Obicetrapib and ezetimibe combination treatment and fixed dose pharmaceutical compositions

Abstract

The present disclosure relates to combinations of obicetrapib and ezetimibe, or their salts, solvates or derivatives thereof. The disclosure further describes the use of ezetimibe and obicetrapib, e.g. in the form of a fixed dose combination product, for preparation of medicaments and method of treatment of subjects requiring reduction in LDL-cholesterol or those suffering from hyperlipidemia or mixed dyslipidemia.

Description

OBICETRAPIB AND EZETIMIBE COMBINATION TREATMENT AND FIXED DOSE PHARMACEUTICAL COMPOSITIONS1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Application Nos.63 / 722,542, filed November 19, 2024, and 63 / 891,043, filed September 30, 2025, which are incorporated herein by reference in their entireties for all purposes.2. TECHNICAL FIELD

[0002] The present disclosure relates to a fixed dose pharmaceutical composition comprising obicetrapib and ezetimibe, and its use for preparation of medicaments and treatment of subjects requiring reduction of LDL cholesterol or in patients with heterozygous familial hypercholesterolemia (HeFH) and / or with established atherosclerotic cardiovascular disease (ASCVD).3. BACKGROUND

[0003] Despite advances in treatment, cardiovascular disease (CVD) is still a leading cause of death globally, with over 17 million deaths annually. For many years it has been known that abnormal cholesterol levels have been associated with increased risk of cardiovascular disease (CVD), such as cardiomyopathy, atherosclerosis and myocardial infarction. In particular, individuals presenting with high levels of low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol combined with low levels of high-density lipoprotein (HDL) cholesterol were observed to be at the highest risk of developing a cardiovascular disease.

[0004] The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve target blood lipid levels with statin therapy or have partial or complete intolerance to them. To reduce the risk of a recurrent non-fatal or fatal cardiovascular disease, such patients are advised to take combinations of alternative lipid lowering agents.

[0005] Updates to risk-based LDL-C goals inevitably mean that greater use of combination therapies in addition to (high intensity) statins will be needed. Currently available oral add-on lipid lowering therapies reduce LDL-C individually by up to (about) 25%. The costs and inconvenience of more potent injectable therapies have limited their uptake. As a result, there remains a high-unmet need for new effective, safe oral therapies as an adjunct to statin therapy.4. SUMMARY

[0006] As will be explained in much more detail herein below, the present inventors have found that remarkable improvements in blood lipid profiles are attained with obicetrapib and ezetimibe combination treatment.

[0007] More in particular, the present inventors found that remarkable improvements in blood lipid profiles are attained with obicetrapib and ezetimibe combination treatment, even in subjects that did not adequately respond to (high intensity) statin treatment. More in particular, as described in the experimental part of this document, it is shown, in a phase 2b clinical trial (‘ROSE2’; NCT05266586), that an obicetrapib (10 mg) and ezetimibe (10 mg) combination was well tolerated and achieved a median reduction in LDL-C of 59%, which is clearly indicative of a supra additive (i.e. synergistic) effect. In particular, patients treated with Obicetrapib achieved a median reduction of LDL-C of 39%, meaning that ezetimibe, added on top of obicetrapib, resulted in an additional / incremental (median) reduction of LDL-C of about 32%. This (greatly) exceeds LDL-C reductions normally attained with ezetimibe: with ezetimibe mono-therapy LDL-C levels are typically reduced by 15-22% (in hyperlipidemic patients), while in combination with statins, ezetimibe typically provides an incremental reduction in LDL-C levels of 15-20% (see, for instance, Catapano et al. European Heart Journal (2016) 37, 2999-3058). Significant improvements in ApoB, and Lp(a) levels were also demonstrated in the trial.

[0008] To further elucidate the effects of the combination treatment, further studies were carried out using a standard human CETP transgenic knock-in mouse. As can be inferred from the experimental results reported herein, Obicetrapib alone and the combination with ezetimibe reduce non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels accompanied by an enhanced fecal bile acid and neutral sterol excretion.

[0009] Using the same human CETP transgenic knock-in mouse, it has further been demonstrated that obicetrapib alone, and in combination with ezetimibe, reduces atherosclerotic lesion prevalence, size, and severity.

[0010] The data mouse model data further support the supra additivity of Obicetrapib and ezetimibe in improving blood lipid profiles and reducing ASCVD related risks in patients in need thereof. Without being bound to any particular theory, the data now generated implicates TICE in the mechanism of action of obicetrapib. More particularly, it is believed that obicetrapib, apart from inhibiting CETP mediated (net) mass Transfer of cholesterol esters from HDL to Particles in VLDL / LDL, also shunts cholesterol to the intestine via Transintestinal cholesterol Excretion (TICE), thereby increasing clearance and excretion. Addition of Ezetimibe Blocks Reabsorption of Cholesterol in the Intestine, working synergistically to enhance fecal sterol excretion.

[0011] Additionally, the present inventors sought to evaluate the effects of obicetrapib in combination with ezetimibe in adults with HeFH and / or atherosclerotic cardiovascular disease (ASCVD) using a fixed dose combination (FDC) tablet. The inventors therefore embarked on a further trial, a phase 3 study evaluating the effect of an obicetrapib (10 mg) and ezetimibe (10 mg) fixed dose combination (FDC) tablet on top of maximally tolerated lipid-modifying therapy in patients with heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) or multiple ASCVD risk factors (NCT06005597). The primary goal was to assess the impact of a 10 mg obicetrapib and 10 mg ezetimibe FDC on LDL-C levels from baseline, against the effects of 10 mg ezetimibe and 10 mg obicetrapib monotherapies. The results confirmed that the FDC comprising 10 mg obicetrapib and 10 mg ezetimibe provides synergistic effects in combination when compared to 10 mg obicetrapib monotherapy. The data from this trial also showed significant reduction in LDL-C, non-HDL-C, ApoB and Lp(a) for the 10 mg obicetrapib and 10 mg ezetimibe FDC combination compared to 10 mg obicetrapib or 10 mg ezetimibe monotherapy. The data also showed positive improvement in HDL-C for the 10 mg obicetrapib and 10 mg ezetimibe FDC compared to 10 mg obicetrapib or 10 mg ezetimibe monotherapy.

[0012] One aspect of the invention thus relates to a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof;ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients.

[0013] A second aspect relates to a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, for use in reducing LDL cholesterol in patients requiring a reduction in LDL cholesterol and / or increase in HDL cholesterol, patients with heterozygous familial hypercholesterolemia (HeFH) and / or patients with established atherosclerotic cardiovascular disease (ASCVD).

[0014] The present invention also provides methods of treating a subject in need thereof, said method comprising the concomitant treatment of the subject with obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, preferably in the form of the fixed dose pharmaceutical composition as defined herein.

[0015] One particular aspect of the invention concerns a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising the concomitant treatment of the subject with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0016] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, wherein the method comprises the concomitant treatment of the subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said pharmaceutical composition is the fixed dose pharmaceutical composition as defined herein.

[0017] A further aspect of the invention concerns a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the concomitant treatment of said subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0018] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib or a pharmaceutically acceptable salt, solvate thereof or co-crystal thereof, for use in a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0019] A further aspect of the invention concerns a method of synergistically slowing the development and / or progression of CVD, more in particular ASCVD, and / or synergistically reducing the risk and / or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0020] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of synergistically slowing the development and / or progression of CVD, more in particular ASCVD, and / or synergistically reducing the risk and / or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the concomitant treatment of the subject with ezetimibe, or a pharmaceutically acceptable salt, solvate or cocrystal thereof, and obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystalthereof. In a preferred embodiment, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0021] A further aspect of the invention concerns a method of enhancement, preferably the synergistic enhancement, of the LDL-C lowering effect of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in a subject in need thereof, said method comprising the concomitant treatment of the subject with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0022] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of enhancement, preferably the synergistic enhancement, of the LDL-C lowering effect of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0023] A further aspect of the invention concerns a method of enhancement, preferably the synergistic enhancement, of the therapeutic efficacy of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in particular of the therapeutic efficacy in the treatment and / or prevention of CVD, more in particular ASCVD, in a subject in need thereof, said method comprising the concomitant administration of ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0024] A further aspect of the invention concerns a pharmaceutical composition comprising ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, for use in a method of enhancement, preferably the synergistic enhancement of the therapeutic efficacy of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in particular of the therapeutic efficacy in the treatment and / or prevention of CVD, more in particular ASCVD, in a subject in need thereof, said method comprising the concomitant administration ofezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In a preferred embodiment of the invention, said method comprises the administration of the fixed dose pharmaceutical composition as defined herein.

[0025] Yet, a further aspect of the invention concerns the use of obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and / or ezetimibe, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, in the manufacture of a medicament for use in any one of the afore defined methods. In a preferred embodiment of the invention, said medicament is the fixed dose pharmaceutical composition as defined herein.

[0026] Other aspects of the invention concern a kit comprising a package containing a plurality of pharmaceutical unit dosage forms comprising or a pharmaceutically acceptable salt, hydrate or solvate thereof, such as the fixed dose pharmaceutical compositions as defined herein, as well as a leaflet containing printed instructions to repeatedly self-administer said unit dosage forms in order to treat and / or prevent CVD, in particular ASCVD, by combined obicetrapib treatment and ezetimibe therapy.

[0027] It will be understood that these aspects of the invention all involve the same compositions, the same methods of treatment, the same subjects, etc. unless specifically stated otherwise.

[0028] In certain preferred embodiments of the invention, the salt of obicetrapib, contained in the present pharmaceutical compositions, used in the present methods, contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is an amorphous calcium salt of obicetrapib.

[0029] Specific details and preferred embodiments of the afore-mentioned methods as well as of the compositions and pharmaceutical kits used therein will become evident to those skilled in the art on the basis of the following detailed description and the appended experimental part.5. DEFINITIONS

[0030] Obicetrapib, also referred to as “TA-8995”, has the following chemical name and chemical structure:{4-[(2-{[3,5-bis(trifluoromethyl)benzyl] [(2R,4S)-l-(ethoxycarbonyl)-2-ethyl- 6-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid}

[0031] Ezetimibe, also referred to as “Sch-58235”, has the following chemical name and chemical structure:(3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0032] Both obicetrapib and ezetimibe may also be used as different salt forms, solvates or cocrystals. They may also be formulated as pro-drugs.

[0033] The term “ apolipoprotein” as used herein has its conventional meaning and refers to proteins that bind lipids to form lipoproteins.

[0034] The term “apolipoprotein B” (ApoB) as used herein has its conventional meaning and refers to the protein encoded by the ApoB gene.

[0035] The term ‘pharmaceutical composition" as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.

[0036] The term " pharmaceutically acceptable" as used herein has its conventional meaning and refers to compounds, material, compositions and / or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0037] The term “carrier” as used herein has its conventional meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient or vehicle with which a pharmaceutically active ingredient is administered.

[0038] The term "excipient" as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.

[0039] The term "salt" as used herein has its conventional meaning and includes the acid addition and base salts of a pharmaceutically active compound.

[0040] The term “solvate” as used herein has its conventional meaning and refers to a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols, nitriles and polar organic solvents.

[0041] The term “subject"" as used herein refers to humans suffering from or at risk for a certain disease or disorder. The term “subject” and “patient” herein are used interchangeably.

[0042] The term "increased risk" has its conventional meaning and refers to a situation where a subject, preferably a human subject, either male or female, based on his or her risk profile (including an LDL-cholesterol level above 70 mg / dL, such as above 2.6 mmol / 1 [100.54 mg / dL]), such that the subject is at an increased risk of suffering a cardiovascular event, compared to those with lower levels.

[0043] The terms "treating", "treatment", and grammatical variations thereof are used in the broadest sense understood in the clinical arts. Accordingly, the terms do not require cure or complete remission of disease, and encompass obtaining any clinically desired pharmacologic and / or physiologic effect.

[0044] The term ‘ cardiovascular disease" as used herein has its conventional meaning and includes clinical manifestations of arteriosclerosis, peripheral vascular disease angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and cerebral stroke.

[0045] The term “ cardiovascular event' as used herein has its conventional meaning and refers to occurrence of myocardial infarction, stroke, coronary death or the necessity to undergo a coronary revascularization (Ference, 2017).

[0046] The term “hypercholesterolemia:' as used herein has its conventional meaning and refers to the condition in which high levels of cholesterol are present in the blood.

[0047] The term “ hyper lipidaemia" as used herein has its conventional meaning and refers to the condition in which there are high amounts of lipids found in the blood.

[0048] The term “mixed dyslipidaemia"" as used herein has its conventional meaning and refers to the condition in which there are elevations of LDL cholesterol and triglyceride levels that are accompanied by low levels of HDL cholesterol in the blood.

[0049] The term “statin intolerant' as used herein has its conventional meaning and refers to subjects inability to tolerate two or more statins, one at a low dose, due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin was discontinued, reference is in this regard also made to the similar definition approved by the FDA in the bempedoic acid (Esperion) phase III trial.

[0050] The term ‘ cholesterol absorption inhibitor" (CAI) as used herein has its conventional meaning and refers to compounds which are used to lower LDL-C by blocking enteric and biliary absorption of cholesterol. A known cholesterol absorption inhibitor is ezetimibe.

[0051] The term “cholesteryl ester transfer protein inhibitor"" (CETP inhibitor) as used herein has its conventional meaning and refers to a class of compounds that inhibits the CETP receptor in mammals. A known CETP inhibitor is obicetrapib.

[0052] The term ‘ unit dosage form" has its conventional meaning and refers to a dosage form which has the capacity of being administered to a subject, preferably a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stableunit dose comprising the therapeutic agent, i.e. obicetrapib or combination of therapeutic agents, such as obicetrapib and ezetimibe.

[0053] The term ‘ fixed dose combination’ as used herein has its conventional meaning and refers to a combination of defined doses of two or more drugs or active ingredients presented in a single dosage unit (e.g. a tablet or a capsule) and administered as such.

[0054] The term ‘free dose combination ’ as used herein has its conventional meaning and refers to a combination of two drugs or active ingredients administered simultaneously but as two distinct dosage units.

[0055] 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 will 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.

[0056] 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 (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0057] 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 foranother 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 as2H (deuterium),3H (tritium),13C,14C,15N,17O,18O,18F,36Cl,82Br,123I,124I,125I,129I and131I. 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 with3H,14C and / or18F 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.

[0058] Thus, any of the embodiments described herein are meant to include, a single stereoisomer, a mixture of stereoisomers and / or an isotopic form of the compounds.

[0059] Ranges: throughout this disclosure, various aspects of the invention are presented in a range format. Ranges include the recited endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6, should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. as well as individual number within that range, for example, 1, 2, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0060] In this disclosure, “comprises”, “comprising”, “containing”, “having”, “includes”, “including” and linguistic variants thereof have the meaning ascribed to them in U. S. Patent law, permitting the presence of additional components beyond those explicitly recited.

[0061] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.

[0062] Unless specifically stated or apparent from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural. That is, the articles “a” and “an” are used herein to refer to one or to more than one (ie., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0063] Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within range of normal tolerance in the art. Unless otherwise specified, “about” intends ±10% of the stated value. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context.6. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 Cumulative undersize curve of small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0065] Figure 2 Retain curve for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0066] Figure 3 Comparison of dissolution profile by discriminatory dissolution method -ezetimibe at pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0067] Figure 4 Comparison of dissolution profile of obicetrapib by discriminatory dissolution method pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0068] Figure 5 Comparison of dissolution profile of ezetimibe by discriminatory dissolution -pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0069] Figure 6 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459 / 05 / 05 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0070] Figure 7 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459 / 05 / 06 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0071] Figure 8 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459 / 05 / 07 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0072] Figure 9 Comparison of obicetrapib dissolution profile of the stress stability study for batch a4459 / 05 / 08 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0073] Figure 10 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 05 -ph6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0074] Figure 11 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 06 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0075] Figure 12 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 07 - pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0076] Figure 13 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 08 -pH 6.8 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0077] Figure 14 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 05 -pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0078] Figure 15 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 06 -pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0079] Figure 16 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 07 pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0080] Figure 17 Comparison of ezetimibe dissolution profile of the stress stability study for batch a4459 / 05 / 08 -pH 4.5 for small-scale batch of a fixed dose combination composition of 10 mg ezetimibe and 5 mg obicetrapib.

[0081] Figure 18 % cumulative undersize curve of small-scale batch of 10 mg ezetimibe and 10 mg obicetrapib fixed composition.

[0082] Figure 19 Obicetrapib dissolution profiles for small scale 10 mg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0083] Figure 20 Ezetimibe dissolution profiles (50 rpm) for small scale lOmg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0084] Figure 21 Ezetimibe dissolution profiles (75 rpm) for small scale lOmg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0085] Figure 22 Obicetrapib prototype C 200 BN A4459 / 19 / 03 stress stability dissolution results for small scale lOmg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0086] Figure 23 Obicetrapib prototype C scale up BN A4459 / 19 / 02 stress stability dissolution results for small scale lOmg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0087] Figure 24 Ezetimibe prototype C scale up BN A4459 / 19 / 02 stress stability dissolution results for small scale lOmg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0088] Figure 25 Ezetimibe prototype C scale up BN A4459 / 19 / 02 stress stability dissolution results for small scale lOmg ezetimibe and 10 mg obicetrapib (free acid) fixed dose composition.

[0089] Figure 26 Cumulative undersize for small scale FDC1 compositions.

[0090] Figure 27 Obicetrapib dissolution profiles for FDC1 prototypes.

[0091] Figure 28 Ezetimibe dissolution profiles for FDC1 prototypes.

