Average (Min Max) 70 min Average (Min Max) 95 (88- 103) 96 (92-101) 96 (90 - 99) 102 (101 - 104) 103 (102- 104) 102 (102- 103) Water content KF 4.0 % w / w 4.1 % w / w 4.0 % w / w Table 18: XRPD data summary of granules from FDC2 compositions Sample Batch ID XRPD Prototype 1 Final dry Granules A4459 / 20 / 01 OBI + EZE Anhydrous + small amount of EZE hydrate Prototype 2 Final dry Granules A4459 / 25 / 01 OBI + EZE Anhydrous Prototype 3 Final dry Granules A4459 / 25 / 02 OBI + EZE Anhydrous Table 19: XRPD data summary of tablets from FDC2 compositions Sample Batch ID XRPD Prototype 1 Tablet uncoated-coated A4459 / 23 / 01 / -A4459 / 27 / 01 OBI + EZE Anhydrous + small amount of EZE hydrate Prototype 2 Tablet uncoated-coated A4459 / 26 / 01- A4459 / 27 / 02 OBI + EZE Anhydrous Prototype 3 Tablet uncoated-coated A4459 / 26 / 02 - A4459 / 27 / 03 OBI + EZE Anhydrous Stress Stability Prototype 2 coated tablet was selected for the stress stability study with the following design Table 20: Stress stability study design Storage Conditions Time (weeks) T / RH Type 0 2 3 4 25°C / 60%RH Long-term T (T) - (T) 40°C / 75%RH uncovered Stress (T) T - T 40°C / 75%RH closed Accelerated (T) - (T) Key: T= Tested for appearance, assay & related substances, discriminating dissolution, water content by KF, and form check by XRPD (T)= Optional testing Results are reported in Tables 21-23. Table 21: Results for assay, water content and visual appearance of prototype 2 FDC2 stress stability Prototype No. Time point - Storage conditions Assay of Ezetimibe (% Claim) Assay of Obicetrapib (% Claim) Water content (% w / w) Appearance (visual) Prototype 2 BN A4459 / 28 / 02 Initial 102.7 96.4 4.1 White round tablet 2 weeks - 40°C / 75%RH exposed 101.2 95.8 4.6 White round tablets 4 weeks - 40°C / 75%RH exposed 102.1 94.6 5.1 White round tablet 4 weeks - 40°C / 75%RH packed 101.4 96.0 3.1 Not tested Table 22: Results for impurities profile of prototype 2 FDC2 stress stability Batch Time point -Storage conditions Obicetrapib related impurities Ezetimibe related impurities IMP R RT 0.94 (% claim) FRO L (% clai m) MON O-BN FREE (% claim) Total impuriti es (% claim) IMP R RT 0.73 (% a / a) IMP R RT 0.79 (% a / a) EZETIMI BE CYCLIC (% a / a) EZETIMI BE KETONE (% a / a) Total impuriti es (> 0.05) (% a / a) Prototype 2 BN A4459 / 28 / 02 Initial 0.06 0.05 0.16 0.27 N.D. 0.04 N.D 0.04 <QL 2 weeks - 40°C / 75% RH exposed 0.06 0.05 0.16 0.26 N.D. 0.05 N.D. 0.06 0.11 4 weeks - 40°C / 75% RH exposed 0.05 0.05 0.16 0.26 N.D. 0.05 0.06 0.07 0.18 4 weeks -40°C / 75% RH packed 0.06 0.06 0.16 0.28 < QL (0.05%) 0.03 0.05 0.07 0.12 N.D. = Not Detected Table 23: Results of the dissolution characterization of prototype 2 FDC2 stress stability Manufacturing lot number Prototy pe 2 BN A4459 / 28 / 02 Time point and storage conditions Initial 2 weeks - 40°C / 75%RH exposed 4 weeks - 40°C / 75%RH exposed 4 weeks -40°C / 75%RH packed Test Method Result Result Result Obicetrapib Discriminating method at pH 6.80.2 %w / v of Tween 80, 50 rpm paddle speed and 900 mL vessel volume (n=6) (n=6) 51 (45 -53) 71 (68 - 74) 78 (76-81) 86 (84 - 89) 87 (85 - 89) 87 (84 - 90) 97 (95 - 97) (n=6) 5 min Average (Min Max) 10 min Average (Min Max) 15 min Averag (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 59 (51-63) 57 (55 -65) 52 (47 - 57) 79 (77 - 83) 77 (74-81) 80 (78 - 83) 84 (82 - 90) 83 (80 - 88) 88 (87 - 89) 90 (87 - 97) 89 (86-93) 94 (91-96) 90 (88-98) 89 (87 - 92) 93 (87 - 92) 60 min Average (Min Max) 90 (90 - 98) 89 (88-93) 91 (88-93) 70 min Average (Min Max) 97 (95 - 98) 97 (96 - 98) 97 (96 - 98) Time point and storage conditions Initial 2 weeks - 40°C / 75%RH exposed 4 weeks - 40°C / 75%RH exposed 4 weeks -40°C / 75%RH packed Ezetimibe Dissolution method based on USP method conditions at pH 4.5, 75 rpm paddle speed and 500 mL vessel volume (n = 3) (n=6) (n=6) 69 (66 - 73) 81 (77 - 84) 86 (83 - 89) 89 (86-91) 99 (97 - 100) (n=6) (n=6) 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 min Average (Min Max) 70 min Average (Min Max) 84 (78 - 90) 72 (66 - 76) 78 (64 - 87) 92 (87 - 97) 86 (81-90) 90 (79 - 98) 95 (90 - 100) 92 (87 - 96) 94 (85-101) 96 (92-101) 96 (90-101) 96 (88- 102) 103 (102104) 102 (100- 104) 103 (101 - 106) Example 3: Scale-up of FDC1 and FDC2 compositions High shear granulation, drying, iinal blend, tableting and coating

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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 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.

[0236] 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 scale-up trials Component Scale-Up - FDC2 Scale-Up FDC1 A4459 / 29 / 04 A4459 / 29 / 05 A4459 / 29 / 01 A4459 / 29 / 02 Granule (%, w / w) T ablet (%, w / w) Coated tablet (%, w / w) Granule (%, w / w) T ablet (%, w / w) Coated Tablet (%, w / w) Intra-granular Ezetimibe 7.692 4.348 4.348 7.018 6.667 6.667 Obicetrapib N / A N / A N / A 7.200 6.840 6.840 Avicel PH 101 23.614 13.347 13.347 21.950 20.853 20.853 Pharmatose 200 M 61.771 34.914 34.914 57.516 54.640 54.640 KoUidon 30 1.154 0.652 0.652 1.053 1.000 1.000 Glycolys 4.615 2.608 2.608 4.210 4.000 4.000 KoUiphor SLS 1.154 0.652 0.652 1.053 1.000 1.000 Purified Water* 20.000 + 5.000 + 5.000 N / A N / A 20.000 + 5.000 + 5.000 N / A N / A Total Granule 100.000 56.521 56.521 100.000 95.000 95.000 Extra-granular Obicetrapib N / A 4.461 4.461 N / A N / A N / A Avicel PH 200 N / A 23.118 23.118 N / A N / A N / A Pearlitol 200 SD N / A 8.900 8.900 N / A N / A N / A Glycolys N / A 5.000 5.000 N / A 4.000 4.000 Aerosil 200 N / A 1.000 1.000 N / A N / A N / A Ligamed MF-2-V N / A 1.000 1.000 N / A 1.000 1.000 Opadry AMB II N / A N / A 3.000 N / A N / A 3.000 Total Tablet N / A 100.000 103.000 N / A 100.000 103.000 * Water does not appear in the final product. The excipient used in the granulation were adder as a dry powder Results

[0237] 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

[0238] 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

[0239] 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

[0240] 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 up batches Manufacturing lot number A4459 / 29 / 01 A4459 / 29 / 05 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) Test Method Result Result Impurities IMPRRT0.79 (% a / a) Ezetimibe!Ketone (% a / a) Ezetimibe tetrahydropyran analog (%a / a) Total impurities of Ezetimbe > 0.05% HPLC 2731 2731 2731 2731 < QL (0.05%) 0.05 N.D. 0.05 0.05 0.05 N.D. 0.10 Dissolution Obicetrapib Discriminating method at pH 6.80.2 %w / v of Tween 80, 50 rpm paddle speed and 900 mL vessel volume 5 min Average (Min Max) 10 min Average (Min Max) 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 85 (78-95) - 93 (90-95) - 96 (94 - 98) - 97 (95 - 99) - 98 (95 - 100) - 60 min Average (Min Max) 97 (94 - 99) - 70 min Average (Min Max) 97 (94 - 99) - Dissolution Ezetimibe Dissolution method based on USP method conditions at pH 4.5, 75 rpm paddle speed and 500 mL vessel volume 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 min Average (Min Max) 70 min Average (Min Max) 89 (87 - 94) 90 (87-91) 94 (91-99) 99 (96-101) 94 (91 - 100) 101 (98- 103) 95 (92 - 100) 102 (99- 105) 95 (93 - 100) 105 (102- 106) Table 26: Results of the analytical characterization of scale up batches - Uncoated Manufacturing lot number A4459 / 29 / 02 A4459 / 29 / 05 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) Test Method Result Result Uniformity of dosage units USP <905> Table 26: Results of the analytical characterization of scale up batches - Uncoated Manufacturing lot number A4459 / 29 / 02 A4459 / 29 / 05 Obicetrapib Ph.Eur. 2.9.40 or JP 6.02 by UNIC / 1190 Average % Claim: 99.3 Range % Claim: (98.0100.1) AV = 1.6 Average % Claim: 97.0 Range % Claim: (94.0 -99.1) AV = 6.1 Ezetimibe Average % Claim: 102.5 Range % Claim: (100.3 -103.9) AV = 3.2 Average % Claim: 96.4 Range % Claim: (95.4 - 97.8) AV = 4.0 Water content KF 4.6 % w / w 4.3 % w / w Table 27: Ezetimibe dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) at different compression forces Tablet at 4.5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 93.0 93.8 93.5 93.9 95.4 95.5 94.2 1.1 30 102.4 101.8 101.2 101.3 103.4 103.6 102.3 1.0 45 104.9 103.6 103.5 103.4 105.3 105.5 104.4 0.9 60 104.7 103.7 103.8 104.1 105.7 105.4 104.6 0.8 70 105.2 104.0 104.6 104.5 105.9 105.7 105.0 0.7 Tablet at 12.5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 85.0 84.8 86.7 87.9 88.7 90.2 94.2 2.4 30 99.7 99.4 98.8 101.7 99.8 102.3 102.3 1.4 45 103.0 103.5 102.4 104.8 103.3 105.5 104.4 1.1 60 105.0 105.1 104.6 106.6 104.3 106.5 104.6 0.9 70 105.2 105.6 105.1 106.8 105.2 107.7 105.0 1.0 Tablet at 18.5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 80.5 82.5 87.4 88.1 85.6 87.1 87.2 2.4 30 99.0 99.3 101.1 101.8 100.5 101.4 100.3 1.4 45 103.5 104.7 106.0 106.5 104.2 107.3 105.4 1.4 60 104.8 105.2 106.7 107.9 105.3 107.4 106.2 1.2 70 106.6 106.5 107.9 108.4 106.8 108.6 107.4 0.9 Table 28: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) at different compression forces Tablet at 4,5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 60.8 61.0 73.4 74.6 72.6 73.5 69.3 9.4 10 94.1 96.0 98.1 97.3 91.5 95.4 95.4 2.5 15 101.0 103.0 102.6 100.5 96.8 99.0 100.5 2.3 30 102.3 103.3 103.6 102.6 98.5 100.2 101.7 1.9 45 99.1 101.1 101.2 100.9 97.8 98.2 99.7 1.5 60 99.7 99.6 100.0 98.8 97.1 97.6 98.8 1.2 70 104.6 96.9 100.1 99.8 98.4 97.4 99.5 2.8 Tablet at 12,5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 31.7 33.0 41.0 43.4 45.6 43.4 39.7 14.8 10 74.2 76.8 78.9 81.6 83.1 80.1 79.1 4.1 Table 28: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) at different compression forces Tablet at 4,5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 95.3 90.8 93.0 94.0 94.0 93.5 93.4 1.6 30 103.5 98.8 104.1 99.2 99.4 98.6 100.6 2.5 45 100.5 98.7 101.7 98.0 97.7 98.8 99.2 1.6 60 100.5 100.1 101.1 96.9 98.9 99.3 99.5 1.5 70 97.9 97.7 100.9 98.0 98.6 98.7 98.7 1.2 Tablet at 12,5KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 31.7 33.0 41.0 43.4 45.6 43.4 39.7 14.8 10 74.2 76.8 78.9 81.6 83.1 80.1 79.1 4.1 15 95.3 90.8 93.0 94.0 94.0 93.5 93.4 1.6 30 103.5 98.8 104.1 99.2 99.4 98.6 100.6 2.5 45 100.5 98.7 101.7 98.0 97.7 98.8 99.2 1.6 60 100.5 100.1 101.1 96.9 98.9 99.3 99.5 1.5 70 97.9 97.7 100.9 98.0 98.6 98.7 98.7 1.2 Table 29: Ezetimibe dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) at different compression forces T ablet at 5 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 80.4 81.5 88.9 80.3 85.6 84.0 83.4 4.1 30 91.2 90.7 98.5 89.3 94.5 92.4 92.8 3.6 45 95.2 94.5 102.2 92.5 97.8 95.9 96.3 3.5 60 96.9 96.1 103.4 94.1 99.1 97.2 97.8 3.3 70 104.2 103.9 104.9 99.0 104.0 103.1 103.2 2.1 Tablet at 10 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 81.9 79.2 82.9 82.9 79.6 76.2 80.5 3.3 30 92.3 89.4 94.5 93.2 91.4 87.5 91.4 2.8 45 96.6 94.0 98.8 96.8 95.4 92.2 95.6 2.4 60 98.3 95.6 100.9 98.9 98.1 93.9 97.6 2.6 70 101.2 102.0 103.7 103.0 102.5 101.4 102.3 0.9 Tablet at 20 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 62.8 64.5 73.0 73.0 79.6 68.4 70.2 8.9 30 84.4 84.4 89.1 87.8 92.5 87.8 87.7 3.5 45 90.1 90.8 95.0 93.1 96.7 92.4 93.0 2.7 60 93.1 94.1 97.8 96.1 98.8 95.7 95.9 2.2 70 102.7 102.6 102.9 104.0 104.8 102.2 103.2 1.0 Table 30: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) at different compression forces T ablet at 5 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 57.7 60.1 64.5 64.5 65.1 74.2 64.3 8.8 10 78.4 77.5 80.1 78.4 79.2 88.2 80.3 4.9 15 83.7 82.0 83.3 81.9 82.7 90.6 84.0 3.9 30 86.7 84.4 86.3 83.5 85.6 92.7 86.5 3.8 45 88.1 85.5 89.7 83.8 92.2 92.5 88.6 4.0 60 88.2 85.8 89.8 84.1 87.3 93.9 88.2 3.9 70 94.8 93.9 93.9 90.5 94.5 96.2 94.0 2.0 Tablet at 10 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 56.5 56.6 62.2 62.0 66.0 70.2 62.2 8.6 10 75.1 75.0 75.8 76.1 78.4 81.9 77.0 3.4 15 81.7 79.2 80.6 80.7 87.3 86.8 82.7 4.2 30 87.9 85.1 84.2 84.2 92.4 88.9 87.1 3.7 45 88.1 87.7 85.9 85.3 93.8 89.4 88.4 3.5 60 89.5 88.7 86.4 86.5 94.6 90.5 89.4 3.4 70 94.5 94.4 94.1 94.4 95.3 95.5 94.7 0.6 Tablet at 20 KN Table 30: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) at different compression forces T ablet at 5 KN Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD Time (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 56.5 56.6 62.2 62.0 66.0 70.2 62.2 8.6 10 75.1 75.0 75.8 76.1 78.4 81.9 77.0 3.4 15 81.7 79.2 80.6 80.7 87.3 86.8 82.7 4.2 30 87.9 85.1 84.2 84.2 92.4 88.9 87.1 3.7 45 88.1 87.7 85.9 85.3 93.8 89.4 88.4 3.5 60 89.5 88.7 86.4 86.5 94.6 90.5 89.4 3.4 70 94.5 94.4 94.1 94.4 95.3 95.5 94.7 0.6 Table 31: Results of the analytical characterization of scale up batches lOmg ezetimibe 10 mg obicetrapib - Coated Manufacturing lot number A4459 / 29 / 03 A4459 / 29 / 06 Prototype FDC 1 Coated FDC 2 Coated Test Method Result Result Appearance Visual White round coated tablets White round coated tablets Assay Obicetrapib (%claim) Ezetimibe (%claim) HPLC 2730 2731 98.3 101.3 96.9 101.6 Impurities IMPRRT0.94 (% claim) FROL(% claim) MONO-BN FREE(% claim) Total impurities of Obicetrapib > 0.05% IMPRRT0.79 (% a / a) Ezetimibe!Ketone (% a / a) Ezetimibe tetrahydropyran analog (%a / a) Total impurities of Ezetimbe > 0.05% HPLC 2730 2730 2730 2730 2731 2731 2731 2731 0.06 0.07 0.16 0.29 0.05 0.05 N.D. 0.10 0.06 0.06 0.16 0.28 0.05 0.05 N.D. 0.10 Dissolution Obicetrapib Discriminating method at pH 6.80.2 %w / v of Tween 80, 50 rpm paddle speed and 900 mL vessel volume 53 (38-60) 89 (84 - 93) 100 (97- 106) 108 (103-112) 106 (103-111) 103 (101 - 106) 102 (101 - 104) 5 min Average (Min Max) 10 min Average (Min Max) 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 (56-66) 84 (80 - 90) 90 (87 - 97) 98 (95 - 103) 98 (95 - 102) 60 min Average (Min Max) 97 (94 - 102) 70 min Average (Min Max) 98 (96-101) Dissolution Ezetimibe Dissolution method based on USP method conditions at pH 4.5, 75 rpm paddle speed and 500 mL vessel volume 87 (75-91) 100 (98-101) 103 (102- 105) 104 (103- 106) 106 (105- 107) 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 min Average (Min Max) 70 min Average (Min Max) 84 (76 - 87) 94 (87-98) 98 (92-101) 99 (94 - 102) 104 (102- 106) Water content KF 4.5 % w / w 4.2 % w / w Table 32: XRPD data summary of granules / tablets from scale up batch Sample Batch ID XRPD FDCl (INTRA-INTRA) Granules A4459 / 29 / 01 OBI + EZE Anhydrous FDC1 (INTRA-INTRA) Tablet uncoated - coated A4459 / 29 / 02 - A4459 / 29 / 03 OBI + EZE Anhydrous FDC2 (INTRA-EXTRA) Granules A4459 / 29 / 04 OBI + EZE Anhydrous | FDC2 (INTRA- EXTRA) Tablet uncoated - coated | A4459 / 29 / 05- A4459 / 29 / 06        | OBI + EZE Anhydrous | Example 4; Technical batches of FDC1 and FDC2 compositions

[0241] 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

[0242] 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. Final Blend and tableting

[0243] 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.

