WO2024226537A1 - Amorphous obicetrapib and sglt2 inhibitor combination - Google Patents

Abstract

Provided herein is a pharmaceutical composition comprising amorphous calcium salt of obicetrapib and at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. Also provided are dosage forms including the same. In some embodiments, the dosage form is a solid dosage form, such as a tablet. Also provided are processes for the preparation of fixed dose formulations of amorphous obicetrapib calcium and an SGTL2 inhibitor, and methods for using the same in the treatment of a metabolic disorder (e.g., type 2 diabetes) or cardiometabolic disorder. Also provided are methods of treating or preventing a metabolic disorder or cardio-metabolic disorder in a subject who has or is at risk of developing a metabolic disorder or cardio-metabolic disorder, comprising: administering a therapeutically effective amount of obicetrapib, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

Description

AMORPHOUS OBICETRAPIB AND SGLT2 INHIBITOR COMBINATION

1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/497,891, filed April 24, 2023, which is hereby incorporated by reference in its entirety.

2. INTRODUCTION

[0002] Type 2 diabetes is an increasingly prevalent disease. Due to a high frequency of complications, type 2 diabetes leads to a significant reduction of life expectancy. Type 2 diabetes also causes significant morbidity. Because of diabetes-associated microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two- to five-fold increase in cardiovascular disease risk. [0003] It is now widely accepted that glycemic control makes a difference in type II diabetes patients. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in the blood. Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as sulfonylureas, biguanides (metformin), thiazolidinediones (TZDs), and alpha-glucosidase inhibitors. The active agents from each class are generally administered to patients alone. However, once monotherapy becomes inadequate, combination therapy is feasible, despite the known side effect of weight gain associated with sulfonylurea and thiazolidinedione therapies.

[0004] After long duration of disease, most patients with type 2 diabetes will eventually fail on oral therapy and become insulin-dependent, with the necessity for daily injections and multiple daily glucose measurements.

[0005] Thus, there is a need for alternative therapies that can better treat Type 2 diabetes and delay progression to insulin-dependence in type 2 diabetes and similar metabolic disorders.

3. SUMMARY OF THE INVENTION

[0006] The present disclosure provides a pharmaceutical composition comprising amorphous obicetrapib, or the calcium salt thereof, and an SGTL2 inhibitor, or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical dosage forms including the same. In some embodiments, the dosage form is a solid dosage form, such as a tablet. Also provided are processes for the preparation of (i) amorphous obicetrapib and calcium salts thereof, and (ii) fixed dose combination formulations of amorphous obicetrapib or calcium salt thereof and an SGTL2 inhibitor, or pharmaceutically acceptable salt thereof. Also provided are (a) methods for using fixed dose combinations of amorphous obicetrapib or calcium salt thereof and SGLT2 inhibitor or pharmaceutically acceptable salt thereof for treating or preventing a metabolic disorder (e.g., type 2 diabetes) or cardio-metabolic disorder in a subject who has or is at risk of developing a metabolic or cardiometabolic disorder, and (b) methods for treating or preventing a metabolic disorder or cardiometabolic disorder in a subject who has or is at risk of developing a metabolic or cardiometabolic disorder, comprising administering a therapeutically effective amount of amorphous obicetrapib or calcium salt thereof and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0007] A first aspect of this disclosure includes a pharmaceutical composition comprising: a) a therapeutically effective amount of amorphous obicetrapib, or the calcium salt thereof; and b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0008] A second aspect of this disclosure includes a pharmaceutical composition comprising: a) a therapeutically effective amount of amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof; and b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0009] A third aspect of this disclosure includes a pharmaceutical dosage form including a pharmaceutical composition comprising amorphous calcium salt of obicetrapib or amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof (e.g., as described herein). [0010] A fourth aspect of this disclosure includes a method of treating or preventing a metabolic disorder, comprising administering to a subject having or at risk of developing a metabolic disorder a therapeutically effective amount of a pharmaceutical composition comprising amorphous calcium salt of obicetrapib or amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof (e.g., as described herein). [0011] A fifth aspect of this disclosure includes a method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, comprising: administering a therapeutically effective amount of amorphous calcium salt of obicetrapib or amorphous obicetrapib hemicalcium, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0012] In certain embodiments, the metabolic disorder is type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, or metabolic syndrome.

4. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0014] FIGS. 1A-B are x-ray diffraction patterns. FIG. 1A is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium. FIG. IB is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0015] FIG. 2 is an x-ray powder diffraction pattern of crystalline obicetrapib hemi calcium.

[0016] FIGS. 3A-B are polarized light micrographs. FIG. 3A is a polarized light micrograph of amorphous obicetrapib hemicalcium. FIG. 3B is a polarized light micrograph of crystalline obicetrapib hemicalcium.

[0017] FIG. 4 is a thermogravimetric analysis plot of amorphous obicetrapib hemi calcium.

[0018] FIGS. 5A-B are modulated differential scanning calorimetry thermogram plots. FIG. 5A is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium. FIG. 5B is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.

[0019] FIGS. 6A-C are solid-state ¹³C-NMR spectrums. FIG. 6A is a solid-state ¹³C- NMR spectrum of amorphous and crystalline obicetrapib hemicalcium. FIG. 6B is a solid- state ¹³C-NMR spectrum of crystalline obicetrapib hemicalcium. FIG. 6C is a solid-state ¹³C-NMR spectrum of amorphous obicetrapib hemicalcium. [0020] FIGS. 7A-7B are x-ray powder diffraction patterns. FIG. 7A is an x-ray powder diffraction pattern of crystalline HC1 obicetrapib and at least partially desolvated crystalline HC1 obicetrapib. FIG. 7B is an x-ray powder diffraction pattern of crystalline HC1 obicetrapib.

[0021] FIGS. 8A-8B are displays of constructed genetic scores. FIG 8A is a genetic score mimicking CETP inhibition. FIG. 8B is a genetic score mimicking effect of SGLT2 inhibition on glycated hemoglobin levels.

[0022] FIGS. 9A-9B are forest plots. FIG. 9A is a forest plot displaying SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on diabetes incidence relative to control. FIG 9B is a forest plot displaying SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on diabetes incidence relative to each other.

[0023] FIGS. 10A-10B are forest plots. FIG. 10A is a forest plot displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control. FIG. 10B is a forest plot displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to each other.

[0024] FIGS. 11A-11D are forest plots displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels or diabetes relative to control or each other without inclusion of SBP and BMI covariates in the discovery cohort. FIG. 11A displays the according effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control. FIG. 11B displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to SGLT2 inhibition monotherapy, SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to CETP inhibition monotherapy and CETP inhibition monotherapy relative to SGLT2 inhibition monotherapy. FIG. 11C displays the according effect of SGLT2 inhibition monotherapy relative to control, CETP inhibition monotherapy on diabetes relative to control, and SGLT2 inhibition and CETP inhibition combination therapy relative to control. FIG. 11D displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on diabetes relative to SGLT2 inhibition monotherapy, SGLT2 inhibition and CETP inhibition combination therapy relative to CETP inhibition monotherapy, and SGLT2 inhibition monotherapy relative to CETP inhibition monotherapy.

[0025] FIGS. 12A-12D are forest plots displaying the effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control or each other in the replication cohort. FIG. 12A displays the according effect of SGLT2 inhibition monotherapy, CETP inhibition monotherapy, or SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to control. FIG. 12B displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to SGLT2 inhibition monotherapy, of SGLT2 inhibition and CETP inhibition combination therapy on glycated hemoglobin levels relative to CETP inhibition monotherapy, and CETP inhibition monotherapy relative to SGLT2 inhibition monotherapy. FIG. 12C displays the according effect of SGLT2 inhibition monotherapy relative to control, CETP inhibition monotherapy on diabetes relative to control, and SGLT2 inhibition and CETP inhibition combination therapy relative to control. FIG. 12D displays the according effect of SGLT2 inhibition and CETP inhibition combination therapy on diabetes relative to SGLT2 inhibition monotherapy, SGLT2 inhibition and CETP inhibition combination therapy relative to CETP inhibition monotherapy, and SGLT2 inhibition monotherapy relative to CETP inhibition monotherapy.

[0026] FIG. 13 is forest plot displaying CETP genetic score regressed against relevant biomarkers.

[0027] FIG. 14 is a forest plot displaying SGLT2 genetic score regressed against relevant biomarkers.

5. DETAILED DESCRIPTION OF THE INVENTION

[0028] As summarized above, the present disclosure provides a pharmaceutical composition comprising amorphous obicetrapib or the calcium salt thereof and an SGTL2 inhibitor or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical dosage forms including the same. In some embodiments, the dosage form is a solid dosage form, such as a tablet. Also provided are processes for the preparation of (i) amorphous obicetrapib and calcium salts thereof, and (ii) fixed dose combination formulations of amorphous obicetrapib or calcium salt thereof and an SGTL2 inhibitor. Also provided are (a) methods for using fixed dose combinations of amorphous obicetrapib or calcium salt thereof and SGLT2 inhibitor or pharmaceutically acceptable salt thereof for treating or preventing a metabolic disorder (e.g., type 2 diabetes) or cardio-metabolic disorder in a subject who has or is at risk of developing a metabolic or cardiometabolic disorder, and (b) methods for treating or preventing a metabolic disorder or cardiometabolic disorder in a subject who has or is at risk of developing a metabolic or cardiometabolic disorder, comprising administering a therapeutically effective amount of amorphous obicetrapib or calcium salt thereof and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0029] The pharmaceutical compositions of this disclosure are described in greater detail below. The obicetrapib active compound is described, and SGLT2 inhibitors are described. Also described are pharmaceutical compositions including amorphous obicetrapib or calcium salt thereof and a SGTL2 inhibitor or pharmaceutically acceptable salt thereof, pharmaceutical dosage forms comprising amorphous obicetrapib or amorphous obicetrapib calcium, and SGLT2 inhibitors or pharmaceutically acceptable salts thereof, and processes for the preparation of fixed dose formulations of the same. Methods in which the pharmaceutical compositions of this disclosure find use are also described.

5.1. Pharmaceutical Compositions

[0030] As summarized above, this disclosure provides a pharmaceutical composition comprising amorphous obicetrapib, or a calcium salt thereof, and an SGTL2 inhibitor, or a pharmaceutically acceptable salt thereof.

5.1.1. Amorphous obicetrapib

[0031] The pharmaceutical compositions disclosed herein include amorphous obicetrapib, or the calcium salt thereof. Crystalline obicetrapib has previously been described (see, for example, in U.S. Patent No. 7,872,126 and WO 2005/095409A2).

[0032] Obicetrapib, or (2R,4S)-4-{[3,5-bis(trifhroromethyl)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:

[0033] Compared to other known CETP -inhibitors, only a relatively low dose of the compound of Formula (I) is needed to reach near complete CETP inhibition. Typically, repeated daily dosages (once a day) as low as 2.5 mg of the compound of Formula (I) have been shown to be sufficient to reach near complete CETP-inhibition. These are considerably lower dosages than had to be used for other CETP -inhibitors. Moreover, clinical studies have also shown that the compound of Formula (I) is well tolerated and that it does not lead to serious side effects.

[0034] Inhibiting CETP can reduce low-density lipoprotein cholesterol (LDL-C) and elevates high-density lipoprotein cholesterol (HDL-C) levels. CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (Apo B)-containing particles (mainly low-density lipoprotein (LDL) and very low-density lipoprotein VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of that in (V)LDL.

[0035] In some embodiments, the pharmaceutical compositions comprise amorphous obicetrapib calcium salt. In particular embodiments, the pharmaceutical composition comprises amorphous obicetrapib hemicalcium. Furthermore, the compositions can comprise amorphous 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.

[0036] Amorphous obicetrapib or calcium salt thereof 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 with an SGLT2 inhibitor), 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 with an SGLT2 inhibitor), 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.

[0037] In some embodiments, the pharmaceutical composition comprises from about 1% to about 25% w/w of amorphous obicetrapib, or a calcium salt, 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 amorphous obicetrapib or calcium salt, 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 amorphous obicetrapib, or calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.