[0092] Figure 29 Cumulative undersize for small scale FDC2 compositions.

[0093] Figure 30 Obicetrapib dissolution profiles for small scale FDC2 compositions.

[0094] Figure 31 Ezetimibe dissolution profiles for small scale FDC2 compositions.

[0095] Figure 32 Obicetrapib dissolution profiles for small scale FDC2 coated tablets by discriminating method.

[0096] Figure 33 Obicetrapib dissolution profiles for small scale FDC2 coated tablets by QC method.

[0097] Figure 34 Ezetimibe dissolution profiles for small scale FDC2 coated tablets by QC method.

[0098] Figure 35 Obicetrapib dissolution profiles for small scale prototype 2 of FDC2 coated tablets from stress stability.

[0099] Figure 36 Ezetimibe dissolution profile for prototype 2 of FDC2 coated tablets from stress stability.

[0100] Figure 37 Cumulative undersize curve for scale-up batches.

[0101] Figure 38 Obicetrapib dissolution profile for FDC1 granule from scale up batch.

[0102] Figure 39 Ezetimibe dissolution profile for FDC1 granule from scale up batch.

[0103] Figure 40 Ezetimibe dissolution profile for FDC2 final blend from scale up batch.

[0104] Figure 41 Obicetrapib dissolution profile for uncoated tablets of FDC1 scale up batch at different compression forces.

[0105] Figure 42 Ezetimibe dissolution profiles for uncoated tablets of FDC1 scale up batch at different compression forces.

[0106] Figure 43 Obicetrapib dissolution profile for uncoated tablets of FDC2 scale up batch at different compression forces.

[0107] Figure 44 Ezetimibe dissolution profiles for uncoated tablets of FDC2 scale up batch at different compression forces.

[0108] Figure 45 Cumulative undersize curve for technical batches.

[0109] Figure 46 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches.

[0110] Figure 47 Obicetrapib dissolution profiles for FDC1 and FDC 2 technical batches.

[0111] Figure 48 Particle size distribution (PSD) data of granules from technical batches.

[0112] Figure 49 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0113] Figure 50 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0114] Figure 51 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0115] Figure 52 is an infrared spectrum of amorphous obicetrapib hemicalcium.

[0116] Figure 53 is a1H-NMR spectrum of amorphous obicetrapib hemicalcium.

[0117] Figure 54 is an x-ray powder diffraction pattern of crystalline obicetrapib hemicalcium.

[0118] Figure 55 is an x-ray powder diffraction pattern stackplot from a stability study of crystalline obicetrapib hemicalcium.

[0119] Figure 56 is an x-ray powder diffraction pattern stackplot from a stability study of amorphous obicetrapib hemicalcium.

[0120] Figure 57 is a polarized light micrograph of amorphous obicetrapib hemi calcium.

[0121] Figure 58 is a polarized light micrograph of crystalline obicetrapib hemicalcium.

[0122] Figure 59 is a thermogravimetric analysis plot of amorphous obicetrapib hemicalcium.

[0123] Figure 60 is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.

[0124] Figure 61 a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.

[0125] Figure 62 is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.

[0126] Figure 63 is a solid-state13C-NMR spectrum of amorphous and crystalline obicetrapib hemi calcium.

[0127] Figure 64 is a solid-state13C-NMR spectrum of crystalline obicetrapib hemicalcium.

[0128] Figure 65 is a solid-state13C-NMR spectrum of amorphous obicetrapib hemicalcium.

[0129] Figure 66 is an x-ray powder diffraction pattern of crystalline obicetrapib HC1 and at least partially desolvated crystalline obicetrapib HC1.

[0130] Figure 67 is an x-ray powder diffraction pattern of crystalline obicetrapib HC1.

[0131] Figure 68 is an x-ray powder diffraction pattern of crystalline Compound ID.

[0132] Figure 69 is1H-NMR spectrum of Compound 1D.

[0133] Figure 70 schematically depicts the mechanism(s) of action that are presumed to be responsible for the the therapeutic effects of obicetrapib, ezetimibe and the combination thereof.

[0134] Figure 71 summarizes the design of the study into the effects of obicetrapib / ezetimibe combination treatment in a translational mouse model for hyperlipidemia and atherosclerosis (ApoE*3-Leiden. CETP transgenic mice)

[0135] Figure 72 shows the effect of study treatments on total cholesterol and non-HDL-cholesterol levels in ApoE*3-Leiden. CETP transgenic mice.

[0136] Figure 73 shows the effect of study treatments on HDL-cholesterol and ApoAl levels in ApoE*3-Leiden. CETP transgenic mice.

[0137] Figure 74 shows the effect of study treatments on triglycerides levels in ApoE*3-Leiden. CETP transgenic mice.

[0138] Figure 75 shows the effect of study treatments on lipoprotein profiles in ApoE*3-Leiden. CETP transgenic mice.

[0139] Figure 76 shows the effect of study treatments on half-life of VLDL like particles in ApoE*3-Leiden. CETP transgenic mice.

[0140] Figure 77 shows the effect of study treatments on liver uptake of VLDL like particles in ApoE*3-Leiden. CETP transgenic mice.

[0141] Figure 78 shows the effect of study treatments on plasma pcsk-9 levels and hepatic LDLr levels in ApoE*3-Leiden. CETP transgenic mice.

[0142] Figure 79 shows the effect of study treatments on liver weight and liver lipids in ApoE*3-Leiden. CETP transgenic mice.

[0143] Figure 80 shows the effect of study treatments on fecal bile acids and fecal neutral sterols in ApoE*3-Leiden. CETP transgenic mice.

[0144] Figure 81 shows the effect of study treatments on cholesterol balance in ApoE*3-Leiden. CETP transgenic mice.

[0145] Figure 82 summarizes the experimental protocol for assessing the effect of coadministration of obicetrapib and ezetimibe on atherosclerotic lesion prevalence, size, and severity in ApoE*3-Leiden. CETP mice, as further described in Example 13.

[0146] Figure 83 charts body weight (FIG. 83 A) and food intake (FIG. 83B) during the course of the experiment further described in Example 13.

[0147] Figure 84 charts plasma total cholesterol (FIG. 84A), HDL-cholesterol (FIG. 84B), and non-HDL cholesterol (FIG. 84C) during the course of the experiment described in Example 13. Measures of statistical significance are shown.

[0148] Figure 85 is a histogram calculating the total non-HDL exposure across the entire duration of the experiment described in Example 13. Measures of statistical significance are shown.

[0149] Figure 86 shows lipoprotein profiles of the mice in the experiment described in Example 13, with FIG. 86A showing baseline (t=0 weeks) levels of cholesterol fractions and FIG. 86B showing profiles at 28 weeks (t=28 weeks).

[0150] Figure 87 shows measures of CETP activity (FIG. 87A) and CETP mass (FIG. 87B) in the experiment described in Example 13.

[0151] Figure 88 illustrates the aortic root anatomic location used for assessment of atherosclerosis lesions in the mice in the experiment described in Example 13.

[0152] Figure 89 charts total lesion area (FIG. 89A) and lesion area in the aortic root by AHA classification (FIG. 89B) in all 4 groups of mice in the experiment described in Example 13.

[0153] Figure 90 shows lesion severity (% of segments) (FIG. 90A) and lesion number (# per cross-section) in all 4 groups of mice in the experiment described in Example 13, with measures of statistical significance.

[0154] Figure 91 is a bar graph showing least squares (LS) percent mean change in LDL-C versus baseline (BL) measured by preparative ultracentrifugation (PUC) at Day 84 in the intention-to-treat (ITT) population in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in fixed dose combination (FDC).

[0155] Figure 92 is a bar graph showing LS percent mean change in LDL-C measured by PUC at Day 84 in the ITT population comparing 10 mg obicetrapib plus 10 mg ezetimibe fixed dose combination (FDC) versus obicetrapib (obi), ezetimibe (Eze) and placebo, as well as obicetrapib (obi) versus placebo.

[0156] Figure 93 is a bar graph showing percent mean change in LDL-C measured by PUC versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0157] Figure 94 is a bar graph showing percent median change in LDL-C versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0158] Figure 95 is a bar graph showing percent mean change in LDL-C by PUC versus baseline in the modified intention to treat (mITT) population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0159] Figure 96 is a bar graph showing percent median change in LDL-C by PUC versus baseline in the mITT on treatment population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0160] Figure 97 is a line graph showing the mean percent change from baseline in LDL-C as calculated using Friedewald Equation for Week 0 to Week 12 (Day 84) for patients receiving once daily administration of placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC). It also provides a data point for mean LDL-C percent reduction at Day 28.

[0161] Figure 98 is a line graph showing the mean percent change from baseline in LDL-C reduction as calculated using Martin / Hopkins Equation for Week 0 to Week 12 (Day 84) for patients receiving once daily administration of placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC). It also provides a data point for mean LDL-C percent reduction at Day 28.

[0162] Figure 99 is a bar graph showing LS percent mean change in non-HDL-C in the ITT population at Day 84 for 10 mg obicetrapib plus 10 mg ezetimibe fixed dose combination (FDC) versus obicetrapib (Obi), ezetimibe (Eze) and placebo, as well as obicetrapib (Obi) versus placebo.

[0163] Figure 100 is a bar graph showing percent LS mean change in non-HDL-C versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0164] Figure 101 is a bar graph showing percent LS mean change in ApoB in the ITT population at Day 84 for 10 mg obicetrapib plus 10 mg ezetimibe fixed dose combination (FDC) versus obicetrapib (Obi), ezetimibe (Eze) and placebo, as well as obicetrapib (Obi) versus placebo.

[0165] Figure 102 is a bar graph showing percent LS mean change in ApoB versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0166] Figure 103 is a bar graph showing percent LS mean change in HDL-C versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0167] Figure 104 is a bar graph showing percent LS mean change in Lp(a) in the ITT population at Day 84 for 10 mg obicetrapib plus 10 mg ezetimibe fixed dose combination (FDC) versus obicetrapib (Obi), ezetimibe (Eze) and placebo, as well as obicetrapib (Obi) versus placebo.

[0168] Figure 105 is a bar graph showing percent LS mean change in Lp(a) versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0169] Figure 106 is a bar graph showing mean change versus baseline in Lp(a) mg / dL at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0170] Figure 107 is a bar graph showing percent mean change in small dense low-density lipoprotein-cholesterol (sdLDL-C) versus baseline in the ITT population at Day 84 in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC).

[0171] Figure 108 is a line graph showing mean percent change from baseline in systolic blood pressure in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC) from Day 0 to Day 112.

[0172] Figure 109 is a line graph showing mean percent change from baseline in diastolic blood pressure in patients administered once daily placebo, 10 mg ezetimibe, 10 mg obicetrapib, and 10 mg obicetrapib plus 10 mg ezetimibe in a fixed dose combination (FDC) from Day 0 to Day 112.

[0173] Figure 110 shows a calculation of synergy observed with the 10 mg obicetrapib plus 10 mg ezetimibe fixed dose combination (FDC).7. DETAILED DESCRIPTION7.1. Obicetrapib

[0174] Obicetrapib, formerly known as TA-8995, is a compound of formula (I):(2R,4S){[3,5Bis(trifluoromethyl)benzyl]-[5(3-carboxypropoxy)pyrimidin-2-yl] amino}-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester

[0175] Methods of synthesizing obicetrapib are known. See, e.g., U. S. Patent Nos. 7,872,126; 8,084,611; and 10,112,904, the disclosures of which are incorporated herein by reference in their entireties.

[0176] The preparation of obicetrapib is disclosed, for example, in U. S. Patent Number 7,872,126 (“US ‘ 126”). US ‘ 126 Example 177 teaches the formation of obicetrapib, which, as seen in Formula (I), is a free acid. US ‘ 126 Example 178 teaches the formation of a sodium salt of obicetrapib from obicetrapib by exchanging the acidic proton of the free acid moiety of obicetrapib with a sodium atom. In US ‘126 Example 179, a calcium salt of obicetrapib is taught. Because calcium is an alkaline earth metal, when it ionizes, it has a +2 charge. Thus, a neutral salt will have two obicetrapib anions (each being obicetrapib minus a proton from its carboxylic acid group) for each calcium cation. The resulting salt of Example 179 is a hemicalcium salt of Formula II, in that there are only half as many calcium atoms as obicetrapib anions in a neutral amorphous obicetrapib calcium salt molecule.[Formula II]wherein Et is ethyl.

[0177] The molecular formula of amorphous obicetrapib hemi calcium is (C32H3oN40sF9)2Ca. When discussing salts of obicetrapib, such as calcium salts and in particular the hemicalcium salt, it is understood that obicetrapib has lost a proton in order to make such a salt. Thus, the terms obicetrapib hemicalcium and amorphous obicetrapib hemicalcium means that each obicetrapib moiety portion of the salt is not Formula (I) (i.e., obicetrapib) but Formula (I) minus a proton.

[0178] US ‘ 126 Example 179 expressly teaches that the hemicalcium salt of obicetrapib resulting is crystalline; however, the crystalline form has undesirable properties, such as its poor physical stability.7.2. Amorphous Obicetrapib Hemicalcium

[0179] The preparation and physico-chemical characteristics of amorphous obicetrapib hemicalcium are disclosed in U. S. Patent Number 12,006,305, (“US ‘305”). Examples 1-16 of US ‘305 teach methods for preparation of amorphous obicetrapib hemicalcium. The disclosure of US ‘305 is incorporated herein by reference in its entirety. Methods of preparing amorphous obicetrapib hemicalcium are also disclosed in Example 11 herein below.7.3. Ezetimibe

[0180] Ezetimibe, also referred to as “Sch-58235”, has the following chemical name and chemical structure:(3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0181] Ezetimibe is a practically insoluble drug and poor solubility across the physiological pH range. Ezetimibe is also incompatible with many commonly used excipients and presents stability problems, for example presence of polyethylene glycol (PEG) in coating layers can cause increase in the tetrahydropyran impurity of ezetimibe. Furthermore, ezetimibe is an inherently non-compressible and poorly flowable API as disclosed in EP 2349211 Bl.Preparation of tablet formulations of ezetimibe is therefore quite challenging.

[0182] Both obicetrapib and ezetimibe may also be used as different salt forms, solvates or cocrystals. They may also be formulated as pro-drugs.7.4. The Fixed Dose Pharmaceutical Composition

[0183] A first aspect relates to a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0184] In one particularly preferred embodiment of the invention, the fixed dose pharmaceutical composition comprises:(a) an LDL-C lowering amount of obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and(b) an LDL-C lowering amount of ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof; and(c) pharmaceutically acceptable excipients.

[0185] In one of the embodiments, upon oral administration of the said fixed dose pharmaceutical composition to a subject, 90% confidence interval for the geometric mean of thearea under the curve (AUC o-® and / or AUC o-t) and / or Cmax for obicetrapib is within a range of about 75%-125%, preferably about 80%-125%, and more preferably about 90%-l 10% of the area under the curve (AUCo-® and / or AUC o-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0186] In another embodiment, upon oral administration of the said fixed pharmaceutical composition to a subject, 90% confidence interval for the geometric mean of area under the curve (AUC o- / and / or AUC o-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of about 75% - 125%, preferably about 80% - 125%, and more preferably about 90% - 110% of the area under the curve (AUC o-® and / or AUC o-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0187] Ezetimibe is practically insoluble in water and with poor solubility across the physiological pH range. Achieving desired dissolution and thereby bioavailability in in vivo conditions is quite challenging for ezetimibe. This problem is further enhanced as obicetrapib slows down the rate of dissolution and the total amount of ezetimibe that can be dissolved (unpublished data). It has surprisingly been found that from the fixed dose pharmaceutical composition at least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved within about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5°C. In apreferred embodiment, it is surprisingly found that from the fixed dose pharmaceutical composition at least about 60%, preferably at least about 70% and more preferably at least about 80% of ezetimibe is dissolved within about 20 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 500 ml solution comprising 0.45% SLS in 0.05 M sodium acetate buffer of pH 4.5 at a rotation speed of about 75 rpm at 37 ± 0.5°C.

[0188] It was further surprisingly found that from the fixed dose pharmaceutical composition at least about 70%, preferably at least about 80%, more preferably at least about 85%, and even more preferably at least about 90% of obicetrapib is dissolved within about 30 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w / v Polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5°C. In a preferred embodiment, it is surprisingly found that from the fixed dose pharmaceutical composition at least about 70%, preferably at least about 80%, and more preferably at least about 85% of obicetrapib is dissolved within about 15 minutes when the said pharmaceutical composition is dissolved in a USP type II apparatus in a 1000 ml solution comprising phosphate buffer solution of pH 6.8 + 0.2 %w / v Polysorbate 80 at a rotation speed of about 75 rpm at 37 ± 0.5°C.

[0189] Ezetimibe is inherently a poorly / non-compressible API (see for example EP 2168573 Al, EP 2349211 Bl) along with poor flowability. It is therefore very challenging for the formulation scientists to prepare a tablet formulation that not only satisfies the requirements with respect to hardness, disintegration time, friability, shape and size, but also provides the desired stability and dissolution, of ezetimibe. It has been surprisingly found that the composition not only meets the required specifications for dissolution and stability for being suitable to the claimed uses, but also qualifies the criteria’s of the processability parameters, namely flowability, compressibility, disintegration time, friability, hardness, shape and size.

[0190] The fixed dose pharmaceutical composition may comprise a combination of 1 to 10 mg obicetrapib and 5 to 20 mg ezetimibe. In a preferred embodiment, the composition comprises 5 mg obicetrapib and 10 mg ezetimibe. In a more preferred embodiment the composition comprises 10 mg obicetrapib and 10 mg ezetimibe.