[0244] 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

[0245] 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.

[0246] 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 and FDC2 technical batches Component FDC2 (ezeetimibe intra - obicetrapib extra) FDC1 (ezetimibe intra — obicetrapib intra) A4459 / 30 / 0 1 A4459 / 31 / 01 A4459 / 30 / 0 2 A4459 / 31 / 02 Granule (%, w / w) T ablet (%, w / w) Table t (mg) Coated T ablet (%, w / w) Coate d tablet (mg) Granule (%, w / w) T ablet (%, w / w) Table t (mg) Tablet (%, w / w) Coate d tablet (mg) Intra-granule Ezetimibe 7.692 4.348 10.00 4.348 10.00 7.018 6.667 10.00 6.667 10.00 Obicetrapib N / A N / A N / A N / A N / A 7.200 6.840 10.26 6.840 10.26 Avicel PH 101 23.614 13.347 30.70 13.347 30.70 21.950 20.853 31.28 20.853 31.28 Pharmatose 200 M 61.771 34.914 80.30 34.914 80.30 57.516 54.640 81.96 54.640 81.96 KolUdon 30 1.154 0.652 1.50 0.652 1.50 1.053 1.000 1.50 1.000 1.50 Glycolys 4.615 2.608 6.00 2.608 6.00 4.210 4.000 6.00 4.000 6.00 KolUphor SLS 1.154 0.652 1.50 0.652 1.50 1.053 1.000 1.50 1.000 1.50 Purified Water 30.000 N / A N / A N / A N / A 30.000 N / A N / A N / A N / A T otal Granule 100.000 56.521 130.0 0 56.521 130.00 100.000 95.000 142.5 0 95.000 142.50 Extra-granule Obicetrapib N / A 4.461 10.26 4.461 10.26 N / A N / A N / A N / A N / A Avicel PH 200 N / A 23.118 53.17 23.118 53.17 N / A N / A N / A N / A N / A Pearlltol 200 SD N / A 8.900 20.47 8.900 20.47 N / A N / A N / A N / A N / A Glycolys N / A 5.000 11.50 5.000 11.50 N / A 4.000 6.00 4.000 6.00 Aerosil 200 N / A 1.000 2.30 1.000 2.30 N / A N / A N / A N / A N / A Ligamed MF-2-V N / A 1.000 2.30 1.000 2.30 N / A 1.000 1.50 1.000 1.50 Opadry AMB II N / A N / A N / A 3.000 6.90 N / A N / A N / A 3.000 4.50 Total Tablet N / A 100.000 230.0 0 103.00 0 236.90 N / A 100.000 150.0 0 103.00 0 154.50 Results: Technical batches ofFDCl andFDC2 compositions

[0247] 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 pm was ca. 70 % - 73 %) (FIG. 20). No relevant differences were observed in comparison to the scale-up batches.

[0248] 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, the time of disintegration between these batches was very similar for a given value of tablet hardness. Granules chemical characterization