[0038] In some embodiments, the pharmaceutical composition comprises from 1% to 25% w/w of amorphous obicetrapib or calcium salt, 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 amorphous obicetrapib, or a calcium salt, 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. 5.1.1.1 Amorphous obicetrapib hemicalcium

[0039] 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 FIGs. 1 A and IB. These patterns have the familiar “halo” features that are associated with amorphous materials. The x-ray powder diffraction pattern from FIG. IB has peaks at about 3.4°20, about 7.O°20, and about 9.2°29. The x-ray powder diffraction patterns of either FIG. 1 A or FIG. IB 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°20 (such as in FIG. IB), and that peak, when present, is due to sodium chloride. The x-ray powder pattern of crystalline obicetrapib hemicalcium is shown in FIG. 2. It too exhibits halo-like behavior which may be indicative of disorder.

[0040] Operations 11 and 11 A described in Section 4.1.1.2 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 FIGs 1 and 2; Operation 11 A was generally used for FIG. IB.

[0041] 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.

[0042] In FIG. 3 A, amorphous obicetrapib hemicalcium was analyzed by polarized light microscopy as set forth in Operation 10. As FIG. 3 A shows, the materials under study do not birefringe, indicating that the material is amorphous. By comparison, FIG. 3B is a polarized light micrograph of crystalline obicetrapib hemicalcium. Notably, the compounds shown in FIG. 3B are multi-colored which indicates crystallinity. In addition, the crystals in FIG. 3B are larger than the particles provided in the amorphous obicetrapib hemicalcium polarized light micrograph of FIG. 3 A. Accordingly, PLM and/or the lack of birefringence can be used to characterize amorphous obicetrapib hemicalcium.

[0043] 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. 5A, 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. 5A, 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. 5B 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.

[0044] 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.

[0045] Other thermal techniques may also be used to analyze and characterize amorphous obicetrapib calcium such as thermogravimetric analysis (TGA). FIG. 4 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. 4, 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. [0046] Solid-state ¹³C-NMR spectroscopy is another technique which may be used to characterize amorphous materials. FIG. 6A shows a solid-state ¹³C-NMR spectrum of both crystalline and amorphous obicetrapib hemicalcium with FIGs 6A and 6B 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. 6C may be used to characterize amorphous obicetrapib hemicalcium.

[0047] 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.

[0048] 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.

[0049] 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. [0050] 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.

[0051] 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., methyl sulfate), 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).

[0052] 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.

[0053] In many aspects of the disclosure, the disclosure includes methods for preparing amorphous obicetrapib calcium salts, such as amorphous obicetrapib hemicalcium. The disclosure further includes amorphous 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 calcium, such as amorphous obicetrapib hemicalcium.

[0054] In many aspects of the disclosure, amorphous obicetrapib hemicalcium is prepared via a chemical synthesis where an intermediate is used denoted by Formula (IH):

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.

[0055] 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.

[0056] 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 Figure 7A. 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. [0057] HC1 obicetrapib, as used herein, is not limited to crystalline HC1 obicetrapib. Indeed, upon desolvation, crystalline HC1 obicetrapib may become amorphous.

[0058] Upon stress, crystalline HC1 obicetrapib loses its crystallinity. In Figure 7A, 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.

[0059] 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 A 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 Figure 7B.

Table A

5.1.1.2 Preparation of Amorphous Obicetrapib Hemicalcium

[0060] 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.

[0061] 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).

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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);

(IIA) (IIIA) (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):

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):

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.

[0066] 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.

[0067] In some embodiments, the amorphous obicetrapib hemicalcium is prepared by the method set out in Scheme 1.

Scheme 1

[0068] 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- butoxy carbonylpropoxy )pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline (compound 1C), which was not isolated but directly reacted with excess ethyl chloroformate in the presence of pyridine to produce (2R,4S)-4-[5-(3-t- butoxy carbonylpropoxy )pyrimidin-2 -yl)]amino-2-ethyl-6-tri fluoromethyl-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- butoxy carbonylpropoxy) 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.

[0069] 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.

[0070] 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- guinoline (Compound 1A Free Base)

[0071] (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 recti on 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 1 C)

[0072] 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 1C) dissolved in acetonitrile.

Compound 1C was not isolated but used directly in Operation 3.

Operation 3 Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2- yl)]amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester, as a crystalline mesylate salt (Compound ID)

[0073] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) in acetonitrile (approximately 620 L) was cooled to an internal temperature of <10°C and pyridine (72 L, 900 mol, 4.9 equiv.) was added. Ethyl chloroformate (136 L, 1428 mol, 7.84 equiv.) was then added through an addition funnel while keeping the internal temperature of the reactor contents <10°C. The internal temperature of the reaction mixture was then increased linearly to 20°C over the course of 3.5 hours. The mixture was then distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation (155 L). Isopropyl acetate (471 L, 6.6 vol.) was then added to the reaction vessel and distillation was continued under vacuum at an internal temperature of 60°C or less until roughly 2.50 volumes remained by visual observation (155 L). Then isopropyl acetate (471 L, 6.6 vol.), 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-l -carboxylic acid ethyl ester (corresponding free base of compound ID) in isopropyl acetate based on the weight of the solution.

[0074] 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- butoxy carbonylpropoxy )pyrimidin-2-yl)]amino-2-ethyl-6-tri fluoromethyl-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-f[3,5-bis(trifluoromethyl)benzyll-[5-(3- tbutoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hauinoline- 1 -carboxylic acid ethyl ester (compound IF)

[0075] (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-tbutoxy carbonylpropoxy) 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-yllamino -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-guinoline-l -carboxylic acid ethyl ester (compound 1)

[0076] A solution of 37 wt.% (2R,4S)-4-{[3,5-bis(trifhroromethyl)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 HCI (109.9 kg, 2.32 wt, prepared in situ with 66.1 kg of cone. HCI 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

[0077] The 33.7 weight percent solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]- [5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (compound 1, 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/w-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 HC1 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.

[0078] 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/zz-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)

[0079] (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 (IP AC, 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.

[0080] 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.”

[0081] 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

[0082] 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

[0083] 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)

[0084] 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)

[0085] 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 B below.

Table B

Parameters for XRPD test

Parameters Reflection Mode

Cu, ka

Kai (A): 1.540598,

X-Ray wavelength

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

3-40

(° 2TH)

Scan step time [s] 18.87

Step size

0.0131

(° 2TH)

Test Time 4 min 15 s

Operation HA -FIG. 5B

[0086] 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

Seller 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 Theta)

Rotation 1 Rev/s Operation 11B - X-ray Powder diffraction Methodology for Crystalline HCl Obicetrapib (FIG. 7 A and FIG. 7B)

[0087] 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 Kai radiation, and a position sensitive gas-ionization detector.

[0088] 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 HCl 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.

5.1.2. SGLT2 inhibitors

[0089] The pharmaceutical compositions disclosed herein also include a SGTL2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0090] The term “SGLT2 inhibitor” refers to a compound, in particular to a glucopyranosyl-derivative, i.e. compound having a glucopyranosyl-moiety, which shows an inhibitory effect on the sodium-glucose transporter 2 (SGLT2), in particular the human SGLT2. In some embodiments, the activity of the SGLT2 inhibitor is determined by an inhibition assay, e.g., by an assay that determines the level of activity of the enzyme either in a cell-free system or in a cell after treatment with a subject compound, relative to a control, by measuring the ICso or ECso value, respectively. In certain embodiments, the SGLT2 inhibitor has an ICso value (or ECso value) of 19 pM or less, such as 3 pM or less, 1 pM or less, 599 nM or less, 399 nM or less, 299nM or less, 199 nM or less, 59 nM or less, 39 nM or less, 1 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower. The inhibitory effect on human SGLT2 can be determined by methods known in the literature, in particular as described in the application WO 2995/992877 or WO 2997/993619 (pages 23/24), which are incorporated herein by reference in their entirety. The term “SGLT2 inhibitor” also comprises any pharmaceutically acceptable salts thereof, hydrates and solvates thereof, including the respective crystalline forms.

[0091] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin, remogliflozin etabonate, sergliflozin, sergliflozin etabonate, atigliflozin, and sotagliflozin. [0092] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, and sotagliflozin.

[0093] In certain embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.

[0094] In some embodiments, the SGLT2 inhibitor is empagliflozin.

[0095] In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0096] In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0097] In some embodiments, the SGLT2 inhibitor is ertugliflozin.

[0098] In certain embodiments, the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (II):

or a hydrate, solvent, or pharmaceutically acceptable salt thereof, wherein:

R¹ is halogen (e.g., chloro), (Ci-3)alkyl, or cyano; each R² is independently H, (Ci-3)alkyl, (Ci-3)alkoxy or hydroxy;

R³ is (Ci-3)alkyl, cycloalkyl, alkynyl, (Ci-3)alkoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and n is 0 to 3.

[0099] In certain embodiments, the SGLT2 inhibitor is a prodrug of any of the beforementioned SGLT2 inhibitors.

[0100] In certain embodiments, the SGLT2 inhibitor of formula (II) and methods of their synthesis are described, for example, in the following international patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870, the disclosures of which are incorporated herein by reference.

[0101] In some embodiments of formula (II), R¹ is methyl. In some cases, R¹ is halogen. In certain cases, the halogen is chloride. In some other cases, R¹ is cyano. [0102] In some embodiments of formula (II), each R² is H. In certain some embodiments, n is 1 and R² is methyl. In certain embodiments, n is 1 and R² is methoxy. In certain embodiments, n is i and R² is hydroxy.

[0103] In certain embodiments of formula (II), R³ is ethyl, cyclopropyl, ethynyl, (R)- tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. In some cases, R³ is cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. In certain cases, R³ is ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[0104] In certain cases, the SGLT2 inhibitor is selected from any one of the following compounds:

[0105] It is to be understood that the definitions of the above listed SGLT2 inhibitors, including the glucopyranosyl-substituted benzene derivatives of the formula (II), also comprise their hydrates, solvates, polymorphic forms thereof. The term “empagliflozin” as used herein refers to empagliflozin, including hydrates, solvates, and crystalline forms thereof. In one embodiment, the SGLT2 inhibitor is in the crystalline form as described in the international patent application WO 2006/117360, which hereby is incorporated herein in its entirety. In certain some embodiments, the SGLT2 inhibitor is in the crystalline form as described in the international patent application WO 2006/117359, which hereby is incorporated herein in its entirety. In certain some embodiments, the SGLT2 inhibitor is in the crystalline form as described in the international patent application WO 2008/049923, which hereby is incorporated herein in its entirety. These crystalline forms possess good solubility properties which can enable good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline forms are physico-chemically stable and thus provide a good shelf-life stability of the pharmaceutical composition.

[0106] The term “dapagliflozin” as used herein refers to dapagliflozin, including hydrates, solvates, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 03/099836 for example. Hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/002824, for example. [0107] The term “canagliflozin” as used herein refers to canagliflozin, including hydrates, solvates, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969, for example. Certain hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327, for example.

[0108] The term “atigliflozin” as used herein refers to atigliflozin, including hydrates, solvates, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2004/007517, for example.

[0109] The term “ipragliflozin” as used herein refers to ipragliflozin, including hydrates, solvates, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475, for example.

[0110] The term “tofogliflozin” as employed herein refers to tofogliflozin, including hydrates, solvates, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280, for example.

[OHl] The term “remogliflozin” as used herein refers to remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates, solvates, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888, for example.

[0112] The term “sergliflozin” as employed herein refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates, solvates, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089, for example.

[0113] The disclosure of each of the foregoing documents cited above in connection with the specified SGLT2 inhibitors is specifically incorporated herein by reference in its entirety. [0114] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a SGLT2 inhibitor (e.g., as described herein). With respect to the SGLT2 inhibitor, a “therapeutically effective amount” refers to an amount effective to inhibit SGLT2, and/or lower glucose reabsorption. In some embodiments, a “therapeutically effective amount” of an SGLT2 inhibitor is an amount that, when administered to an individual in one or more doses, in combination therapy (e.g., as described herein with obicetrapib), is effective to lower glucose reabsorption in the subject by 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 glucose reabsorption level in the individual in the absence of treatment with the combination, or alternatively, compared to the glucose level in the subject before or after treatment with the combination.