[0191] In a preferred embodiment, the pharmaceutical composition is provided as a unit dosage form comprising 5 mg obicetrapib and 10 mg ezetimibe. In a more preferred embodiment thecomposition is provided as a unit dosage form comprising 10 mg obicetrapib and 10 mg ezetimibe.

[0192] Wherever the dose of either obicetrapib or ezetimibe is mentioned in this disclosure as mg and / or in relative amounts (by weight), it means obicetrapib or ezetimib in its free form. Whenever a salt, solvate or co-crystal of ezetimibe or obicetrapib is used, for the purpose the said dose shall mean a dose equivalent to the weight of ezetimibe or obicetrapib in its free form, respectively.

[0193] In certain embodiments, the pharmaceutical composition is provided in the form of a solid oral dosage selected form caplets, minitablets, lozenges, granules, beads, pellets, tablets, capsules, pill, and the like, or liquid oral dosage forms which may be used for the pharmaceutical preparation include, but are not limited to drinks, solutions, suspensions, syrups, beverages and emulsions.

[0194] In one embodiment, the solid oral dosage form is provided as a dual component pharmaceutical composition. In a preferred embodiment, one of the components of the dual component pharmaceutical composition comprises ezetimibe and another component comprises obicetrapib. In another preferred embodiment, only one of the components of the dual component pharmaceutical composition comprises both ezetimibe and obicetrapib.

[0195] In certain embodiments, the two-component composition is a bilayer tablet formulation. In a preferred embodiment, ezetimibe is present in one of the two layers and obicetrapib in the other layer of bilayer tablet.

[0196] In another embodiment, the two-component system is capsule formulation. In a preferred embodiment, the capsule may have two types of granules wherein one granule type comprises ezetimibe and another granule type comprises obicetrapib. In yet another preferred embodiment, the capsule may comprise two different type of blends or minitablets each comprising ezetimibe or obicetrapib, and optionally, such blends or minitablets may be filled in two components of a capsule which are segregated from each other. In a certain embodiments, each blend or minitablet is filled in a smaller capsule or such blend is compressed into a tablet / caplet / minitablet and then the tablets / caplets / minitablets are filled in a capsule formulation.

[0197] In another embodiment, the fixed dose pharmaceutical composition is a compressed tablet formulation comprising an extragranular component and an intragranular component. In a preferred embodiment, the intragranular component comprises ezetimibe and extragranular component comprises obicetrapib. In a more preferred embodiment, the intragranular component comprises both ezetimibe and obicetrapib. In another embodiment, the intragranular component comprises obicetrapib and the extragranular component comprises ezetimibe. In yet another embodiment, the extragranular component comprises both ezetimibe and obicetrapib.

[0198] The intragranular components and extragranular components are present in a ratio from about 1:99 to about 99:1, preferably about 3: 97 to about 97:3, and more preferably from about 5:95 to about 95:5. In another embodiment, intragranular components and extragranular components are present in a ratio from about 10:90 to about 90:10, preferably about 20:80 to about 80:20 or about 30:70 to about 70:30, and even more preferably about 40:60 to about 60:40 or about 50:50.

[0199] The term “Intragranular” refers to being or occurring within granules of the composition i.e. granules comprising a first set of pharmaceutically acceptable excipients including but not limited to a binder, a disintegrant, a diluent, a glidant and a solvent, and optionally one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and / or obicetrapib.

[0200] The term “Extra granular” refers to addition of pharmaceutically acceptable component to a material following granulation i.e. an extra-granular fraction comprising a second set of pharmaceutically acceptable excipients including but not limited to a disintegrant, a diluent, a lubricant, a glidant or the like. Optionally, the extra-granular component may comprise one or more pharmaceutically acceptable active ingredients, in this case ezetimibe and / or obicetrapib.

[0201] The pharmaceutical composition can be obtained by a known conventional method like dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot -melt extrusion or the like. In a preferred embodiment, the composition is obtained by wet granulation followed by compression of the granules in a tablet formulation or filling such granules in a capsule.

[0202] In one embodiment, the pharmaceutical composition comprises ezetimibe as anhydrous ezetimibe. In another embodiment, the pharmaceutical composition comprises ezetimibe as ezetimibe hydrate, preferably ezetimibe monohydrate. In yet another embodiment, thepharmaceutical composition comprises a mixture of ezetimibe anhydrous and ezetimibe hydrate, preferably ezetimibe monohydrate. The molar ratio of anhydrous ezetimibe: ezetimibe hydrate, preferably ezetimibe monohydrate, in the pharmaceutical composition could be in the range of 100:0 to 0:100, 99.09:0.01 to 0.01:99.09, 99.08:0.02 to 0.02:99.08, 99.07:0.03 to 0.03:99.07, 99.06:0.04 to 0.04:99.06, 99.05:0.05 to 0.05:99.05, 99.04:0.06 to 0.06:99.04, 99.03:0.07 to 0.07:99.03, 99.02:0.08 to 0.02:99.02, 99.01:0.09 to 0.09:99.01, 99:1 to 1:99, 98:2 to 2:98, 90:10 to 10:90, 70:30 to 30:70 or 50:50. In a preferred embodiment, the composition is substantially free of the ezetimibe hydrate and about 100% of ezetimibe is in the form of ezetimibe anhydrous. In another preferred embodiment, about 99.5% ezetimibe is present in the form of ezetimibe anhydrous and about 0.5% of ezetimibe is present in the form of ezetimibe hydrate, preferably ezetimibe monohydrate. In a more preferred embodiment, the composition is substantially free of the ezetimibe anhydrous and about 100% of ezetimibe is in the form of ezetimibe hydrate, preferably ezetimibe monohydrate.

[0203] Ezetimibe or obicetrapib or both could be present in the form of a pharmaceutically acceptable salt, solvate or a co-crystal thereof. Solvates include but are not limited to hydrates. Further, “salt” refers to a compound prepared by the reaction of an organic acid or base drug with a pharmaceutically acceptable mineral or organic acid or base; as used herein, “salt” includes hydrates and solvates of the salts. Exemplary pharmaceutically acceptable mineral or organic acids or bases are as listed in Tables 1-8 in Handbook of Pharmaceutical Salts, P. H. Stahl and C. G. Wermuth (eds.), VHCA, Zurich 2002, pp. 334-345. A pharmaceutically acceptable salt of obicetrapib or ezetimibe may be readily prepared by mixing together solutions of such compounds and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. In one embodiment, salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate and besylate salt forms. In one of the preferred embodiments, the composition comprises obicetrapib as an alkali metal or alkali earth metal salt of obicetrapib, preferably obicetrapib sodium, obicetrapib potassium or obicetrapib calcium, and more preferably obicetrapib calcium salt. The term "co-crystal" as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion, with the exception that, if specifically stated, the active pharmaceutical ingredient may be a liquid at room temperature. The co-crystals maycomprise a co-crystal former H-bonded to obicetrapib and / or ezetimibe. The co-crystal former may be H-bonded directly to the active pharmaceutical ingredient or may be H-bonded to an additional molecule which is bound to obicetrapib and / or ezetimibe. In one of the embodiments, a co-crystal could be made between obicetrapib and ezetimibe or their salts or solvates. Solvates of active compounds that do not further comprise a co-crystal former are not co-crystals. The cocrystals may also be a co-crystal between a co-crystal former and a salt of ezetimibe or obicetrapib or both. Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions. Of the interactions listed above, hydrogen-bonding is the dominant interaction in the formation of the co-crystal, whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other. In another embodiment the co-crystal comprises two cocrystal formers. Co-crystal formers include, but are not limited to a free acid, free base, or zwitter ion; a salt, an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminum salts or organic base addition salts, or an inorganic acid addition salts such as HBr, HC1, sulfuric, nitric, or phosphoric acid addition salts or an organic acid addition salt such as acetic, proprionic, pyruvic, malanic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulforic, stearic or lactic acid addition salt; an anhydrate or hydrate of a free form or salt, or more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate, pentahydrate; or a solvate of a free form or salt. The ratio of active ingredient to co-crystal former may be stoichiometric or non-stoichiometric for the purposes. For example, 1:1, 1:1.5, 1:2 and 2:1 ratios of active ingredient (obicetrapib or ezetimibe or both, including theirs salts or solvates): co-crystal former are acceptable.

[0204] In one of the embodiments, the said fixed dose pharmaceutical composition comprises either ezetimibe or obicetrapib, or both as a micronized API. Particle size distribution for such micronized API can be determined by a skilled person using the methods commonly known in the art. These methods include but are not limited to laser diffraction (LD), dynamic light scattering (DLS), dynamic image analysis (DIA) or sieve analysis. Preferably, the method employed is laser diffraction dry powder dispersion which provides the particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laserbeam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating a cumulative undersize discrete distribution curve that gives particle size distribution by volume. The particle size from this method is usually reported as a volume equivalent sphere diameter (Dv). The most common percentiles reported are the Dv10, Dv50 and Dv90 (also referred as X10, X50and X90). Dv90 means 90% of the particles by volume are below a particular size & 10% above;, Dv50 means 50% of the particles by volume are below a particular size & 50% above, and Dv10 means 10% of the particles by volume are below this size & 90% above.

[0205] In one of the preferred embodiments, the composition comprises micronized ezetimibe having a Dv90 not more than 10pm, preferably in the range of 4- 10pm, more preferably not more than 8.5 pm; Dv50 not more than 4 pm, preferably in the range of about 1-4 pm more, more preferably not more than 3.8pm, and DvlO not more than 1pm.

[0206] In another preferred embodiment, the composition comprises micronized obicetrapib having a Dv90 not more than 14 pm, preferably in the range of about 5-14 pm; Dv50 not more than 5pm, preferably in the range of about 3-5pm; and DvlO not more than 3pm.

[0207] The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Excipients include but are not limited to one or more binders, surfactants, disintegrants, glidant, lubricant, diluent, chelating agents, desiccants or absorbents. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See “The Handbook of Pharmaceutical Excipients’", 9th edition, Rowe etal., Eds., American Pharmaceuticals Association (2020); and “Remington: The Science and Practice of Pharmacy”, 22ndedition, Gennaro, Ed., Lippincott Williams & Wilkins (2013).

[0208] The one or more binders used in the pharmaceutical composition are preferably selected from cellulose derivatives such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, glucose, sucrose, lactose dextrose, xylitol, sorbitol, maltitol, polymethacrylates, polyvinylpyrrolidone and its copolymers, starch paste, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites. In a preferred embodiment, the binder is polyvinylpyrrolidone or copolymers ofpolyvinylpyrrolidone. In a more preferred embodiment, the binder is copovidone. In an even more preferred embodiment, the binder is Kollidon 30.

[0209] The binders may typically be present in an amount from about 0.2% to about 10%, from about 0.5% to about 5%, from about 0.5% to about 2% or from about 0.5% to about 1%, preferably about 1.0+0.5% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0210] The one or more surfactants used in the composition preferably are the surfactants having an HLB value selected from at least about 15, at least about 20, at least about 30 or at least about 40. One or more such surfactants are selected from lauric, palmitic, stearic and oleic acid or salts thereof, polyethylene glycol glycerides, polyoxyethylene monoesters, polyoxyethylethylene monostearate, polyoxyethylene monolaurate, polyoxyethylene sorbitan monooleate, polyethoxylated castor oils, polyethylene glycol having molecular weight in the range of about 2000 to 10000, propylene glycol caprylates, glycerol oleates and caprylates, esters of glycerol and fatty acids. In a preferred embodiment, one or more surfactants are selected from dioctyl sodium sulfosuccinate, Capmul PG-8, Capryol 90, Capmul MCM, polysorbate 20, Polysorbate 40 or polysorbate 80 or sodium lauryl sulphate. In a more preferred embodiment the surfactant is sodium lauryl sulphate such as Kolliphor SLS.

[0211] The surfactants typically may be present in an amount from about 0.2% to 10%, from about 0.5% to about 5%, from about 0.5% to about 2% or from about 0.5% to about 1%, preferably about 1.0 + 0.5% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0212] In one of the embodiments, the composition comprises a binder: surfactant ratio in the range of about 0.05:5.0 to about 5.0: 0.05, preferably from about 0.5:4.5 to about 4.5: 0.5, more preferably from about 1:4 to about 4:1, even more preferably from about 1:2 to about 2: 1 and most preferably about 1:1. Such ratios of binder: surfactants may be for the granule composition such as intragranular composition or the extragranular composition or for the total composition of the tablet.

[0213] The pharmaceutical composition typically further comprises one or more disintegrants selected from cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate,microcrystalline cellulose, sodium starch glycolate or pregelatinized starch. In a preferred embodiment, the disintegrant is croscarmellose sodium or sodium starch glycolate. In a more preferred embodiment the disintegrant is sodium starch glycolate.

[0214] The disintegrants may be present in an amount from about 0.5% to about 10%, from about 1% to about 8%, from about 2% to about 5%, preferably 2% to about 3%, from about 4% to about 5%, or from about 7% to about 8% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0215] The one or more diluents used in the pharmaceutical composition preferably are selected from the group consisting of: an inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomaltose, or celluloses like microcrystalline cellulose or powdered celluloses or the like. In a preferred embodiment, the diluent selected from Lactose such as lactose monohydrate, microcrystalline cellulose and mannitol, or a mixture thereof. In a more preferred embodiment, intragranular component comprises microcrystalline cellulose and lactose monohydrate as diluent. In another preferred embodiment, microcrystalline cellulose and mannitol are present as diluent in the extragranular component. The diluents may present in an amount from about 10% to about 95%, preferably from about 40% to about 90%, more preferably from about 60% to about 85%, even more preferably from about 70% to about 85% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0216] The pharmaceutical composition may optionally be film-coated using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using the hot melt technique. The film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents. Examples of film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; polyvinyl alcohol, waxes; fat substances; or mixtures thereof. Alternatively, commercially available coating compositionscomprising film forming polymers marketed under various trade names, such as Opadry®, may be used for coating.

[0217] Examples of solvents used for preparing the coating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof. In a preferred embodiment, the film coating is a primary alcohol free coating. Preferably, the primary alcohol free coating is a coating made using water.

[0218] Glidants present in the pharmaceutical dosage form preferably are selected from silicon dioxide, talc, magnesium stearate and the like. A preferred glidant is silicon dioxide such as Aerosil® or magnesium stearate such as Ligamed MF 2V or a mixture thereof. Glidants may typically be present in amount from about 0.1% to 10%, from about 0.% to about 5%, or from about 1% to about 2% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0219] Lubricants present in the pharmaceutical composition are preferably selected from fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and / or palmitic acid and the like. A preferred lubricant is magnesium stearate and may typically be present in amount from about 0.1% to 10%, from about 0.% to about 5% or from about 1% to about 2% by weight of the granule composition in one embodiment and by weight of the total tablet in another embodiment.

[0220] Stability is an essential quality attribute for pharmaceutical formulations that determines the shelflife of the composition during which the composition is suitable for its intended use both from an efficacy and a safety point of view. The term stability of a pharmaceutical composition of a stable pharmaceutical composition means that one or more parameters governing the physical and chemical integrity of the active pharmaceutical ingredients (APIs) remain within a pharmaceutically acceptable criteria during the shelf life of the product.Typically one or more such parameters are selected from identification of the active ingredient(s) in the composition by methods, for example, HPLC and / or UV spectroscopy; visual appearance of the composition, assay percentage of the active ingredient(s) in the composition, individual and / or total percentage of the related substances and / or impurities in the composition, contentuniformity of the composition with respect to the active ingredient(s), dissolution rate, microbial limits, and the like.

[0221] Pharmaceutical compositions often lose their efficacy and / or safety over time because of the loss or degradation or conversion of the active ingredient(s) into impurities commonly known as related substance(s). A stable fixed dose pharmaceutical composition retains at least up to about 90%(w / w) of the claimed potency for ezetimibe as well as obicetrapib.

[0222] Ezetimibe is known to give rise to stability problems associated with its formulations because of interactions with excipients and / or the combination drug partner. It has been surprisingly found that the fixed dose pharmaceutical composition effectively controls the levels of individual and total related substances of ezetimibe during the preparation as well as storage of the fixed dose composition. In an embodiment, the stable fixed dose pharmaceutical composition has not more than about 5% (w / w), preferably not more than about 2%(w / w), more preferably not more than about 1% (w / w) and even more preferably not more than about 0.2% (w / w) of an individual related substance of ezetimibe; and not more than about 5% (w / w), preferably not more than about 2%(w / w), more preferably not more than about l%(w / w), and even more preferably not more than about 0.5%(w / w) of total related substances of ezetimibe. In a preferred embodiment, the fixed dose pharmaceutical composition comprising ezetimibe and obicetrapib wherein the ezetimibe tetrahydropyran analog impurity is not more than about 2% (w / w), preferably not more than about 0.5% (w / w), more preferably not more than about 0.3% (w / w), even more preferably not more than about 0.2% (w / w).

[0223] In another embodiment, the stable fixed dose pharmaceutical composition has not more than about 5% (w / w), preferably not more than about 2%(w / w), more preferably not more than about 0.5% (w / w), even more preferably not more than about 0.3%(w / w), and most preferably not more than about 0.2%(w / w) of any unspecified individual obicetrapib related substance; and not more than about 5%(w / w), preferably not more than about 2%(w / w), more preferably not more than about l%(w / w), and even more preferably not more than about 0.5%(w / w) of total related substances of obicetrapib.