[0249] 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

[0250] 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

[0251] 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

[0252] 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 Manufacturing lot number A4459 / 31 / 02 A4459 / 31 / 01 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) Test Method Result Result Appearance Visual White round coated tablet White round coated tablet Assay Obicetrapib (%claim) Ezetimibe (%claim) HPLC 2730 2731 96.8 100.8 94.3 100.7 Impurities IMPRRT0.93 (% claim) IMPRRT0.94 (% claim) FROL(% claim) MONO-BN FREE(% claim) Total impurities of Obicetrapib > 0.05% IMPRRT0.73 (% a / a) IMPRRT0.79 (% a / a) Ezetimibe!Ketone (% a / a) Ezetimibe tetrahydropyran analog (%a / a) Total impurities of Ezetimbe > 0.05% HPLC 2730 2730 2730 2730 2730 2731 2731 2731 2731 2731 0.07 N.D 0.11 0.15 0.33 N.D. 0.05 0.05 N.D. 0.10 < QL (0.05 %) 0.05 0.06 0.16 0.26 N.D. < QL (0.05 %) 0.05 N.D. 0.05 Uniformity of dosage units Obicetrapib USP <905> Ph.Eur. 2.9.40 or JP 6.02 by UNIC / 1190 Average % Claim: 98.3 Range % Claim: (97.1 -100.4) AV = 2.4 Average % Claim: 96.1 Range % Claim: (93.9 - 99.0) AV = 4.0 Ezetimibe Average % Claim: 100.8 Range % Claim: (99.3 -101.5) AV = 2.4 Average % Claim: 99.2 Range % Claim: (97.7 - 101.5) AV = 2.7 Dissolution Obicetrapib 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) Medium pH 6.8+ 0.2 %w / v of Tween 80, 75 rpm paddle speed and 1000 mL vessel volume 90 (89 - 92) 85 (82 - 86) 96 (94 - 97) 93 (92 - 94) 97 (95 -98) 95 (93 - 96) 60 min Average (Min Max) 97 (96 - 98) 95 (94 - 97) 70 min Average (Min Max) 97 (96 - 98) 96 (94 - 97) Dissolution Ezetimibe Dissolution method based on USP method conditions at pH 4.5, 75 rpm paddle speed and 500 mL vessel volume 15 min Average (Min Max) 30 min Average (Min Max) 45 min Average (Min Max) 60 min Average (Min Max) 70 min Average (Min Max) 84 (82 - 87) 81 (72 - 83) 96 (93 - 99) 92 (88 - 94) 99 (97- 103) 96 (95 - 97) 102 (99- 105) 98 (97 - 99) 104 (101 - 107) 102 (101 - 104) Water content KF 4.0 % w / w 3.7 % w / w Table 35: XRPD data summary of granules / tablets from technical batches Sample Batch ID XRPD FDC2 (INTRA-EXTRA) Granules A4459 / 30 / 01 OBI + EZE Anhydrous + small amount EZE hydrate FDC2 (INTRA- EXTRA) Tablet coated A4459 / 31 / 01 OBI + EZE Anhydrous FDC1 (INTRA-INTRA) Granules A4459 / 30 / 02 OBI + EZE Anhydrous FDC1 (INTRA- INTRA) Tablet coated A4459 / 31 / 02 OBI + EZE Anhydrous Table 36: PSD data summary of granules from technical batches DvlO( xlO) Dv50 (x50) Dv90 (x90) Span Granules FDC2 A4459 / 30 / 01 38.70 87.20 184.73 1.67 Granules FDC1 A4459 / 30 / 02 34.17 82.42 275.71 2.92 Table 37: Long-term and accelerated storage stability results for FDC2 technical batch no. A4459 / 31 / 01 (without desiccant) Storage Condition Time (Months ) Appearan. / Colou r APP / 1001 (Individual) OBICETRAPI B (TA-8995) Amount HPLC / 2730 (% claim) (Mean) DIASTEREOISOME R Amount HPLC / 2730 (% claim) (Mean) ETHYL ESTER Amount HPLC / 273 0 (% claim) (Mean) FROL Amount HPLC / 273 0 (% claim) (Mean) MONO BN FREE Amount HPLC / 273 0 (% claim) (Mean) Specificatio n N / A White to off-white     round coated tablet 90.0-110.0% claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim Initial 0 White    round coated tablet 94.3 <0.05 <0.05 0.06 0.16 25°C / 60% RH Packaged 1 White    round coated tablet 96.7 <0.05 <0.05 0.07 0.16 3 White    round coated tablet 95.5 <0.05 <0.05 0.07 0.16 30°C / 65% RH Packaged 1 White    round coated tablet 95.6 <0.05 <0.05 0.07 0.16 40°C / 75% RH Packaged 1 White    round coated tablet 95.5 <0.05 <0.05 0.07 0.16 3 White    round coated tablet 95.3 <0.05 <0.05 0.07 0.16 Table 37(Contd.) Storage Condition Time (Months) IMPRRT0.93 Amount HPLC / 2730 (% claim) (Mean) IMPRRT0.94 Amount HPLC / 2730 (% claim) (Mean) Total degradation products equal / greater than 0.05% claim (% claim) (Mean) EZETIMIBE Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE CYCLIC Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE KETONE Amount HPLC / 2731 (% claim) (Mean) Specification N / A NGT 0.3 % claim NGT 0.3 % claim NGT 2.0 % claim 90.0-110.0% claim NGT 0.5 % claim NGT 0.5 % claim Initial 0 <0.05 0.05 0.26 100.7 <0.05 0.05 25°C / 60% RH Packaged 1 <0.05 <0.05 0.23 103.0 <0.05 0.05 3 <0.05 0.06 0.29 103.2 <0.05 <0.05 30°C / 65% RH Packaged 1 <0.05 <0.05 0.23 102.2 <0.05 0.05 40°C / 75% RH Packaged 1 <0.05 <0.05 0.23 101.6 <0.05 0.06 3 <0.05 0.07 0.30 103.1 <0.05 0.05 Table 37(contd.) Storage Condition Time (Months) IMPRRT0.73 Amount HPLC / 2731 (% claim) (Mean) IMPRRT0.79 Amount HPLC / 2731 (%claim) (Mean) IMP_RRT3.11 Amount HPLC / 2731 (%claim) (Mean) Total degradation products greater / equal than 0.05% claim (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Specification N / A NGT 0.5 % claim NGT 0.5 % claim NGT 0.5 % claim NGT 2.0 % claim Report result Report result Initial 0 <0.05 <0.05 - 0.05 85 82-86 25°C / 60% RH Packaged 1 <0.05 0.05 <0.05 0.10 85 80-91 3 <0.05 0.05 <0.05 0.05 87 85-95 30°C / 65% RH Packaged 1 <0.05 0.05 <0.05 0.10 89 87-91 1 <0.05 0.05 <0.05 0.10 85 84-88 Storage Condition Time (Months) IMPRRT0.73 Amount HPLC / 2731 (% claim) (Mean) IMPRRT0.79 Amount HPLC / 2731 (%claim) (Mean) IMP_RRT3.11 Amount HPLC / 2731 (%claim) (Mean) Total degradation products greater / equal than 0.05% claim (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Specification N / A NGT 0.5 % claim NGT 0.5 % claim NGT 0.5 % claim NGT 2.0 % claim Report result Report result 40°C / 75% RH Packaged 3 <0.05 0.05 <0.05 0.10 85 83-88 Table 37(contd.) Storage Condition Time (Months ) Time point(min) 30 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 30 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Specificatio n N / A Report result Report result Complies with EP, USP, JP where Q = 75% at 45 minutes Report result Report result Report result Initial 0 93 92-94 95 93-96 95 94-97 25°C / 60% RH Packaged 1 98 94-104 98 94-104 99 95 - 104 3 96 94-98 98 96-99 97 96 - 100 30°C / 65% RH Packaged 1 99 97-101 99 97-101 100 97-102 40°C / 75% RH Packaged 1 95 93-98 96 94-99 97 95 - 100 3 95 93-97 97 95-99 97 94-98 Table 37(contd.) Storage Condition Time (Months) Time point(min) 70 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 70 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Range) Specification N / A Report result Report result Report result Report result Report result Report result Initial 0 96 94-97 81 72-83 92 88-94 25°C / 60% RH 1 99 96 - 104 79 65-87 95 87-101 Packaged 3 97 96 - 100 85 82-88 95 92 - 100 30°C / 65% RH Packaged 1 100 97-102 88 86-90 95 93-97 40°C / 75% RH 1 97 95 - 100 80 58-88 91 74-97 Packaged 3 97 94-99 80 75-84 93 90-94 Table 37(contd.) Storage Condition Time (Months) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Range) Specification N / A Complies with     EP, USP,     JP where Q = 75% at 45 minutes Report result Report result Report result Report result Report result Initial 0 96 95-97 98 97-99 102 101 - 104 25°C / 60% RH Packaged 1 99 94-105 99 96 - 103 106 103-108 3 98 95 - 103 100 96-105 103 100-105 30°C / 65% RH Packaged 1 98 96-101 99 97-102 103 100-105 40°C / 75% RH Packaged 1 94 79-101 97 82 - 102 104 101 - 106 3 98 97-101 101 101 - 104 105 102-107 Table 37(contd.) Storage Condition Time (Months) Water content UMID / 1231 (% w / w) (Mean) Strength RESR / 1001 (N) (Mean) Strength RESR / 1001 (N) (Range) Strength RESR / 1001 (Kp) (Mean) Strength RESR / 1001 (Kp) (Range) Specification N / A Report Results Report Results Report Results Report Results Report Results Initial 0 3.7 92 81-99 9.36 8.26-10.10 25°C / 60%     RH Packaged 1 3.8 109 98-123 11.15 9.99-12.54 3 4.1 116 104-124 11.81 10.61 - 12.64 30°C / 65%     RH Packaged 1 4.0 109 97-128 11.09 9.89-13.05 40°C / 75%     RH Packaged 1 4.2 100 95-105 10.22 9.69-10.71 3 4.8 93 84-107 9.45 8.57-10.91 N / A: Not Applicable Table 38: Long-term and accelerated storage stability results for FDC1 technical batch no. A4459 / 31 / 02 (without desiccant) Storage Condition Time (Months ) Appearan. / Colou r APP / 1001 (Individual) OBICETRAPI B (TA-8995) Amount HPLC / 2730 (% claim) (Mean) DIASTEREOISOME R Amount HPLC / 2730 (% claim) (Mean) ETHYL ESTER Amount HPLC / 273 0 (% claim) (Mean) FROL Amount HPLC / 273 0 (% claim) (Mean) MONO BN FREE Amount HPLC / 273 0 (% claim) (Mean) Specificatio n N / A White to off-white     round coated tablet 90.0-110.0% claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim Initial 0 White    round coated tablet 96.7 <0.05 <0.05 0.11 0.15 25°C / 60% RH Packaged 1 White    round coated tablet 97.7 <0.05 <0.05 0.11 0.16 3 White    round coated tablet 98.4 <0.05 <0.05 0.11 0.16 30°C / 65% RH Packaged 1 White    round coated tablet 97.7 <0.05 <0.05 0.11 0.16 40°C / 75% RH Packaged 1 White    round coated tablet 97.4 <0.05 <0.05 0.12 0.16 3 White    round coated tablet 98.2 <0.05 <0.05 0.11 0.16 Table 38(contd.) Storage Condition Time (Months) IMPRRT0.93 Amount HPLC / 2730 (% claim) (Mean) IMPRRT0.94 Amount HPLC / 2730 (% claim) (Mean) Total degradation products equal / greater than 0.05% claim (% claim) (Mean) EZETIMIBE Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE CYCLIC Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE KETONE Amount HPLC / 2731 (%claim) (Mean) Specification N / A NGT 0.3 % claim NGT 0.3 % claim NGT 2.0 % claim 90.0-110.0% claim NGT 0.5 % claim NGT 0.5 % claim Initial 0 0.07 <0.05 0.33 100.8 <0.05 0.05 25°C / 60% RH Packaged 1 0.07 <0.05 0.35 102.6 <0.05 0.05 3 0.06 <0.05 0.33 104.0 <0.05 <0.05 30°C / 65% RH Packaged 1 0.07 <0.05 0.35 103.1 <0.05 0.05 40°C / 75% RH Packaged 1 0.07 <0.05 0.34 103.6 <0.05 0.05 3 0.07 <0.05 0.34 104.3 <0.05 <0.05 Table 38(contd.) Storage Condition Time (Months) IMPRRT0.73 Amount HPLC / 2731 (% claim) (Mean) IMPRRT0.79 Amount HPLC / 2731 (%claim) (Mean) IMP_RRT3.11 Amount HPLC / 2731 (%claim) (Mean) Total degradation products greater / equal than 0.05% claim (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Specification N / A NGT 0.5 % claim NGT 0.5 % claim NGT 0.5 % claim NGT 2.0 % claim Report result Report result Initial 0 <0.05 0.05 - 0.10 90 89-92 25°C / 60% RH 1 <0.05 0.05 <0.05 0.10 94 93-95 Packaged 3 <0.05 0.05 <0.05 0.05 91 90-95 30°C / 65% RH Packaged 1 <0.05 0.05 <0.05 0.10 94 93-95 Storage Condition Time (Months) IMPRRT0.73 Amount HPLC / 2731 (% claim) (Mean) IMPRRT0.79 Amount HPLC / 2731 (%claim) (Mean) IMP_RRT3.11 Amount HPLC / 2731 (%claim) (Mean) Total degradation products greater / equal than 0.05% claim (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Specification N / A NGT 0.5 % claim NGT 0.5 % claim NGT 0.5 % claim NGT 2.0 % claim Report result Report result 40°C / 75% RH 1 <0.05 0.05 <0.05 0.10 93 91-94 Packaged 3 <0.05 0.05 <0.05 0.05 90 89-91 Table 38(contd.) Storage Condition Time (Months ) Time point(min) 30 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 30 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Specificatio n N / A Report results Report results Complies with EP, USP, JP where Q = 75% at 45 minutes Report results Report results Report results Initial 0 96 94-97 97 95-98 97 96-98 25°C / 60% RH Packaged 1 99 97-100 99 99 - 100 99 98-101 3 100 97-102 101 97-108 99 97-102 30°C / 65% RH Packaged 1 100 97-103 100 98-101 100 98-101 40°C / 75% RH Packaged 1 99 98-100 100 98-101 100 98-101 3 99 97-101 99 98-101 99 98-101 Table 38(contd.) Storage Condition Time (Months) Time point(min) 70 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 70 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Range) Specification N / A Report result Report result Report result Report result Report result Report result Initial 0 97 96-98 84 82-87 96 93-99 25°C / 60% RH 1 99 98-101 85 73-89 98 97-100 Packaged 3 99 96-101 89 85-91 99 94-101 30°C / 65% RH Packaged 1 100 98-101 89 83-93 96 91 - 100 40°C / 75% RH 1 100 99-101 90 87-91 98 96 - 100 Packaged 3 99 98-101 86 81-90 98 92 - 102 Table 38(contd.) Storage Condition Time (Months) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Range) Specification N / A Complies with     EP, USP,     JP where Q = 75% at 45 minutes Report result Report result Report result Report result Report result Initial 0 99 97-103 102 99-105 104 101 - 107 25°C / 60% RH Packaged 1 104 103-105 105 104-107 107 105-109 3 103 98-105 105 100-106 106 102-107 30°C / 65% RH Packaged 1 98 94-103 101 96-105 104 102-107 40°C / 75% RH Packaged 1 101 98-103 103 100-104 105 103-107 3 102 96 - 107 104 98-108 106 102-109 Table 38(contd.) Storage Condition Time (Months) Water content UMID / 1231 (% w / w) (Mean) Strength RESR / 1001 (N) (Mean) Strength RESR / 1001 (N) (Range) Strength RESR / 1001 (Kp) (Mean) Strength RESR / 1001 (Kp) (Range) Specification NA Report result Report result Report result Report result Report result Initial 0 4.0 - - - - 25°C / 60%     RH Packaged 1 4.2 74 70-76 7.58 7.14-7.75 3 4.6 70 66-78 7.17 6.73-7.95 30°C / 65%     RH Packaged 1 4.4 73 70-77 7.46 7.14-7.85 40°C / 75%     RH Packaged 1 4.8 65 61-69 6.62 6.22-7.04 3 5.5 60 57-63 6.10 5.81-6.42 N / A: Not Applicable Table 39: Long-term and accelerated storage condition results for FDC2 technical batch no A4459 / 31 / 01 (with desiccant! Storage Condition Time (Months ) Appearan. / Colou r APP / 1001 (Individual) OBICETRAPI B (TA-8995) Amount HPLC / 2730 (% claim) (Mean) DIASTEREOISOME R Amount HPLC / 2730 (% claim) (Mean) ETHYL ESTER Amount HPLC / 273 0 (% claim) (Mean) FROL Amount HPLC / 273 0 (% claim) (Mean) MONO BN FREE Amount HPLC / 273 0 (% claim) (Mean) Specificatio n White to off-white     round coated tablet 90.0-110.0 % claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim Initial 0 White    round coated tablet 94.3 <0.05 <0.05 0.06 0.16 25°C / 60% RH Packaged 3 White    round coated tablet 96.4 <0.05 <0.05 0.07 0.16 40°C / 75% RH Packaged 3 White    round coated tablet 96.3 <0.05 <0.05 0.07 0.16 Table 39(contd.) Storage Condition Time (Months) IMPRRT0.93 Amount HPLC / 2730 (% claim) (Mean) IMPRRT0.94 Amount HPLC / 2730 (% claim) (Mean) Total degradation products equal / greater than 0.05% claim (% claim) (Mean) EZETIMIBE Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE CYCLIC Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE KETONE Amount HPLC / 2731 (% claim) (Mean) Specification NGT 0.3 % claim NGT 0.3 % claim NGT 2.0 % claim 90.0-110.0 % claim NGT 0.5 % claim NGT 0.5 % claim Initial 0 <0.05 0.05 0.26 100.7 <0.05 0.05 25°C / 60% RH Packaged 3 <0.05 0.07 0.30 103.5 <0.05 <0.05 40°C / 75% RH Packaged 3 <0.05 0.06 0.29 104.1 <0.05 <0.05 Table 39(contd.) Storage Condition Time (Months ) IMPRRT0.7 3 Amount HPLC / 2731 (%claim) (Mean) IMPRRT0.79 Amount HPLC / 2731 (%claim) (Mean) Total degradation products greater / equal than 0.05% claim (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 30 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Specificatio n NGT 0.5 % claim NGT 0.5 % claim NGT 2.0 % claim Report Results Report Results Report Results Initial 0 <0.05 <0.05 0.05 85 82-86 93 25°C / 60% RH Packaged 3 <0.05 0.05 0.05 85 83-86 93 40°C / 75% RH Packaged 3 <0.05 0.06 0.06 83 82-85 92 Table 39(contd.) Storage Condition Time (Months ) Time point(min) 30 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 70 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Specificatio n Report Results Complies with EP, USP, JP where Q = 75% at 45 minutes Report Results Report Results Report Results Report Results Initial 0 92-94 95 93-96 95 94-97 96 25°C / 60% RH Packaged 3 92-95 95 93-97 95 93-97 95 40°C / 75% RH Packaged 3 91-93 95 93-95 95 93-96 95 Table 39(contd.) Storage Condition Time (Months) Time point(min) 70 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Mean) Specification Report Results Report Results Report Results Report Results Report Results Complies with    EP, USP,     JP where Q = 75% at 45 minutes Initial 0 94-97 81 72-83 92 88-94 96 25°C / 60% RH Packaged 3 93-97 81 60-87 95 85-99 97 40°C / 75% RH Packaged 3 93-96 86 83-88 94 91-96 96 Table 39(contd.) Storage Condition Time (Months) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Range) Water content UMID / 1231 (% w / w) (Mean) Specification Report Results Report Results Report Results Report Results Report Results Report Results Initial 0 95-97 98 97-99 102 101 - 104 3.7 25°C / 60% RH Packaged 3 89-101 99 92 - 103 103 100-104 2.9 40°C / 75% RH Packaged 3 93-98 98 95 - 100 103 102-104 3.3 Table 39(contd.) Storage Condition Time (Months) Strength RESR / 1001 (N) (Mean) Strength RESR / 1001 (N) (Range) Strength RESR / 1001 (Kp) (Mean) Strength RESR / 1001 (Kp) (Range) Specification Report Results Report Results Report Results Report Results Initial 0 92 81-99 9.36 8.26-10.10 25°C / 60% RH Packaged 3 115 110-120 11.70 11.22-12.24 40°C / 75% RH Packaged 3 114 102-127 11.59 10.40-12.95 Table 40: Long-term and accelerated storage condition results for FDC1 technical batch no A4459 / 31 / 02 (with desiccant! Storage Condition Time (Months ) Appearan. / Colou r APP / 1001 (Individual) OBICETRAPI B (TA-8995) Amount HPLC / 2730 (% claim) (Mean) DIASTEREOISOME R Amount HPLC / 2730 (% claim) (Mean) ETHYL ESTER Amount HPLC / 273 0 (% claim) (Mean) FROL Amount HPLC / 273 0 (% claim) (Mean) MONO BN FREE Amount HPLC / 273 0 (% claim) (Mean) Specificatio n NA White to off-white     round coated tablet 90.0-110.0% claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim NGT 0.3 % claim Initial 0 White    round coated tablet 96.7 <0.05 <0.05 0.11 0.15 25°C / 60% RH Packaged 3 White    round coated tablet 98.0 <0.05 <0.05 0.11 0.16 40°C / 75% RH Packaged 3 White    round coated tablet 98.1 <0.05 <0.05 0.11 0.16 Table 40(contd.) Storage Condition Time (Months) IMPRRT0.93 Amount HPLC / 2730 (% claim) (Mean) IMPRRT0.94 Amount HPLC / 2730 (% claim) (Mean) Total degradation products equal / greater than 0.05% claim (% claim) (Mean) EZETIMIBE Amount HPLC / 2731 (% claim) (Mean) EZETIMIBE CYCLIC Amount HPLC / 2731 (%claim) (Mean) EZETIMIBE KETONE Amount HPLC / 2731 (%claim) (Mean) Specification NGT 0.3 % claim NGT 0.3 % claim NGT 2.0 % claim 90.0-110.0 % claim NGT 0.5 % claim NGT 0.5 % claim Initial 0 0.07 <0.05 0.33 100.8 <0.05 0.05 25°C / 60% RH Packaged 3 0.06 <0.05 0.34 104.7 <0.05 <0.05 40°C / 75% RH Packaged 3 0.07 <0.05 0.34 105.3 <0.05 <0.05 Table 40(contd.) Storage Condition Time (Months ) IMPRRT0.7 3 Amount HPLC / 2731 (%claim) (Mean) IMPRRT0.79 Amount HPLC / 2731 (% claim) (Mean) Total degradation products greater / equal than 0.05% claim (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 15 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 30 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Mean) Specificatio n NGT 0.5 % claim NGT 0.5 % claim NGT 2.0 % claim Report Results Report Results Report Results Initial 0 <0.05 0.05 0.10 90 89-92 96 25°C / 60% RH Packaged 3 <0.05 0.05 0.05 89 88-90 97 40°C / 75% RH Packaged 3 <0.05 0.05 0.05 88 87-89 95 Table 40(contd.) Storage Condition Time (Months ) Time point(min) 30 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 45 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Time point(min) 60 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 70 OBICETRAPI B (TA-8995) DISS / 1295 (% claim) (Mean) Specificatio n Report Results Complies with EP, USP, JP where Q = 75% at 45 minutes Report Results Report Results Report Results Report Results Initial 0 94-97 97 95-98 97 96-98 97 25°C / 60% RH Packaged 3 96-98 98 97-98 98 97-98 98 40°C / 75% RH Packaged 3 94-97 96 95-97 96 95-98 96 Table 40(contd.) Storage Condition Time (Months) Time point(min) 70 OBICETRAPIB (TA-8995) DISS / 1295 (% claim) (Range) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 15 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 30 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Mean) Specification Report Results Report Results Report Results Report Results Report Results Complies with    EP, USP,     JP where Q = 75% at 45 minutes Initial 0 96-98 84 82-87 96 93-99 99 25°C / 60% RH Packaged 3 97-99 92 90-94 100 98-102 104 40°C / 75% RH Packaged 3 95-97 90 87-92 102 98-104 105 Table 40(contd.) Storage Condition Time (Months) Time point(min) 45 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 60 EZETIMIBE DISS / 1298 (% claim) (Range) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Mean) Time point(min) 70 EZETIMIBE DISS / 1298 (% claim) (Range) Water content UMID / 1231 (% w / w) (Mean) Specification Report Results Report Results Report Results Report Results Report Results Report Results Initial 0 97-103 102 99-105 104 101 - 107 4.0 25°C / 60% RH Packaged 3 102-105 106 104-107 108 106-109 3.5 40°C / 75% RH Packaged 3 102-109 107 103-109 107 105-110 3.7 Table 40(contd.) Storage Condition Time (Months) Strength RESR / 1001 (N) (Mean) Strength RESR / 1001 (N) (Range) Strength RESR / 1001 (Kp) (Mean) Strength RESR / 1001 (Kp) (Range) Specification NA Report Results Report Results Report Results Report Results Initial 0 - - - - 25°C / 60% RH Packaged 3 77 69-84 7.89 7.04-8.57 40°C / 75% RH Packaged 3 77 69-82 7.86 7.04-8.36 N / A: Not Applicable Example 5: Study to evaluate the comparative bioavailability of two fixed-dose combination formulations of obicetrapib / ezetimibe 10 mg / 10 mg (fdcl and fdc2) with obicetrapib, 10 mg co-administered with ezetimibe, 10 mg in healthy adult subjects under fasted conditions. Study design

[0253] 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 received either Treatment T1 (1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC1 tablet [Formulation #1]), Treatment T2 (lx obicetrapib, 10 mg and ezetimibe, 10 mg FDC2 tablet [Formulation #2]), or Treatment R (1 X obicetrapib tablet, 10 mg co-administered with 1 x ZETIA® (ezetimibe) tablet, 10 mg) following an overnight fast of at least 10 hours. The order of administration followed a six-sequence randomization schedule. Blood samples were collected at pre-dose and at intervals over 336 hours after dosing in each study period. Subjects were confined at the clinical facility from at least 10 horns before dosing until 24 hours after dosing in each study period and returned to the clinical facility for the 48-, 72-, 96-, 144-, 192-, 240-, and 336-hour post-dose blood sample collections. The interval between doses were at least 49 days.