[0115] In some embodiments, the pharmaceutical composition comprises from about 1% to about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises from about 1% to about 50% w/w, or from about 1% to about 40% w/w, about 1% to about 30% w/w, about 1% to about 20%, about 1% to 10%, or from about 5% to about 15% w/w, or from about 10% to about 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. [0116] In some embodiments, the pharmaceutical composition comprises from 1% to 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises from 1% to 50% w/w, or from 1% to 40% w/w, 1% to 30% w/w, 1% to 20%, 1% to 10%, or from 5% to 15% w/w, or from 10% to 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical composition comprises 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical composition comprises 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

5.1.3. Additional active agents

[0117] The pharmaceutical compositions disclosed herein may optionally include one or more additional active agents. In some embodiments, at least one of the one or more additional active agents is an antidiabetic agent. In certain embodiments, at least of the one or more additional actives is an antidiabetic agent selected from biguanides, thiazolidinediones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, insulin, glucagon- like peptide-1 (GLP-1) agonist, dipeptidyl peptidase-4 (DPP -4) inhibitors and amylin analogs, including pharmaceutically acceptable salts of the beforementioned agents. [0118] In some embodiments, the combination of obicetrapib, a SGLT2 inhibitor, and one or more additional active agents according to the present disclosure can allow for a reduction in the dose of either the obicetrapib or the SGLT2.

[0119] A dose reduction can be beneficial for patients who otherwise would potentially suffer from side effects in a therapy using a higher dose of one or more of the active ingredients. Thus, the pharmaceutical composition and methods according to the present disclosure can exhibit fewer side effects to a corresponding monotherapy with any of the active agents (e.g., obicetrapib or the SGLT2 inhibitor), thereby making the therapy more tolerable and improving an individual’s compliance with the treatment.

[0120] In certain embodiments, the additional active agent is a biguanide. Examples of biguanides include metformin, phenformin and buformin. In certain cases, the additional active agent is metformin. The term "metformin" as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2: 1) fumarate salt, and the metformin (2: 1) succinate salt, the hydrobromide salt, the p- chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids. It one embodiment, the metformin employed herein is the metformin hydrochloride salt.

[0121] In certain embodiments, the pharmaceutical composition comprises from 1 to 50 % w/w of metformin hydrochloride salt, such as 1 to 45% w/w, 1 to 40% w/w, 1 to 35% w/w, 1 to 30% w/w, 1 to 25% w/w, 1 to 20% w/w, 1 to 15% w/w, 1 to 10% w/w, or 1 to 5% w/w of metformin hydrochloride salt.

[0122] In certain embodiments, the additional active agent is a DPP-4 inhibitor.

Examples of DPP -4 inhibitors are linagliptin, sitagliptin, vildagliptin, saxagliptin, denagliptin, alogliptin, carmegliptin, melogliptin, dutogliptin, including pharmaceutically acceptable salts, hydrates and solvates thereof. In certain embodiments, the DPP-4 inhibitor is linagliptin.

[0123] In certain embodiments, the pharmaceutical composition comprises from 1 to 10 % w/w of linagliptin, such as 1 to 9% w/w, 1 to 8% w/w, 1 to 7% w/w, 1 to 6% w/w, 1 to 5% w/w, 2 to 5% w/w, 2 to 4% w/w, of linagliptin, or a salt, solvate or hydrate thereof. In certain cases, the pharmaceutical composition comprises 2.5% w/w of linagliptin, or a salt, solvate or hydrate thereof. In certain cases, the pharmaceutical composition comprises 5% w/w of linagliptin, or a salt, solvate or hydrate thereof.

[0124] In certain embodiments, the additional active agent is a GLP-1 agonist. Examples of GLP-1 agonists are semaglutide, exenatide, dulaglutide, liraglutide, lixisenatide or tirzepatide, including pharmaceutically acceptable salts, hydrates and solvates thereof. In certain embodiments, the GLP-1 agonist is liraglutide. In certain embodiments, the GLP-1 agonist is semaglutide. In certain embodiments, the GLP-1 agonist is dulaglutide.

[0125] In certain embodiments, the additional active agent is a thiazolidinedione. Examples of thiazolidinediones (TZDs) includes pioglitazone and rosiglitazone. The term "pioglitazone" as employed herein refers to pioglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the hydrochloride salt. The term "rosiglitazone" as employed herein refers to rosiglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the maleate salt.

[0126] In certain embodiments, the additional active agent is a sulfonylurea. Examples of sulfonylureas are glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibomuride, glyburide, glisoxepide and gliclazide. In certain cases, the sulfonylurea is selected from tolbutamide, gliquidone, glibenclamide, glipizide and glimepiride. In certain cases, the sulfonylurea is selected from glibenclamide, glipizide and glimepiride. Each term of the group "glibenclamide", "glimepiride", "gliquidone", "glibomuride", "gliclazide", "glisoxepide", "tolbutamide" and "glipizide" as employed herein refers to the respective active drug or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the additional active agent is a glinide. Examples of glinides are nateglinide, repaglinide and mitiglinide. The term "nateglinide" as employed herein refers to nateglinide, including its enantiomers, mixtures thereof and its racemate, or pharmaceutically acceptable salts and esters thereof. The term "repaglinide" as employed herein refers to repaglinide, including its enantiomers, mixtures thereof and its racemate, or pharmaceutically acceptable salts and esters thereof.

[0128] In certain embodiments, the additional active agent is an inhibitor of alphaglucosidase. Examples of inhibitors of alpha- glucosidase are acarbose, voglibose and miglitol. Each term of the group "acarbose", "voglibose" and "miglitol" as employed herein refers to the respective active drug or a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments, the additional active is an amylin analog. An example of an amylin analog is pramlintide, including pharmaceutically acceptable salts, hydrates and solvates thereof. For example pramlintide acetate is marketed under the tradename Symlin. [0130] According to a further embodiment, the pharmaceutical compositions disclosed herein include a combination of obicetrapib, an SGLT2 inhibitor and one or more further antidiabetic agents. In certain embodiments, the further antidiabetic agent is metformin, linagliptin, or a combination thereof. 5.1.4. Excipients

[0131] In typical embodiments, the pharmaceutical compositions that comprise amorphous obicetrapib or calcium salt thereof and an SGLT2 inhibitor or pharmaceutically acceptable salt thereof further comprise one or more pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, surfactants, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington: The Science and Practice of Pharmacy (23rd Edition, ISBN-13: 978- 0128200070); and Modern Pharmaceutics, Marcel Dekker, Inc., 4th Ed. (G. S. Banker & C. T. Rhodes, Eds.).

[0132] In preferred embodiments, the pharmaceutical compositions provided in accordance with the present disclosure are administered orally and the pharmaceutical composition is formulated for oral delivery.

[0133] As discussed further hereinbelow, the pharmaceutical composition may be in the form of an oral unit dosage form. Administration may be via capsule, tablet, or the like. In one embodiment, the amorphous obicetrapib or calcium salt thereof and the SGLT2 inhibitor or pharmaceutically acceptable salt thereof combination is in the form of a tablet. In a further embodiment, the tablet is a compressed tablet. In making the pharmaceutical compositions that include the solid dosage forms described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, tablet, sachet, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.

[0134] The pharmaceutical composition may be formulated for immediate release or sustained release. A “sustained release formulation” is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time, whereas an “immediate release formulation” is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time. In some cases the immediate release formulation may be coated such that the therapeutic agent is only released once it reached the desired target in the body (e.g. the stomach). In a specific embodiment, the pharmaceutical composition is formulated for immediate release.

[0135] The pharmaceutical composition may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0136] In some embodiments, the pharmaceutical composition comprises a diluent selected from the group consisting of dicalcium phosphate, cellulose, microcrystalline cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, mannitol, tribasic calcium phosphate, and combinations thereof. In certain cases, the diluent comprises microcrystalline cellulose. In certain cases, the diluent comprises mannitol. In certain cases, the diluent comprises lactose anhydrous or lactose monohydrate.

[0137] In some embodiments, the pharmaceutical composition comprises a controlled release matrix. In certain cases, the diluent is polyethylene oxide and hypromellose.

[0138] In further embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount from about 1 to about 100% w/w, or from about 1 to about 80% w/w, or from about 1% to about 75% w/w, or from about 5 to about 75% w/w, or from about 10 to about 70% w/w, or from about 15 to about 70% w/w. In specific embodiments, the microcrystalline cellulose is present in an amount of about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75% w/w. In a further specific embodiment, the microcrystalline cellulose is in an amount of about 60% w/w. In a further specific embodiment, the microcrystalline cellulose is in an amount of about 65% w/w.

[0139] In further embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount from 1 to 100% vi/vi, or from 1 to 80% w/w, or from 1% to 75% w/w, or from 5 to 75% w/w, or from 10 to 70% w/w, or from 15 to 70% w/w. In specific embodiments, the microcrystalline cellulose is present in an amount of 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75% w/w. In a further specific embodiment, the microcrystalline cellulose is in an amount of 60% w/w. In a further specific embodiment, the microcrystalline cellulose is in an amount of 65% w/w. [0140] In yet further embodiments, the pharmaceutical composition comprises mannitol in an amount from about 1 to about 40% w/w, or from about 1 to about 35% w/w, or from about 1% to about 25% w/w, or from about 5 to about 35% w/w, or from about 10 to about 30% w/w, or from about 15 to about 25% w/w. In specific embodiments, the mannitol is present in an amount of about 5%, or about 20%, or about 15%, or about 30%, or about 22%, or about 23%, or about 24%, or about 25% w/w. In a further specific embodiment, the microcrystalline cellulose is in an amount of about 20% w/w.

[0141] In yet further embodiments, the pharmaceutical composition comprises mannitol in an amount from 1 to 40% w/w, or from 1 to 35% w/w, or from 1% to 25% w/w, or from 5 to 35% w/w, or from 10 to 30% w/w, or from 15 to 25% w/w. In specific embodiments, the mannitol is present in an amount of 5%, or 20%, or 15%, or 30%, or 22%, or 23%, or 24%, or 25% w/w. In a further specific embodiment, the microcrystalline cellulose is in an amount of 20% w/w.

[0142] In some embodiments, the pharmaceutical composition comprises a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.

[0143] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount 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 1 to about 8% w/w, or from about 2 to about 8% w/w. In specific embodiments, the croscarmellose sodium is present in an amount of about 1%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 10% w/w. In a further specific embodiment, the croscarmellose sodium is in an amount of about 5% w/w.

[0144] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount from 1 to 20% w/w, or from 1 to 15% w/w, or from 1 to 10% w/w, or from 1 to 8% w/w, or from 2 to 8% w/w. In specific embodiments, the croscarmellose sodium is present in an amount of 1%, or 3%, or 4%, or 5%, or 6%, or 7%, or 10% w/w. In a further specific embodiment, the croscarmellose sodium is in an amount of 5% w/w.

[0145] In some embodiments, the pharmaceutical composition comprises a glidant selected from the group consisting of colloidal silicon dioxide, talc, and combinations thereof.

[0146] In further embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount from about 0.1 to about 5% w/w, or from about 0.1 to about 4.5% w/w, or from about 0.1 to about 4% w/w, or from about 0.5 to about 5.0% w/w, or from about 0.5 to about 3% w/w, or from about 0.5 to about 2% w/w, or from about 0.5 to about 1.5% w/w. In specific embodiments, the colloidal silicon dioxide is present in an amount of about 0.1% w/w, 0.5% w/w, 0.75% w/w, 0.95% w/w, 1.0% w/w, or 1.2% w/w. In a further specific embodiment, the colloidal silicon dioxide is present in an amount of about 1% w/w. [0147] In further embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount from 0.1 to 5% vi/vi, or from 0.1 to 4.5% vi/vi, or from 0.1 to 4% w/w, or from 0.5 to 5.0% w/w, or from 0.5 to 3% w/w, or from 0.5 to 2% w/w, or from 0.5 to 1.5% w/w. In specific embodiments, the colloidal silicon dioxide is present in an amount of 0.1% w/w, 0.5% w/w, 0.75% w/w, 0.95% w/w, 1.0% w/w, or 1.2% w/w. In a further specific embodiment, the colloidal silicon dioxide is present in an amount of 1% w/w. [0148] In some embodiments, the pharmaceutical composition comprises a lubricant selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and combinations thereof.