[0224] It has surprisingly been found the pharmaceutical composition remains stable for at least up to 1 month, preferably at least up to 3 months, more preferably at least upto 6 months under stability conditions of 40°C temperature and 75% relative humidity. In a preferred embodiment,the composition remains stable at least up to 3 months, preferably at least upto 6 months under stability conditions of 40°C temperature and 75% relative humidity. In another preferred embodiment, the composition remains stable for at least up to 3 months, 6 months or 12 months under stability conditions of 25°C temperature and 60% relative humidity. In yet another preferred embodiment, the composition remains stable for at least up to 6 months, 12 months, 18 months or 24 months at room temperature.

[0225] In one of the preferred embodiments, the pharmaceutical composition is a tablet formulation comprising or consisting of:a. an intragranular component comprising:i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid;ii. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe monohydrate equivalent to ezetimibe 10 mg;iii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate;iv. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; v. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;b. An extragranular component comprising:i. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w / w sodium starch glycolate;ii. optionally, a lubricant, preferably magnesium stearate, more preferably about l%-2% w / w magnesium stearate;iii. optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about l%-2% w / w colloidal silicon dioxide or talk or both; iv. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol. c. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.

[0226] In another preferred embodiment, the pharmaceutical composition comprises tablet formulation comprising or consisting of:a. an intragranular component comprising:i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mg;ii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone or polyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate;iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferablycellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;b. an extra-granular component comprising:i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid;ii. a disintegrant selected from microcrystalline cellulose, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate, even more preferably about 4%-6% w / w sodium starch glycollate;iii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1% w / w magnesium stearate;iv. optionally, a glidant, preferably colloidal silicon dioxide or talk or both, more preferably about l%-2% w / w colloidal silicon dioxide or talk or both;v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.c. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.

[0227] In yet another preferred embodiment, the pharmaceutical composition is a tablet formulation comprising or consisting of:a. an intragranular component comprising:i. Obicetrapib calcium equivalent to 10 mg obicetrapib free acid;ii. a binder and a surfactant in a ratio of 1:1, preferably the binder and the surfactant each are about 1+0.5% w / w of the granule of intragranular component; more preferably the binder is 1+0.5% w / w polyvidone orpolyvinylpyrrolidone and the surfactant is 1+0.5% w / w sodium lauryl sulphate;iii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; preferably the disintegrant is about 2-8% w / w the granule of intragranular component, preferable 3-6% w / w, more preferably about 4.5+0.5% w / w; iv. One or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol;b. an extra-granular component comprising:i. Ezetimibe anhydrous or a mixture of ezetimibe anhydrous and ezetimibe hydrate equivalent to ezetimibe 10 mgii. a disintegrant selected from croscarmellose sodium, pregelatinized starch or sodium starch glycolate, more preferably sodium starch glycolate; even more preferably about 4%-6% w / w sodium starch glycollate iii. optionally, a lubricant, preferably magnesium stearate, more preferably about 1-2% w / w magnesium stearateiv. optionally, a glidant, preferably colloidal silicon dioxide or talc or both, more preferably about 1-2% colloidal silicon dioxide or talc or both; v. optionally, one or more diluents selected from disaccharides, preferably lactose or sucrose, more preferably anhydrous lactose or lactose monohydrate, even more preferably lactose monohydrate; polysaccharides, preferably cellulose, more preferably microcrystalline cellulose; sugar alcohols, preferably sorbitol, xylitol or mannitol; more preferably mannitol or microcrystalline cellulose, even more preferably about 20% to about 50% w / w microcrystalline cellulose and about 1% to about 20% mannitol.c. Optionally, the composition comprises a film coating, preferably the film coating is free from a primary alcohol, more preferably the film coating is free from polyethylene glycol.

[0228] Another aspect relates to a pharmaceutical composition comprising obicetrapib and ezetimibe or pharmaceutically acceptable salts, solvates or co-crystals thereof and a pharmaceutically acceptable carrier for use in the treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0229] A second aspect relates to the use of a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients for preparation of a medicament for treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol.

[0230] In one of the embodiments, the said subjects are suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).

[0231] In one embodiment, the said subjects [are partially or completely intolerant to statins.

[0232] In one embodiment, the use of a pharmaceutical composition is for treatment of subjects requiring additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0233] A third aspect relates to a method of treatment of subjects requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol, wherein the method comprises administering to the said subject a therapeutically effective dose of a fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0234] In one of the embodiments, the said method is for the treatment of subjects suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).

[0235] In one embodiment, the subject requires additional lowering of low-density lipoprotein cholesterol as an adjunct to diet and / or as maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD).

[0236] In one embodiment, the said are partially or completely intolerant to statins.

[0237] A fourth aspect relates to a fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the said pharmaceutical composition is considered to be suitable for the said use according to the second aspect or said method of treatment according to the third aspect, when:a. the fixed dose pharmaceutical composition is orally administered to a subject; b. the concentration of obicetrapib in the subject’s blood is determined at one or more time points after administration to provide a set of obicetrapib concentration / time data points to provide an area-under the curve (AUC); andc. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for obicetrapib is within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of the area under the curve (AUC0-∞ and / or AUC 0-t) and / or Cmax, respectively, of obicetrapib as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein said reference composition comprises an equivalent dose of obicetrapib or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0238] A fifth aspect relates to a fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe, wherein the said pharmaceutical composition is considered to be suitable for the said use according to the second aspect or said method of treatment according to the third aspect, when:a. the said fixed dose pharmaceutical composition is orally administered to a subject, ezetimibe and / or ezetimibe glucoronide in the subject’s blood is determined at one or more time points after administration to provide a set of ezetimibe and / or ezetimibe glucoronide concentration / time data points, respectively, to provide an area-under the curve (AUC) for ezetimibe and / or ezetimibe glucoronide, respectively; and,b. if 90% confidence interval for the geometric mean of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax for ezetimibe and / or ezetimibe glucoronide is within a range of 75% - 125%, preferably 80% - 125%, and more preferably 90% - 110% of the area under the curve (AUC 0-∞ and / or AUC 0-t) and / or Cmax, respectively, of ezetimibe and / or ezetimibe glucoronide, respectively, as obtained upon oral administration of a reference pharmaceutical composition to a similar subject, wherein the reference composition comprises an equivalent dose of ezetimibe or its pharmaceutically acceptable salt, solvate or co-crystal thereof, and wherein the reference composition is administered alone, or as a simultaneous or sequential co-administration with another pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof, or as a fixed-dose combination with ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof.

[0239] In one of the embodiments for the use according to the above aspects, t for AUC 0-t is selected from 48 hours (AUC 0-48), 72 hours (AUC0-72), 96 hours (AUC 0-96), 144 hours (AUC 0-144), 192 hours (AUC 0-192), 240 hours (AUC 0-240), 336 hours (AUC 0-336) or AUC0-∞, preferably 48 hours (AUC 0-48), and more preferably 72 hours (AUC0-72) or AUC0-∞.

[0240] In one embodiment, the subject is a subject, preferably a non -tobacco, non-nicotine using adult male or female human, more preferably of 18-65 years of age, and optionally, the said human has a body mass index of 18.5 to 29.9 Kg / m2.

[0241] In another embodiment, the subject is human requiring reduction in LDL cholesterol and / or an increase in HDL cholesterol. In a preferred embodiment, the is human is suffering from or having hyperlipidemia or mixed dyslipidemia, heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).

[0242] In one embodiment, the said human is partially or completely intolerant to statins.

[0243] Preferably the human subject has LDL-cholesterol levels >70 mg / dL, and optionally the said humans are not adequately controlled by their current lipid-modifying therapies.

[0244] For the use of a pharmaceutical composition or a method of treatment according to the other aspects, the subject in need thereof may be administered with the said composition to deliver a total daily oral dose of 5 mg obicetrapib and 10 mg ezetimibe, 10 mg obicetrapib and 10 mg ezetimibe, or 20 mg obicetrapib and 20 mg ezetimibe, preferably the subject is administered with the said composition to deliver a daily oral dose of 10 mg obicetrapib and 10 mg ezetimibe.

[0245] It has been surprisingly found that the dissolution profile of ezetimibe from the fixed dose combination was found to be non-inferior or sometime superior as compared to the commercial formulation of ezetimibe (Zetia®) which is discussed in detail in the examples section. It was also surprisingly found that the fixed dose combination composition disclosed herein is bioequivalent to a combination of monotherapy drugs co-administered to human subjects. The confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo-∞ and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide from two of the representative compositions -FDC1 and FDC2 were found to be within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-110% of AUCo-t, AUCo-∞ and Cmax of obicetrapib, ezetimibe and ezetimibe glucoronide, respectively as obtained from co-administration of single drug formulations of same dose of ezetimibe and obicetrapib, which is discussed in detail in the examples section below.

[0246] The fixed dose combination pharmaceutical composition of obicetrapib and ezetimibe will be illustrated further by means of the non-limiting examples herein below.7.5. Methods of Treatment

[0247] As explained herein before, the invention provides methods for the curative and / or prophylactic treatment of a subject in need thereof. More in particular, the invention provides methods for the treatment and / or prevention of cardiovascular disease, in particular Atherosclerotic cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and / or prevention of one ormore symptoms associated with (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and / or prevention of one or more pathologies associated with and / or caused by (atherosclerotic) cardiovascular disease, in such subjects, using the compositions as defined herein. The invention further provides methods for the treatment and / or prevention of one or more aetiological factors associated with (atherosclerotic) cardiovascular disease, such as elevated LDL-C levels and / or elevated ApoB levels, in such subjects, using the compositions as defined herein. The invention further provides methods for mitigating and / or ameliorating resistance or hypo-responsiveness to statin therapy, in particular high intensity statin therapy, in such subjects, using the compositions as defined herein.

[0248] The terms "treat", "treating" or "treatment", when used in conjunction with a specific disease or symptom (for example: “method of treating disease...”) refers to curing, alleviating or abrogating said disease and / or accompanying symptoms, diminishing extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, ameliorating the disease state, prolonging survival (as compared to expected survival without treatment), etc. The terms "prevent", "preventing" or "prevention", as used herein, refer to reducing the risk for a subject to acquire a disease and / or accompanying symptoms, delaying the moment a subject acquires disease, etc. The terms “treat”, “treating” or “treatment”, when used in relation to a patient or subject (for example: “method of treating a subject”), typically refers to the act of administering a therapeutic compound to said patient or subject for whatever therapeutic and / or prophylactic purpose.

[0249] The term “cardiovascular disease” as used herein has its conventional meaning as referring to a disease or condition in which the function of a subject's cardiovascular system becomes impaired. Examples of cardiovascular diseases include thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart); atherosclerosis; hypertensive heart disease; coronary artery disease; carotid artery disease; stroke; peripheral artery disease involving atherosclerosis; restenosis; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction (AMI); myocardialinfarction; ischemic heart disease; cardiac ischemia; ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary arterial thrombosis; cerebral arterial thrombosis, cerebral embolism; kidney embolism; pulmonary embolism; etc.

[0250] As used herein, the term “atherosclerotic cardiovascular disease” refers to a specific subset of cardiovascular diseases that include atherosclerosis as a component or precursor to the particular type of cardiovascular disease. Atherosclerosis is a chronic inflammatory response that occurs in the walls of arterial blood vessels associated with retained LDL-C. It involves the formation of atheromatous plaques that can lead to narrowing ("stenosis") of the artery, and can eventually lead to partial or complete closure of the arterial opening and / or plaque ruptures. Thus atherosclerotic diseases or disorders include the consequences of atheromatous plaque formation and rupture including, without limitation, stenosis or narrowing of arteries, heart failure, aneurysm formation including aortic aneurysm, aortic dissection, and ischemic events such as myocardial infarction and stroke.

[0251] In particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is selected from the group consisting of arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia betalipoproteinemia, hypoalphalipoproteinemia, hypercholesteremia, hypertriglyceridemia, familial-hypercholesteremia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and cerebral stroke.

[0252] In another particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is heterozygous familial hypercholesterolemia (HeFH).

[0253] In another particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is established ASCVD.

[0254] In another particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is non-familial hypercholesterolemia.

[0255] In another particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is primary hyperlipidemia.

[0256] In another particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathology associated with atherosclerotic cardiovascular disease that may advantageously be treated and / or prevented according to the present invention is primary hypercholesterolemia.

[0257] As will be apparent from the present teachings, the methods of the present invention are effective in and / or intended for reducing and / or normalizing LDL-C plasma levels. In some embodiments, the methods are effective in and / or intended for reducing LDL-C plasma levels from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe, by at least 5 %. In some embodiments the methods are effective in reducing LDL-C plasma levels as compared to baseline by at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0258] In further embodiments, the methods are effective in and / or intended for reducing LDL-C plasma levels from baseline by at least 5 mg / dL, from baseline, wherein baseline is defined as the point in time immediately prior to the start of treatment with obicetrapib and ezetimibe. In some embodiments the methods are effective in reducing LDL-C plasma levels at least 10 mg / dL, 11 mg / dL, 12 mg / dL, 13 mg / dL, 14 mg / dL, 15 mg / dL, 16 mg / dL, 17 mg / dL, 18 mg / dL, 19 mg / dL, 20 mg / dL, 21 mg / dL, 22 mg / dL, 23 mg / dL, 24 mg / dL, 25 mg / dL, 26 mg / dL, 27 mg / dL, 28 mg / dL, 29 mg / dL, 30 mg / dL, 31 mg / dL, 32 mg / dL, 33 mg / dL, 34 mg / dL, 35 mg / dL, 36 mg / dL, 37 mg / dL, 38 mg / dL, 39 mg / dL, 40 mg / dL, 41 mg / dL, 42 mg / dL, 43 mg / dL, 44 mg / dL, 45 mg / dL, 46 mg / dL, 47 mg / dL, 48 mg / dL, 49 mg / dL, 50 mg / dL, 51 mg / dL, 52 mg / dL, 53 mg / dL, 54 mg / dL, or 55 mg / dL.

[0259] In further embodiments, the methods are effective in and / or intended for reducing LDL-C plasma levels, to a level below 85 mg / dL, 84 mg / dL, 83 mg / dL, 82 mg / dL, 81 mg / dL, 80 mg / dL, 79 mg / dL, 78 mg / dL, 77 mg / dL, 76 mg / dL, 75 mg / dL, 74 mg / dL, 73 mg / dL, 72 mg / dL, 71 mg / dL, 70 mg / dL, 69 mg / dL, 68 mg / dL, 67 mg / dL, 66 mg / dL, 65 mg / dL, 64 mg / dL, 63 mg / dL, 62 mg / dL, 61 mg / dL, 60 mg / dL, 59 mg / dL, 58 mg / dL, 57 mg / dL, 56 mg / dL, 55 mg / dL, 54 mg / dL, 53 mg / dL, 52 mg / dL, 51 mg / dL, or 50 mg / dL.

[0260] In certain embodiments, the method is effective to lower LDL-C from baseline regardless of whether the subject is less than 65 years old, between 65 years old and 74 years old, or equal to or greater than 75 years old.

[0261] In certain embodiments, the method is effective to lower LDL-C from baseline regardless of whether the subject is male or female.

[0262] In various embodiments, the method is effective to lower LDL-C from baseline regardless of whether the subject is on high intensity statin therapy or not.

[0263] In certain embodiments, the method is effective to lower LDL-C from baseline regardless of whether the subject has a history of atherosclerotic cardiovascular disease (ASCVD).

[0264] In some embodiments, the method is effective to lower LDL-C from baseline regardless of whether the subject has lipoprotein (a) levels of <125 or > 125 (nmol / L).

[0265] In various embodiments, the method is effective to lower LDL-C from baseline regardless of whether the subject has hypertension or not.

[0266] As will be apparent from the present teachings, the administration of ezetimibe (or a pharmaceutically acceptable salt, solvate or co-crystal thereof) in addition to obicetrapib (or a pharmaceutically acceptable salt, solvate or co-crystal thereof) results in remarkable enhancement, notably supra-additive or synergistic enhancement, of LDL-C reduction. More in particular, the present methods of administering ezetimibe (or a pharmaceutically acceptable salt, solvate or co-crystal thereof), in order to enhance the LDL-C lowering effect of obicetrapib as defined herein, are effective in and / or intended for further reducing LDL-C plasma levels, with at least 20 %, as compared to methods based on therapy with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, alone (or, at least, without ezetimibe), more preferably at least 22.5 %, at least 25 %, at least 26 %, at least 27 %, at least 28 %, at least 29 %or at least 30 %. In further embodiments, these methods are effective in and / or intended for further reducing LDL-C plasma levels, with at least 20 mg / dL as compared to methods based on therapy with obicetrapib, or a pharmaceutically acceptable salt, solvate or co-crystal thereof, alone (or, at least, without ezetimibe), more preferably at least 22.5 mg / dL, at least 25 mg / dL, at least 27.5 mg / dL, at least 30 mg / dL, at least 32.5 mg / dL or at least 35 mg / dL.

[0267] In some embodiments, LDL-C concentrations are estimated according to the Friedewald Equation. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972, 18;499-502, herein incorporated by reference.

[0268] In some embodiments, LDL-C concentrations are estimated according to the Martin / Hopkins Equation. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile. JAMA. 2013;310(19):2061-2068, herein incorporated by reference.

[0269] In some embodiments, LDL-C concentrations are measured by preparative ultracentrifugation (PUC).