[0254] The Formulation #1 formulation (also referred to herein as FDC1 and Tl) used in this Example and in Example 6 is set forth below in Table 41. Similarly, the Formulation #1 formulation (also referred to herein as FDC2 and T2) used in this Example and in Example 6 is set forth below in Table 42. The reference formulation (Treatment R) of obicetrapib does not contain sodium lauryl sulfate or any other surfactant. Instead, the excipients in Treatment R are microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate in the core. The Treatment R tablets were coated with Hypromellose, lactose monohydrate, titanium dioxide and triacetin. Table 41: Composition Table for Obicetrapib lOmg Ezetimibe lOmg FDC Tablets (FDC-1) Component Quantity (mg / Tablet) % w / w Function Specifications Intra-Granular Components Obicetrapib calcium[l,2] (Obicetrapib) 10.26 (10.00) 6.840 Active ingredient In-house Ezetimibe[2] 10.00 6.667 Active ingredient Supplier Microcrystalline cellulose 31.28 20.853 Diluent Ph. Eur, USP / NF, JP Lactose monohydrate[2] 81.96 54.640 Diluent Ph. Eur, USP / NF, JP Povidone 1.50 1.000 Binder Ph. Eur, USP / NF, JP Sodium starch glycolate 6.00 4.000 Disintegrant Ph. Eur, USP / NF, JP Sodium lauryl sulfate 1.50 1.000 Wetting agent Ph. Eur, USP / NF, JP Purified water[3] q.s. q.s. Granulating Solvent Ph. Eur, USP / NF Extra-Granular Components Sodium starch glycolate 6.00 4.000 Disintegrant Ph. Eur, USP / NF, JP Magnesium stearate 1.50 1.000 Lubricant Ph. Eur, USP / NF, JP Total core weight (mg) 150.00 100.000 Film-Coating Components Opadry® AMBII white 88A180040 containing: Polyvinyl alcohol Talc Titanium dioxide Glyceryl mono and dicap rylo cap rate Sodium lauryl sulfate 4.50[4] 3.0[4] Film Coating Supplier Specifications USP, Ph.Eur, JPE Ph. Eur, USP / NF, JP Ph. Eur, USP / NF, JP Ph. Eur, USP / NF, JSFA Ph. Eur, USP / NF, JP Purified water [3] q.s. q.s. Suspending fluid Ph. Eur, USP / NF Total tablet weight             154.50         103.0 1. The theoretical quantity of obicetrapib free acid is determined based on the salt factor of 1.0263. The molecular weights of obicetrapib calcium and obicetrapib free acid are 1483.26 g / mol and 722.6 g / mol respectively. 2. The actual quantities of obicetrapib calcium and ezetimibe are adjusted based on the assay of each batch of drug substance. A corresponding quantity of lactose monohydrate is adjusted to maintain a target core tablet weight of 150 mg 3. Removed during drying 4. Target weight of film coating applied to cores. Percent added based on core tablet weight. JP = Japanese Pharmacopoeia; JPE = Japanese pharmaceutical excipients; NF = national formulary; Ph. Eur = European Pharmacopoeia; JSFA = Japan’s specifications and standards for food additives; q.s. = quantum sufficit; USP = United States Pharmacopoeia. Table 42: Composition Table for Obicetrapib lOmg Ezetimibe lOmg FDC Tablets (FDC-_______________________________________________2) Component Quantity (mg / Tablet) % w / w Function Specifications Intra-Granular Components Ezetimibe[l] 10.00 4.348 Active ingredient Supplier Microcrystalline cellulose 30.70 13.347 Diluent Ph. Eur, USP / NF, JP Lactose monohydrate[l] 80.30 34.914 Diluent Ph. Eur, USP / NF, JP Povidone 1.50 0.652 Binder Ph. Eur, USP / NF, JP Sodium starch glycolate 6.00 2.608 Disintegrant Ph. Eur, USP / NF, JP Sodium lauryl sulfate 1.50 0.652 Wetting agent Ph. Eur, USP / NF, JP Purified water[2] q.s. q.s. Granulating Solvent Ph. Eur, USP / NF Extra-Granular Components Obicetrapib calcium [3,4] (Obicetrapib) 10.26 (10.00) 4.461 Active ingredient In-house Microcrystalline cellulose 53.17 23.118 Diluent Ph. Eur, USP / NF, JP Mannitol 20.47 8.900 Diluent Ph. Eur, USP / NF, JP Sodium starch glycolate 11.50 5.000 Disintegrant Ph. Eur, USP / NF, JP Colloidal silicon dioxide 2.30 1.000 Glidant Ph. Eur, USP / NF, JP Magnesium stearate 2.30 1.000 Lubricant Ph. Eur, USP / NF, JP Total core weight (mg) 230.00 100.000 Film-Coating Components Opadry® AMBII white 88A180040 containing: Polyvinyl alcohol Talc Titanium dioxide Glyceryl mono and dicap rylo cap rate Sodium lauryl sulfate 6.90[5] 3.0[5] Film Coating Supplier Specifications Ph.Eur, USP / NF, JPE Ph. Eur, USP / NF, JP Ph. Eur, USP / NF, JP Ph. Eur, NF, JSFA Ph. Eur, USP / NF, JP Purified water [2] q.s. q.s. Suspending fluid Ph. Eur, USP / NF Total tablet weight 236.90 103.0 1. The actual quantity of ezetimibe is adjusted based on the purity of each batch of drug substance. A corresponding quantity of lactose monohydrate is adjusted to maintain a target dried granulation weight of 130 mg. 2. Removed during drying. 3. The theoretical quantity of obicetrapib free acid is determined based on the salt factor of 1.0263. The molecular weights of obicetrapib calcium and obicetrapib free acid are 1483.26 g / mol and 722.6 g / mol respectively. 4. The actual quantity of obicetrapib calcium is adjusted based on the assay of each batch of drug substance. A corresponding quantity of microcrystalline cellulose (extragranular) is adjusted to maintain a target core tablet weight of 230 mg. 5. Target weight of film coating applied to cores. Percent added based on core tablet weight. JP = Japanese Pharmacopoeia; JPE = Japanese pharmaceutical excipients; NF = national formulary; Ph. Eur = European Pharmacopoeia; JSFA = Japan’s specifications and standards for food additives; q.s. = quantum sufficit; USP = United States Pharmacopoeia.

[0255] The plasma concentrations of obicetrapib, ezetimibe and its metabolite, ezetimibe glucuronide were measured by fully validated analytical methods. Statistical analysis using average bioequivalence methodology were performed to evaluate the bioavailability of each of the test formulations relative to that of the coadministration of the reference products. Selection of study population

[0256] The subject population included 36 healthy, non-tobacco-, non-nicotine-using, adult male and female subjects. Treatment administration

[0257] The subjects received Treatment Tl, Treatment T2, or Treatment R according to a three treatment, three-period, six-sequence randomization schedule (Table 43) under direct observation following an overnight fast of at least 10 hours. • Treatment Tl:l x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #1) • Treatment T2: 1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #2) • Treatment R: 1 X obicetrapib Tablet, 10 mg co-administered with 1 X ZETIA® (ezetimibe) Tablet, 10 mg Table 43 : Randomization Schedule Sequence Period 1 Period 2 Period 3 1 Tl T2 R 2 T2 Tl R 3 R Tl T2 4 Tl T2 R 5 T2 Tl R 6 R Tl T2

[0258] Each dose was administered with 240 mL of room temperature water. Subjects were instructed to swallow the tablet(s) whole without chewing or biting. Sample Collection, Handling and Bioanalytical Plans Sample Size

[0259] 4 mL collections (K2EDTA vacutainers) for analysis of obicetrapib

[0260] 4 mL collections (K2EDTA vacutainers) for analysis of ezetimibe and ezetimibe glucuronide Collection Times

[0261] Pre-dose samples were collected within 60 minutes before dosing. All times are relative to the dosing minute.

[0262] For analysis of obicetrapib: Pre-dose (0-hour) and at 0.50, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0*, 96.0*, 144.0*, 192.0*, 240.0* and 336.0* hours post-dose (*return sample)

[0263] For analysis of ezetimibe and ezetimibe glucuronide: Pre-dose (0-hour) and at 0.25, 0.50, 0.75,1.0, 1.333, 1.667, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0* and 96.0* hours post-dose (*retum sample)

[0264] Total number of collections per period / per subject: 49

[0265] Total blood volume per subject: The total volume of blood collected for pharmacokinetic sampling was approximately 588 mL.

[0266] Sample Processing for analysis of obicetrapib: Blood samples were collected in room temperature 4 mL K2EDTA vacutainers. After collection, the samples were mixed by gently inverting the tube several (i.e., 8-10) times and placed in an ice / water bath. The samples were then placed in the centrifuge and spin at 3000 rpm for 10 minutes at 4°C. The resulting plasma was separated into two aliquots (at least 1.0 mL in Aliquot 1 and remainder in aliquot 2) and transferred into polypropylene sample storage tubes and stored at -70°C (± 10°C) until ready for shipment to the bioanalytical laboratory. The plasma aliquots were placed in the freezer within 30 minutes after sample collection. After collection until placement in the freezer, blood / plasma samples were kept cooled in an ice / water bath.

[0267] Sample Processing for analysis of ezetimibe and ezetimibe glucuronide: Blood samples were collected in room temperature 4 mL K2EDT A vacutainers. After collection, the samples were mixed gently by inverting the tube several (at least 8) times and placed in an ice / water bath. The samples were then placed in the centrifuge and spin at 3000 rpm for 10 minutes at 4°C. The resulting plasma was separated into two aliquots (at least 1.0 mL in Aliquot 1 and remainder in Aliquot 2) and transferred into polypropylene sample storage tubes (e.g., Sarstedt #60.546) and stored at -70°C (or colder) until ready for shipment to the bioanalytical laboratory. After collection until placement in the freezer, blood / plasma samples were kept cooled in an ice / water bath. Pharmacokinetic analysis

[0268] For all treatments, the following pharmacokinetic parameters were calculated for obicetrapib, ezetimibe and its metabolite, ezetimibe glucuronide. Primary PK parameters

[0269] Cmax: Maximum measured plasma concentration.

[0270] AUCo-t: Area under the plasma concentration versus time curve from time zero to the last measurable plasma concentration, as calculated by linear trapezoidal method.

[0271] AUCo-«>: Area under the plasma concentration versus time curve from time zero to infinity where AUCo- / = AUCo-t + Ct / kz. Ct is the last measurable concentration and A is the terminal disposition rate constant. Secondary PK parameters

[0272] Tmax: Time of the maximum measured plasma concentration. If the maximum value occurred at more than one time point, Tmax is defined as the first time point with this value.

[0273] Xz: Apparent first-order terminal disposition rate constant. This parameter was calculated from the negative of the slope of the dataset with the best-fit least-squares linear regression analysis of the terminal in-linear concentration-time data. The number of data points (3 or more) in the terminal phase (not including Cmax) was included in the final regression analysis for an evaluable kz was determined from the dataset that has the highest adjusted Rsquared (R2) value of 0.7 or more. Xz was considered non-evaluable if (1) the last three terminal points were used to determine Xz and either the middle or the last point was higher than the preceding point or (2) the resulting adjusted R2 value was less than 0.7. An evaluable K was considered not reliable and not reportable if the resulting apparent first-order terminal half-life (ti / 2,) value was longer than the time interval over which Xz was estimated. If the resulting 11 / 2, value was longer than the time interval over which Xz was determined, an interval that was longer than the estimated ti / 2, was explored. The interval with the next highest adjusted R2 value was chosen and the decrease in the adjusted R2 value was assessed to determine if a reliable estimation of the K was possible. If K was deemed not reliable then no ti / 2, and AUCo- / values were reported for that dataset.

[0274] ti / 2: The first-order terminal disposition half-life was calculated as ln(2) / kz Data set for analysis and statistical methods

[0275] Linear and semi-logarithmic graphs of the concentration-time profiles for each subject were provided, using the actual times of sample collections. Actual sample collection time were used for calculating the pharmacokinetic parameters. Plasma concentration data from all evaluable subjects with no significant protocol deviation(s) were used for estimation of Cmax and / or AUCs from at least two periods of the study, one of which includes Treatment R.

[0276] PK parameters from any subject who experienced emesis within two times the median Tmax of obicetrapib or ezetimibe, respectively, calculated from the observed data of the specific treatment arm were excluded from the statistical analysis for the respective analyte.

[0277] Analyses of Variance was performed on In-transformed AUCo-t, AUCo- / , and Cmax using an analysis of variance model (ANOVA). The ANOVA was conducted separately for Treatment T1 versus Treatment R analysis and for Treatment T2 versus Treatment R analysis, using an incomplete block design. Treatment T2 was excluded from ANOVA for comparison of Treatments T1 versus R and Treatment T1 was excluded from ANOVA for comparison of Treatments T2 versus R.

[0278] Confidence intervals (90%) on the geometric mean ratios (obtained from logarithmic transformed data) for AUCo-t, AUCo-oo and Cmax for the comparison of each of the FDC formulations (T1 and T2) to Treatment R was constructed to test two one-sided hypotheses at the a = 0.05 level of significance. Example 6: Pharmacokinetic Evaluation of the Phase 1 Study of Example 5

[0279] The study of Example 5 was designed to evaluate the comparative bioavailability of obicetrapib and ezetimibe after a single dose of each of the two fixed-dose combination formulations of obicetrapib / ezetimibe, 10 mg / 10 mg relative to a single dose of one (1) obicetrapib tablet, 10 mg co-administered with one (1) ezetimibe tablet [ZETIA®], 10 mg. Plasma concentrations of obicetrapib, ezetimibe and its metabolite, ezetimibe glucuronide were measured from pre-dose to 336 hours post-dose for obicetrapib and from pre-dose to 96 hours for ezetimibe and ezetimibe glucuronide and used to estimate the pharmacokinetic parameters: AUCo-t, AUCo- / , Cmax, Tmax, Xz, t’A, for obicetrapib, ezetimibe, and ezetimibe glucuronide. Evaluation of comparative bioavailability was based on the confidence intervals (90%) on the geometric mean ratios (obtained from logarithmic transformed data) for AUCo-t, AUCo- / and Cmax. Safety was assessed through monitoring of vital signs, ECGs, adverse events, and clinical laboratory evaluations. Adverse events were collected through both solicited and unsolicited means. Blood samples were collected at the time of the last pharmacokinetic blood sample collection of the study for post-study hematology and clinical chemistry determination.

[0280] The comparison of the pharmacokinetic parameters of the test and reference products is the generally accepted methodology for determining relative bioavailability. Physical examination, adverse event solicitation, vital sign assessment, 12 lead ECG and clinical laboratory testing are typical safety measures in this type of study.

[0281] Plasma concentrations of obicetrapib, ezetimibe and ezetimibe glucuronide were measured from pre-dose to 336 hours post-dose and used to estimate the pharmacokinetic parameters: AUCo-t, AUCo-®, Cmax, Tmax, Xz, t’A, for obicetrapib, ezetimibe, and ezetimibe glucuronide. Evaluation of comparative bioavailability was based on the confidence intervals (90%) on the geometric mean ratios (obtained from logarithmic transformed data) for AUCo-t, AUCo-oo and Cmax-

[0282] Confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo- / and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide (from T1 and T2 for formulation #1 as well as formulation #2) were found to be within a range of 75%-125%, typically 80%-125%, and more typically 90%-110% of AUCo-t, AUCo-® and Cmax of obicetrapib, ezetimibe and ezetimibe glucoronide, respectively. The test formulations #1 and #2 were found to be bioequivalent with reference treatment arm (R). The adverse events observed with T1 or T2 arm of the treatment were statistically not significantly different from the R arm.

[0283] Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are one alternative to statins. However, there are several limitations with these therapies, including high costs, limited long-term outcome data relative to statins, and muscle-related events. In addition, because PCSK9 inhibitors are injectable, this poses a less attractive option for patients who prefer oral medications.

[0284] The results further show that T1 (formula based on FDC1) had greater plasma concentrations of obicetrapib than either the reference formulation or the T2 (formula based on FD2). The difference between the FDC1 formulation and the obicetrapib extragranular portion of the FDC2 formulation is that FDC2 has mannitol and colloidal silicon dioxide and FDC1 lacks both in the entire tablet. Both mannitol and colloidal silicon dioxide and mannitol are, however, present in the reference formulation. With regards to FDC1, the microcrystalline cellulose, lactose monohydrate, povidone, and sodium starch glycolate are each found in either the reference formulation, FDC2 or both. The only excipient found in FDC1 not found in the obicetrapib portion of FDC2 or the Reference formulation is the surfactant sodium lauryl sulfate.

[0285] Table 44 summarizes the AUCo-t, AUCo-® and Cmax for Tl, T2, and R. Table 45 shows the geometric least square means of In-transformed data of Tl vs. R. The percent ratio of Tl / R shows that each of AUCo-t, AUCo-® and Cmax was significantly higher than when compared with R. Table 46 shows the same parameters but with respect to T2 compared with R. Comparing Table 45 to Table 46 shows a substantial increase of the Cmax and AUC parameters of Tl, which contains a surfactant (sodium laurel sulphate) as compared with T2, which does not. Table 44: Summary of Pharmacokinetic Parameters of Untransformed Data: __________________________________Obicetrapib_________ Pharmacokinetic Parameter Treatment N (# datasets) Arithmetic mean ± SD (%CV) Tl 29 18178.755 ± 4051.1982(22.3) AUCo-t (ng.h / mL) T2 30 16549.748 ± 3866.4869 (23.4) R 30 15236.076 ± 4969.3677 (32.6) AUCo-m (ng.h / mL) T1 29 24387.936 ± 7415.0828 (30.4) T2 30 22253.253 ± 6732.5263 (30.3) R 30 21043.612± 8930.2988 (42.4) Cmax (ng / mL) T1 30 289.633 ±77.7216 (26.8) T2 31 249.516 ±76.2080 (30.5) R 31 218.939 ±95.9956 (43.8) Table 45: Summary of Study Results Based on Plasma Obicetrapib Concentrations (Ln__________________________transformed): T1 vs. R_________________ Parameters N (# subjects) Geometric Least Squares Means Test Treatment T1 Reference Treatment R Ratio (Tl / R) % InCmax 30 283.041 198.032 142.9 InAUCo-t 29 17863.849 14229.670 125.5 lnAUCo-m 29 24190.035 19402.700 124.7 Table 46: Summary of Study Results Based on Plasma Obicetrapib Concentrations (Ln__________________________transformed): T2 vs. R_________________ Parameters N (# subjects) Geometric Least Squares Means Test Treatment T2 Reference Treatment R Ratio (T2 / R) % InCmax 31 239.501 197.705 121.1 InAUCo-t 30 16018.333 14297.010 112.0 lnAUCo-m 30 21519.514 19689.044 109.3 Example 7: Wet granulation operations followed by direct compression to make FDC1 and FDC2 formulations

[0286] The fixed-close combination pharmaceutical formulations FDC1 and FDC2 were prepared as tablets according to general process parameters found in Figure 24 (FDC1) and Figure 25 (FDC2).

[0287] In Figure 24, granules containing ezetimibe, obicetrapib calcium and sodium lauryl sulphate were sieved and wet granulated to form granules. Extragranular sodium starch glycolate and magnesium stearate (e.g., Ligamed MF-2-V) were then blended and compressed with the granules to form tablets which were then coated.