[0149] In further embodiments, the pharmaceutical composition comprises magnesium stearate in an amount from about 0.1 to about 3% w/w, or from about 0.1 to about 2.5% w/w, or from about 0.5 to about 3% w/w, or from about 0.5 to about 2.5% w/w, or from about 0.5 to about 2% w/w, or from about 1 to about 3% w/w, or from about 1 to about 2% w/w. In specific embodiments, the magnesium stearate is present in an amount of about 0.1%, or about 0.5, or about 0.7%, or about 0.9%, or about 1.0%, or about 1.2% w/w. In a further specific embodiment, the magnesium stearate is in an amount of about 1% w/w.

[0150] In further embodiments, the pharmaceutical composition comprises magnesium stearate in an amount from 0.1 to 3% w/w, or from 0.1 to 2.5% w/w, or from 0.5 to 3% w/w, or from 0.5 to 2.5% vi/vi, or from 0.5 to 2% w/w, or from 1 to 3% w/w, or from 1 to 2% w/w. In specific embodiments, the magnesium stearate is present in an amount of 0.1%, or 0.5, or 0.7%, or 0.9%, or 1.0%, or 1.2% w/w. In a further specific embodiment, the magnesium stearate is in an amount of 1% w/w.

[0151] In one embodiment, the pharmaceutical composition comprises a) about 1 to about 10% w/w of amorphous obicetrapib, or calcium salt, solvate or hydrate thereof, and b) about 5 to about 20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a related embodiment, the composition comprises a) about 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) about 5-20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In another embodiment, the composition comprises a) about 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) about 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In yet a further related embodiment, the composition further comprises a) about 40 to about 65% w/w microcrystalline cellulose, b) about 5 to about 23% w/w mannitol, c) about 1 to about 10% w/w sodium starch glycolate, d) about 0.5 to about 3% w/w colloidal silicon dioxide, and e) about 0.1 to about 3% w/w magnesium stearate. In another embodiment, the composition comprises a) about 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) about 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof, c) about 40 to about 65% w/w microcrystalline cellulose, d) about 5 to about 23% w/w mannitol, e) about 1 to about 10% w/w sodium starch glycolate, f) about 0.5 to about 3% w/w colloidal silicon dioxide, and g) about 0.1 to about 3% w/w magnesium stearate.

[0152] In one embodiment, the pharmaceutical composition comprises a) 1 to 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5 to 20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a related embodiment, the composition comprises a) 5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5-20% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In another embodiment, the composition comprises a) 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In yet a further related embodiment, the composition further comprises a) 40 to 65% w/w microcrystalline cellulose, b) 5 to 23% w/w mannitol, c) 1 to 10% w/w sodium starch glycolate, d) 0.5 to 3% w/w colloidal silicon dioxide, and e) 0.1 to 3% w/w magnesium stearate. In another embodiment, the composition comprises a) 10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof, and b) 5-25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof, c) 40 to 65% w/w microcrystalline cellulose, d) 5 to 23% w/w mannitol, e) 1 to 10% w/w sodium starch glycolate, f) 0.5 to 3% w/w colloidal silicon dioxide, and g) 0.1 to 3% w/w magnesium stearate.

[0153] In certain embodiments, the pharmaceutical composition comprises:

[0154] In certain embodiments, the pharmaceutical composition comprises:

[0155] In certain embodiments, the SGLT2 inhibitor is empagliflozin, in an amount of 7- 9% w/w, or 18-20% w/w; and the obicetrapib is in an amount of 3.5-5% w/w, or 7-10% w/w.

[0156] In certain embodiments, the pharmaceutical composition comprises:

[0157] In certain embodiments, the SGLT2 inhibitor is dapagliflozin, in an amount of 4- 5% w/w, or 8-10% w/w; and the obicetrapib is in an amount of 4-5% w/w, or 8-10% w/w. [0158] In certain embodiments, the pharmaceutical composition comprises:

[0159] In certain embodiments, the SGLT2 inhibitor is ertugliflozin, in an amount of 4- 5% w/w, or 11-13% w/w; and the obicetrapib is in an amount of 4-5% w/w, or 8-10% w/w. [0160] In certain embodiments, the pharmaceutical composition comprises:

[0161] In certain embodiments, the SGLT2 inhibitor is canagliflozin, in an amount of 45-50% w/w, or 70-75% w/w; and the obicetrapib is in an amount of 1-3% w/w, or 3-5% w/w.

[0162] The pharmaceutical compositions described herein can be formulated with amorphous obicetrapib or calcium salt thereof and an SGLT2 inhibitor or pharmaceutically acceptable salt thereof as the two sole pharmaceutically active ingredients in the composition or can be combined with other active ingredients (e.g., as described herein).

[0163] In certain embodiments, the pharmaceutical composition is formulated into one or more suitable pharmaceutical preparations, such as solutions, suspensions, powders, sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers. [0164] In compositions provided herein, obicetrapib and the SGLT2 inhibitor described herein may be mixed with a suitable pharmaceutical carrier. The concentration of the each active in the compositions can, for example, be effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates a condition or disorder described herein or a symptom thereof.

[0165] In certain embodiments, the pharmaceutical compositions provided herein are formulated for single dosage administration. To formulate a composition, the weight fraction of each active is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.

[0166] Concentrations of the amorphous obicetrapib and SGLT2 inhibitor in a pharmaceutical composition provided herein will depend on, e.g., the physicochemical characteristics of the compounds, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, if the composition comprises a salt of obicetrapib the amount of said salt to be administered and/or to be incorporated into a pharmaceutical composition (i.e., pharmaceutical dosage form) needs to be adjusted to take account of the molecular weight difference between the free base and salt form. For instance, in expressing dose amounts in the label and/or product information of authorized medicinal products comprising a salt form of an active compound that can also be used in free base form, it is customary practice to specify the dose of the free base to which the dose of the salt as used is equivalent.

[0167] Pharmaceutical compositions described herein are provided for administration to a subject, for example, humans or animals (e.g., mammals) in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. Pharmaceutical compositions are also provided for administration to humans and animals in unit dosage form, including oral or nasal solutions or suspensions and oil-water emulsions containing suitable quantities of a conjugate or pharmaceutically acceptable derivatives thereof. The conjugate is, in certain embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human or animal (e.g., mammal) subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of obicetrapib and SGLT2 inhibitor sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets. Unit-dose forms can be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of capsules or bottles. Hence, in specific aspects, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

[0168] In certain embodiments, the obicetrapib and SGLT2 inhibitor described herein are in a liquid pharmaceutical formulation. Liquid pharmaceutically administrable formulations can, for example, be prepared by dissolving, dispersing, or otherwise mixing the active compounds and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, and the like, to thereby form a solution or suspension. In certain embodiments, a pharmaceutical composition provided herein to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents and the like. [0169] Methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see, e.g., Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978- 0128200070). Dosage forms or compositions containing obicetrapib and an SGLT2 inhibitor in the ranges disclosed herein with the balance made up from non-toxic carrier can be prepared.

[0170] In certain embodiments, the pharmaceutical composition is formulated as a solid dosage form, such as a tablet or a capsule (e.g., as described herein below).

5.2. Unit Dosage forms

[0171] As summarized above, this disclosure provides a pharmaceutical unit dosage form comprising the pharmaceutical composition described herein. The disclosure provides for tablets, pills, and the like, comprising the pharmaceutical compositions or dosage forms described herein. The tablets or pills of the present disclosure may be coated to provide a dosage form affording the advantage of prolonged action or to protect from the acid conditions of the stomach. The tablets may also be formulated for immediate release as previously described. In certain embodiments, the tablet comprises a film coating. A film coating may be useful for limiting photolytic degradation. Suitable film coatings are selected by routine screening of commercially available preparations. In one embodiment, the film coating is a hypromellose-based coating. In certain embodiments, the coating represents 2- 5% by weight of the total tablet composition and comprises a film-forming agent, a plasticizer, a glidant and optionally one or more pigments. In certain cases, the coating represents 3% of the total tablet composition. An exemplary film coating composition may comprise hydroxypropyl methylcellulose (HPMC), lactose monohydrate, titanium dioxide, and triglyceride 1,2,3-triacetoxypropane (triacetin). In certain cases, the film coating composition may comprise hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and optionally iron oxide, including iron oxide red and/or yellow.

[0172] The tablets may be formulated into a monolayer or bilayer tablet. Typically, monolayer tablets comprise the active ingredients (i.e., obicetrapib and the SGLT2 inhibitor) co-mixed in a single uniform layer. For making monolayer tablets, exemplary methods include direct compression, wet granulation and dry granulation. The direct compression tablet process uses two primary process steps: blending the active ingredients with the excipients and compressing the finished tablet.

[0173] In one embodiment, the present disclosure provides a wet granulation process for making the subject pharmaceutical dosage form, wherein said process comprises the steps of:

(1) Premixing the active ingredient and the main portion of the excipients including the binder in a mixer to obtain a pre-mixture;

(2) granulating the pre-mixture of step (1) by adding the granulation liquid, e.g., purified water;

(3) drying the granules of step (2) in a fluidized bed dryer or a drying oven;

(4) optionally dry sieving of the dried granules of step (3);

(5) mixing the dried granules of step (4) with the remaining excipients like glidant and lubricant in a mixer to obtain the final mixture;

(6) tableting the final mixture of step (5) by compressing it on a suitable tablet press to produce tablets cores;

(7) optionally film-coating of the tablet cores of step (6) with a non-functional coat.

[0174] In certain embodiments, the present invention provides a pharmaceutical dosage form (e.g., as described herein) obtainable by a wet granulation process.

[0175] In another embodiment, the present disclosure provides a direct compression process for making the subject pharmaceutical dosage form, wherein said process comprises the steps of:

(1) Premixing the active ingredient and the main portion of the excipients in a mixer to obtain a pre-mixture; (2) optionally dry screening the pre-mixture through a screen in order to segregate cohesive particles and to improve content uniformity;

(3) mixing the pre-mixture of step (1) or (2) in a mixer, optionally by adding remaining excipients to the mixture and continuing mixing;

(4) tableting the final mixture of step (3) by compressing it on a suitable tablet press to produce the tablet cores;

(5) optionally film-coating of the tablet cores of step (4) with a non-functional coat.

[0176] In certain embodiments, the present invention provides a pharmaceutical dosage form obtainable (e.g., as described herein) by a direct compression process.

[0177] In another embodiment, the present disclosure provides a dry granulation process for making the subject pharmaceutical dosage form, wherein said process comprises the steps of:

(1) mixing the active ingredient with either all or a portion of the excipients in a mixer;

(2) compaction of the mixture of step (1) on a suitable roller compactor;

(3) reducing the ribbons obtained during step (2) to granules, preferably small granules, by suitable milling or sieving steps;

(4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain the final mixture;

(5) tableting the granules of step (3) or the final mixture of step (4) by compressing it on a suitable tablet press to produce the tablet cores;

(6) optionally film-coating of the tablet cores of step (5) with a non-functional coat.

[0178] In certain embodiments, the present invention provides a pharmaceutical dosage form (e.g., as described herein) obtainable by a dry granulation process.

[0179] Bilayer tablets comprise the active ingredients (i.e., obicetrapib and the SGLT2 inhibitor) in separate layers and can be made by making a blend comprising excipients and one active ingredient (i.e., obicetrapib), and making a separate blend comprising the second active ingredient (i.e., the SGLT2 inhibitor) and excipients. One blend may then be precompressed, and the second blend may then be added on top of the first pre-compressed blends. The resulting tablet comprises two separate layers, each layer comprising a different active ingredient. [0180] In certain embodiments, the pharmaceutical dosage form comprises the obicetrapib in a therapeutically effective amount (e.g., as described herein for obicetrapib). [0181] In certain embodiments, the pharmaceutical dosage form comprises from about 1% to about 25% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 3-5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 7-10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.

[0182] In certain embodiments, the pharmaceutical dosage form comprises from 1% to 25% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form 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 amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 3-5% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 7-10% w/w of amorphous obicetrapib, or a calcium salt, solvate or hydrate thereof.

[0183] In some embodiments, the pharmaceutical dosage form comprises from about 1 mg to about 25 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of obicetrapib in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from about 1 mg to about 20 mg of amorphous obicetrapib, or from about 1 mg to about 15 mg of amorphous obicetrapib, or from about 1 mg to about 10 mg of amorphous obicetrapib, or from about 5 mg to about 15 mg of amorphous obicetrapib, or from about 5 mg to about 12 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of obicetrapib in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as the amorphous calcium salt. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obicetrapib as the amorphous calcium salt.