[0270] In preferred embodiments of the invention, the methods are effective in and / or intended for reducing and / or normalizing sdLDL-C (small dense low-density lipoprotein cholesterol) plasma levels. More in particular, the methods are effective in and / or intended for reducing sdLDL-C plasma levels, by at least 5% from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe, more preferably at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, or 33%.

[0271] In preferred embodiments of the invention, the methods are effective in and / or intended for reducing and / or normalizing ApoB plasma levels. More in particular, the methods are effective in and / or intended for reducing ApoB plasma levels, by at least 5% from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe, more preferably at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%.

[0272] In further embodiments, the methods are effective in and / or intended for reducing ApoB plasma levels at least 5 mg / dL from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe, more preferably at least 5 mg / dL, 5.5 mg / dL, 6 mg / dL, 6.5 mg / dL, 7 mg / dL, 7.5 mg / dL, 8 mg / dL, 8.5 mg / dL, 9 mg / dL, 9.5 mg / dL, 10 mg / dL, 10.5 mg / dL, 11 mg / dL, 11.5 mg / dL, 12 mg / dL, 12.5 mg / dL, 13 mg / dL, 13.5 mg / dL, 14 mg / dL, 14.5 mg / dL, 15 mg / dL, 15.5 mg / dL, 16 mg / dL, 16.5 mg / dL, 17 mg / dL, 17.5 mg / dL, 18 mg / dL, 18.5 mg / dL, 19 mg / dL, 19.5 mg / dL, 20 mg / dL, 20.5 mg / dL, 21 mg / dL, 21.5 mg / dL, 22 mg / dL, 22.5 mg / dL, 23 mg / dL, 23.5 mg / dL, 24 mg / dL, 24.5 mg / dL, 25 mg / dL, 25.5 mg / dL, 26 mg / dL, 26.5 mg / dL, 27 mg / dL, or 27.5 mg / dL.

[0273] In further embodiments, the methods are effective in and / or intended for reducing ApoB plasma levels, to a level below 80 mg / dL, 79.5 mg / dL, 79 mg / dL, 78.5 mg / dL, 78 mg / dL, 77.5 mg / dL, 77 mg / dL, 76.5 mg / dL, 76 mg / dL, 75.5 mg / dL, 75 mg / dL, 74.5 mg / dL, 74 mg / dL, 73.5 mg / dL, 73 mg / dL, 72.5 mg / dL, 72 mg / dL, 71.5 mg / dL, 71 mg / dL, 70.5 mg / dL, 70 mg / dL, 69.5 mg / dL, 69 mg / dL, 68.5 mg / dL, 68 mg / dL, 67.5 mg / dL, 67 mg / dL, 66.5 mg / dL, 66 mg / dL, 65.5 mg / dL, 65 mg / dL, 64.5 mg / dL, 64 mg / dL, 63.5 mg / dL, 63 mg / dL, 62.5 mg / dL, 62 mg / dL, 61.5 mg / dL, 61 mg / dL, 60.5 mg / dL, 60 mg / dL, 59.5 mg / dL, 59 mg / dL, 58.5 mg / dL, 58 mg / dL, 57.5 mg / dL, 57 mg / dL, 56.5 mg / dL, 56 mg / dL, 55.5 mg / dL, or 55 mg / dL.

[0274] In preferred embodiments of the invention, the methods are effective in and / or intended for reducing and / or normalizing Lp(a) plasma levels. More in particular, the methods are effective in and / or intended for reducing Lp(a) plasma levels at least 5% from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe. In some embodiments, the methods are effective for reducing Lp(a) levels by at least 7.5 %, at least 10 %, at least 12.5 %, at least 15 %, at least 17.5 % or at least 20 % from baseline. In further embodiments, the methods are effective in and / or intended for reducing Lp(a) plasma levels by at least 5 nmol / L from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe, more preferably at least 10 nmol / L, at least 15 nmol / L, at least 20 nmol / L, at least 25 nmol / L, at least 30 nmol / L, at least 35 nmol / L or at least 40 nmol / L. In further embodiments, the methods are effective in and / or intended for reducing Lp(a) plasma levels, to a level below 110 nmol / L, preferably below 105 nmol / L, below 100 nmol / L, below 95 nmol / L, below 90 nmol / L, below 85 nmol / L or below 80 nmol / L.

[0275] In some embodiments of the invention, the methods are effective in and / or intended for mitigating and / or ameliorating resistance or hypo-responsiveness to statin therapy, in particular high intensity statin therapy. High intensity statin therapy is a term conventionally used in the art to denote the regimens based on the highest allowed dosages of the statins having the highest efficacy in reducing LDL-C, notably regimens that typically display a LDL-C reduction ≥ 50 % in normally responsive subjects. Of the statins currently used in clinical practice, only 20 mg (daily) or 40 mg (daily) of rosuvastatin and 40 mg (daily) or 80 mg (daily) of atorvastatin meet the criteria. In the context of the present invention hypo-responsiveness to HIS therapy means that a subject receiving HIS therapy fails to reach a 35 % LDL-C reduction, preferably it means that a subject receiving HIS therapy fails to reach a 30 % LDL-C reduction, a 25 % LDL-C reduction, a 20 % LDL-C reduction, a 15 % LDL-C reduction, or a 10 % LDL-C reduction. Mitigating and / or ameliorating hypo-responsiveness to HIS therapy, means that the difference between the subject’s response (LDL-C reduction) and the (average) response of normo-responsive subjects is reduced. In further embodiments of the invention, the methods are effective in and / or intended for normalizing the responsiveness to statin therapy.

[0276] In some embodiments, the methods are effective in and / or intended for increasing HDL-C plasma levels by at least 5 % from baseline, wherein baseline is defined as the point in time immediately prior to the start of the treatment with obicetrapib and ezetimibe. In some embodiments the methods are effective in increasing HDL-C plasma levels at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0277] In further embodiments, the methods are effective in and / or intended for increasing HDL-C plasma levels by at least 5 mg / dL from baseline, wherein baseline is defined as the point in time immediately prior to the start of treatment with obicetrapib and ezetimibe. In some embodiments the methods are effective in improving HDL-C plasma levels at least 10 mg / dL, 11 mg / dL, 12 mg / dL, 13 mg / dL, 14 mg / dL, 15 mg / dL, 16 mg / dL, 17 mg / dL, 18 mg / dL, 19 mg / dL, 20 mg / dL, 21 mg / dL, 22 mg / dL, 23 mg / dL, 24 mg / dL, 25 mg / dL, 26 mg / dL, 27 mg / dL, 28 mg / dL, 29 mg / dL, 30 mg / dL, 31 mg / dL, 32 mg / dL, 33 mg / dL, 34 mg / dL, 35 mg / dL, 36 mg / dL, 37 mg / dL, 38 mg / dL, 39 mg / dL, 40 mg / dL, 41 mg / dL, 42 mg / dL, 43 mg / dL, 44 mg / dL,45 mg / dL, 46 mg / dL, 47 mg / dL, 48 mg / dL, 49 mg / dL, 50 mg / dL, 51 mg / dL, 52 mg / dL, 53 mg / dL, 54 mg / dL, or 55 mg / dL.

[0278] As explained herein above, the methods of the invention are directed at the treatment and / or prevention of a subject suffering from or at risk of suffering from CVD, in particular ASCVD.

[0279] In some embodiments, the term “a subject " refers to a living organism, typically a mammal, in particular a human subject, suffering from or prone to a disease or condition that can be treated by using the composition provided herein.

[0280] In particularly preferred embodiments of the invention, the subject is a subject that has been diagnosed with CVD, in particular ASCVD.

[0281] In particularly preferred embodiments of the invention, the subject, is a subject preferably an adult, that has established ASCVD.

[0282] In particularly preferred embodiments of the invention, the subject, is a subject preferably an adult, that has HeFH.

[0283] In particularly preferred embodiments of the invention, the subject, is a subject preferably an adult, that has mixed dyslipidemia.

[0284] In further preferred embodiments of the invention, the subject is a subject that is considered to be at risk, typically at above-average risk, of developing CVD, in particular ASCVD, as can e.g. be judged by healthcare professionals.

[0285] In preferred embodiments of the invention, the subject is a subject suffering from one or more conditions known to bear a causal and / or epidemiological correlation with the occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including, overweight / obesity, metabolic syndrome, etc. In further preferred embodiments of the invention, the subject is a subject that is genetically predisposed to develop (AS)CVD. In further preferred embodiments of the invention, the subject is a subject prone to develop (AS)CVD as a consequence of life-style / habitual factors, such as unhealthy diet, lack of exercise, alcohol consumption, smoking.

[0286] In accordance with a preferred embodiment of the invention, the subject to be treated has elevated plasma levels of LDL-C, typically an LDL-C plasma level of at least 70 mg / dL, morepreferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Furthermore, in accordance with preferred embodiments of the invention, the subject has an LDL-C plasma level that is at least 125 % of the average LDL-C plasma level in healthy subjects, e.g. at least 150 %, at least 175 %, or at least 200 %. Normal LDL-C (reference) values typically depend on gender and age.

[0287] In accordance with another preferred embodiment of the invention, the subject to be treated is a subject that is unable to reach LDL-C goals with the maximum tolerated dose of a statin.

[0288] In accordance with another preferred embodiment of the invention, the subject to be treated is a subject that is intolerant to statin and is unable to reach LDL-C goals with ezetimibe alone.

[0289] In accordance with another preferred embodiment of the invention, the subject to be treated is a subject that is unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe.

[0290] As used herein, the term ‘LDL-C goal’ refers to the level of plasma LDL-C that is considered to significantly reduce the risk of cardiovascular events, compared to the patients baseline level, and, on that basis, is selected as the target level to be reached with lipid-lowering therapy. For instance, The European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) guidelines, recommend tailoring treatment to each patient’s level of cardiovascular risk and have set an LDL-C goal of < 70 mg / dL for patients considered to be at very high cardiovascular risk. Patients in this risk category have documented cardiovascular disease (e.g., prior myocardial infarction [MI]), or a 10% or greater 10-year risk of fatal cardiovascular disease, and in randomized controlled trials, the guideline-specified LDL-C goal has been shown to reduce the risk of recurrent cardiovascular events. Hence, in certain embodiments of the invention, the term ‘LDL-C goals’ refers to an LDL-C plasma level of < 70 mg / dL. In preferred embodiments, the subject to be treated is a subject that is unable to reach an LDL-C plasma level of < 70 mg / dL, with the maximum tolerated dose of a statin, with ezetimibe or with the maximum tolerated dose of a statin in combination with ezetimibe.

[0291] In accordance with another embodiment of the invention, the subject to be treated is a subject requiring additional lowering of LDL-C as an adjunct to diet and / or to maximallytolerated lipid-lowering therapy, wherein said lipid-lowering therapy is not obicetrapib / ezetimibe combination therapy.

[0292] In accordance with a preferred embodiment of the invention, the subject to be treated has elevated plasma levels of ApoB, typically an ApoB plasma level of at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Furthermore, in accordance with preferred embodiments of the invention, the subject has an ApoB plasma level that is at least 125 % of the average ApoB plasma level in healthy subjects, e.g. at least 150 %, at least 175 %, or at least 200 %. Normal ApoB (reference) values typically depend on gender and age.

[0293] In accordance with a preferred embodiment of the invention, the subject to be treated has elevated plasma levels of non-HDL-C, typically a non-HDL-C plasma level of at least 100 mg / dL, more preferably at least 105 mg / dL, at least 110 mg / dL, at least 115 mg / dL, at least 120 mg / dL, at least 125 mg / dL or at least 130 mg / dL. Furthermore, in accordance with preferred embodiments of the invention, the subject has a non-HDL-C plasma level that is at least 125 % of the average non-HDL-C plasma level in healthy subjects, e.g. at least 150 %, at least 175 %, or at least 200 %. Normal non-HDL-C (reference) values typically depend on gender and age.

[0294] In one embodiment of the invention, the subject is human male. In another embodiment of the invention, the subject is human female.

[0295] In further preferred embodiments of the invention, the subject is at increased risk based on age, such as a subject being over 35 years of age, over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age or over 70 years of age; typically in combination with one or more other risk factors as defined herein.

[0296] In accordance with certain embodiments of the invention, the subjects to be treated display hypo-responsiveness to statin therapy, in particular HIS therapy. High intensity statin therapy is a term conventionally used in the art, to denote the regimens based on the highest allowed dosages of statins having the highest efficacy in reducing LDL-C, notably regimens that typically display a LDL-C reduction ≥ 50 % in normally responsive subjects. In current clinical practice, only rosuvastatin 20 mg / day or 40 mg / day and atorvastatin 40 mg / day or 80 mg / day are considered HIS therapy. In preferred embodiments of the invention, the subject is a subject that is receiving HIS therapy and fails to reach a 35 % LDL-C reduction, preferably a subjectreceiving HIS therapy that fails to reach a 30 % LDL-C reduction, a 25 % LDL-C reduction, a 20 % LDL-C reduction, a 15 % LDL-C reduction, or a 10 % LDL-C reduction. In preferred embodiments of the invention, the subject’s hypo-responsiveness to statin therapy, in particular HIS therapy, is established after at least 1 month of (continuous) HIS therapy, more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months.

[0297] The various aspects of the present invention as defined herein, all relate to methods of treatment involving the administration, typically the repeated administration, of a composition comprising obicetrapib (or a salt or solvate or co-crystal thereof), preferably any composition as defined herein before. In particularly preferred embodiments of the invention, the methods of treatment comprise the administration, typically the repeated administration, of a composition comprising an LDL-C lowering amount of obicetrapib or a salt or solvate or co-crystal thereof.

[0298] Hence, in particularly preferred embodiments of the invention, the method comprises the administration of obicetrapib in a dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, or at least 9 mg, e.g. about 10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose. In accordance with the various aspects of the invention, the method comprises the administration of obicetrapib in a dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose. In accordance with the various aspects of the invention, the method comprises the administration of obicetrapib in a dose within the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg or 5-10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose. In certain preferred embodiments, the method comprises the administration of obicetrapib in a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose. In certain particularly preferred embodiments, the method comprises the administration obicetrapib in a dose of 5, 7.5, 10, 12.5 or 15 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dose.

[0299] In particularly preferred embodiments of the invention, the treatment comprises the repeated administration of the composition containing obicetrapib or a salt, hydrate or solvate thereof, preferably in a dose within the ranges defined herein before. In particularly preferredembodiments of the invention, the treatment comprises the repeated administration of the composition, preferably in a dose within the ranges defined herein before, at a frequency of at least once every two days or at least once every day. In particularly preferred embodiments of the invention, the treatment comprises the repeated administration of the composition, preferably in the dose as defined herein before, at a frequency of once to four times every day. In particularly preferred embodiments of the invention, the method comprises the once or twice daily administration of the composition containing obicetrapib or a salt, hydrate or solvate thereof, in the dose ranges as defined here above, most preferably twice daily.

[0300] Hence, in particularly preferred embodiments of the invention, the method comprises the administration of obicetrapib at a daily dosage of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, or at least 9 mg, e.g. about 10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage. In accordance with the various aspects of the invention, the method comprises the administration of obicetrapib at a daily dosage of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less, or 11 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage. In accordance with the various aspects of the invention, the method comprises the administration of obicetrapib at a daily dosage within the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg or 5-10 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage. In certain preferred embodiments, the method comprises the administration of obicetrapib at a daily dosage of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage. In certain particularly preferred embodiments, the method comprises the administration of obicetrapib at a daily dosage of 4 of 5, 7.5, 10, 12.5 or 15 mg; or a salt, solvate or co-crystal of obicetrapib in the equipotent dosage.

[0301] As will be apparent to those skilled in the art, based on the present teachings, the methods of the invention further comprise the concurrent treatment with ezetimibe (or a salt or solvate or co-crystal thereof). In particularly preferred embodiments of the invention, the methods of treatment comprise the administration, typically the repeated administration, of a composition comprising an LDL-C lowering amount of ezetimibe or a salt or solvate or co-crystal thereof.

[0302] To this end, ezetimibe and obicetrapib (or a therapeutically acceptable salt, solvate or cocrystal thereof) may be administered at or around the same time, sequentially or concurrently, or they may be administered at different time points. In preferred embodiments of the invention, the frequency and administration intervals of obicetrapib and ezetimibe are equal, more preferably each is administered once daily, still more preferably at the same time of the day, sequentially or concurrently as two separate unit dosage forms, preferably in the form of the fixed dose combination product as defined herein. In preferred embodiments, the methods of the invention comprise the administration of ezetimibe at a daily dosage of 1-30 mg, 2-25 mg, 3-20 mg, 4-17.5 mg, or 5-15 mg e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg, most preferably about 10 mg; or a salt, solvate or co-crystal of ezetimibe, in the equipotent dosage.

[0303] As will be apparent to those skilled in the art, based on the present teachings, the methods of the invention, in some embodiments, further comprises the concurrent treatment with a HMG CoA reductase inhibitor, preferably concurrent HIS therapy. To this end, the HMG CoA reductase inhibitor and obicetrapib (or a therapeutically acceptable salt, solvate or co-crystal thereof) may be administered at or around the same time, sequentially or concurrently, or they may be administered at different time points. In preferred embodiments of the invention, the frequency and administration intervals of obicetrapib and the HMG CoA reductase inhibitor are equal, more preferably each is administered once daily, still more preferably at the same time of the day, sequentially or concurrently as two separate unit dosage forms, or in the form of a fixed dose combination product. In preferred embodiments, the methods of the invention comprise the administration of rosuvastatin at a daily dosage of 10-50 mg, 15-45 mg, 17.5-42.5 mg, or 20-40 mg, e.g. 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 mg, most preferably about 20 mg or 40 mg; or a salt, solvate or co-crystal of rosuvastatin in the equipotent dosage. In preferred embodiments, the methods of the invention comprise the administration of atorvastatin at a daily dosage of 30-90 mg, 35-85 mg, 37.5-82.5 mg, or 40-80 mg, e.g. 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85 mg, most preferably about 40 mg or 80 mg; or a salt, solvate or co-crystal of atorvastatin in the equipotent dosage. In certain preferred embodiments, the methods of the invention do not comprise the concomitant treatment with a HMG CoA reductase inhibitor.