[0288] In Figure 25, granules were likewise made via an aqueous process, but while containing ezetimibe and sodium laurel sulphate, they did not contain obicetrapib. Rather, obicetrapib calcium was blended in extragranularly without a surfactant, compressed into tablets with the granules, and subsequently coated. List of Abbreviations: API      Active Pharmaceutical Ingredient °C        degree Celsius CC Compaction compressibility (= 100 x (TBD-IBD) / TBD) CFM     cubic feet per minute CoA      Certificate of analysis DBD     Dynamic bulk density (= (TBD - IBD)2 / TBD] + IBD) e.g.       for example eze / EZE Ezetimibe FDC1    Formulation development composition 1 FDC2    Formulation development composition 2 g        gram H       Hausner ratio (= TBD / IBD) HPLC    High Performance Liquid Chromatography IBD      Initial bulk density (= mass / initial volume) KF       Karl Fisher kp       Kilopound KN     Kilonewton LC       Label claim LLS      Laser Light Scattering Lt        Liter mg       milligram min      minute mL       millilitre mm      millimeter N.R     Not recorded N.D      Not detected Obi / OBI Obicetrapib (Known also as TA-8995) pH       -log [H+] or pH = - log an+ PSD      Particle Size Distribution RH      Relative Humidity (aw * 100) rpm      rotation per minute RRT     Relative retention time RSD     Relative standard deviation sec       second SD       Standard deviation SLS Kolliphor SLS Fine, EP & USP / NF & JP T        Temperature (°C) TBD     Tapped bulk density (= mass / tapped volume) vs        versus w / w     weight / weight XRPD   X-Ray Powder Diffraction pm      microns 0        diameter % a / a % area of impurity to the total area of peaks not being present in the blank Cmax.     Maximum measured plasma concentration. AUCo-t. Area under the plasma concentration versus time curve from time zero to the last measurable plasma concentration, as calculated by linear trapezoidal method. AUCo-oo. Area under the plasma concentration versus time curve from time zero to infinity where AUCo- / = AUCo-t + Ct / Xz. Ct is the last measurable concentration, and Xz is the terminal disposition rate constant Tmax. Time of the maximum measured plasma concentration. If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this value. Xz. First order rate constant associated with the terminal (log-linear) portion of the curve. This parameter will be calculated by linear least squares regression analysis using at least last three or more non-zero plasma or blood concentration values, not including Cmax- t%. The first-order terminal disposition half-life will be calculated as ln(2) / Xz. R2 adjusted. Goodness of fit statistic for the terminal phase, adjusted for the number of points used in the estimation of Xz. Example 8: 10 mg amorphous obicetrapib hemicalcium single active formulation made by direct compression

[0289] Manufacturing steps for making 10 mg tablets containing amorphous obicetrapib hemicalcium by direct compression are set forth in Table 47 below Table 47: Manufacturing steps of Obicetrapib Tablets 10 mg Direct Compression Sr. No. Manufacturing Steps for Direct Compression (Batch Size: 10000 Tablets) Step-1 All the materials were dispensed as per formula composition. Step-2 Half quantity of microcrystalline cellulose was sifted through ASTM # 20 and added in 3L conta blender for saturation for 2 min at 23 RPM. Step-3 API and all the materials (except magnesium stearate) were co-sifted (Obicetrapib calcium, remaining microcrystalline cellulose, mannitol, surfactant (*except tween 80) sodium starch glycolate and colloidal silicon dioxide) through ASTM # 20 sieve. *Note: After co-sifting tween 80 was added dropwise on the mixture with continuous manual mixing until a uniform mixture was obtained. Step-4 The materials of Step-3 were added in conta blender containing material of Step-2 and blended for 10 min at 23 RPM. Step-5 Materials of step-4 were milled through 1.143 mm round screen in Quadro Co-mil(U5) at 2000 rpm. Step-6 Materials of Step-5 were added in conta blender and blended for 10 min at 23 RPM. Step-7 Magnesium stearate was sifted through ASTM #30 and added to conta blender containing Step-6 material and lubrication was performed for 5 min at 23 RPM. Step-8 Final lubricated blend was compressed in compression machine using 6.25 mm, round shaped, plain on both sides B-tooling. Step-9 The tablets were coated using 250 mm auto-coater to a target weight gain of 3.0% w / w.

[0290] Eight batches of tablets were made having the ingredients set forth in Table 48. Table 48: Composition details of Surfactant evaluation trials of Obicetrapib Tablets 10 mg Direct Compression Batch No. 111AJ(1192 )01 111AJ(1192 )H 111AJ(1192 )12 111AJ(1192 )13 111AJ(1192 )18 111AJ(1192 )19 111AJ(1214 )19 111AJ(1214 )20 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Sr. No Batch Size 10000 Tablets Ingredients . , %w / mg / tab w . , %w / mgrtab w . , %w / mgrtab w . , %w / mgAab w . , %w / mg / tab w . , %w / mg / tab w . , %w / mg / tab w . , %w / mg / tab w Obicetrapib calcium 10.260 10.26 10.260 10.26 10.260 10.26 10.260 10.26 10.260 10.26 10.260 10.26 10.260 10.26 10.260 10.26 2 Micro cry stall ine cellulose (Avicel PH 200) 59.740 59.74 58.740 58.74 54.740 54.74 44.740 44.74 58.740 58.74 54.740 54.74 59.240 59.24 58.240 58.24 3 Mannitol (Pearlitol 200 SD) 23.000 23.00 23.000 23.00 23.000 23.00 23.000 23.00 23.000 23.00 23.000 23.00 23.000 23.00 23.000 23.00 4 Surfactant 0.000 00.00 1.000 1.00 5.000 5.00 15.000 15.00 1.000 1.00 5.000 5.00 0.500 0.50 1.500 1.50 5 Sodium starch glycolate Type A (Glycolys) 5.000 5.00 5.000 5.00 5.000 5.00 5.000 5.00 5.000 5.00 5.000 5.00 5.000 5.00 5.000 5.00 6 Colloidal silicon dioxide (Aerosil 200 Pharma) 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 7 Magnesium stearate (Ligamed MF-2-V) 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 1.000 1.00 Total weight of Core Tablet 100.00 0 100.0 0 100.00 0 100.0 0 100.00 0 100.0 0 100.00 0 100.0 0 100.00 0 100.0 0 100.00 0 100.0 0 100.00 0 100.0 0 100.00 0 100.0 0 8 Opadry ® II white 32K280000 3.000 3.00 3.000 3.00 3.000 3.00 3.000 3.00 3.000 3.00 3.000 3.00 3.000 3.00 3.000 3.00 Total weight of Coated Tablet 103.00 0 NA 103.00 0 NA 103.00 0 NA 103.00 0 NA 103.00 0 NA 103.00 0 NA 103.00 0 NA 103.00 0 NA SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0291] The tablets were characterized according to the methods set forth in Table 49. Table 49: In-process characterization of lubricated blend of Obicetrapib Tablets 10 mg Direct Compression Batch No. 111AJ(1192 )01 111AJ(1192) 11 111AJ(1192 )12 111AJ(1192 )13 111AJ(1192 )18 111AJ(1192 )19 111AJ(1214) 19 111AJ(1214 )20 Batch Details Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Bulk Density (g / mL) 0.4285 0.4411 0.4348 0.4348 0.4477 0.4225 0.4477 0.4411 Tapped Density (g / mL) 0.5660 0.5555 0.5660 0.5882 0.5555 0.5172 0.5882 0.56660 Compressib ility Index (%) 24.2857 20.5882 23.1884 26.0869 19.4030 18.3098 23.8806 22.0588 Hausner Ratio 1.3207 1.2592 1.3019 1.3529 1.2407 1.2241 1.3137 1.2830 Flowability index 90 (Disc no. H) (Medium) 90 (Disc no. H) (Medium) 90 (Disc no. H) (Medium) 59 (Disc no. 17) (Medium) 83 (Disc no. 12) (Medium) 200 (Disc no. 5) (Excellent) 71 (Disc no. 14) (Medium) 77 (Disc no. 13) (Medium) ASTM Sieve # % wt. retain ed % cum. wt. retain ed % wt. retain ed % cum. wt. Retain ed % wt. retain ed % cum. wt. retain ed % wt. retain ed % cum. wt. retain ed % wt. retain ed % cum. wt. retain ed % wt. retain ed % cum. wt. retain ed % wt. retain ed % cum. wt. Retain ed % wt. retain ed % cum. wt. retain ed 20# (850 pm) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 30# (600 pm) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.67 0.67 0.00 0.00 0.00 0.00 0.00 0.00 40# (425 pm) 0.67 0.67 0.67 0.67 0.67 0.67 0.67 0.67 1.33 2.00 2.00 2.00 0.00 0.00 0.00 0.00 60# (250 pm) 15.44 16.11 14.67 15.33 12.67 13.33 13.33 14.00 14.67 16.67 16.00 18.00 16.00 16.00 20.00 20.00 80# (180 pm) 22.15 38.26 22.00 37.33 18.67 32.00 17.33 31.33 20.67 37.33 24.67 42.67 22.00 38.00 22.70 42.70 100# (150 pm) 14.77 53.02 14.00 51.33 15.33 47.33 14.00 45.33 13.33 50.67 6.00 48.67 12.00 50.00 11.30 54.00 200#(75 pm) 34.23 87.25 32.67 84.00 30.67 78.00 31.33 76.67 33.33 84.00 42.00 90.67 34.00 84.00 31.30 85.30 Pan 12.75 100.0 0 16.00 100.0 0 22.00 100.0 0 23.33 100.0 0 16.00 100.0 0 9.33 100.0 0 16.00 100.0 0 14.70 100.0 0 SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0292] The tablets were coated in accordance with Table 50, and the disintegration time ranges are also provided in Table 50. Table 50: Coating parameters of Obicetrapib Tablets 10 mg Direct Compression Mfg. Approach Direct Compression Batch No. 111AJ(11 92)01 111AJ(119 2)11 111AJ(119 2)12 111AJ(119 2)13 111AJ(119 2)18 111AJ(119 2)19 111AJ(121 4)19 111AJ(121 4)20 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Coating parameters Coating Pan size 250 mm 250 mm 250 mm 250 mm 250 mm 250 mm 250 mm 250 mm Inlet temp. (°C) 60.1 to 61.3 68.3 to 69.1 68.0 to 68.1 60.9 to 61.2 60.0 to 60.9 59.8 to 60.9 59.8 to 60.2 60.8 to 61.5 Bed temp. (°C) 38.3 to 39.1 39.2 to 41.4 38.3 to 41.1 39.4 to 40.4 39.2 to 40.8 39.0 to 40.2 39.3 to 40.1 39.2 to 40.4 Exhaust temp. (°C) 46.2 to 47.4 53.1 to 53.5 50.8 to 51.9 46.9 to 47.1 46.2 to 47.5 46.1 to 47.0 46.6 to 47.6 48.2 to 46.8 Spray Rate (g / min) 6.5 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Atomiza tion (kg / cm2) 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 Fan air (kg / cm2) 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 % Weight gain 3.01 3.18 3.01 3.08 3.14 3.12 3.08 3.17 Avg. tablet weight (range / %RSD )(mg) 103.96 (102.5 to 105.8 / 1.04%) 103.76 (103.2 to 104.7 / 0.57%) 103.79 (102.0 to 104.9 / 0.84 %) 103.24 (102.6 to 104.4 / 0.54%) 103.50 (102.4 to 105.4 / 1.12%) 103.44 (101.5 to 105.3 / 1.36%) 103.23 (102.0 to 104.1 / 0.75 %) 103.35 (102.3 to 103.8 / 0.46 %) Tablet hardness Avg. (Range) (kP) 9.0 (8.2 to 9.7) 9.2 (8.3 to 10.2) 10.0 (8.3 to 11.7) 8.0 (7.7 to 8.3) 9.0 ( 8.2 to 9.8) 5.6 (5.2 to 6.1) 10.2 (9.1 to 10.9) 9.7 (9.0 to 10.4) Tablet thickness Avg.(Range) (mm) 3.12 (3.11 to 3.15) 3.10 (3.07 to 3.13) 3.08 (3.05 to 3.13) 3.00 (2.98 to 3.03) 2.96 (2.97 to 3.03) 2.88 (2.82 to 2.96) 3.11 (3.05 to 3.14) 3.16 (3.14 to 3.17) Disintegration time (min: sec) 01:12 to 01:54 03:18 to 05:14 06:58 to 08:57 10:25 to 11:05 02:12 to 02:43 08:47 to 09:26 01:40 to 02:14 00:54 to 01:56 SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0293] The tablets were exposed to various dissolution media including those set forth in Table 51 and Table 51 A, and the dissolution results are provided therein. Table 51: Dissolution results of Obicetrapib Tablets 10 mg for 0.2%w / v Tween 80 in 50mM Phosphate buffer pH 6.8 Direct Compression Batch No. 111AJ(1192) 01 111AJ(1192) 11 111AJ(1192) 12 111AJ(1192) 13 111AJ(1192) 18 111AJ(1192) 19 111AJ(1214) 19 111AJ(1214) 20 Remar k Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Media Conditi on 0.2%w / v Tween 80 in 50mM Phosphate buffer pH 6.8,1000 mL_USP Type II_75 RPM (n=6) (Coated Tablets) Time point Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D 5 min 49 7.8 38 6.0 20 13.8 17 30.5 30 7.6 8 16.4 33 4.5 32 4.2 10 min 61 2.0 60 2.8 51 11.7 40 6.2 53 5.3 28 8.7 53 3.4 50 4.1 15 min 68 3.3 71 3.2 70 7.5 62 3.7 65 3.8 48 2.2 64 2.7 63 2.7 20 min 75 5.1 78 3.1 79 5.5 76 2.4 72 3.2 59 1.3 72 2.6 71 2.4 30 min 83 4.5 85 3.1 87 4.4 87 1.0 81 2.6 72 1.4 81 2.3 81 1.9 45 min 88 5.2 89 3.4 91 3.8 92 0.8 87 2.2 83 1.5 88 1.6 88 1.7 60 min 90 5.2 91 3.4 93 3.6 94 1.0 91 2.1 90 1.4 91 1.1 91 1.6 Table 51A: Dissolution results of Obicetrapib Tablets 10 mg for 0.05%w / v Tween 80 in 50mM Phosphate buffer pH 6.8 Direct Compression Batch No. 111AJ(1192)O1 111AJ(1192)11 111AJ(1192)18 Remark Control 1 mg SLS 1 mg Tween 80 Media Condition 0.05%w / v Tween 80 in 50mM Phosphate buffer pH 6.8,1000 mL_USP Type II 75 RPM (n=6) (Coated Tablets) Time point Mean %RSD Mean %RSD Mean %RSD 5 min 15 11.3 17 17.4 21 5.1 10 min 26 7.5 33 6.9 32 4.6 15 min 36 5.4 43 7.7 44 3.4 20 min 44 5.0 52 4.4 52 2.8 30 min 56 3.8 62 3.5 63 2.5 45 min 67 2.8 71 3.4 72 2.1 60 min 74 3.3 77 3.3 78 1.9 90 min (Recovery) 84 2.5 84 3.1 86 1.6$ SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0294] The dissolution data are also presented with various figures herein. In Figure 26, control tablets and tablets containing 1 mg SLS are compared in media containing either 0.2% Tween 80 or 0.05% Tween 80. As Figure 26 shows, at the higher Tween level, there is faster release from both the control and the SLS tablets than the lower tween level. However, there is better separation between the control and the SLS tablets at the lower Tween concentration level. Although the SLS had a substantially longer disintegration time, it should comparable or higher release characteristics.

[0295] In some media no significant differences were observed by and between the control, 1 mg SLS, 1 mg Tween 80, and 0.5 mg CPC tablets in dissolution. However, by using a more discriminating media, a slight positive effect was seen in the Tween 80 and SLS tablet formulations even with the disintegration times of the surfactant-containing tablets were higher (Fig. 27). FCT stands for film coated tablets.