[0184] In some embodiments, the pharmaceutical dosage form comprises from 1 mg to 25 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from 1 mg to 20 mg, or from 1 mg to 15 mg, or from 1 mg to 10 mg, or from 5 mg to 15 mg, or from 5 mg to 12 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose. In another embodiment, the pharmaceutical dosage form comprises 5 mg of obicetrapib as the amorphous calcium salt. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of obicetrapib as the amorphous calcium salt.

[0185] In certain embodiments, the pharmaceutical dosage form comprises the SGLT2 inhibitor in a therapeutically effective amount (e.g., as described herein for the subject SGLT2 inhibitors).

[0186] In some embodiments, the pharmaceutical dosage form comprises from about 1% to about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from about 1% to about 40% w/w, or from about 1% to about 30% w/w, about 1% to about 20% w/w, about 1% to about 10%, or from about 5% to about 15% w/w, or from about 10% to about 25% w/w, or from about 45% to about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, or about 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises about 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. [0187] In some embodiments, the pharmaceutical dosage form comprises from 1% to 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises from 1% to 40% w/w, or from 1% to 30% w/w, 1% to 20% w/w, 1% to 10%, or from 5% to 15% w/w, or from 10% to 25% w/w, or from 45% to 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In further embodiments, the pharmaceutical dosage form comprises 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, or 75% w/w, of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 5% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 10% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 15% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 25% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 50% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof. In a specific embodiment, the pharmaceutical dosage form comprises 75% w/w of the SGLT2 inhibitor, or a salt, solvate or hydrate thereof.

[0188] In some embodiments, the pharmaceutical dosage form comprises from about 1 mg to about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from about 5 mg to about 100 mg of the SGLT2 inhibitor, or from about 5 mg to about 50 mg of the SGLT2 inhibitor, or from about 10 mg to about 25 mg of the SGLT2 inhibitor, or from about 5 mg to about 15 mg of the SGLT2 inhibitor, or from about 5 mg to about 10 mg of SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In further embodiments, the pharmaceutical composition comprises about 100 mg, about 300 mg, about 150 mg to 250 mg, or about 100 mg to 200 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the pharmaceutical dosage form comprises about 5 mg, about 7 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, any of the above amounts are of the free base form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain some embodiments, the amounts are of a salt form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.

[0189] In some embodiments, the pharmaceutical dosage form comprises from 1 mg to 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In further embodiments, the pharmaceutical dosage form comprises from 5 mg to 100 mg of the SGLT2 inhibitor, or from 5 mg to 50 mg of the SGLT2 inhibitor, or from 10 mg to 25 mg of the SGLT2 inhibitor, or from 5 mg to 15 mg of the SGLT2 inhibitor, or from 5 mg to 10 mg of SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In further embodiments, the pharmaceutical composition comprises 100 mg, 300 mg, 150 mg to 250 mg, or 100 mg to 200 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the pharmaceutical dosage form comprises 5 mg, 7 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 30 mg, 40 mg, or 50 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a specific embodiment, the pharmaceutical dosage form comprises 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, any of the above amounts are of the free base form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain some embodiments, the amounts are of a salt form of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.

[0190] In one embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and, b) about 10 mg to about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is empagliflozin.

[0191] In one embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and, b) 10 mg to 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 25 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is empagliflozin.

[0192] In another embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg to about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is ertugliflozin.

[0193] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg to 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose.

In another embodiment, the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 15 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is ertugliflozin.

[0194] In another embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 5 mg to about 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is dapagliflozin. [0195] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 5 mg to 10 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is dapagliflozin.

[0196] In another embodiment, the pharmaceutical dosage form comprises a) about 5 mg to about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 100 mg to about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) about 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) about 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and b) about 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is canagliflozin.

[0197] In another embodiment, the pharmaceutical dosage form comprises a) 5 mg to 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 100 mg to 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 5 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In a related embodiment, the dosage form comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose, and b) 100 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In another embodiment, the tablet comprises a) 10 mg of amorphous obicetrapib, or a calcium salt, solvate, or hydrate of amorphous obicetrapib in an equivalent dose and b) 300 mg of the SGLT2 inhibitor, or a salt, solvate, or hydrate of the SGLT2 inhibitor in an equivalent dose. In certain embodiments, the SGLT2 inhibitor is canagliflozin.

[0198] As used herein the term “equivalent dose” refers to an amount of a given compound “equivalent” to a specified amount of a reference compound (e.g., a free base form of a compound). For example, if the dosage form comprises the salt of obicetrapib, the amount of the salt to be incorporated in the pharmaceutical dosage form needs to be adjusted to take account of the molecular weight difference between obicetrapib as the free base form and the salt form.

[0199] In certain embodiments, the pharmaceutical dosage form comprises one or more additional active compounds (e.g., as described herein). In certain embodiments, the pharmaceutical dosage form further comprises a therapeutically effective amount of metformin (e.g., metformin hydrochloride). In certain embodiments, the pharmaceutical dosage form comprises from 500 mg to 1000 mg of metformin, such as 500 mg to 900 mg, 500 mg to 800 mg, 500 mg to 700 mg, or 500 mg to 600 mg of metformin (e.g., metformin hydrochloride).

[0200] In certain embodiments, the pharmaceutical form further comprises a therapeutically effective amount of linagliptin. In certain embodiments, the pharmaceutical dosage form comprises from 1 mg to 10 mg of linagliptin, such as 1 mg to 9 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg, 2 mg to 4 mg, of linagliptin, or a salt, solvate, or hydrate of linagliptin in an equivalent dose. In certain cases, the pharmaceutical composition comprises 2.5 mg of linagliptin, or a salt, solvate, or hydrate of linagliptin in an equivalent dose. In certain cases, the pharmaceutical composition comprises 5 mg of linagliptin, or a salt, solvate, or hydrate of linagliptin in an equivalent dose.

[0201] In certain embodiments, the pharmaceutical dosage form comprises one or more excipients (e.g., as described herein). In certain embodiments, the pharmaceutical dosage form comprises one or more diluents. In certain embodiments, the pharmaceutical dosage from comprises microcrystalline cellulose, mannitol, or a combination of both.

[0202] In certain embodiments, the pharmaceutical dosage form comprises microcrystalline cellulose in an amount from about 40 mg to 80 mg, such as 45 mg to 75 mg, 45 mg to 70 mg, 45 mg to 65 mg, or 50 to 65 mg. In a specific embodiment, the microcrystalline cellulose is in an amount of about 60 mg. In a further specific embodiment, the microcrystalline cellulose is in an amount of about 65 mg.

[0203] In certain embodiments, the pharmaceutical dosage form comprises microcrystalline cellulose in an amount from 40 mg to 80 mg, such as 45 mg to 75 mg, 45 mg to 70 mg, 45 mg to 65 mg, or 50 to 65 mg. In a specific embodiment, the microcrystalline cellulose is in an amount of 60 mg. In a further specific embodiment, the microcrystalline cellulose is in an amount of 65 mg.

[0204] In certain embodiments, the pharmaceutical dosage form comprises mannitol in an amount from about 1 mg to 35 mg, such as 1 mg to 30 mg, 1 mg to 30 mg, 1 mg to 25 mg, or 10 to 25 mg. In a specific embodiment, the microcrystalline cellulose is in an amount of about 23 mg.

[0205] In embodiments, the pharmaceutical dosage form comprises mannitol in an amount from 1 mg to 35 mg, such as 1 mg to 30 mg, 1 mg to 30 mg, 1 mg to 25 mg, or 10 to 25 mg. In a specific embodiment, the microcrystalline cellulose is in an amount of 23 mg. [0206] In certain embodiments, the pharmaceutical dosage form comprises one or more disintegrants. In certain cases, the disintegrant is sodium starch glycolate. In certain embodiments, the pharmaceutical dosage form comprises sodium starch glycolate in an amount from about 1 mg to 15 mg, such as 1 mg to 10 mg, 1 mg to 8 mg, 2 mg to 7 mg, or 4 to 6 mg. In a specific embodiment, the sodium starch glycolate is in an amount of about 5 mg.

[0207] In certain embodiments, the pharmaceutical dosage form comprises sodium starch glycolate in an amount from 1 mg to 15 mg, such as 1 mg to 10 mg, 1 mg to 8 mg, 2 mg to 7 mg, or 4 to 6 mg. In a specific embodiment, the sodium starch glycolate is in an amount of 5 mg.

[0208] In certain embodiments, the pharmaceutical dosage form comprises one or more glidants. In certain cases, the glidant is colloidal silicon dioxide. In certain embodiments, the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount from about 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of about 1 mg.

[0209] In certain embodiments, the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount from 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of 1 mg. [0210] In certain embodiments, the pharmaceutical dosage form comprises one or more lubricants. In certain cases, the lubricant is magnesium stearate. In certain embodiments, the pharmaceutical dosage form comprises magnesium stearate in an amount from about 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of about 1 mg.

[0211] In certain embodiments, the pharmaceutical dosage form comprises magnesium stearate in an amount from 0.1 mg to 5 mg, such as 0.1 mg to 4 mg, 0.5 mg to 5 mg, 0.5 mg to 3 mg, or 0.5 to 2 mg. In a specific embodiment, the colloidal silicon dioxide is in an amount of 1 mg.

[0212] In further embodiments, the pharmaceutical composition, pharmaceutical dosage form, or tablet as described herein is free of negative drug-drug interactions. In a related embodiment, the pharmaceutical composition, pharmaceutical dosage form, or tablet is free of negative drug-drug interactions with other antidiabetic agents. In a further embodiment, the pharmaceutical composition, pharmaceutical dosage form, or tablet as described herein is administrable without regard to food and with or without regard to the patient being on another antidiabetic agent.

5.3. Methods of use

[0213] As summarized above, also provided herein are methods of treating or preventing a metabolic disorder or cardio-metabolic disorder, the method comprising administering to a subject having or at risk of developing a metabolic or cardio-metabolic disorder, a therapeutically effective amount of a pharmaceutical composition, or a pharmaceutical dosage form comprising a pharmaceutical composition, that comprises a combination of amorphous obicetrapib or calcium salt thereof and an SGLT2 inhibitor or pharmaceutically acceptable salt thereof, as described herein.

[0214] In another aspect, methods are provided for treating or preventing a metabolic disorder or cardio-metabolic disorder, the method comprising administering to a subject having or at risk of developing a metabolic disorder or cardio-metabolic disorder a therapeutically effective amount of amorphous obicetrapib or calcium salt thereof and administering a therapeutically effective amount of an SGLT2 inhibitor or pharmaceutically acceptable salt thereof.

[0215] Without being bound to any particular theory, a pharmaceutical composition or dosage form comprising a pharmaceutical composition comprising a combination of amorphous obicetrapib or calcium salt thereof and a SGLT2 inhibitor or pharmaceutically acceptable salt thereof as defined herein, or separately administering both obicetrapib and an SGLT2 inhibitor, can be used for preventing, slowing progression of, delaying or treating a metabolic disorder, and in particular for delaying progression to insulin-dependence. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, obesity, complications of diabetes mellitus and of neighboring disease states.

[0216] In some embodiments a pharmaceutical composition or dosage form comprising a pharmaceutical composition comprising a combination of amorphous obicetrapib or calcium salt thereof and a SGLT2 inhibitor or pharmaceutically acceptable salt thereof as defined herein, or separately administering both obicetrapib and an SGLT2 inhibitor, can be used for improving health outcomes in a subject

[0217] Accordingly, the present disclosure provides a method for preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity and metabolic syndrome in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or separately administering both obicetrapib and an SGLT2 inhibitor.

[0218] The pharmaceutical composition according to the present disclosure, or the separate administration of both obicetrapib and an SGLT2 inhibitor, may also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome.

[0219] Also provided herein is a method for preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.

[0220] As such, the pharmaceutical compositions and dosage forms described herein can be effective to treat conditions and/or diseases related to or caused by an increased blood glucose level.

[0221] In various embodiments, there is provided a method for preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and vascular restenosis, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor. In particular, one or more aspects of diabetic nephropathy such as hyperperfusion, proteinuria and albuminuria may be treated, their progression slowed or their onset delayed or prevented. The term “tissue ischemia” particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer.