[0304] As will be apparent to the skilled person, on the basis of the present teachings, the daily doses indicated herein may be contained in a single unit dosage form as well as in a plurality ofunit dosage forms. In a most preferred embodiment of the invention, the method comprises the administration of obicetrapib (or a salt, hydrate or solvate thereof) in the dosages recited herein once daily. However, methods are also envisaged comprising the administration of 2 unit dose forms, each comprising approximately half of the daily dosage as indicated above, at certain predetermined moments during the day, e.g. one in the morning, such as shortly after the subject wakes up, and one in the evening, such as around the time the subject has his evening meal or goes to sleep. Embodiments wherein unit dosage forms are used comprising higher amounts of obicetrapib and / or ezetimibe than the daily dose indicated herein are also contemplated. This may e.g. involve the use of extended release dosage forms that remain in the body and keep releasing the active ingredient for a sufficiently long time.

[0305] In embodiments, methods and / or compositions for use according to the invention are provided, wherein the methods and / or use comprise the administration, preferably the repeated administration, of obicetrapib and ezetimibe (or a salt, hydrate or solvate thereof), preferably in the form of the fixed dose pharmaceutical composition as defined herein, to the subject, at a dose and frequency effective to reduce the subject’s LDL-C plasma levels, the subject’s ApoB plasma levels and / or the subjects Lp(a) plasma levels, more preferably to accomplish a reduction in one or more of the subject’s LDL-C plasma levels, the subject’s ApoB plasma levels and / or the subjects Lp(a) plasma levels within the ranges recited herein elsewhere. In particularly preferred embodiments of the invention, these treatments comprise the repeated administration of obicetrapib and ezetimibe (or a salt, hydrate or solvate of obicetrapib and / or ezetimibe), preferably in the form of the fixed dose pharmaceutical composition as defined herein, in accordance with the above-defined regimens, during a period of at least one month, at least three months, at least four months, at least six months, at least nine months, at least one year, at least two year, at least three year, at least 5 year, at least 10 year, at least 20 year, at least 30 year. There is no particular upper limit; treatment may be continued for as long as it is deemed beneficial to the subject’s overall health and well-being (as determined by appropriately qualified healthcare professional), e.g. for the rest of the subject’s life.7.6. Pharmaceutical Kits

[0306] Another aspect of the invention is directed to a pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a leaflet, wherein said unit dosage forms containthe pharmaceutical composition according to the invention and wherein said leaflet contains printed instructions to repeatedly self-administer said unit dosage forms in order to accomplish any of the therapeutic objectives as defined herein, such as to treat and / or prevent any cardiac disease or dysfunction as defined herein.

[0307] In accordance with embodiments of the invention, the pharmaceutical kit comprises a container, such as a cardboard box, holding one or more blister packs, said one or more blister packs containing a plurality of solid unit dosage forms as defined herein before, preferably a plurality of tablets as defined herein before. In particularly preferred embodiments of the invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit dosage forms, e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In one embodiment of the invention, the pharmaceutical kit only comprises unit dosage forms as defined herein that contain obicetrapib as the sole active ingredient. In one embodiment of the invention, the pharmaceutical kit only comprises a plurality of unit dosage forms as defined herein that contain obicetrapib (or a salt, hydrate or solvate thereof) as the sole active ingredient and a plurality, preferably an equal number, of unit dosage forms that contain ezetimibe as the sole active, typically in the dose amounts recited herein elsewhere. In one embodiment of the invention, the pharmaceutical kit only comprises a plurality of unit dosage forms as defined, wherein each unit dosage form comprises obicetrapib (or a salt, hydrate or solvate thereof) and ezetimibe (or a salt, hydrate or solvate thereof), more preferably a plurality of the fixed dose pharmaceutical composition as defined herein. In some embodiments, pharmaceutical kits as defined herein may further comprise a plurality of unit dosage forms that contain a HMG CoA reductase inhibitor as the sole active, preferably atorvastatin or rosuvastatin (or a salt, hydrate or solvate thereof), typically in the dose amounts recited herein elsewhere.

[0308] In accordance with the invention, the pharmaceutical kit comprises a leaflet inserted into the container, typically a patient information leaflet containing printed information, which information may include a description of the form and composition of the unit dosage forms contained in the kit, an indication of the therapeutic indications for which the product is intended, instructions as to how the product is to be used and information and warnings concerning adverse effects and contraindications associated with the use. It will be understood by those of average skill in the art, based on the information presented herein, that the leaflet that is part of the kit according to the invention, will typically contain the information concerning thetherapeutic indications, uses, treatment regimens, etc. as described here above in relation to the methods of treatment of the present invention. In particularly preferred embodiments of the invention, the leaflet contains printed instructions to repeatedly (self-)administer the unit dosage forms in order to treat and / or prevent CVD, in particular ASCVD.

[0309] The methods of treatment of the invention, based on obicetrapib and ezetimibe combination therapy will be illustrated further by means of the non-limiting examples herein below.8. EXAMPLES8.1. Analytical and physical characterization methods:

[0310] The methods used throughout the study are summarised in Table A. The specific parameters and conditions for analytical and physical assessments used for each non-limiting example is described in relevant section of such example.Table ATest TitleTransmission method for phase identification using X-Ray Powder XRPDDiffractionMethod for particle size distribution by laser diffraction dry powder PSDdispersionstandard test method for tapped bulk density analysis using drop height TBDdensity testerKF determination of water content by indirect (coulometric) karl fischer titration Discriminating discriminating dissolution method for obicetrapib at ph 6.8 and 50 rpm paddle Dissolution speed.Content Uniformity determination of content uniformity of obicetrapib and ezetimibe by hplc-UV. Assay and relatedidentity, assay and impurities / related substances profile determination of substances / impuritiesobicetrapib by hplc-UV.for obicetrapibAssay andimpurities / related identity, assay and impurities / related substances profile determination of substances for ezetimibe by hplc-UVezetimibeVisual Appearance determination of appearance using the Munsell colour systemXRPD

[0311] The XRPD analyses were run in transmission mode on an X'pert Pro / Empyrean X-Ray Diffractometer (PANalytical) equipped with an X’Celerator detector using a standard XRPD Aptuit method. The data were evaluated using the Highscore Plus software. The instrumental parameters used are listed in table B below.Table BInstrumental Parameter Value2-theta range 2-45°Step size [°2-theta] 0.0167Time per step [sec] 59.690 secScan Mode ContinuousSample Movement Spinning. 1.0sec rotation timeWavelength [nm] Cu Kai =1.54060 Ka2=1.54443Inc. Beam Cu W / Si focusing MPD. Acceptance Angle 0.8°C. X-ray MirrorLength 55.3 mmSlitsSlit Fixed 1 / 2° / Slit Fixed 1 / 2° / 10 mm Inc Beam Mask Divergence / Anti scatter / MaskTemperature / RH Room temperature. Lab RHFixed Slits Soller slits 0.02 rad on Incident and Diffracted beam Detector type X’Celerator (active length 2.122°)Scanning mode TransmissionTransmission sample holder. Samples are mounted as a thick film, to minimise preferred orientation effects between Mylar Sample holderfilm) using a tin plated stainless steel spacer to afford a compact that is 1 mm thick and up to 1 cm in diameter. Configuration TransmissionGenerator voltage / current 40 Kv / 40 mA8.2. Particle size distribution (PSD)

[0312] The PSD analyses were run on a Sympatec Helos laser diffraction instrument equipped with the RODOS / M for dispersion and the ASPIROS or VIBRI for sample delivery. The powder dispersion is achieved by the use of compressed air and through a gun that uses the Venturi effect. PSD method details are listed in table C.Table CInstrumental Parameter ValueSoftware Sympatec Windox 5 Version 5.1.2.0Dispersing Accessory VibriTable CInstrumental Parameter ValueOptical concentration 2-10%Lens R6Density: 1.0000 g / cm3Product details Shape factor 1.000Calculation mode: HRLDReference measurement: duration 10s / single Time base: 100 msMeasurement: standard modeTrigger ConditionStart 0.000s opt. concentration >1.0%Stop after 5.000s opt. concentration <1.0%Trigger timeout 20 sRODOSDisperser Type: OASISDRYDisperser ConditionInjector: 4 mmPrimary pressure 0.5 barFeeder Vibri 70% 0.5 mm gapVacuum Nilfisk / delay 3 s from start of extraction to start of measurementTable D. Discriminating dissolution method pH 6.8 (obicetrapib)Instrumental Parameter ValueApparatus USP apparatus IIDissolution medium Phosphate buffer solution pH 6.8 + 0.2 %w / v of Polysorbate 80 Dissolution medium volume900[mL]Dissolution medium37 ± 0.5Temperature [°C]Rotation Speed [rpm] 50 - Infinity point 250 rpmSampling Time [min] 5; 10; 15; 30; 45; 60 and 70 (70 as Infinity point)Sampling Volume [mL] 1Separative technique (*) PVDF 0.45μm membraneFilter Pre-wetting volume 9 (sampling 10mL and discarding the first 9mL back to the[mL] vessel)Detection HPLC-UVTable E. Discriminating Dissolution method pH 4.5 (ezetimibe)Instrumental Parameter ValueApparatus USP apparatus IIDissolution medium Acetate buffer solution pH 4.5 + 0.45 %w / v of SLSDissolution medium volume500[mL]Dissolution medium37 ± 0.5Temperature [°C]Rotation Speed [rpm] 50 - Infinity point 250 rpmSampling Time [min] 15; 30; 45; 60 and 70 (70' as Infinity point).Sampling Volume [mL] 1Separative technique (*) ww / PTFE 0.45 um membraneFilter Pre-wetting volume 9 (sampling 10mL and discarding the first 9mL back to the[mL] vessel)Detection HPLC-UVTable F. QC Dissolution method pH 6.8 (obicetrapib)Instrumental Parameter ValueApparatus USP apparatus IIDissolution medium Phosphate buffer solution pH 6.8 + 0.2 %w / v of Polysorbate 80 Dissolution medium volume [mL] 1000Dissolution medium Temperature37 ±0.5[°C]Rotation Speed [rpm] 75 - Infinity point 250 rpmSampling Time [min] 15; 30; 45; 60 and 70 (70' as Infinity point at 250 rpm) Sampling Volume [mL] 1Separative technique (*) PVDF 0.45μm membraneFilter Pre-wetting volume [mL] 9 (sampling 10mL and discarding the first 9mL back to the vessel)Detection HPLC-UVTable G. QC Dissolution method pH 4.5 (ezetimibe)Instrumental Parameter ValueApparatus USP apparatus IIDissolution medium Acetate buffer solution pH 4.5 + 0.45 %w / v of SLS Dissolution medium volume500[mL]Dissolution medium37 ± 0.5Temperature [°C]Rotation Speed [rpm] 75 - Infinity point 250 rpmSampling Time [min] 15; 30; 45; 60 and 70 (70' as Infinity point).Sampling Volume [mL] 1Separative technique (*) ww / PTFE 0.45Filter Pre-wetting volume 9 (sampling 10mL and discarding the first 9mL back to the[mL] vessel)Detection HPLC-UVTable H. Assay and Impurities / Related Substances (obicetrapib)Intrumental Parameters ValueColumn Kinetex PFP, 100mm x 4.6mm (particle size: 2.6μm)Mobile Phase A): 70 / 30 % v / v Water / Methanol + TFA 0.025%B): 30 / 70 % v / v Methanol / Acetonitrile + TFA 0.025%Gradient Program Time Flow Rate Mobile Phase (A) Mobile Phase (B)(min) [mL / min]0.0 70 30 5.0 50 50 8.0 50 501.030.0 3 97 30.1 70 30 35.0 70 30 Column Temperature [°C] 35Auto Sampler Temperature R. T.[°C]Detector UV, MWD or DAD (DAD for release ID)Detector Wavelength [nm] 245Injection Volume [μL] 10Diluent (Standard, sensitivity Water / Acetonitrile, 50 / 50 %v / vand resolution check solutions)Diluent (Sample solutions) Diluent A: Water 100%Diluent B: Acetonitrile 100 %Run Time [min] 30 (5 minutes next injection delay)Typical Retention Time [min] 16.7Table I. Assay and Impurities / Related Substances (ezetimibe)Intrumental Parameters ValueColumn Kinetex PFP F5, 150mm x 4.6mm (particle size: 5.0μm)Mobile Phase A): Water / Methanol 90 / 10 % v / vB): Acetonitrile / Methanol 90 / 10 % v / vGradient Program Time Flow Rate Mobile Phase (A) Mobile Phase (B)(min) [mL / min]0.0 70 30 37.0 70 30 60.0 44.4 55.6 70.0 44.4 55.62.080.0 11.1 88.9 90.0 11.1 88.9 90.1 70 30 100.0 70 30 Column Temperature [°C] 25Auto Sampler Temperature R. T.[°C]Detector 0 - 5 min: 215 nm and 5 - 100 min: 248 nmDetector Wavelength [nm] UV, MWD or DAD (DAD for release ID if required)Injection Volume [μL] 60Diluent (Standard, sensitivity Water / Acetonitrile / Methanol 63 / 27 / 10 %v / v with 0.1% of acetic acid and identification checksolutions)Diluent (Sample solutions) Diluent A: Water with 0.1% of acetic acidDiluent B: Acetonitrile 1 with 0.1% of acetic acidDiluent C: Methanol with 0.1% of acetic acidRun Time [min] 100.0Typical Retention Time [min] 21.08.3. Example 1: Fixed dose combination tablet of 10 mg ezetimibe, 5 mg obicetrapib (small scale batch ~500 g)8.3.1. High shear granulation and fluid bed drying

[0313] Four prototype formulations were assessed. The excipients contained in the granule were plastic filler (Avicel PH101), brittle filler (Pharmatose 200M), binder (Kollidon 30), disintegrant (glycolys) and surfactant (Kolliphor SLS fine). In the preliminary four trials (granule batches A4459 / 05 / 01, A4459 / 05 / 02, A4459 / 05 / 03 and A4459 / 05 / 04) the quantity of the plastic filler and the brittle filler was assessed at high or low level and two high shear granulation processing conditions were tested. In the last two trials (granule batches A4459 / 07 / 01 and A4459 / 08 / 01) the formulations were prepared at a high level of lactose and a lower impeller speed (as per processing condition 2). The composition and method of the addition of the excipients was amended as detailed in Table 1.

[0314] The materials were dispensed at the target weight and ezetimibe, obicetrapib and the intra-granular excipients were manually sieved and transferred into a granulation bowl. The granulation solution was prepared by solubilising the required excipients in water.