[0296] Table 52 shows various data collected on the tablets such as assay, content uniformity, and related substances. Table 52 Assay, Content uniformity and Related Substances results of Obicetrapib Tablets 10 mg Direct Compression Batch No. 111AJ(1192) 01 111AJ(1192) 11 111AJ(1192) 12 111AJ(1192) 13 111AJ(1192) 18 111AJ(1192) 19 111AJ(1214) 19 111AJ(1214) 20 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Assay (%) Blend 86.1 82.6 89.8 87.9 NA NA NA NA Tablet 95.5 93.1 94.3 96.2 96.1 98.2 95.2 95.4 Content Uniformity (%) Sample Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Sample-1 103.9 97.0 104.3 2 95.3 105.1 7 95.1 104.3 70 95.8 104.0 00 95.5 103.0 15 96.4 102.7 50 93.9 103.7 90 93.1 Sample-2 106.8 98.8 105.1 5 96.7 103.7 3 95.4 104.9 40 95.9 103.6 24 96.3 102.4 37 96.2 103.1 60 92.7 103.8 30 93.3 Sample-3 107.1 104.8 103.5 3 93.0 101.9 4 90.0 104.6 00 96.1 103.2 02 94.6 104.8 66 98.7 101.9 10 93.8 106.8 50 95.0 Sample-4 105.4 101.5 106.0 0 97.0 104.3 6 87.7 103.1 80 92.7 104.5 01 95.2 103.1 13 98.1 103.1 20 92.5 105.9 50 94.1 Sample-5 108.3 101.2 104.9 3 95.1 104.4 4 94.3 104.3 40 96.3 103.6 84 92.3 104.5 16 101.5 103.1 50 94.1 104.7 80 97.3 Sample-6 101.4 90.7 104.1 6 92.0 104.5 3 96.6 102.3 10 94.4 103.9 74 95.4 104.0 48 101.7 101.3 70 93.9 105.1 00 96.5 Sample-7 105.7 97.0 105.3 1 95.1 105.7 2 95.5 106.1 30 96.0 104.9 04 93.7 103.1 33 100.1 103.1 90 92.6 104.1 80 94.7 Sample-8 106.9 100.9 104.9 4 93.8 104.1 4 92.2 104.3 20 96.4 103.2 03 96.0 104.5 54 100.2 99.53 0 91.2 103.2 80 96.7 Sample-9 105.6 99.4 101.8 9 92.4 105.4 0 95.7 104.3 20 96.6 104.1 22 95.6 102.8 78 101.2 103.2 30 95.4 103.8 00 95.1 Sample-10 105.4 93.7 103.7 9 91.1 103.3 8 95.9 104.3 50 96.3 104.5 92 95.2 103.9 42 102.9 101.0 90 92.4 101.9 80 94.6 Mean 98.5 94.1 93.8 95.7 95.0 99.7 93.2 95.0 Min. 90.7 91.1 87.7 92.7 92.3 96.2 91.2 93.1 Max. 104.8 97.0 96.6 96.6 96.3 102.9 95.4 97.3 % RSD 4.2 2.1 3.1 5.7 6.4 5.5 1.3 1.5 AV 9.8 9.2 11.7 1.3 1.2 2.3 8.1 6.9 Related Substances (%) RRT-0.749 ND ND ND ND ND ND 0.27* 1.55* RRT-0.916 BQL BQL BQL BQL BQL BQL BQL BQL RRT-0.922 0.05 0.05 0.05 0.05 0.05 0.06 BQL BQL 2-methyl OTRA-09 BQL BQL BQL BQL BQL BQL BQL BQL Batch No. 111AJ(1192) 01 111AJ(1192) 11 111AJ(1192) 12 111AJ(1192) 13 111AJ(1192) 18 111AJ(1192) 19 111AJ(1214) 19 111AJ(1214) 20 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC MONO BN Free 0.07 0.07 0.07 0.07 0.07 0.07 0.06 0.07 Total 0.12 0.12 0.12 0.12 0.12 0.12 0.33 1.62 Single max unknown 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.06 (RRT-0.922) 0.27 RRT-0.749) 1.55 (RRT-0.749) SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride * Unknown peak observed which might be due to mfg. process contamination or due to CPC (Surfactant) Example 9: 10 mg amorphous obicetrapib hemicalcium single active formulation made by wet granulation

[0297] Manufacturing steps for making 10 mg tablets containing amorphous obicetrapib hemicalcium by wet granulation are set forth in Table 53 below Table 53: Manufacturing steps of Obicetrapib Tablets 10 mg Wet granulation Sr. No. Manufacturing Steps for Wet Granulation (Batch Size : 7000 Tablets) Step-1 All the materials were dispensed as per formula composition. Step-2 Half quantity of mannitol was sifted through ASTM # 20 and transferred to 5L RMG for bowl saturation for 2 min. Step-3 API and all intra granular materials (Obicetrapib calcium, microcry stalline cellulose, remaining mannitol, sodium starch glycolate and povidone) were co-sifted through ASTM # 20. These cosifted materials were added to RMG bowl and mixed at slow impeller (280 rpm) speed for 5 min. Step -4 Binder preparation: Surfactant was dissolved in required quantity of purified water. Step-5 The dry mixed blend of Step-3 was granulated using binder solution of step-4 at slow impeller (280 rpm)and slow chopper (1440 rpm) speed. The blend was then kneaded for 30 sec at slow impeller (280 rpm) and slow chopper (1440 rpm) speed. Step-6 The wet granules of Step-5 were dried using fluid bed dryer (6L Retsch TG 200 dryer) at inlet temperature of approximately 60 °C to achieve the target LOD of NMT 2.5 %. Step- 7 Dried granules of Step-6 were passed through ASTM # 20. Step-8 ASTM # 20 retained granules of Step-7 were (wherever necessary) milled through 1.143 mm round screen in Quadro Co-mil(U5) at 2000 RPM. Step-9 The ASTM #20 passed granules and Step-8 milled granules were mixed and blended in 3L conta blender for 5 min at 23 RPM. Step-10 Extra granular sodium starch glycolate was sifted through ASTM # 30 and added into the conta blender containing Step-9 material and mixed for 5 min at 23 RPM. Step-11 Extra granular magnesium stearate was sifted through ASTM #30 and added into conta blender containing material of Step-10 and lubrication was performed for 5 min at 23 RPM. Step-12 Final lubricated blend was compressed in compression machine using 7.00 mm, round shaped, plain on both sides- tooling. Step-13 The tablets were coated using 250 mm auto-coater to a target weight gain of 3.0% w / w.

[0298] Eight batches of tablets were made having the ingredients set forth in Table 54. Table 54: Composition details of Surfactant evaluation trials of Obicetrapib Tablets 10 mg Wet Granulation Batch No. 111AJ(11 92)33 111AJ(1192 )44 111AJ(1192 )46 111AJ(1192 )48 111AJ(1192 )81 111AJ(1192 )83 111AJ(1214 )31 111AJ(1214 )33 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Sr. No Batch Size 7000 Tablets Ingredients mg / tab %w / w mg / ta b %w / w mg / ta b %w / w mg / ta b %w / w mg / ta b %w / w mg / ta b %w / w mg / ta b %w / w mg / ta b %w / w Intra granular 1 Obicetrapib calcium 10.2 60 6.84 10.26 0 6.84 10.26 0 6.84 10.26 0 6.84 10.26 0 6.84 10.26 0 6.84 10.26 0 6.84 10.26 0 6.84 2 Microcrystallin e cellulose (Avicel PH 101) 62.3 70 41.58 61.37 0 40.91 57.37 0 38.25 47.37 0 31.58 61.37 0 40.91 57.37 0 38.25 61.87 0 41.25 60.87 0 40.58 3 Mannitol (Pearlitol 50 C) 62.3 70 41.58 62.37 0 41.58 62.37 0 41.58 62.37 0 41.58 62.37 0 41.58 62.37 0 41.58 62.37 0 41.58 62.37 0 41.58 4 Surfactant ss till 1.000 0.67 5.000 3.33 15.00 0 10.00 1.000 0.67 5.000 3.33 0.500 0.33 1.500 1.00 5 Sodium starch glycolate Type A (Glycolys) 6.00 0 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6 Povidone (Kollidon 30) 1.50 0 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 7 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Extra granular 8 Sodium starch glycolate Type A (Glycolys) 6.00 0 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 6.000 4.00 9 Magnesium stearate (LigamedMF-2-V) 1.50 0 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 1.500 1.00 Total weight of Core Tablet 150. 000 100.0 0 150.0 00 100.0 0 150.0 00 100.0 0 150.0 00 100.0 0 150.0 00 100.0 0 150.0 00 100.0 0 150.0 00 100.0 0 150.0 00 100.0 0 10 Opadry ® II white 32K280000 4.50 0 3.00 4.500 3.00 4.500 3.00 4.500 3.00 4.500 3.00 4.500 3.00 4.500 3.00 4.500 3.00 Total weight of Coated Tablet 154. 500 NA 154.5 00 NA 154.5 00 NA 154.5 00 NA 154.5 00 NA 154.5 00 NA 154.5 00 NA 154.5 00 NA SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0299] The tablets were characterized according to the methods set forth in Table 55. Table 55: In-process characterization of lubricated blend of Obicetrapib Tablets 10 mg Wet Granulation Batch No. 111AJ(11 92)33 111AJ(11 92)44 111AJ(11 92)46 111AJ(11 92)48 111AJ(11 92)81 111AJ(11 92)83 111AJ(121 4)31 111AJ(121 4)33 Remar k Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Bulk Density (g / mL) 0.4411 0.4225 0.4615 0.5454 0.4109 0.4411 0.4109 0.4166 Tapped Density (g / mL) 0.5769 0.5769 0.5882 0.8333 0.5555 0.5660 0.5555 0.5263 Compre ssibility Index (%) 23.5294 26.7605 21.5384 34.5454 26.0274 22.0588 26.0274 20.8333 Hausne r Ratio 1.3077 1.3654 1.2745 1.5277 1.3518 1.2830 1.3518 1.2631 Flowab ility index 333 (Disc no. 3) (Excellent) 71 (Disc no. 14) (Medium) 76 (Disc no. 13) (Medium) 45 (Disc no. 22) (Poor) 76 (Disc no. 13) (Medium) 52 (Disc no. 19) (Medium) 250 (Disc no. 4) (Excellent) 333 (Disc no. 3) (Excellent) ASTM Sieve # % wt. reta ine d % cu m. wt. reta ine d % wt. reta ine d % cu m. wt. reta ine d % wt. reta ine d % cu m. wt. reta ine d % wt. reta ine d % cu m. wt. reta ine d % wt. reta ine d % cu m. wt. reta ine d % wt. reta ine d % cu m. wt. reta ine d % wt. reta ine d % cum . wt. Ret aine d % wt. reta ine d % cum . wt. Ret aine d 20# (850 hm) 0.0 0 0.0 0 0.0 0.0 0.0 0.0 0.7 0.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 30# (600 hm) 0.6 7 0.6 7 2.7 2.7 3.3 3.3 12. 0 12. 7 3.3 3.3 4.0 4.0 3.0 3.0 6.0 6.0 40# (425 Hm) 0.6 7 1.3 3 2.7 5.3 4.0 7.3 14. 7 27. 3 3.3 6.7 4.7 8.7 2.7 6.0 4.7 10.7 60# (250 hm) 11. 33 12. 67 4.7 10. 0 6.7 14. 0 14. 0 41. 3 3.3 10. 0 6.3 14. 0 3.3 9.3 5.3 16.0 80# (180 Hm) 3.3 3 16. 00 4.0 14. 0 9.3 23. 3 13. 3 54. 7 4.0 14. 0 6.0 20. 0 4.0 13.3 6.0 22.0 100# (150 hm) 6.0 0 22. 00 4.0 18. 0 8.0 31. 3 8.7 63. 3 4.0 18. 0 5.3 25. 3 3.3 16.7 5.3 27.3 200# (75 gm) 30. 00 52. 00 42. 7 60. 7 41. 3 72. 7 28. 0 91. 3 45. 3 63. 3 36. 0 61. 3 35. 3 52.0 36. 0 63.3 Pan 48. 00 100 .00 39. 3 100 .0 27. 3 100 .0 8.7 100 .0 36. 7 100 .0 38. 7 100 .0 48. 0 100. 0 36. 7 100. 0 SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0300] The tablets were coated in accordance with Table 56, and the disintegration time ranges are also provided in Table 56. Table 56: Coating parameters of Obicetrapib Tablets 10 mg Wet Granulation Batch No. 111AJ(119 2)33 111AJ(119 2)44 111AJ(119 2)46 111AJ(119 2)48 111AJ(119 2)81 111AJ(119 2)83 111AJ(121 4)31 111AJ(121 4)33 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Coating paramet ers Coating Pan size 250 mm 250 mm 250 mm 250 mm 250 mm 250 mm 250 mm 250 mm Inlet temp. (°C) 62.8 to 63.5 64.8 to 64.9 62.8 to 63.4 64.8 to 65.2 62.9 to 63.8 64.4 to 64.9 65.2 to 66.3 66.3 to 66.7 Bed temp. (°C) 39.1 to 39.6 40.1 to 40.8 39.5 to 40.4 39.8 to 40.9 38.8 to 40.1 38.7 to 39.9 39.6 to 40.3 38.5 to 39.4 Exhaust temp. (°C) 46.5 to 47.7 47.1 to 47.4 45.8 to 48.2 46.8 to 47.1 45.7 to 49.9 49.5 to 49.9 50.7 to 51.4 50.3 to 50.8 Spray Rate (g / min) 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Atomizat ion (kg / cm2) 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 Fan air (kg / cm2) 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 % Weight gain 3.15 3.10 3.16 3.08 3.01 3.09 3.10 3.12 Avg. tablet weight (range / %RSD)(mg ) 155.07 (154.3 to 155.8 / 0.33%) 154.91 (153.8 to 155.8 / 0.45 %) 155.36 (153.9 to 157.0 / 0.61 %) 155.42 (154.1 to 156.2 / 0.45%) 155.13 (154.4 to 156.0 / 0.35%) 154.95 (154.1 to 156.3 / 0.51%) 154.47 (153.5 to 155.8 / 0.47 %) 154.94 (153.6 to 156.0 / 0.50 %) Tablet hardness Avg. (Range) (kP) 9.2 (8.2 to 9.1 (7.3 to 9.3 (8.7 to 6.7 (6.2 to 9.4 ( 8.9 to 9.4 (8.9 to 10.1 (9.8 to 8.9 (7.5 to 10.2) 10.4) 9.8) 7.4) 10.6) 10.3) 10.7) 9.6) Tablet thickness 3.75 3.77 3.71 3.72 3.71 3.71 3.37 3.68 Avg.(Range) (3.73 to (3.71 to (3.66 to (3.69 to (3.69 to (3.68 to (3.65 to (3.65 to (mm) 3.79) 3.85) 3.74) 3.75) 3.74) 3.74) 3.68) 3.72) Disintegration time (min: sec) 03:57 to 05:50 to 07:27 to 14:01 to 04:26 to 07:56 to 08:21 to 07:56 to 06:03 06:31 08:28 16:21 05:26 08:59 09:48 10:02 SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0301] The tablets were exposed to various dissolution media including those set forth in Table 57, and the dissolution results are provided therein. Table 57: Dissolution results of Obicetrapib Tablets 10 mg for 0.2%w / v Tween 80 in 50mM Phosphate buffer pH 6.8 Wet Granulation Batch No. 111AJ(1192) 33 111AJ(1192) 44 111AJ(1192) 46 111AJ(1192) 48 111AJ(U92) 81 111AJ(1192) 83 111AJ(1214) 31 111AJ(1214) 33 Remar k Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Media Conditi on 0.2%w / v Tween 80 in 50mM Phosphate buffer pH 6.8,1000 mL_USP Type II_75 RPM (n=6) (Coated Tablets) Time point Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D Mean %RS D 5 min 44 21.3 61 21.5 33 5.6 18 15.3 47 8.7 32 4.0 20 2.8 11 5.7 10 min 81 5.0 92 4.3 70 3.7 43 11.7 83 2.1 68 2.4 52 1.6 32 4.0 15 min 94 1.8 99 1.0 90 1.2 64 8.6 95 1.3 87 1.3 77 1.0 56 3.1 20 min 99 0.8 101 0.7 96 1.1 81 5.5 100 1.4 94 0.7 88 0.7 71 2.0 30 min 101 0.7 102 0.6 99 1.2 98 1.5 103 1.4 100 1.0 96 0.7 85 0.7 45 min 102 0.7 102 0.6 100 1.5 101 1.8 104 1.4 103 1.1 99 0.4 93 1.1 60 min 102 0.7 102 0.8 100 1.5 101 2.5 105 1.4 104 0.9 100 0.8 96 0.8 SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0302] Table 58 shows various data collected on the tablets such as assay, content uniformity, and related substances. Table 58 Assay and Content uniformity results of Obicetrapib Tablets 10 mg _ Wet Granulation Batch No. 111AJ(1192) 33 111AJ(1192) 44 111AJ(1192) 46 111AJ(1192) 48 111AJ(U92) 81 111AJ(U92) 83 111AJ(1214) 31 111AJ(1214) 33 Remar k Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Blend Assay (%) 97.2 (1X-3X) 96.9 (3X-5X) NA Tablet Assay (%) 99.3 100.4 97.5 100.5 102.4 101.9 100.3 101.1 Batch No. 111AJ(1192) 33 111AJ(1192) 44 111AJ(1192) 46 111AJ(1192) 48 111AJ(1192) 81 111AJ(1192) 83 111AJ(1214) 31 111AJ(1214) 33 Remar k Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Content Uniformity Sample Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Tablet wt.(m g) Assay (%) Sample -1 155.9 12 99.2 153.8 99.2 154.1 95.7 156.3 95.9 157.7 101.2 157.2 101.2 155.1 99.5 155.7 6 100.9 Sample -2 155.8 09 98.4 155.0 99.8 157.1 95.0 156.2 101.3 156.1 103.4 155.8 100.4 155.9 9 99.6 158.1 8 102.0 Sample -3 154.0 01 98.3 155.8 100.5 154.9 96.2 156.2 98.3 154.8 102.9 154.6 99.6 153.9 8 99.5 153.9 3 101.2 Sample -4 156.5 59 100.1 156.2 100.1 155.2 96.6 156.2 98.7 155.3 101.9 156.9 101.4 156.4 2 100.0 153.7 4 100.2 Sample -5 157.9 92 100.1 157.1 102.1 157.3 97.0 157.3 103.7 156.8 101.6 157.4 101.6 155.3 8 100.6 153.3 9 99.7 Sample -6 156.9 85 96.3 156.1 99.3 156.9 93.7 159.0 100.4 153.8 101.3 155.3 100.8 156.9 7 98.5 154.4 2 101.2 Sample -7 157.8 93 99.9 156.5 101.5 155.3 94.2 156.3 100.3 156.6 102.6 156.4 102.8 156.7 2 101.1 156.1 6 100.6 Sample -8 159.4 22 100.7 156.2 101.2 154.5 96.7 160.1 104.7 156.8 102.3 157.0 101.6 154.7 2 98.2 157.9 3 100.9 Sample -9 155.5 55 98.4 154.6 99.9 154.6 95.0 154.8 98.8 155.3 102.6 155.6 98.5 153.9 99.7 155.6 6 99.6 Sample -10 156.7 08 99.1 154.4 100.5 154.4 95.1 156.4 102.4 156.1 103.5 155.9 102.8 155.2 9 100.5 156.6 1 100.3 Mean 99.0 100.4 95.5 100.5 102.3 101.1 99.7 100.7 Min. 96.3 99.2 93.7 95.9 101.2 98.5 98.2 99.6 Max. 100.7 102.1 97.0 104.7 103.5 102.8 101.1 102.0 % RSD 3.1 0.9 1.1 2.7 0.8 1.3 0.9 0.7 AV 1.3 2.3 5.6 6.4 2.8 3.2 2.2 1.8 Related Substances RRT-0.749 ND ND ND ND ND ND 0.37* ND RRT-0.916 BQL BQL BQL BQL BQL BQL BQL BQL RRT-0.922 0.05 0.05 0.05 0.05 0.05 0.06 0.05 BQL 2-methyl OTRA-09 BQL BQL BQL BQL BQL BQL BQL BQL MONO BN Free 0.07 0.08 0.07 0.07 0.07 0.08 0.07 0.07 Total 0.12 0.13 0.12 0.12 0.12 0.14 0.49 0.07 Single max unkno wn 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.05 (RRT-0.922) 0.06 (RRT-0.922) 0.37 (RRT-0.749) NA SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0303] In Figure 28 and Figure 29, release of various tablets is depicted versus a control. It was observed that CPC (a cationic surfactant) had a release that was slower than the control. At low surfactant concentrations (Img SLS and 1 mg Tween 80), and increase in dissolution rate was observed for roughly equivalent disintegration times of 5-6 minutes. While higher surfactant contents had lower release rates (Fig. 29), their disintegration times were higher by about 60%-70%. Example 10: 10 mg amorphous obicetrapib hemicalcium single active formulation made by wet granulation - II