[0222] By the administration of a pharmaceutical composition according to the present disclosure, or by separately administering both obicetrapib and an SGLT2 inhibitor, and due to the activity of the obicetrapib and SGLT2 inhibitor, excessive blood glucose levels may not be converted to insoluble storage forms, like fat, but excreted through the urine of the patient, and LDL cholesterol levels are reduced. As such, the pharmaceutical compositions and dosage forms described herein do not cause weight gain, and in some cases can even result in a reduction in body weight.

[0223] Accordingly, in some embodiments of the subject methods there is provided a method for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.

[0224] The pharmacological effect of the combination of obicetrapib and an SGLT2 inhibitor in the pharmaceutical composition, or through separate administration, according to the present disclosure is independent of insulin. Therefore, an improvement of the glycemic control is possible without an additional strain on the pancreatic beta cells, and an improvement in beta cell health and function is possible by reduction of lipid-induced toxicity. By an administration of a pharmaceutical composition according to the present disclosure, or separate administration of both obicetrapib and an SGLT2 inhibitor, beta-cell degeneration and a decline of beta-cell functionality, such as for example apoptosis or necrosis of pancreatic beta cells, can be delayed or prevented. Furthermore, the functionality of pancreatic cells can be improved or restored, and the number and size of pancreatic beta cells increased. It may be shown that the differentiation status and hyperplasia of pancreatic beta-cells disturbed by hyperglycemia and hyperlipidemia or dyslipidemia can be normalized by treatment with a pharmaceutical composition or dosage form according to the present disclosure.

[0225] Accordingly, also provided herein is a method for preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor.

[0226] By the administration of a pharmaceutical composition according to the present disclosure, or separate administration of both obicetrapib and an SGLT2 inhibitor, and due to the activity of the obicetrapib and SGLT2 inhibitor, an abnormal accumulation of fat in the liver may be reduced or inhibited. Therefore, according to present disclosure, there is also provided a method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor. Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, diabetic fatty liver, alcoholic- induced fatty liver or toxic fatty liver.

[0227] As such, also provided herein is a method for maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof, by administering a therapeutically effective amount of a pharmaceutical composition or a pharmaceutical dosage form of the present disclosure to the patient, or by separately administering both obicetrapib and an SGLT2 inhibitor. 5.4. Kits

[0228] Also provided herein is a pharmaceutical kit comprising a package containing a plurality of unit pharmaceutical dosage forms (e.g., as described herein) and instructions for use.

[0229] In accordance with embodiments of the invention, the pharmaceutical kit comprises a container, such as a high-density polyethylene (HDPE) bottles, or a box including one or more blister packs, wherein the bottles or blister packs can contain a plurality of solid unit pharmaceutical dosage forms as described herein. In certain embodiments, the container or pack comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit pharmaceutical 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.

[0230] In accordance with the invention, the pharmaceutical kit comprises instructions (e.g., a leaflet) inserted into the container or box, typically a patient information leaflet containing printed information, which information may include a description of the form and composition of the unit pharmaceutical 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. In accordance with the present disclosure, the leaflet will usually contain the information concerning the therapeutic indications, uses, treatment regimens, etc. as described herein in relation to the methods of treatment of the present invention. In certain cases, the leaflet contains printed instructions to repeatedly (self-)administer the pharmaceutical unit dosage forms in order to treat and/or prevent a metabolic disorder, in particular type 2 diabetes mellitus.

5.5. Definitions

[0231] A “subject” can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, goats, rabbits, rats, mice, etc.) or a primate (e.g., monkey and human), for example a human. “Patient” refers to a human subject. In certain embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In a specific embodiment, the subject is human.

[0232] The terms “therapy”, “treat”, and “treating” are used in their broadest sense understood in the clinical arts. [0233] The term “pharmaceutically acceptable” indicates that the material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.

[0234] The term “carrier” refers to a glidant, diluent, adjuvant, excipient, or vehicle etc. with which the compound is administered, without limitation. Examples of carriers are described herein and also in Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070).

[0235] The term “diluent” refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also serve to stabilize compounds. Nonlimiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate.

[0236] The term “binder” when used herein relates to any pharmaceutically acceptable film which can be used to bind together the active and inert components of the carrier together to maintain cohesive and discrete portions. Non-limiting examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, copovidone, and ethyl cellulose.

[0237] The term “disintegranf ’ refers to a substance which, upon addition to a solid preparation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution. Non-limiting examples of disintegrants include maize starch, sodium starch glycolate, croscarmellose sodium, modified corn starch, sodium carboxymethyl starch, crospovidone, pregelatinized starch, and alginic acid.

[0238] The term “lubricant” refers to an excipient which is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It aids the ejection of the tablet form the dies, and can improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc; and solubilizers such as fatty acids including lauric acid, oleic acid, and C8/C10 fatty acid. [0239] The term “film coating” refers to a thin, uniform, film on the surface of a substrate (e.g. tablet). Film coatings are particularly useful for protecting the active ingredient from photolytic degradation. Non-limiting examples of film coatings include polyvinylalcohol based, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate film coatings.

[0240] The term “glidanf ’ as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0241] The term “effective amount” or “therapeutically effective amount” refers to an amount that is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment. The therapeutically effective amount may vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0242] The term "unit dosage forms" or "pharmaceutical dosage forms" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet).

[0243] The term “% w/w” as used herein refers to the weight of a component based on the total weight of a composition comprising the component. For example, if component A is present in an amount of 50% w/w in a 100 mg composition, component A is present in an amount of 50 mg.

[0244] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers, are intended to be encompassed within the scope of the claimed subject matter. For example, when a compound is described as a particular optical isomer D- or L-, it is intended that both optical isomers be encompassed herein. For example, where a compound is described as having one of two tautomeric forms, it is intended that both tautomers be encompassed herein. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. The compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (5) configurations, or may be a mixture thereof. The chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (A) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5) form.

[0245] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³⁶C1, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Compounds labelled with ³H, ¹⁴C and/or ¹⁸F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, “deuterated” as applied to a chemical group and unless otherwise indicated, refers to a chemical group that is isotopically enriched with deuterium in an amount substantially greater than its natural abundance.

Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.

[0246] Thus, any of the embodiments described herein are meant to include a salt, a single stereoisomer, a mixture of stereoisomers and/or an isotopic form of the compounds. [0247] Unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1% or 0.05% of a given value or range. Unless otherwise specified, the term “about” means within plus or minus 10% of a the explicitly recited value, rounded either up or down to the nearest value based on the expressed degree of precision.

6. EXAMPLES

[0248] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples 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.

6.1. Example 1: A 2x2 Factorial Mendelian Randomization Analysis of the Effect of Combined SGLT2 and CETP Genetic Variation on Diabetes Incidence in the UK Biobank

Introduction

[0249] A post-hoc meta-analysis of data gathered from clinical trials of CETP inhibitors demonstrated that CETP inhibitor usage, either alone or combined with other lipid-lowering drugs, was associated with decreased incidence of diabetes (see, e.g., W. Masson et al., Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk, Diabetes & Metabolism, Volume 44, Issue 6, 2018, Pages 508-513). In the current study described below, we investigated whether or not a combination of a CETP inhibitor and a SGLT2 inhibitor would lead to decreased incidence of diabetes when compared to SGLT2 or CETP inhibitor monotherapy through a 2x2 factorial Mendelian Randomization (MR) design using 233,763 individuals from the UK Biobank.

Methods

[0250] Constructing CETP genetic score: To construct a genetic score to mimic the effects of CETP inhibitors, a score of 4 single nucleotide polymorphisms (SNPs) in the CETP region that are strongly correlated with HDL was built. The genetic score uses all available SNPs in the UK Biobank genotyping information that were included in the CETP score described in Ference et al. (Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of Genetic Variants Related to CETP Inhibitors and Statins with Lipoprotein Levels and Cardiovascular Risk. JAMA. 2017;318(10):947-956). A higher CETP genetic score mimics a greater degree of pharmaceutical CETP inhibition (FIG. 8 A).

[0251] Constructing SGLT2 genetic score: To construct a genetic score to mimic the effects of SGLT2 inhibitors, a score of 2 single nucleotide polymorphisms (SNPs) in the SGLT2 region that are strongly correlated with SGLT2 expression was built. The genetic score uses all available SNPs in the UK Biobank genotyping information that were included in the SGLT2 score described in Katzmann et al. (Katzmann, J.L., Mason, A.M., Marz, W., Kleber, M.E., Niessner, A., Bluher, M., Speer, T. and Laufs, U. (2021), Genetic Variation in Sodium-glucose Cotransporter 2 and Heart Failure. Clin. Pharmacol. Ther., 110: 149-158). A higher SGLT2 genetic score mimics a greater degree of pharmaceutical SGLT2 inhibition (FIG. 8B).

[0252] Included individuals: For the 2x2 factorial MR analysis, all individuals in the UK Biobank that have genotyping information containing all SNPs needed to construct the genetic scores were included, as well as all biomarker values. Furthermore, only individuals of British descent were included in the analysis to control for population stratification bias. In total, 233,763 individuals fulfilled all inclusion criteria.

[0253] Separation into cohorts and groups: Individuals were randomly assigned to one of two cohorts: discovery (75%) and replication (25%). Within each cohort, individuals were separated into two groups based on whether their CETP genetic score was greater than or less than the median CETP score. In each group, individuals were then separated into two additional groups based on whether their SGLT2 genetic score was greater than or less than the median SGLT2 genetic score. In total, four groups were formed. The mean age, sex, HDL, LDL, TG, ApoB, weight, systolic blood pressure, glycated hemoglobin, and diabetes incidence rates are recorded for each of the four groups in both the discovery and replication cohorts.

[0254] Group 1 was referred to as the “control group,” Group 2 was referred to as the “SGLT2 monotherapy group,” Group 3 was referred to as the “CETP monotherapy group,” and Group 4 was referred to as the “combination therapy group.” Statistical Analysis

[0255] Comparisons between quantitative traits in each group were made using one-way ANOVA and linear regression. Where differences were detected between groups, each group was compared to every other group pairwise using one-way ANOVA to characterize the differences between the groups. Comparison of gender composition was performed using chi squared. Comparisons in incidence of diabetes between groups was performed using logistic regression. Additionally, we conducted analysis controlling for body mass index (BMI) and systolic blood pressure using linear regression for glycated hemoglobin and logistic regression for diabetes. The covariates of BMI and SBP are included in the regression models because the SGLT2 genetic score used to mimic SGLT2 inhibition is associated with increased SBP and BMI, which is the opposite direction of effect that pharmaceutical SGLT2 inhibition has on these variables. Diabetes incidence was defined by ICD-10 codes retrieved from the electronic health records database associated with the UK Biobank.

Results and Discussion

[0256] Pharmaceutical SGLT2 inhibition is known to decrease glycated hemoglobin levels, therefore our separation of individuals into groups based on degree of genetic SGLT2 inhibition is designed to reflect this observation as well. In the discovery cohort, we assessed whether this is observed by regressing the SGLT2 genetic score against glycated hemoglobin values in all individuals (Table 1). This provided a p value of 0.000977 (Table 2), suggesting that increased genetic SGLT2 inhibition is associated with decreased glycated hemoglobin. As an additional layer of validation, SGLT2 scores are regressed against systolic blood pressure (SBP) and body mass index (BMI), since pharmaceutical SGLT2 inhibition is associated with reduced SBP and BMI. Regression results suggest that the SGLT2 genetic score used is associated with SBP (p=0.000708), but not BMI (p=0.141); however, greater genetic SGLT2 inhibition was found to be associated with increased SBP and BMI, the opposite direction as expected. See FIG. 8A and Table 2. Given that the opposite direction of effect as pharmaceutical SGLT2 inhibition is observed in our genetic score with SBP significant and BMI trending towards significance, we include SBP and BMI as covariates in all analyses to isolate the effect that genetic SGLT2 inhibition has on phenotypes of interest independent of SBP and BMI. A similar validation process is repeated for our genetic CETP score with respect to HDL levels, since pharmaceutical CETP inhibition is associated with elevated HDL levels, yielding p<2e-16 and confirming the CETP genetic score works as intended. As further validation, the CETP score is regressed against LDL and ApoB levels, since pharmaceutical CETP inhibition is associated with a reduction in all three variables, and the same association is observed at p<2e-16 for all regressions. Therefore, our CETP score functions as intended. All regressions performed to confirm genetic score function are linear regressions with age and biological sex included as covariates.