[0315] The small-scale granules were dried using a STREA fluid bed granulator and the material was fluidised in the bowl by adjusting the air volume as required and until the LOD of the dried granule was equal or lower than the initial LOD. The inlet air temperature, product temperature, exhaust temperature as well as the air flow volume were registered throughout drying. Following drying, the granules were tested for granule homogeneity of APIs, LOD, sieve analysis, TBD and XRPD.8.3.2. Preparation of the final blend and tableting

[0316] The final blends were prepared by weighing accurately the required amount of extra-granular excipients. Then, the excipients (with the exception of Magnessium Stearate (MgSt)) were manually sieved, added with the granule to a bin of suitable volume and blended using a Pharmatech mixer. The MgSt was sieved separately and added to the bin. For the compression, a single punch compression machine (specifically, the EKO tableting machine) was used to generate the compression profile and manufacture tablets with 150.0 mg target weight. Based on the information collected for the compression profile, a small-scale tablet manufacture was performed. These tablets were tested for appearance, assay and impurities content, discriminating dissolution, ezetimibe USP tablet dissolution method, content uniformity, water content by KF and XRPD. All the intermediates of production and the uncoated tablets were stored in double LDPE bags closed with a cable tie and transferred into a sealed aluminium bag with silica.Table 1: Composition (% w / w) of granule and tablet of small scale 10 mg ezetimibe and 5 mg obicetrapib trialsFormulation prototype1 2 3 4Processing conditionConditio Condition Condition ConditionCondition 2 Condition 2 n 1 2 1 2Granule Batch numberComponen A4459 / 05 A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 07 / 01 A4459 / 08 / 01 t / 01 02 03 04Tablet Batch numberA4459 / 05 A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 07 / 02 A4459 / 08 / 02 / 05 06 07 08%% (w / w) % (w / w) % (w / w) % (w / w) (w / w) % (w / w) % (w / w) % (w / w) granule tablet granule tablet granul tablet granule tablet eEzetimibe 7.168 6.666 7.168 6.666 7.017 6.666 7.073 6.666 Obicetrapi 3.678 3.421 3.678 3.421 3.601 3.421 3.630 3.421 b (salt)Avicel PH 20.9626.826 24.948 53.651 49.895 19.920 21.775 20.717 101 8Pharmatos 57.8853.651 49.895 26.826 24.948 54.993 60.095 57.196 e 200M 7Kollidon 5.018 4.2114.667 5.018 (out) 4.667 4.000 1.061 (in) 1.000 30 (out) (in)Glycolys 3.301 3.070 3.301 3.070 4.211 4.000 4.244 4.000 Kolliphor 0.358 2.105 2.1220.333 0.358 (out) 0.333 2.000 2.000 SLS fine (out) (out) (out)MilliQ 20.0030.000 N / A 30.000 N / A N / A 20.000 N / A water * 0Total 100.0100.000 93.000 100.000 93.000 95.000 100.000 95.000 granule 00Avicel PH N / A 3.000 N / A 3.000 N / A N / A N / A N / A 101Glycolys N / A 2.500 N / A 2.500 N / A 4.000 N / A 4.000 Aerosil 200 N / A 0.750 N / A 0.750 N / A N / A N / A N / A Ligamed N / A 0.750 N / A 0.750 N / A 1.000 N / A 1.000 MF-2-VTotal N / A 100.000 N / A 100.000 N / A 100.000 N / A 100.000tabletResults:Small-scale trials to develop 10 mg ezetimibe, 5 mg obicetrapib tablets

[0317] The manufactures of the granule for the small-scale batches were conducted successfully. During granulation the energy consumption increased upon addition of the granulation solution and, after drying, the LOD of the granule was lower than the initial LOD (Table 2). The granules A4459 / 05 / 01 and A4459 / 05 / 02 presented coarser particles in comparison to granule batches A4459 / 05 / 03 and A4459 / 05 / 04. This was linked to a higher level of lactose in the formulationrather than to the parameters of granulation (process condition 1 vs process condition 2). As the quantity of the binder and water for granulation was reduced and the level of surfactant increased, the granule batches A4459 / 07 / 01 and A4459 / 08 / 01 (that were manufactured with a higher level of lactose), presented particles with a larger portion of fines in comparison to batches A4459 / 05 / 01 and A4459 / 05 / 02 (Figure 1 and Figure 2). Briefly, the tablets with higher content of microcrystalline cellulose (batches A4459 / 05 / 07 and A4459 / 05 / 08) showed faster disintegration time, lower friability and higher hardness values than those containing a higher quantity of lactose (batches A4459 / 05 / 05 and A4459 / 05 / 06). Overall, these tablet batches presented a suitable appearance. The tablet batches A4459 / 07 / 02 and A4459 / 08 / 02 (containing high level of lactose) presented faster time of disintegration and suitable dissolution profile of both drug substances. However, the hardness and friability of the tablets could not be improvedto a level considered acceptable due to capping and failure of the friability test. The tablet hardness was lower compared to that obtained with the previous trials (batch A4459 / 05 / 05 and A4459 / 05 / 06).A / / 44590503Table 2: LOD of 10 mg ezetimibe, 5 mg obicetrapib P 2ttroopey small-scale trialsiid 1t cononA / / 44590504LOD(%) P 2ttroopeyiid 2t cononA / / 44590701Blend for granulation (prior to spraying) 3.62% 2.84% 4.00% 3.49% 2.79% 2.17% Granule following spraying (prior to drying) 16.79% 26.78% 26.42% 27.68% 20.06% 20.35% Granule following drying 2.26% 2.33% 2.70% 3.07% 1.97% 1.14%A / / 44590801 Granule following milling 3.82% 2.58% 2.70% 2.51% 2.07% 1.55%Granule following additional drying 2.95% N / A N / A N / A N / A N / Aiid 2t conon Granules characterizationChemical characterization analysis

[0318] The granules were tested for homogeneity of both obicetrapib and ezetimibe, results are reported in Table 3. Both APIs were homogenously dispersed in the granule with maximum RSD % values obtained for batch A4459 / 05 / 03, nonetheless within the typical acceptable range for granule homogeneity.Table 3: Granule uniformity of 500 g batch scale prototypesA4459 / 05 / 01 A4459 / 05 / 02 A4459 / 05 / 03 A4459 / 05 / 04 A4459 / 07 / 01 A4459 / 08 / 01 Prototype 1 Prototype 1 Prototype 2 Prototype 2 Prototype 3 Prototype 4 condition 1 condition 2 condition 1 condition 2 condition 2 condition 2 Ezeti Obi Ezetimi Obi Ezetimi Obi Ezetimi Obi Ezetimi Obi Ezetimi Obi mibe cetr be cetr be cetr be cetr be cetr be cetr (%C1 apib (%Clai apib (%Clai apib (%Clai apib (%Clai apib (%Clai apib aim) (%c m) (%c m) (%c m) (%c m) (%c m) (%c laim laim laim laim laim laim ) ) ) ) ) ) Sam#1 101.9 97.9 102.5 98.5 99.4 98.1 102.2 98.3 102.4 98.5 103.0 101.8 Sam#2 101.1 97.6 103.3 99.6 101.8 98.8 101.7 97.9 102.1 98.1 99.5 97.9 Sam#3 103.0 98.8 103.4 99.2 103.7 100. 103.1 98.5 101.4 97.4 101.8 100.9 3 Sam#4 101.7 97.9 103.6 99.7 101.6 98.9 102.9 98.6 99.3 95.2 99.5 98.2 Sam#5 102.6 98.8 103.1 98.8 101.6 98.6 102.3 98.0 98.9 94.7 100.6 99.3 Sam#6 103.3 99.1 103.9 98.6 101.8 98.7 102.3 98.5 102.6 98.5 101.7 99.6 Mean 102.3 98.4 103.1 99.1 101.7 99.0 102.8 98.3 101.1 97.1 101.0 99.5 RSD 0.82 0.66 0.40 0.55 1.32 0.99 0.53 0.31 1.6 1.7 1.4 1.4%Physical properties characterization

[0319] As reported in Table 4, a small amount of ezetimibe (EZE) hydrate was found in all the wet granules samples. However, during the drying process the formed EZE hydrate converts back to EZE anhydrous with exception of batch 05 / 01 in which small trace of the hydrate polymorphic form appears to be still present.Table 4. XRPD data summary small scale lOmg ezetimibe and 5mg obicetrapib blends and wet and dry granulesSample Batch ID XRPD Prototype 1 condition 1 Blend OBI + EZE Anhydrous OBI + EZE Anhydrous + some EZE Prototype 1 condition 1 Wet Granules A4459 / 05 / 01 HydrateOBI + EZE Anhydrous+ small EZE Prototype 1 condition 1 Dry GranulesHydratePrototype 1 condition 2 Blend OBI + EZE Anhydrous OBI + EZE Anhydrous +small EZE Prototype 1 condition 2 Wet Granules A4459 / 05 / 02HydratePrototype 1 condition 2 Dry Granules OBI + EZE AnhydrousPrototype 2 condition 1 Blend A4459 / 05 / 03 OBI + EZE AnhydrousOBI + EZE Anhydrous +small EZE Prototype 2 condition 1 Wet GranulesHydratePrototype 2 condition 1 Dry Granules OBI + EZE Anhydrous Prototype 2 condition 2 Blend OBI + EZE Anhydrous OBI + EZE Anhydrous +small EZE Prototype 2 condition 2 Wet Granules A4459 / 05 / 04HydratePrototype 2 condition 2 Dry Granules OBI + EZE Anhydrous Tablets characterizationChemical characterization analysis

[0320] Results for the characterization of the small scale batch are reported in Table 5. Results for assay and impurities met the expectation and the impurity profile was consistent with both input APIs. All the prototypes were also found with an homogenous APIs content as the content uniformity results was with AV values significantly lower than the pharmacopeial requirement of AV. Water content results were found to be in range from 4.5 and 5.0%, and no defects were observed on the appearance.Table 5: Results of the analytical characterization of small scale 10mg ezetimibe and 5mg obicetrapib Manufacturing lot number A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 07 / A4459 / 08 / 05 06 07 08 02 02 Prototype and Process 1 - high 2 - low 1 - high 2 - low Prototype Prototype condition impeller impeller impeller impeller 3 4speed & 3 speed & 1 speed & 3 speed & 1 condition condition min wet min wet min wet min wet 2 2 massing massing massing massing (4% (1%Binder) Binder) MCC: Lactose Ratio 24.9: 49.9 24.9: 49.9 49.9: 24.9 49.9: 24.9 N / A N / A Test Method Result Result Result Result Result Result Appearance Visual White White White White White White round round round round round round coated coated coated coated coated coated tablets tablets tablets tablets tablets tablets Assay HPLCObicetrapib 2730 100.2 101.5 99.5 98.5 100.5 101.9 (%claim)Ezetimibe 2731 102.3 98.4 99.2 101.4 102.8 101.2 (%claim)Impurities HPLCIMP RRT0.92 2730 N. A. N. A. N. A. N. A. 0.05 N. A. (% claim)IMP RRT0.94 2730 O.05 O.05 O.05 O.05 0.07 O.07 (% claim)FROL(% 2730 0.05 0.05 0.05 0.05 0.07 0.07 claim)MONO-BN 2730 0.17 0.17 0.17 0.17 0.18 0.18FREE(% claim)Table 5: Results of the analytical characterization of small scale 10mg ezetimibe and 5mg obicetrapib Manufacturing lot number A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 07 / A4459 / 08 / 05 06 07 08 02 02 Total impurities 2730 0.27 0.27 0.27 0.26 0.37 0.32 of Obicetrapib> 0.05%Ezetimibe □Ket 2731 N. D. N. D. N. D. 0.05 N. D. N. D. one (% a / a)Ezetimibe 2731 N. D. N. D. N. D. 0.07 N. D. O.05 tetrahydropyrananalog (%a / a)Total impurities 2731 O.06 O.06 O.07 N. D. N. D. 0.05 of Ezetimibe > T30.05% iUniformity ofdosage unitsObicetrapib Average Average Average Average Average Average % Claim: % Claim: % Claim: % Claim: % Claim: % Claim: 98.5 98.3 98.4 97.2 99.2 100.7 Range % Range % Range % Range % Range % Range % USP <905> Claim: Claim: Claim: Claim: Claim: Claim: Ph. Eur. (96.7- (97.4 - (97.9 -99.1) (96.6 - (96.7 - (99.6 - 2.9.40 or 99.7) 99.7) AV = 0.9 97.7) 100.7) 101.9) JP 6.02 by AV = 2.3 AV = 1.8 AV = 2.1 AV = 4.0 AV= 1.9 Ezetimibe UNIC / Average Average Average Average Average Average 1190 % Claim: % Claim: % Claim: % Claim: % Claim: % Claim:101.2 100.7 99.2 99.4 103.3 102.1 Range % Range % Range % Range % Range % Range % Claim: Claim: Claim: Claim: Claim: Claim: (99.5 - (100.1 - (99.0 - (98.8 - (101.3 - (100.6 - 102.3) 102.1) 99.8) 99.8) 105.0) 103.1) AV = 2.2 AV = 1.4 AV = 0.5 AV = 0.9 AV = 5.8 AV = 2.9 DissolutionObicetrapib5 min Average 7 20 22 36 68 91 (Min Max) (6 - 8) (15 -25) (20 - 26) (29 -41) (64 - 72) (77 - 95) 10 min Average 17 49 57 73 89 98 (Min Max) Discriminati (16 - 19) (40 - 57) (52 -61) (65 - 77) (73 - 98) (97 - 99) 15 min Average ng method 33 73 80 91 95 95 (Min Max) at pH 6.8, (31 - 35) (70 - 76) (79 - 82) (89 - 93) (79 - 99) (77 - 101) 30 min Average 50 rpm 53 97 98 101 100 100 (Min Max) paddle (51 - 56) (96 - 99) (97 - 100) (98 - 105) (92 - 103) (99 - 101) 45 min Average speed and 105 103 102(M n 900 mL 64 101 100 i Max) (104 - (100 - (101 - vessel (63 - 68) (99 - 103) (99 - 102)106) 107) 103)60 min Average volume 108 10172 100 96 98 (Min Max) (106 - (100 - (70 - 73) (97 - 11) (70 - 102) (80 - 105)110) 103)70 min Average 108 101 102 10279 101(Min Max) (107 - (100 - (101 - (100 - (78 - 81) (98 - 105)109) 103) 102) 105) Dissolution DiscriminatiEzetimibe ng method5 min Average at pH 6.80.2 7 6 15 - -(Min Max) %w / v of (5 - 9) (5 -7) (12 - 17)Table 5: Results of the analytical characterization of small scale 10mg ezetimibe and 5mg obicetrapib Manufacturing lot number A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 05 / A4459 / 07 / A4459 / 08 / 05 06 07 08 02 02 10 min Average Tween 80, 5 18 17 33- - (Min Max) 50 rpm (4 -6) (15 -22) (16 - 18) (28 - 35)15 min Average paddle 9 28 26 45(Min Max) speed and - - (8 - 10) (27 - 29) (25 - 27) (43 - 48)30 min Average 900 mL 16 40 40 63(Min Max) vessel - - (15 - 18) (39 -42) (39 -41) (61 -64)45 min Average volume 19 47 49 73(Min Max) (19 -21) (45 - 50) (47 - 50) (70 - 77) - - 60 min Average 22 52 55 76- - (Min Max) (21 -23) (51 - 54) (53 - 56) (73 - 84)70 min Average 27 58 61 84- - (Min Max) (26 - 27) (57 -61) (60 - 62) (82 - 88)DissolutionEzetimibe Dissolution(n=3) method15 min Average based on 11 26 29 46 47 78 (Min Max) USP (11 - 12) (25 - 26) (28 - 31) (42 - 49) (46 - 52) (73 - 80) 30 min Average method 19 41 42 59 61 87 (Min Max) conditions (18 - 19) (40 - 41) (41 - 43) (55 - 61) (59 - 65) (83 - 90) at pH 4.5,45 min Average 50 rpm 24 51 49 65 69 91 (Min Max) (23 - 25) (50 - 51) (49 - 50) (62 - 67) (67 - 72) (86 - 94) paddle60 min Average speed and 29 57 55 69 75 93 (Min Max) 500 mL (27 - 29) (57 - 58) (55 - 55) (67 -71) (73 - 78) (88 - 96) 70 min Average vessel 10138 67 71 86 85(Min Max) volume (100 - (36 - 40) (66 - 68) (71 -71) (85 - 87) (82 - 87)102)Water content KF 5.0 % w / w 4.5 % w / w 4.5 % w / w 4.4% w / w 6.1 %w / w 5.4 % w / w

[0321] The dissolution profiles for Obicetrapib showed for Prototypes A4459 / 05 / 08, A4459 / 05 / 06 and A4459 / 05 / 07 a similar trend in dissolution with Prototype A4459 / 05 / 08 (high amount of Avicel & low impeller speed) dissolving rapidly in the range 5-15 minutes. Prototype A4459 / 05 / 05 (high Lactose & high impeller speed) dissolved significantly slower. Dissolution results in USP ezetimibe method pH 4.5 were consistent with what observed in pH 6.8. For prototypes 3 and 4 batches A4459 / 07 / 02 (4 % Binder) and A4459 / 08 / 02 (1 % binder) a significant improvement was observed in dissolution characterization which shows for prototype 4 a profile consistent with the reference commercial ezetimibe tablet. Dissolution profiles are presented in Figure 3, Figure 4 and Figure 5. Assay, content uniformity and impurities profile showed no significant differences across the four formulations for both obicetrapib and ezetimibe.Stress Stability