[0304] Manufacturing steps for making 10 mg tablets containing amorphous obicetrapib hemicalcium by wet granulation were made in a similar manner as in Example 9. With these tablets however, it was attempted to have tablets with similar disintegration times. The primary difference between these sets of tablets and those of Example 9 was the amount of water used in the granulation process. For the tablets of Example 9, the granulation process parameters of Table 59 were used. Table 59: Granulation process parameters of Obicetrapib Tablets 10 mg _ Wet Granulation (Example 9) Batch No. 111AJ(1192 )33 111AJ(1192 )44 111AJ(1192 )46 111AJ(1192 )48 111AJ(1192 )81 111AJ(1192 )83 111AJ(1214 )31 111AJ(1214 )33 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Process Steps In 5L RMG In 5L RMG In 5L RMG In 5L RMG In 5L RMG In 5L RMG In 5L RMG In 5L RMG Dry mixing Intra 5 min at Impeller 280 rpm (Slow) LOD of dry mixture* 2.35 % 2.79 % 2.27 % 2.73 % 2.63 % 2.94 % 3.17% 2.92 % Granulation %   w / w water of Intra 30+5= 35 % w / w 30+5= 35 % w / w 30+5= 35 % w / w 30+5= 35 % w / w 30+5= 35 % w / w 30+5= 35 % w / w 30+5= 35 % w / w 30+5= 35 % w / w Water addition time 04:58 (min: sec) 04:46 (min: sec) 04:37 (min: sec) 05:03 (min: sec) 04:39 (min: sec) 04:39 (min: sec) 04:43 (min: sec) 04:41 (min: sec) Kneading ti me 30 sec 30 sec 30 sec 30 sec 30 sec 30 sec 30 sec 30 sec Note During granulation Impeller kept at 280 rpm (Slow) and Chopper at 1440 rpm (Slow) LOD of wet granules* 25.49 % 26.19% 25.51 % 25.64 % 26.81 % 26.86 % 26.10% 24.22 % Drying (Retsch Dryer) Inlet Temperatur e 60°C 60°C 60°C 60°C 60°C 60°C 60°C 60°C Air Flow 15% 15% 15% 15% 15% 15% 15% 15% Drying Time 38 min 40 min 40 min 50 min 50 min 50 min 40 min 40 min LOD of dried granules* 2.05 % 2.04 % 2.21 % 2.44 % 1.79% 1.75% 1.49% 1.63% Sifting and Milling Sifting through ASTM # 20 Performed Performed Performed Performed Performed Performed Performed Performed ASTM#20 retained granules -3.0 g$ -12.0 g$ - 260.0 g (27%) - 942.0 g (98%) ~40.0g$ - 240.4 g (25%) -21.0 g$ ~36.0g$ Batch No. 111AJ(1192 )33 111AJ(1192 )44 111AJ(1192 )46 111AJ(1192 )48 111AJ(U92 )81 111AJ(1192 )83 111AJ(1214 )31 111AJ(1214 )33 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Co-milling (1.143 mm round -2000 rpm) Not Required Not Required Performed Performed Not Required Performed Not Required Not Required *at 105°C for 5 min #at 105 °C for 10 min $Manually passed through ASTM # 20 sieve SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0305] 35% water was used in the granulation of Example 9 tablets which, when combined with surfactants, led to large undesirable agglomerates as seen in Table 60 from the sieve analysis. Larger agglomerates tend to make for poor compressibility. Table 60: In-process characterization of lubricated blend of Obicetrapib Tablets 10 mg Wet Granulation (Example 9) Batch No. 111AJ(1 192)33 111AJ(1 192)44 111AJ(1 192)46 111AJ(1 192)48 111AJ(1 192)81 111AJ(1 192)83 111AJ(1 214)31 111AJ(1 214)33 Remark Control 1 mg SLS 5 mg SLS 15 mg SLS 1 mg Tween 80 5 mg Tween 80 0.5 mg CPC 1.5 mg CPC Bulk Density (g / mL) 0.4411 0.4225 0.4615 0.5454 0.4109 0.4411 0.4109 0.4166 Tapped Density (g / mL) 0.5769 0.5769 0.5882 0.8333 0.5555 0.5660 0.5555 0.5263 Compre ssibility Index (%) 23.5294 26.7605 21.5384 34.5454 26.0274 22.0588 26.0274 20.8333 Hausner Ratio 1.3077 1.3654 1.2745 1.5277 1.3518 1.2830 1.3518 1.2631 Flowabi lity index 333 (Disc no. 3) (Excellen t) 71 (Disc no. 14) (Medium 76 (Disc no. 13) (Medium 45 (Disc no. 22) (Poor) 76 (Disc no. 13) (Medium 52 (Disc no. 19) (Medium 250 (Disc no. 4) (Excellen t) 333 (Disc no. 3) (Excellen t) ASTM Sieve # % wt. reta ined % cum . wt. retai ned % wt. retai ned % cum . wt. retai ned % wt. retai ned % cum . wt. retai ned % wt. retai ned % cum . wt. retai ned % wt. retai ned % cum . wt. retai ned % wt. retai ned % cum . wt. retai ned % wt. reta ined % cum . wt. Reta ined % wt. reta ined % cum . wt. Reta ined 20# (850 pm) 0.0 0 0.0 0 0.0 0.0 0.0 0.0 0.7 0.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 30# (600 pm) 0.6 7 0.6 7 2.7 2.7 3.3 3.3 12. 0 12. 7 3.3 3.3 4.0 4.0 3.0 3.0 6.0 6.0 40# (425 pm) 0.6 7 1.3 3 2.7 5.3 4.0 7.3 14. 7 27. 3 3.3 6.7 4.7 8.7 2.7 6.0 4.7 10. 7 60# (250 pm) 11. 33 12. 67 4.7 10. 0 6.7 14. 0 14. 0 41. 3 3.3 10. 0 6.3 14. 0 3.3 9.3 5.3 16. 0 80# (180 pm) 3.3 3 16. 00 4.0 14. 0 9.3 23. 3 13. 3 54. 7 4.0 14. 0 6.0 20. 0 4.0 13. 3 6.0 22. 0 100# (150 pm) 6.0 0 22. 00 4.0 18. 0 8.0 31. 3 8.7 63. 3 4.0 18. 0 5.3 25. 3 3.3 16. 7 5.3 27. 3 200# 30. 52. 42. 60. 41. 72. 28. 91. 45. 63. 36. 61. 35. 52. 36. 63. (75 pm) 00 00 7 7 3 7 0 3 3 3 0 3 3 0 0 3 Pan 48. 100 39. 10 27. 10 8.7 10 36. 10 38. 10 48. 100 36. 100 00 .00 3 0.0 3 0.0 0.0 7 0.0 7 0.0 0 .0 7 .0 SLS = Sodium lauryl sulphate CPC = Cetylpyridinium chloride

[0306] In the tablets of Example 10, 2 tablet batches were made, 2.5 mg SLS and 5 mg SLS with 18% and 15% water respectively, as shown in Table 61. Table 61: Granulation process parameters of Obicetrapib Tablets 10 mg _ Wet Granulation (Example 10) Batch No. 111AJ(1192)33 111AJ(1214)55 111AJ(1214)57 Remark Control (Reference) 2.5 mg SLS 5 mg SLS Process Steps In 5L RMG In 5L RMG In 5L RMG Dry mixing Intra 5 min at Impeller 280 rpm (Slow) LOD of dry mixture* 2.35 % 2.93 % 2.19% Granulation % w / w water of Intra 30+5= 35 % w / w 15+3=18% w / w 15 % w / w Water addition time 04:58 (min:sec) 05:08 (min:sec) 04:48 (min:sec) Kneading time 30 sec 1 min 1 min Note During granulation Impeller kept at 280 rpm (Slow) and Chopper at 1440 rpm (Slow) LOD of wet granules* 25.49 % 15.18% 14.91% Drying (Retsch Dryer) Inlet Temperature 60°C 60°C 60°C Air Flow 15% 10% 10% Drying Time 38 min 25 min 25 min LOD of dried granules* 2.05 % 1.58% 1.35% Sifting and Milling Sifting through ASTM # 20 Performed Performed Performed ASTM # 20 retained granules ~3.0g$ ~ 18.0 g$ 40.0 g (4%) Co-milling (1.143 mm round - 2000 rpm) Not Required Not Required Performed *At 105°C for 5 min     | #At 105°C for 10 min | $Manually passed through ASTM # 20 sieve

[0307] The sieve analysis is set forth in Table 62. Table 62: In-process characterization of lubricated blend of Obicetrapib Tablets 10 mg _ Wet Granulation (Example 10) Batch No 111AJ(1192)33 111AJ(1214)55 111AJ(1214)57 Batch Details Control_ 35%w / w water 2.5 mg SLS_ 18%w / w water 5 mg SLS_ 15%w / w water Bulk Density (g / mL) 0.4411 0.4838 0.5000 Tapped Density (g / mL) 0.5769 0.6000 0.6122 Compressibility Index (%) 23.5294 19.3548 18.3333 Hausner Ratio 1.3077 1.2400 1.2245 Flowability index 333 (Disc no. 3) 200 (Disc no. 5) 200 (Disc no. 5) (Excellent) (Excellent) (Excellent) ASTM Sieve # % wt. retained % cum. wt. retained % wt. retained % cum. wt. retained % wt. retained % cum. wt. retained 20# (850 pm) 0.00 0.00 0.00 0.00 1.33 1.33 30# (600 pm) 0.67 0.67 4.67 4.67 11.33 12.67 40# (425 pm) 0.67 1.33 4.00 8.67 8.67 21.33 60# (250 pm) 11.33 12.67 6.00 14.67 8.00 29.33 80# (180 pm) 3.33 16.00 4.00 18.67 4.00 33.33 100# (150 pm) 6.00 22.00 4.00 22.67 2.67 36.00 200# (75 pm) 30.00 52.00 30.00 52.67 23.33 59.33 Pan 48.00 100.00 47.33 100.00 40.67 100.00 SLS = Sodium lauryl sulphate

[0308] These tablets led to a smaller partial size distribution based on the Pan results. The amount left on the pan are fines of small particle size. In Example 9, for the 5 mg SLS, the Pan percentage was 27.3% whereas for Example 10, it was 40.67%.

[0309] With respect to dissolution, in 0.05% Tween 80 (a solution which is more discriminating than 0.2% Tween 80), Figure 30 shows faster release for tablets made according to Example 10 with less water and more fines.

[0310] The composition of the two batches were made (and a control) are set forth in Table 63. Table 63: Composition details of Surfactant evaluation trials of Obicetrapib Tablets 10 mg Wet Granulation Batch No. 111AJ(1192)33 111AJ(1214)55 111AJ(1214)57 Remark Control (Reference) 2.5 mg SLS 5 mg SLS Sr. No. Batch Size 7000 Tablets Ingredients mg / tab %w / w mg / tab %w / w mg / tab %w / w Intra granular 1 Obicetrapib calcium 10.260 6.84 10.260 6.84 10.260 6.84 2 Microcrystalline cellulose (AvicelPH 101) 62.370 41.58 59.870 39.91 57.370 38.25 3 Mannitol (Pearlitol 50 C) 62.370 41.58 62.370 41.58 62.370 41.58 4 Surfactant NA NA 2.500 1.67 5.000 3.33 5 Sodium starch glycolate Type A (Glycolys) 6.000 4.00 6.000 4.00 6.000 4.00 6 Povidone (Kollidon 30) 1.500 1.00 1.500 1.00 1.500 1.00 7 Purified water q.s. q.s. q.s. q.s. q.s. q.s. Extra granular 8 Sodium starch glycolate Type A (Glycolys) 6.000 4.00 6.000 4.00 6.000 4.00 9 Magnesium stearate (Ligamed MF-2-V) 1.500 1.00 1.500 1.00 1.500 1.00 Total weight of Core Tablet 150.000 100.00 150.000 100.00 150.000 100.00 10 Opadry ® II white 32K280000 4.500 3.00 4.500 3.00 4.500 3.00 Total weight of Coated Tablet 154.500 NA 154.500 NA 154.500 NA SLS = Sodium lauryl sulphate

[0311] The tablets were characterized according to the methods set forth in Table 64. Table 64: In-process characterization of lubricated blend of Obicetrapib Tablets 10 mg _ Wet Granulation Batch No 111AJ(1192)33 111AJ(1214)55 111AJ(1214)57 Batch Details Control_ 35%w / w water 2.5 mg SLS_ 18%w / w water 5 mg SLS_ 15%w / w water Bulk Density (g / mL) 0.4411 0.4838 0.5000 Tapped Density (g / mL) 0.5769 0.6000 0.6122 Compressibility Index (%) 23.5294 19.3548 18.3333 Hausner Ratio 1.3077 1.2400 1.2245 Flowability index 333 (Disc no. 3) (Excellent) 200 (Disc no. 5) (Excellent) 200 (Disc no. 5) (Excellent) ASTM Sieve # % wt. retained % cum. wt. retained % wt. retained % cum. wt. retained % wt. retained % cum. wt. retained 20# (850 gm) 0.00 0.00 0.00 0.00 1.33 1.33 30# (600 gm) 0.67 0.67 4.67 4.67 11.33 12.67 40# (425 gm) 0.67 1.33 4.00 8.67 8.67 21.33 60# (250 gm) 11.33 12.67 6.00 14.67 8.00 29.33 80# (180 gm) 3.33 16.00 4.00 18.67 4.00 33.33 100# (150 gm) 6.00 22.00 4.00 22.67 2.67 36.00 200# (75 gm) 30.00 52.00 30.00 52.67 23.33 59.33 Pan 48.00 100.00 47.33 100.00 40.67 100.00 SLS = Sodium lauryl sulphate