[0257] Following confirmation that our CETP genetic scores functioned as intended and controlling out the unexpected associations present in the SGLT2 score, we characterized each genetic score’s effect on glycemic control on diabetes incidence relative to the control group. To do so, we compared the incidence of diabetes between Groups 2, 3, and 4 (monotherapies or combination therapy) with that of Group 1 (control) using logistic regression and include age, sex, SBP, and BMI as covariates. We found that Group 4 (corresponding to combination therapy) was the only group associated with a statistically significant decrease in diabetes incidence relative to control (FIG. 9A).

[0258] Then, we investigated whether combination therapy of SGLT2 inhibitors and CETP inhibitors conferred decreased incidence of diabetes relative to SGLT2 inhibitor or CETP inhibitor monotherapy. We found that Group 4 was associated with a statistically significant decrease in diabetes incidence relative to Group 2 (SGLT2 inhibitor monotherapy) but not Group 3 (CETP inhibitor monotherapy), while Groups 2 and 3 were not significantly different from each other with respect to diabetes incidence (FIG. 9B).

[0259] Next, we investigated whether therapy with SGLT2i, CETPi, or both resulted in a greater reduction of glycated hemoglobin levels compared to control. We used linear regression controlling for age, sex, SBP, and BMI. We found that Groups 2, 3, and 4 were all associated with decreased glycated hemoglobin levels compared to control (FIG. 10A). Subsequently, we investigated whether combination therapy of SGLT2 inhibitors and CETP inhibitors conferred decreased incidence of diabetes relative to SGLT2 inhibitor or CETP inhibitor monotherapy. We found that Group 4 was associated with a statistically significant decrease in glycated hemoglobin relative to Group 2 (SGLT2 inhibitor monotherapy) and Group 3 (CETP inhibitor monotherapy), while Groups 2 and 3 were not significantly different from each other with respect to glycated hemoglobin levels (FIG. 10B). We also found that BMI, weight, age, sex and blood pressure did not differ significantly between groups.

Sensitivity Analysis

[0260] Analysis with all regressions between groups were conducted without inclusion of SBP and BMI as covariates, and in all regressions we find that Group 4 is associated with lower glycated hemoglobin levels compared to all other groups and lower diabetes incidence when compared to both control and Group 2 (SGLT2 inhibitor monotherapy). Results shown in FIG. 11 A-D. These results indicate that the conclusions reached in our discovery cohort are robust against the presence or absence of SBP and BMI as covariates in our regressions. [0261] In the discovery cohort of our UK Biobank analysis, we found that relative to SGLT2i monotherapy alone, combination therapy with CETPi reduced the incidence of diabetes and decreased glycated hemoglobin levels.

[0262] However, these results were not replicated at significance in the replication cohort (FIG. 12A-D) - though the actual estimates of effect were similar, the p-values were only trending towards significance due to lower sample size (relative to discovery cohort) as the effects were nearly all in the same direction (10/12 regressions yielded same direction of effect). CETP and SGLT2 genetic score function in the replication cohort was assessed using the same method as in the discovery cohort and regressed against relevant biomarkers of interest. The CETP score was significantly associated with HDL, LDL and ApoB, with directions and magnitudes of effect nearly identical to those observed in the discovery cohort (FIG. 13). However, SGLT2 genetic scores fell short of significant associations against glycated hemoglobin (p=0.08) and SBP (p=0.25), though it was significantly associated with BMI (p=0.04); all directions of effect were replicated (FIG. 14). We do note, however, that the SGLT2 score is significantly associated with BMI but not with SBP, reversing the associations seen in the discovery cohort (though all non-significant associations in both cohorts appear trending towards significance). Due to this trend toward significance and recapitulation of effect directions, the SGLT2 genetic score is interpreted as functioning as intended in the replication cohort, despite falling short of statistical significance likely due to decreased sample size (58,550 individuals in replication cohort vs. 175,213 individuals in the discovery cohort).

Discovery cohort Sensitivity Tables

[0263] HDL is strongly correlated with diabetes (higher HDL associated with lower diabetes) and also with glycated hemoglobin (high HDL associated with lower glycated hemoglobin in the overall cohort and all groups individually at p<2e-16 for all.

Replication Cohort Data Tables Sensitivity Tables

[0264] The mean glycated hemoglobin levels between group 1 and group 4 and group 1 and group 2 are statistically significant after the inclusion of the covariates in the sensitivity analysis, though the difference in mean glycated hemoglobin levels between Group 2 and Group 4 remain statistically insignificant in the replication cohort (Tables 15 -17).

[0265] Overall, we interpret the results of the statistical analysis in the replication cohort as a lack of replication for the significant signals obtained in the discovery cohort, though we note that the mean glycated hemoglobin levels in the replication cohort for each group are not significantly different than those in the discovery cohort when subjected to a t-test, suggesting that the lack of statistical significance in the replication cohort may be due to lower sample size (Table 20).

[0266] Furthermore, even in the discovery cohort that is 3 times the size of the replication cohort, the significant signals observed were mostly on the same order of magnitude as the significance level of 0.05. In the much smaller replication cohort, the smaller sample size may also prevent interactions from reaching statistical significance.

[0267] In summary, the results of the sensitivity analysis shown in Tables 5 - 9 are consistent with the results from the analysis described herein above (e.g., in the Results and Discussion section). The significance of the tests with respect to glycated hemoglobin and diabetes incidence are not affected by BMI, BP, weight, age, or sex.

6.2. Example 2: Preparation of fixed dose tablet

[0268] The following examples are illustrative procedures of how obicetrapib and SGLT2 fixed dose combination tablets described herein can be prepared and tested.

6.2.1. Example 2A: Composition

[0269] Exemplary pharmaceutical dosage forms (e.g., as disclosed herein) are formulated as a 6 mm diameter, white, film-coated, round, biconvex tablet with no identifying markings. Tablets can be manufactured in the dosage strengths shown in tables 21-24 below (dose of obicetrapib expressed as the calcium salt).

[0270] A complete description of the components and quantitative composition of fixed dose tablets including obicetrapib 5 mg, or 10 mg, and a SGLT2 inhibitor are provided in tables 21-24 (quantities expressed as %w/w)

6.2.1. Example 2B: Preparation

[0271] A general manufacturing process for the fixed dose tablets described above by direct compression is described as follows:

(1) amorphous obicetrapib, typically amorphous obicetrapib calcium salt, and the SGLT2 inhibitor are blended with microcrystalline cellulose, mannitol, sodium starch glycolate, and colloidal silicon dioxide in a mixer to obtain a pre-mixture;

(2) magnesium stearate is added to the pre-mixture of step (1) and mixing continued;

(3) tableting the final mixture of step (1) by compressing it into 6 mm biconvex tablet cores on a suitable tablet press;

(4) Film-coating the 6 mm biconvex tablet cores with a proprietary aesthetic film coating.

7. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0272] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0273] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising: a) a therapeutically effective amount of amorphous obicetrapib or calcium salt thereof; and b) a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the composition comprises amorphous obicetrapib hemicalcium.

3. The pharmaceutical composition according to claim 1 or 2, wherein the amorphous obicetrapib calcium salt is substantially free of any crystalline salt of obicetrapib calcium.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the amorphous obicetrapib calcium has an x-ray powder diffraction pattern substantially the same as either that of Figure 1 A or IB.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the amorphous obicetrapib calcium has an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°29, about 7.0°29, and about 9.2°29.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amorphous obicetrapib calcium does not birefringe.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the amorphous obicetrapib calcium has a glass transition temperature at a value between about 107°C and about 112°C.

8. The pharmaceutical composition according to claim 7, wherein the glass transition temperature is measured with modulated differential scanning calorimetry.

9. The pharmaceutical composition according to claim 8, wherein the measurement with modulated differential scanning calorimetry uses a sample pan which is open.

10. The pharmaceutical composition according to claim 9, wherein the opening is a pinhole.

11. The pharmaceutical composition according to any one of claims 6 to 10, wherein the glass transition temperature is at a value between about 110°C and about 112°C.

12. The pharmaceutical composition according to any one of claims 1-13, wherein the amorphous obicetrapib calcium has a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan.

13. The pharmaceutical composition according to claim 12, wherein the amorphous obicetrapib calcium has a glass transition temperature at a value between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan.

14. The pharmaceutical composition according to claim 13, wherein the amorphous obicetrapib calcium has a loss in weight of less than about 1% when heated to about 200°C.

15. The pharmaceutical composition according to claim 14, wherein the amorphous obicetrapib calcium loss in weight is between about 0.8% and about 0.95%.

16. The pharmaceutical composition according to claim 15, wherein the amorphous obicetrapib calcium loss in weight is between about 0.84% and about 0.92%.

17. The pharmaceutical composition according to any one of claims 1-16, wherein the amorphous obicetrapib calcium has a water content of less than about 5%.

18. The pharmaceutical composition according to claim 17, wherein the amorphous obicetrapib calcium water content is less than about 4%.

19. The pharmaceutical composition according to claim 18, wherein the amorphous obicetrapib calcium water content is less than about 3%.

20. The pharmaceutical composition according to claim 19, wherein the amorphous obicetrapib calcium water content is between about 0.5% and about 1.5%.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the amorphous obicetrapib calcium is in bulk form or formulated composition, having a particle size distribution wherein about 90% of the particles have a diameter of about 15 microns or less.

22. The pharmaceutical composition according to claim 21, wherein about 90% of the amorphous obicetrapib calcium particles have a diameter of between about 6 microns and about 15 microns.

23. The pharmaceutical composition according to claim 22, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 14 microns or less.

24. The pharmaceutical composition according to claim 23, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 13 microns or less.

25. The pharmaceutical composition according to claim 24, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 12 microns or less.

26. The pharmaceutical composition according to claim 25, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 11 microns or less.

27. The pharmaceutical composition according to claim 26, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 10 microns or less.

28. The pharmaceutical composition according to claim 27, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 9 microns or less.

29. The pharmaceutical composition according to claim 28, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 8 microns or less.

30. The pharmaceutical composition according to claim 29, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 7 microns or less.

31. The pharmaceutical composition according to claim 30, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 6 microns or less.

32. The pharmaceutical composition according to claim 31, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 5 microns or less.

33. The pharmaceutical composition according to claim 32, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 4 microns or less.

34. The pharmaceutical composition according to claim 33, wherein about 90% or more of the amorphous obicetrapib calcium particles have a diameter of about 3 microns or less.

35. The pharmaceutical composition according to any one of claims 1 to 34, wherein the amorphous obicetrapib calcium is in bulk form or formulated composition, having a particle size distribution wherein about 50% of the particles have a diameter of about 5 microns or less.

36. The pharmaceutical composition according to claim 35, wherein about 50% of the amorphous obicetrapib calcium particles have a diameter of about 4 microns or less.

37. The pharmaceutical composition according to claim 36, wherein about 50% of the amorphous obicetrapib calcium particles have a diameter of about 3 microns or less.

38. The pharmaceutical composition according to any one of claims 1 to 37, wherein the amorphous obicetrapib calcium is in bulk form or formulated composition, having a particle size distribution wherein about 10% of the particles have a diameter of about 2 microns or less.

39. The pharmaceutical composition according to any one of claims 1 to 38, wherein the amorphous obicetrapib calcium has a chemical purity of at least 98.0%.

40. The pharmaceutical composition according to claim 39, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.0%.

41. The pharmaceutical composition according to claim 40, wherein the amorphous obicetrapib calcium has a chemical purity of at least 98.0%.

42. The pharmaceutical composition according to claim 41, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.0%.

43. The pharmaceutical composition according to claim 42, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.5%.

44. The pharmaceutical composition according to claim 43, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.6%.

45. The pharmaceutical composition according to claim 44, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.7%.

46. The pharmaceutical composition according to claim 45, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.8%.

47. The pharmaceutical composition according to claim 46, wherein the amorphous obicetrapib calcium has a chemical purity of at least 99.9%.

48. The pharmaceutical composition according to any one of claims 1 to 47, wherein the amorphous obicetrapib calcium has a solid-state 13C-NMR spectrum substantially the same as that of Figure 6C.

49. The pharmaceutical composition according to any one of claims 1 to 48, wherein the amorphous obicetrapib calcium has having a solid-state 13C-NMR spectrum where no peak is present at about 22.1 ppm.