[0312] The tablets were coated in accordance with Table 65, and the disintegration time ranges are also provided in Table 65. of ib Tablets 10 Wet Granulation Table 65: Batch No. 111AJ(1192)33 111AJ(1214)55 111AJ(1214)57 Remark Control-35%w / w water (Reference) 2.5 mg SLS_ 18%w / w water 5 mg SLS_ 15%w / w water Coating parameters Coating Pan size 250 mm 250 mm 250 mm Inlet temp. (°C) 62.8 to 63.5 59.1 to 62.2 60.1 to 60.3 Bed temp. (°C) 39.1 to 39.6 38.6 to 39.3 39.5 to 39.9 Exhaust temp. (°C) 46.5 to 47.7 47.3 to 48.7 48.2 to 48.4 Spray Rate (g / min) 6.0 6.2 6.2 Atomization (kg / cm2) 1.8 1.8 1.8 Fan air (kg / cm2) 1.8 1.8 1.8 % Weight gain 3.15 3.00 3.00 Avg. tablet weight (range / %RSD)(mg) 155.07 (154.3 to 155.8 / 0.33%) 154.56 (153.7 to 155.4 / 0.41 %) 154.59 (152.1 to 156.3 / 0.97%) Tablet hardness Avg. (Range) (kP) 9.2 (8.2 to 10.2) 6.4 (5.6 to 6.9) 5.8 (4.4 to 6.6) Tablet thickness Avg.(Range) (mm) 3.75 (3.73 to 3.79) 3.80 (3.78 to 3.84) 3.82 (3.78 to 3.86) Disintegration time (min: sec) 03:57 to 06:03 03:54 to 04:30 04:00 to 05:10

[0313] The tablets were exposed to various dissolution media including those set forth in Table 66, and the dissolution results are provided therein. ib Tablets 10 Wet Granulation Table 66: Dissolution results Batch No. 111AJ(1192)33 111AJ(1214)55 111AJ(1214)57 Remark Control (Reference) 2.5 mg SLS 5 mg SLS Media Condition 0.05%w / v Tween 80 in 50mM Phosphate buffer pH 6.8, 1000 mL_USP Type II_75 RPM (n=6) (Coated Tablets) Time point Mean %RSD Mean %RSD Mean %RSD 5 min 30 12.1 56 11.0 46 4.0 10 min 60 5.3 83 3.4 80 5.1 15 min 77 3.2 93 3.6 92 3.0 20 min 86 2.4 97 2.1 96 3.3 30 min 95 2.2 101 3.5 98 3.8 45 min 99 1.7 102 3.5 99 4.7 60 min 100 1.2 101 2.7 99 5.1 SLS = Sodium lauryl sulphate Example 11: Manufacture of Tablets of Table 2A

[0314] Excipients (microcrystalline cellulose, mannitol, sodium starch glycolate and colloidal silicon dioxide) and amorphous obicetrapib hemicalcium are added to a suitable sized tumble blender and blended, screened, and blended further. Magnesium stearate is then added and mixed in the blender. The resulting blend is then compressed on a rotary tablet press with press speed and compression force adjusted as required to meet tablet target parameters. The tablets are film-coated in a perforated pan-coater with an aqueous Opadry II suspension to a target weight gain of 3% (2.0 - 4.0%). Example 12: Manufacture of Tablets of Table 2B

[0315] The following steps were used to manufacture the tablets of Table 2B: Step 1. Mix in a granulating bowl the ingredients (ezetimibe, microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, and sodium lauryl sulphate). Step 2. Granulate the blend of ezetimibe and excipients with purified water. Step 3. Dry the wet blend with warm air in a fluid bed dryer to a target LOD. Step 4. Mill the dried powders through a screen with an impact mill. Step 5. Blend the dried granules and pre-screened amorphous obicetrapib hemicalcium calcium, microcrystalline cellulose, mannitol, sodium starch glycolate, and colloidal silicon dioxide in a suitable tumble blender. The blend is passed through a screen and added back to the blender. For larger batches, a blend may be transferred from a mixing bin to another bin through a screener, with a screen opening equivalent to that used in the impact mill. Step 6. Lubricate the blend with pre-screened magnesium stearate in a suitable tumble blender. Step 7. Compress the lubricated granulation on a rotary tablet press to the target tablet weight. Step 8. Film-coat the core tablets with an aqueous Opadry AMB II suspension in a perforated pan coater. CLAUSES

[0316] The following Clauses represent a number of non-limiting embodiments of the disclosure.

[0317] Clause 1. A pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof and a surfactant and, optionally, one or more additional pharmaceutically acceptable excipients.

[0318] Clause 2. The pharmaceutical composition of clause 1, wherein the surfactant is a salt and the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

[0319] Clause 3. The pharmaceutical composition of clauses 1 or 2, wherein the surfactant is an organosulfur compound.

[0320] Clause 4. The pharmaceutical composition of clauses 1, 2, or 3, wherein the surfactant is a substituted alkyl.

[0321] Clause 5. The pharmaceutical composition of clause 4, wherein the surfactant is monosubstituted.

[0322] Clause 6. The pharmaceutical composition of clause 5, wherein the monosubstituted comprises a sulfur atom.

[0323] Clause 7. The pharmaceutical composition of clause 6, wherein the mono substituent is a sulfate.

[0324] Clause 8. The pharmaceutical composition of clause 1, wherein the surfactant is an anionic surfactant.

[0325] Clause 9. The pharmaceutical composition of clause 1, wherein the surfactant is a cationic surfactant.

[0326] Clause 10. The pharmaceutical composition of clause 1, wherein the surfactant is a non-ionic surfactant.

[0327] Clause 11. The pharmaceutical composition of clause 1, wherein the surfactant is a zwitterionic surfactant.

[0328] Clause 12. The pharmaceutical composition of clauses 1 or 8, wherein the surfactant is a carboxylate, a sulfate, a sulfonate, or a phosphate compound.

[0329] Clause 13. The pharmaceutical composition of clauses 1 or 8, wherein the surfactant is a sulfate or sulfonate.

[0330] Clause 14. The pharmaceutical composition of clauses 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.

[0331] Clause 15. The pharmaceutical composition of clauses 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.

[0332] Clause 16. The pharmaceutical composition of clause 1, wherein the surfactant is sodium lauryl sulfate.

[0333] Clause 17. The pharmaceutical composition of clauses 1 or 9, wherein the surfactant is a quaternary ammonium salt.

[0334] Clause 18. The pharmaceutical composition of clause 17, wherein the surfactant is a pyridinium salt.

[0335] Clause 19. The pharmaceutical composition of clauses 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).

[0336] Clause 20. The pharmaceutical composition of clauses 1 or 10, wherein the surfactant is a polyoxyethylene ester, a polazamer, a glucol, a glycol ester, or a sorbitan derivative.

[0337] Clause 21. The pharmaceutical composition of clauses 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, Polyoxyethylene (20) sorbitan tristearate, Polyoxyethylene (20) sorbitan mono-oleate, Polyoxyethylene (20) sorbitan tri-oleate, polysorbate 20, or polysorbate 80.

[0338] Clause 22. The pharmaceutical composition of clauses 1 or 11, wherein the zwitterionic surfactant is lauryl betaine, lauroyl sarcosinate, lauryl sultaine, lauryl amidopropyl betaine, or lauryldimethylamine oxide

[0339] Clause 23. The pharmaceutical composition of any one of clauses 1 to 22, wherein the HLB of the surfactant is at least 15.

[0340] Clause 24. The pharmaceutical composition of clause 23, wherein the HLB of the surfactant is at least 20.

[0341] Clause 25. The pharmaceutical composition of clause 24, wherein the HLB of the surfactant is at least 30.

[0342] Clause 26. The pharmaceutical composition of clause 25, wherein the HLB of the surfactant is at least 35.

[0343] Clause 27. The pharmaceutical composition of clause 23, wherein the surfactant has an HLB of between 15 and 50, including 15 and 50.

[0344] Clause 28. The pharmaceutical composition of clause 27, wherein the surfactant has an HLB of between 30 and 45, including 30 and 45.

[0345] Clause 29. The pharmaceutical composition of clause 27, wherein the surfactant has an HLB of between 40 and 45, including 40 and 45.

[0346] Clause 30. The pharmaceutical composition of clause 27, wherein the surfactant has an HLB of between 38 and 42, including 38 and 42.

[0347] Clause 31. The pharmaceutical composition of clause 27, wherein the surfactant has an HLB of between 39 and 41, including 39 and 41.

[0348] Clause 32. The pharmaceutical composition of clause 27, wherein the surfactant has an HLB of 38, 39, 40, 41, or 42.

[0349] Clause 33. The pharmaceutical composition of clause 27, wherein the surfactant has an HLB of 40.

[0350] Clause 34. The pharmaceutical composition of any one of clauses 1-33, wherein the surfactant is present in the composition from about 0.2% to about 10% by weight.

[0351] Clause 35. The pharmaceutical composition of clause 34, wherein the surfactant is present in the composition from about 0.5% to about 5% by weight.

[0352] Clause 36. The pharmaceutical composition of clause 35, wherein the surfactant is present in the composition from about 0.5% to about 2% by weight.

[0353] Clause 37. The pharmaceutical composition of clause 35, wherein the surfactant is present in the composition from about 0.5% to about 1% by weight.

[0354] Clause 38. The pharmaceutical composition of clause 35, wherein the surfactant is present in the composition from about 0.5% to about 1.5% by weight.

[0355] Clause 39. The pharmaceutical composition of clauses 1 to 38, wherein the composition comprises an intragranular portion and an extragranular portion.

[0356] Clause 40. The pharmaceutical composition of clause 39, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof and the surfactant are in the intragranular portion.

[0357] Clause 41. The pharmaceutical composition of clauses 1-40, wherein the pharmaceutical composition is uncoated.

[0358] Clause 42. The pharmaceutical composition of clauses 1-40, wherein the pharmaceutical composition is coated.

[0359] Clause 43. The pharmaceutical composition of clauses 1-42, further comprising one or more additional pharmaceutically acceptable excipients.

[0360] Clause 44. The pharmaceutical composition of clause 43, wherein the one or more pharmaceutically acceptable excipients are selected from one or more diluents, binders, disintegrants, a second surfactant, and lubricants.

[0361] Clause 45. The pharmaceutical composition of clause 44, wherein the one or more diluents is an inorganic phosphates, a sugars, a sugar analogue, or a sugar derivative.

[0362] Clause 46. The pharmaceutical composition of clause 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.

[0363] Clause 47. The pharmaceutical composition of clause 45 or clause 46, wherein the one or more diluents is in the intragranular component.

[0364] Clause 48. The pharmaceutical composition of clause 45 or clause 46, wherein the diluent is in the extragranular component.

[0365] Clause 49. The pharmaceutical composition of any one of clauses 44 - 49, wherein the one or more binders is a cellulose derivative.

[0366] Clause 50. The pharmaceutical composition of clauses 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.

[0367] Clause 51. The pharmaceutical composition of any one of clauses 44-49, wherein the one or more binders is sodium alginate, polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone.

[0368] Clause 52. The pharmaceutical composition of any one of clauses 44-49, wherein the one or more binders is copovidone or Kollidon 30.

[0369] Clause 53. The pharmaceutical composition of any one of clauses 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.

[0370] Clause 54. The pharmaceutical composition of any one of clauses 44-52, wherein the one or more disintegrants is croscarmellose sodium or sodium starch glycolate.

[0371] Clause 55. The pharmaceutical composition of clauses 44-54, wherein the one or more lubricants is a fatty acid or fatty acid derivatives.

[0372] Clause 56. The pharmaceutical composition of clauses 44-54, wherein the one or more lubricants is an alkali or earth alkali salts of stearic, lauric or palmitic acid.

[0373] Clause 57. The pharmaceutical composition of clauses 44-54, wherein the one or more lubricants is magnesium stearate. The pharmaceutical composition according to anyone of the preceding clauses 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.

[0374] Clause 58. The pharmaceutical composition according to anyone of clauses 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).

[0375] Clause 59. Use of a pharmaceutical composition according to anyone of clauses 1-57 for preparation of a medicament for treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia.

[0376] Clause 60. Use of a pharmaceutical composition according to anyone of clauses 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).

[0377] Clause 61. Use of a pharmaceutical composition according to anyone of clauses 1-57 for preparation of a medicament for reducing the risk for cardiovascular events.

[0378] Clause 62. Use according to anyone of clauses 1-57, wherein the subject suffers from mild dyslipidemia.

[0379] Clause 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 clauses 1-57 to a patient in need thereof.

[0380] Clause 64. A method of treatment of subjects suffering from hyperlipidemia or mixed dyslipidemia, wherein the method comprises administering the pharmaceutical composition of anyone of clauses 1-57 to a patient in need

[0381] Clause 65. The use of a pharmaceutical composition for preparation of a medicament or a method of treatment according to anyone clauses 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.

[0382] Clause 66. The use of a pharmaceutical composition or a method of treatment according to anyone of clauses 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).

[0383] Clause 67. A pharmaceutical composition comprising an effective dose of any one of the pharmaceutical compositions of clauses 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).

[0384] Clause 68. The pharmaceutical composition of any one of clauses 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.

[0385] Clause 69. The pharmaceutical composition of clause 68, wherein the granule is made through wet granulation.

[0386] Clause 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: 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.

[0387] Clause 71. The process of clause 70, further comprising compressing the granules into tablets.

[0388] Clause 72. The process of clause 71, further comprising mixing the granules with an additional powder and compressing into tablets.

[0389] Clause 73. The process of clause 72, wherein the additional powder comprises one or more excipients.

[0390] Clause 74. The process of clause 73, wherein the additional powder comprises obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0391] Clause 75. The process of clause 73, wherein the additional powder comprises an active ingredient other than obicetrapib.

[0392] Clause 76. The process of any one of clauses 70 to 75 wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemi calcium.

[0393] Clause 77. The process of any one of clauses 70 to 76, further comprising coating the tablets.

[0394] Clause 78. A pharmaceutical composition granule made by the process of clause 70.

[0395] Clause 79. A pharmaceutical composition tablet made by the process of any one of clauses 71 to 78.

[0396] Clause 80. A pharmaceutical composition of any one of clauses 1-57 and 78-70 wherein the composition does not contain ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0397] Clause 81. The processes or uses of any one of clauses 58-67 or 71-77 wherein the pharmaceutical composition does not contain ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0398] Clause 82. A pharmaceutical composition of any one of clauses 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.

[0399] Clause 83. The processes or uses of any one of clauses 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.

[0400] Clause 84. The pharmaceutical composition of clause 82, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemi calcium.

[0401] Clause 85. The process of clause 83, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

[0402] Clause 86. The pharmaceutical composition of any one of clauses 39 - 58 or 68-69, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

[0403] Clause 87. The pharmaceutical composition of any one of clause 1-58, 67-69, 78-80, 82, 84, or 86 wherein the amount of obicetrapib in the pharmaceutical composition is between about 5 and 15 mg.

[0404] Clause 88. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 5 mg.

[0405] Clause 89. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 6 mg.

[0406] Clause 90. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 7 mg.

[0407] Clause 91. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 8 mg.

[0408] Clause 92. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 9 mg.

[0409] Clause 93. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 10 mg.

[0410] Clause 94. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 11 mg.

[0411] Clause 95. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 12 mg.

[0412] Clause 96. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 13 mg.

[0413] Clause 97. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 14 mg.

[0414] Clause 98. The pharmaceutical composition of clause 82, wherein the amount of obicetrapib in the pharmaceutical composition is 15 mg.

[0415] Clause 99. A pharmaceutical composition comprising amorphous obicetrapib hemicalcium and one or more of microcrystalline cellulose, mannitol, sodium glycolate, colloidal silicon dioxide and magnesium stearate.

[0416] Clause 100. The pharmaceutical composition of clause 99, wherein the sodium starch glycolate is type A sodium starch glycolate.

[0417] Clause 101. The pharmaceutical composition of clause 100, wherein the composition is a tablet.

[0418] Clause 102. The pharmaceutical composition of clause 101, wherein the tablet is film coated.

Claims

1. A pharmaceutical composition comprising obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof and 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 monosubstituted 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 anionicsurfactant.

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.

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, 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, lauryl amidopropyl betaine, or lauryldimethylamine oxide23. 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.

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.

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 - 49, 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 itscopolymers, 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 poly vi ny Ipy rroli done.

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.

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.

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 need65. 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 adultswith 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: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; andc. 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 additionalpowder 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 composition does not contain ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

81. The processes or uses of any one of claims 58-67 or 71-77 wherein the pharmaceutical composition does not contain ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

82. 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.

83. 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.

84. The pharmaceutical composition of claim 82, wherein the obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof is amorphous obicetrapib hemicalcium.

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

86. 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.

87. The pharmaceutical composition of any one of claim 1-58, 67-69, 78-80, 82, 84, or 86 wherein the amount of obicetrapib in the pharmaceutical composition is between about 5 and 15 mg.

88. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 5 mg.

89. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 6 mg.

90. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 7 mg.

91. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 8 mg.

92. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 9 mg.

93. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 10 mg.

94. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 11 mg.

95. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 12 mg.

96. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 13 mg.

97. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 14 mg.

98. The pharmaceutical composition of claim 82, wherein the amount of obicetrapib in the pharmaceutical composition is 15 mg.

99. A pharmaceutical composition comprising amorphous obicetrapib hemicalcium and one or more of microcrystalline cellulose, mannitol, sodium glycolate, colloidal silicon dioxide and magnesium stearate.

100. The pharmaceutical composition of claim 99, wherein the sodium starch glycolate is type A sodium starch glycolate.

101. The pharmaceutical composition of claim 100, wherein the composition is a tablet.

102. The pharmaceutical composition of claim 101, wherein the tablet is film coated.

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