50. The pharmaceutical composition according to any one of claims 1 to 49, wherein the amorphous obicetrapib calcium has having a solid-state 13C-NMR spectrum where no peak is present at about 29.5 ppm.

51. The pharmaceutical composition according to any one of claims 1 to 50, wherein the amorphous obicetrapib calcium has been milled.

52. The pharmaceutical composition according to any one of claims 1 to 51, wherein the amorphous obicetrapib calcium has been jet milled.

53. The pharmaceutical composition according to any one of claims 1 to 52, wherein the amorphous obicetrapib calcium has been spray dried.

54. The pharmaceutical composition according to any one of claims 1 to 53, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, and sotagliflozin.

55. The pharmaceutical composition according to any one of claims 1 to 54, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.

56. The pharmaceutical composition according to claim 54 or 55, wherein the SGLT2 inhibitor is empagliflozin.

57. The pharmaceutical composition according to claim 54 or 55, wherein the SGLT2 inhibitor is dapagliflozin.

58. The pharmaceutical composition according to claim 54 or 55, wherein the SGLT2 inhibitor is canagliflozin.

59. The pharmaceutical composition according to claim 54 or 55, wherein the SGLT2 inhibitor is ertugliflozin.

60. The pharmaceutical composition according to any one of claims 1 to 59, comprising from 1% to 25% w/w of amorphous obicetrapib.

61. The pharmaceutical composition according to claim 60, comprising from 1% to 10% w/w of amorphous obicetrapib.

62. The pharmaceutical composition according to claim 61, comprising about 5% w/w of amorphous obicetrapib.

63. The pharmaceutical composition according to claim 61, comprising about 10% w/w of amorphous obicetrapib.

64. The pharmaceutical composition according to any one of claims 1 to 63, comprising from 5% to 50% w/w of the SGLT2 inhibitor.

65. The pharmaceutical composition according to claim 64, comprising from 5% to 25% w/w of the SGLT2 inhibitor.

66. The pharmaceutical composition according to any one of claims 1 to 65, further comprising one or more of a diluent, a disintegrant, a glidant, a filler, a lubricant, and any combination thereof.

67. The pharmaceutical composition according to claim 66, wherein the diluent is selected from the group consisting of dicalcium phosphate, cellulose, microcrystalline cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, lactose anhydrous, mannitol, tribasic calcium phosphate, and combinations thereof.

68. The pharmaceutical composition according to claim 66 or 67, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.

69. The pharmaceutical composition according to any one of claims 66 to 68, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, and combinations thereof.

70. The pharmaceutical composition according to any one of claims 66 to 69, wherein the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and combinations thereof.

71. The pharmaceutical composition according to any one of claims 1 to 70, wherein the composition comprises:

72. The pharmaceutical composition according to claim 71, further comprising one or more lubricants.

73. The pharmaceutical composition according to claim 71 or 72, further comprising one or more glidants.

74. The pharmaceutical composition according to any one of claims 1 to 73, further comprising one or more additional active agents.

75. The pharmaceutical composition according to claim 74, wherein the one or more additional active agents is selected from metformin, a GLP-1 agonist, and a DPP -4 inhibitor, or pharmaceutically acceptable salts thereof.

76. The pharmaceutical composition according to claim 75, wherein the DPP -4 inhibitor is linagliptin.

77. The pharmaceutical composition according to any one of claims 1 to 76, wherein the amorphous calcium salt of obicetrapib is prepared by a synthetic process wherein an intermediate in the process comprises HCL obicetrapib.

78. The pharmaceutical composition according to claim 77, wherein the HCL intermediate in the process is crystalline HCL obicetrapib.

79. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of claims 1 to 78.

80. The pharmaceutical dosage form of claim 79, wherein the amorphous obicetrapib is present in an amount of from 1 to 25 mg.

81. The pharmaceutical dosage form of claim 80, wherein the amorphous obicetrapib is present in an amount of from 1 to 10 mg.

82. The pharmaceutical dosage form according to claim 80, wherein the amorphous obicetrapib is present in an amount of 5 mg.

83. The pharmaceutical dosage form according to claim 80, wherein the amorphous obicetrapib is present in an amount of 10 mg.

84. The pharmaceutical dosage form according to any one of claims 79 to 83, wherein the

SGLT2 inhibitor is present in an amount of from 1 to 300 mg.

85. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of from 5 to 100 mg.

86. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of from 5 to 50 mg.

87. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of from 10 to 25 mg.

88. The pharmaceutical dosage form according to claim 87, wherein the SGLT2 inhibitor is empagliflozin.

89. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of from 5 to 15 mg.

90. The pharmaceutical dosage form according to claim 89, wherein the SGLT2 inhibitor is ertugliflozin.

91. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of from 5 to 10 mg.

92. The pharmaceutical dosage form according to claim 91, wherein the SGLT2 inhibitor is dapagliflozin.

93. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of from 100 to 300 mg.

94. The pharmaceutical dosage form according to claim 93, wherein the SGLT2 inhibitor is canagliflozin.

95. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of 5 mg.

96. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of 10 mg.

97. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of 15 mg.

98. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of 25 mg.

99. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of 100 mg.

100. The pharmaceutical dosage form according to claim 84, wherein the SGLT2 inhibitor is present in an amount of 300 mg.

101. The pharmaceutical dosage form according to claim 79, wherein the amorphous obicetrapib is present in an amount of from 5 to 10 mg; and the SGLT2 inhibitor is empagliflozin, present in an amount of from 10 to 25 mg.

102. The pharmaceutical dosage form according to claim 79, wherein the amorphous obicetrapib is present in an amount of from 5 to 10 mg; and the SGLT2 inhibitor is ertugliflozin, present in an amount of from 5 to 15 mg.

103. The pharmaceutical dosage form according to claim 79, wherein the amorphous obicetrapib is present in an amount of from 5 to 10 mg; and the SGLT2 inhibitor is dapagliflozin, present in an amount of from 5 to 10 mg.

104. The pharmaceutical dosage form according to claim 79, wherein the amorphous obicetrapib is present in an amount of from 5 to 10 mg; and the SGLT2 inhibitor is canagliflozin, present in an amount of from 100 to 300 mg.

105. The pharmaceutical dosage form according to any one of claims 79 to 104, wherein the dosage form is a solid dosage form.

106. The pharmaceutical dosage form according to claim 105, wherein the solid dosage form is a tablet.

107. The pharmaceutical dosage form according to claim 106, further comprising a film coating.

108. A method of preparing the pharmaceutical compositions according to any one of claims 1-78, or pharmaceutical dosage forms according to any one of claims 79 to 107, the method comprising: i. treating obicetrapib with HCL to obtain a crystalling HCL obicetrapib compound; ii. isolating the crystalling HCL obicetrapib compound; iii. preparing an amorphous calcium salt of obicetrapib from the crystalline HCL obicetrapib compound isolated in step (ii); iv. isolating an amorphous calcium salt of obicetrapib; and v. combining the isolated amorphous calcium salt of obicetrapib with at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

109. The method of claim 108, wherein the isolated crystalline HC1 obicetrapib compound in step (ii) comprises a compound of formula (IH):

wherein y varies from 0.002 to 1.5.

110. The method according to claims 108 or 109, wherein the preparation of the amorphous calcium salt of formula (I) in step (iii) comprises the following steps:

(iii-1) converting the crystalline HC1 obicetrapib compound of step (ii) to provide obicetrapib in one or more suitable solvents selected from organic solvents and aqueous solvents;

(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 the amorphous calcium salt of obicetrapib wherein the compounds in steps (iii-1) and (iii-2) are optionally not isolated.

111. The method according to claims any one of claims 108 to 110 wherein the amorphous calcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

112. The method according to of any one of claims 108 to 111, wherein the amorphous calcium salt of obicetrapib is isolated with a chemical purity of at least 99%.

113. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.1%.

114. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.2%.

115. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.3%.

116. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.4%.

117. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.5%.

118. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.6%.

119. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.7%.

120. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.8%.

121. The method according to claim 112, wherein the amorphous calcium salt of obicetrapib is isolated with a purity of at least 99.9%.

122. The method according to claims any of claims 112 to 121, wherein the calcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

123. The method according to claims any of claims 108 to 122, wherein the at least one SGLT2 inhibitor, or pharmaceutically acceptable salt thereof, combined with amorphous obicetrapib is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin, remogliflozin etabonate, sergliflozin, sergliflozin etabonate, atigliflozin, and sotagliflozin.

124. The method according to claim 123, wherein SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.

125. The pharmaceutical composition according to claim 123 or 124, wherein the SGLT2 inhibitor is empagliflozin.

126. The pharmaceutical composition according to claim 123 or 124, wherein the SGLT2 inhibitor is dapagliflozin.

127. The pharmaceutical composition according to claim 123 or 124, wherein the SGLT2 inhibitor is canagliflozin.

128. The pharmaceutical composition according to claim 123 or 124, wherein the SGLT2 inhibitor is ertugliflozin.

129. A method of treating or preventing a disorder selected from the group consisting of: type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease, the method comprising: administering to a subject having or at risk of developing one or more disorders from said group a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 78, or a pharmaceutical dosage form of any one of claims 79 to 107.

130. The method according to claim 129, wherein the disorder is selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, or metabolic syndrome.

131. A method of treating or preventing preventing a disorder selected from the group consisting of: type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, comprising: administering a therapeutically effective amount of amorphous calcium salt of obicetrapib; and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

132. The method according to claim 131, wherein the amorphous calcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

133. The method according to claim 131 or 132, wherein the metabolic disorder is selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, and metabolic syndrome.

134. The method according to any one of claims 131 to 133, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, bexagliflozin, tofogliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, and sotagliflozin.

135. The method according to any one of claims 131 to 134, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, ertugliflozin, and empagliflozin.

136. The method according to claim 134 or 135, wherein the SGLT2 inhibitor is empagliflozin.

137. The method according to claim 134 or 135, wherein the SGLT2 inhibitor is dapagliflozin.

138. The method according to claim 134 or 135, wherein the SGLT2 inhibitor is canagliflozin.

139. The method according to claim 134 or 135, wherein the SGLT2 inhibitor is ertugliflozin.

140. The method according to any one of claims 131 to 139, wherein the therapeutically effective amount of amorphous obicetrapib is from 1 to 25 mg per day.

141. The method according to claim 140, wherein the therapeutically effective amount of amorphous obicetrapib is from 1 to 10 mg per day.

142. The method according to claim 140, wherein the therapeutically effective amount of amorphous obicetrapib is 5 mg per day.

143. The method according to claim 140, wherein the therapeutically effective amount of amorphous obicetrapib is 10 mg per day.

144. The method according to any one of claims 131 to 135, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 1 to 300 mg per day.

145. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 5 to 100 mg per day.

146. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 5 to 50 mg per day.

147. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 10 to 25 mg per day.

148. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 5 to 15 mg per day.

149. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 5 to 10 mg per day.

150. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is from 100 to 300 mg per day.

151. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is 5 mg per day.

152. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is 10 mg per day.

153. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is 15 mg per day.

154. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is 25 mg per day.

155. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is 100 mg per day.

156. The method according to claim 144, wherein the therapeutically effective amount of the SGLT2 inhibitor is 300 mg per day.

157. The method according to claim 131, wherein the therapeutically effective amount of amorphous obicetrapib is from 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is from 10 to 25 mg per day; and the SGLT2 inhibitor is empagliflozin.

158. The method according to claim 131, wherein the therapeutically effective amount of amorphous obicetrapib is from 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is from 5 to 15 mg per day; and the SGLT2 inhibitor is ertugliflozin.

159. The method according to claim 131, wherein the therapeutically effective amount of amorphous obicetrapib is from 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is from 5 to 10 mg per day; and the SGLT2 inhibitor is dapagliflozin.

160. The method according to claim 131, wherein the therapeutically effective amount of amorphous obicetrapib is from 5 to 10 mg per day; the therapeutically effective amount of the SGLT2 inhibitor is from 100 to 300 mg per day; and the SGLT2 inhibitor is canagliflozin.

161. The pharmaceutical composition according to claim 75, wherein the GLP-1 agonist is semaglutide, exenatide, dulaglutide, liraglutide, lixisenatide or tirzepatide, including pharmaceutically acceptable salts, hydrates and solvates thereof.