[0322] Prototypes 1 and 2 with different process conditions were evaluated in a stress stability study with the following designTable 6: Stress stability study designStorage Conditions Time (weeks)I7RII Type 0 2 3 425°C / 60%RH Long-term (T) - (T)40°C / 75%RH uncovered Stress (T / H) (T) - T40°C / 75%RH closed Accelerated T (T) - (T)50°C / 75%RH uncovered Stress (T / H) (T) T60°C / 75%RH closed Stress (T) T (T)Key:T= Tested for appearance, assay & related substances, discriminating dissolution, water content by KF, and form check by XRPD(T)= Optional testingResults are reported in Table 7, Table 8 and Table 9.Table 7: Result for Appearance, assay and water content of small scale 10mg ezetimibe and 5mg obicetrapib Appearance Assay AssayStorage Water Content Time point Visual Obicetrapib EzetimibeBatch # conditions (%w / w)(weeks) inspection (%claim) (%ClaimP(°C / %RH)White roundA4459 / 05 / 05 Initial 100.2 101.4 4.99tabletsMCC: Lactose = 60°C / 75% RH Off-white round2 weeks 99.3 101.7 5.25 24.9: 49.9 Packaged tabletsProcess condition 1 50°C / 75% RH Consistent with3 weeks 99.8 100.5 6.40- high impeller exposed T=2wspeed & 3 min wet 40°C / 75% RH Consistent withmassing 4 weeks 99.7 102.7 7.04exposed T=2wWhite roundA4459 / 05 / 06 Initial 101.5 102.3 4.53tabletsMCC: Lactose = 60°C / 75% RH Off-white round2 weeks 101.6 103.2 5.02 24.9: 49.9 Packaged tabletsProcess condition 2 50°C / 75% RH Consistent with3 weeks 102.1 101.8 6.51- low impeller speed exposed T=2w& 1 min wet 40°C / 75% RH Consistent withmassing 4 weeks 101.1 103.2 6.86exposed T=2wWhite roundA4459 / 05 / 07 Initial 99.5 98.4 4.50tabletsMCC: Lactose = 60°C / 75% RH Off-white round2 weeks 98.8 99.2 4.9549.9: 24.9 Packaged tabletsProcess condition 1 50°C / 75% RH Consistent with3 weeks 98.9 98.7 7.01- high impeller exposed T=2wspeed & 3 min wet 40°C / 75% RH Consistent withmassing 4 weeks 98.5 100.4 7.48exposed T=2wA4459 / 05 / 08 White roundInitial 98.5 99.2 4.41tabletsMCC: Lactose = 60°C / 75% RH Off-white round 98.3 4.9149.9: 24.9 2 weeks 101.1Packaged tabletsProcess condition2 - 50°C / 75% RH Consistent with3 weeks 99.0 99.5 7.07 low impeller speed exposed T=2w& 1 min wet 40°C / 75% RH Consistent with 98.4 101.3 7.43massing 4 weeksexposed T=2wTable 8.Table 8: Impurities profile of small scale 10mg ezetimibe and 5mg obicetrapib Obicetrapib related impurities Ezetimibe related impurities StorageTimeconditiopoint Total Total Batch # ns(wee MON Impurit Impurit (°C / %R IMP RRT IMP RRT IMP RRT FR IMP RRT IMP RRT ks) 0.47 0.50 0.94 OL O-BN ies 1.50 2.08 ies H) FREE (>0.05 (>0.05%) %) A4459 / 05N. D. N. D. 0.05 0.05 0.17 0.27 N. D. N. D. <0.05% / 05 InitialMCC: 60°C / 752Lactose = %RHweek N. D. N. D. 0.07 0.06 0.16 0.29 0.53 0.38 0.91 24.9: Package49.9 sdProcesscondition1 - high 50°C / 75 3impeller %RH week 0.05 0.06 0.07 0.06 0.17 0.40 1.25 0.10 1.35 speed & exposed s3 min wetmassing40°C / 75 4%RH week N. D. N. D. 0.08 0.06 0.17 0.31 0.26 0.08 0.33 exposed sA4459 / 05N. D. N. D. 0.05 0.05 0.17 0.27 N. D. N. D. <0.05% / 06 InitialMCC: 60°C / 752Lactose = %RH24.9: week N. D. N. D. 0.07 0.06 0.17 0.31 0.06 0.20 0.26 Package49.9 sdProcesscondition2 - low 50°C / 75 3impeller %RH week <0.05% 0.06 0.07 0.06 0.17 0.35 1.19 0.10 1.29 speed & exposed s1 min wetmassing40°C / 75 4%RH week N. D. N. D. 0.08 0.06 0.16 0.31 0.23 0.09 0.32 exposed sObicetrapib related impurities Ezetimibe related impurities StorageTimeconditio Total Total Batch # pointns(wee IMP RRT IMP RRT IMP RRT MON Impurit IMP R Impurit (°C / %R FR RT IMP RRT ks) O-BN ies ies H) 0.47 0.50 0.94 OL 1.50 2.08 FREE (>0.05 (>0.05 %) %) A4459 / 05N. D. N. D. 0.05 0.05 0.17 0.27 N. D. N. D. Initial <0.05% / 0760°C / 75 MCC: 2%RH Lactose = week N. D. N. D. 0.07 0.06 0.16 0.29 0.05 0.17 0.23 49.9: Package s 24.9 dProcesscondition1 - high 50°C / 75 3impeller %RH week N. D. N. D. 0.05 0.05 0.17 0.24 0.53 0.10 0.63 speed & exposed s3 min wetmassing40°C / 75 4%RH week N. D. N. D. 0.09 0.06 0.16 0.31 0.08 0.08 0.16 exposed sA4459 / 05N. D. N. D. 0.05 0.05 0.17 0.26 N. D. N. D. <0.05% Initial / 0860°C / 75 MCC: 2%RH Lactose = week N. D. N. D. 0.07 0.06 0.16 0.30 N. D. 0.15 0.15 49.9: Packages 24.9 dProcesscondition2 - low 50°C / 75 3impeller %RH week N. D. N. D. 0.07 0.06 0.16 0.30 0.50 0.10 0.60 speed & exposed s1 min wetmassing40°C / 75 4%RH week N. D. N. D. 0.08 0.06 0.16 0.30 0.08 0.09 0.18 exposed sTable 9Table 9: Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stabilityManufacturing lot A4459 / 05 / 05 A4459 / 05 / 06 numberProcess condition 1 - high impeller speed & 3 min wet 2 - low impeller speed & 1 min wet massing massingTime point and storage Initia 2 weeks 3 weeks 4 weeks - Initia 2 weeks 3 weeks 4 weeks - conditions 1 40°C / 75% 1 40°C / 75%60°C / 75 50°C / 75 RH packed 60°C / 75 50°C / 75 RH packed % RH % RH % RH % RHPackage exposed Package exposed d dTest Method Resu Result Result Result Resu Result Result Result lt ltObicetra (n=6 (n=3) (n=3) (n=3) (n=6 (n=3) (n=3) (n=3) pib ) )5 min7 20 26 30Average 9 9 7 25 (6 - (15 - (26 - (29 - (Min (9 - 10) (7 - 10) (6 - 9) (23 - 28) Max) 8) 25) 27)a 31)10 min17 19 19 49 51 45Average 22 54 (16 - (18 - (17 - (40 - (48 - (45 - (Min (20 - 24) (52 - 55)20) 46)Max) Discriminat 19) 21) 57) 52)15 min ing method33 40 34 73 6Average at pH 35 8 56 686.80.2 (31 - (38 - (32 - (70 - (67 - (55 - (Min (31 - 38) (63 - 72)36) 70) 56)Max) %w / v of 35) 41) 76)Tween 80,30 min 50 rpm 53 58 51 97 89 71Average 63 93 paddle (51 - (56 - (51 - (96 - (89 - (70 - (Min (61 - 65) (86 - 103) speed and 56) 99) 89) 73) Max) 59) 51)900 mL45 min vessel 10564 73 60 104 77 105 Average volume 75 (104(63 - (70 - (60 - (103 - (76 - (101 - (Min (73 - 77)68) 105) 77) 112) Max) 75) 61) 106)60 min 10872 81 66 102 82Average 84 (106 99 (70 - (78 - (66 - (98 - (81 - (Min (83 - 85) (97 - 102)73) 83) 107) 85)Max) 67) 110)70 min 10879 84 71 108 83 110 Average 88 (107(78 - (82 - (71 - (97 - (81 - (106 - (Min (87 - 89)85) 72) 118) 84) 117) Max) 81) 109)Time point and storage Initia 2 weeks 3 weeks 4 weeks - Initia 2 weeks 3 weeks 4 weeks - conditions 1 40°C / 75% 1 40°C / 75%60°C / 75 50°C / 75 RH packed 60°C / 75 50°C / 75 RH packed % RH % RH % RH % RHPackage exposed Package exposed d dTest Method Resu Result Result Result Resu Result Result Result lt ltEzetimib Discriminat (n=6 (n=3) (n=3) (n=3) (n=6 (n=3) (n=3) (n=3)e ing method ) )Table 9: Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stabilityManufacturing lot A4459 / 05 / 05 A4459 / 05 / 06 numberProcess condition 1 - high impeller speed & 3 min wet 2 - low impeller speed & 1 min wet massing massing5 min at pH 3 32 7 136.80.2 10 7 Average (3 - 3) (2 - 3)(2 (13- (Min %w / v of - (5 - (9- 10) (6 - 8) Max) Tween 80, 2) 9) 14)10 min 50 rpm 5 5 5paddl 5 18 25 15 Average e (5 - 5) (4 - 6) (5 - 6) 15 (Min speed and (4 - (15 - (24 - (14 - (14 - 16)6) 22) 26)Max) 900 mL 16)15 min vessel 11 9 8volume 9 28 34 19 Average (lO - (8 - 10)(8 - (7 - 9) 21 (27 - (33 - (19 - (Min (20 - 22) ll) 29) 20) 35) 10) Max)30 min 15 14 1616 40 45 26(13 - 31 Average (15 - 17) (15 - (15 - (39 - (44 - (26 - (Min (28 - 34) 15) 15) 42) 26) 45) 18) Max)145 min 20 18 2019 47 52 30(19 - (17 - (19 - 21) 38 Average (19 - (SO (45 - (51 - (Min 20) (37 - 40) 18) 50) SO) 53) 21) Max)60 min 22 20 2422 52 51 35(22 - (20 - (23 - 25) 39 Average (49 - (35 - (21 - (51 - (Min 23) 20) (39 - 40) 23) 54) 54) 35) Max)70 min 25 24 2927 58 54 40(23 - (27 - 30) 49 Average (25 - (26 - (49 - (38 - (57 - (Min 26) 24) (47 - 52) 27) 59) 61) 41) Max)Prototype Initia 2 weeks 3 weeks 4 weeks - Initia 2 weeks 3 weeks 4 weeks - 1 40°C / 75%R 1 40°C / 75%R 60°C / 75 50°C / 75 60°C / 75 50°C / 75 H packed H packed % RH % RH % RH % RHPackage exposed Package exposedd d(n=6 (n=3 (n=3) (n=3) (n=3) (n=3) (n=3) (n=3) Ezetimib Dissolutione method ) )15 min based on 11 26 22 277 11 9 29 Average USP (11 - (22 - (27 - (25 - (Min (8 - 10) (28 - 29) (7 - 7) method (9 - 13) 26) 23) 27) 12) Max) conditionsat pH 4.5, 30 min19 17 22 41 34 3950 rpm 20 41 Average (18 - (17 - (40 - (33 - (39 - (21 - (Min paddle (19 - 21) (40 - 42)24) 40) 35) 19) 18) 41) Max) speed and500 mL 45 min24 23 28 51 43 48 vessel 27 49 Average (23 - (23 - (27 - (50 - (42 - (47 - volume (Min (25 - 28) (48 - 50) 25) 24) 30) 44) 50) 51) Max)Table 9: Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stabilityManufacturing lot A4459 / 05 / 05 A4459 / 05 / 06 numberProcess condition 1 - high impeller speed & 3 min wet 2 - low impeller speed & 1 min wet massing massing60 min29 28 33 57 49 53Average 32 55 (27 - (27 - (31 - (57 - (48 - (52 - (Min (30 - 34) (55 - 56) Max) 29) 29) 35) 58) 50) 53)70 min38 35 39 67 59 62Average 42 67 (36 - (34 - (38 - (66 - (59 - (62 - (Min (40 - 44) (67 - 67)40) 36) 40) 68) 60) 63)Max)Manufacturing lot A4459 / 05 / 07 A4459 / 05 / 08 numberProcess condition 1 - high impeller speed & 3 min wet 2 - low impeller speed & 1 min wet massing massingTime point and storage Initia 2 weeks 3 weeks 4 weeks - Initia 2 weeks 3 weeks 4 weeks - conditions 1 40°C / 75% 1 40°C / 75%60°C / 75 50°C / 75 RH packed 60°C / 75 50°C / 75 RH packed % RH % RH % RH % RHPackage exposed Package exposed d dTest Method Resu Result Result Result Resu Result Result Result lt ltObicetra (n=6 (n=3) (n=3) (n=3) (n=6 (n=3) (n=3) (n=3) pib ) )5 min22 24 49 36 35 61Average 30 54 (20 - (24 - (47 - (29 - (35 - (se (Min (27 - 32) (46 - 61)26) 36) es)Max) 25) 51) 41)10 min57 52 75Aver Discriminat 73 65 85age 67 81 (52 - (48 - (73 - (65 - (58 - (82 - (Min ing method (62 - 71) (78 - 86) Max) at pH 61) 55) 78) 77) 70) 86)6.80.215 min%w / v of 80 71 84 91 82 93 Average 84 92 Tween 80, (79 - (67 - (83 - (89 - (80 - (90 - (Min (83 - 89) (91 - 94)50 rpm 82) 73) 85) 93) 84)Max) 95)paddle30 min speed and 98 84 96 102 101 94 100 111 Average 900 mL (97 - (80 - (96 - (100 - (98 - (94 - (99 - (103 - (Min vessel 100) 86) 97) 105) 105) 102) 117) Max) 95)volume45 min 103101 90 98 98 101 Average 104 (100 103 (99 - (89 - (97 - (97 - (100 - (Min (96 - 111) (99 - 109)103) 99) 99) 102)Max) 91) 107)60 min 10195 99 100 99 100 Average (100 103 102 (94 - (98 - (97 - (98 - (99 - (Min (98 - 107) (99 - 104)99) 110) 100) 101)Max) 103) 95)Table 9: Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stabilityManufacturing lot A4459 / 05 / 05 A4459 / 05 / 06 numberProcess condition 1 - high impeller speed & 3 min wet 2 - low impeller speed & 1 min wet massing massing70 min 10199 99 109 101 101 100 114 Average (100(98 - (98 - (106 - (98 - (99 - (100 - (Min (112 - Max) 103) 100) 99) 113) 105) 102) 101) 117) Time point and storage Initia 2 weeks 3 weeks 4 weeks - Initia 2 weeks 3 weeks 4 weeks - conditions 1 40°C / 75% 1 40°C / 75%60°C / 75 50°C / 75 RH packed 60°C / 75 50°C / 75 RH packed % RH % RH % RH % RHPackage exposed Package exposed d dTest Method Resu Result Result Result Resu Result Result Result lt ltEzetimib (n=6 (n=3) (n=3) (n=3) (n=6 (n=3) (n=3) (n=3) e ) )5 min6 12 15 11 19Average 6 6 15 (5 - (11 - (12 - (18 - (Min (6 - 7) (5 - 7) (Il (13 - 18) Max) 7) 13) 17) li) 21)10 min17 13 21A 16 33 22 31verage 28 (16 - (12 - (20 - (28 - (20 - (29 - (Min (26 - 29)22) (15 - 17)Max) Discriminat 18) 15) 35) 24) 33)15 min ing methodat pH 26 20 26 45 33 40 Average 24 386.80. (25 - (19 - (26 - (43 - (31 - (37 - (Min 2 (24 - 24) (38 - 40)27)a %w / v of 21) 28) 48)M x) 34) 43)Tween 80,30 min 50 rpm 40 30 37 63 46 54Average 39 60 paddle (39 - (28 - (36 - (61 - (46 - (Min (37 - 40) (52 - (56 - 63) speed and 38) 64) 47) 56) Max) 41) 31)900 mL45 min vessel 49 38 45 73 57 63Average volume 47 66 (47 - (36 - (44 - (70 - (56 - (62 - (Min (43 - 51) (64 - 69) Max) 50) 39) 47) 77) 59) 65)60 min55 45 51 76 64 68Average 53 71 (53 - (44 - (50 - (73 - (63 - (67 - (Min (51 - 55) (67 - 74)56) 84) 66) 60)Max) 45) 52)70 min61 52 57 84 72 76Average 62 86 (60 - (52 - (56 - (82 - (71 - (75 - (Min (60 - 65) (84 - 88)62) 58) 88) 73) 78)Max) 53)Table 9: Results of the dissolution characterization of small scale 10mg ezetimibe and 5mg obicetrapib stress stabilityManufacturing lot A4459 / 05 / 05 A4459 / 05 / 06 numberProcess condition 1 - high impeller speed & 3 min wet 2 - low impeller speed & 1 min wet massing massing Prototype Initia 2 weeks 3 weeks 4 weeks - Initia 2 weeks 3 weeks 4 weeks - 1 40°C / 75%R 1 40°C / 75%R 60°C / 75 50°C / 75 H packed 60°C / 75 50°C / 75 H packed % RH % RH % RH % RHPackage exposed Package exposedd dEzetimib (n=3 (n=3) (n=3) (n=3) (n=3 (n=3) (n=3) (n=3) e ) )15 min29 26 31 46 42 43Average 32 45 (28 - (24 - (29 - (42 - (37 - (43 - (Min Dissolution (28 - 34) (42 - 47)27) 33) 49) 44)Max) met o 31) 45)h d30 min based on 42 40 46 59 59 60Average USP 44 59 (41 - (39 - (44 - (55 - (55 - (59 - (Min method (41 - 46) (57 - 59)43) 41) 49) 61) 60)Max) conditions 61)45 min at pH 4.5,49 49 54 65 67 67Average 50 rpm 51 66 (Min paddle (49 - (47 - (52 - (49 - 54) (62 - (65 - (66 - (65 - 66)50) 50) 58) 70) 68)Max) speed and 67)60 min 500 mLAverage vessel 55 55 61 69 74 7358 70 volume (55 - (53 - (58 - (67 - (71 - (72 - (Min (55 - 60) (70 - 70)55) 56) 65) 73)Max) 71) 76)70 min71 69 73 86 87 87Average 71 86 (71 - (67 - (72 - (85 - (85 - (87 - (Min (69 - 72) (86 - 86)70) 87) 88) 88)Max) 71) 75)Physical properties characterization

[0323] With exception of prototype tablet A4459 / 05 / 05 in which the small presence of EZE hydrate is observed in the initial time point sample and in all the samples placed on stability, for the other tablets prototypes a small amount of the EZE hydrate form appears at the 3WK and 4WK time points. XRPD data are summarized in Table 10.Table 10: XRPD data summary of small scale 10mg ezetimibe and 5mg obicetrapib tablets stress stabilitySample Batch ID XRPDPrototype 1 condition 1 A4459 / 05 / 05 Initial OBI + EZE Anhydrous +small EZETablet HydrateA4459 / 05 / 052WK@60 / 75 OBI + EZE Anhydrous +small EZEpack HydrateA4459 / 05 / 053WK@50 / 75 OBI + EZE Anhydrous +small EZEexposed HydrateA4459 / 05 / 054WK@40 / 75 OBI + EZE Anhydrous +small EZEexposed HydratePrototype 1 condition 2 A4459 / 05 / 06 Initial OBI + EZE AnhydrousTablet A4459 / 05 / 062WK@60 / 75 OBI + EZE AnhydrouspackA4459 / 05 / 063WK@50 / 75 OBI + EZE Anhydrous +small EZEexposed HydrateA4459 / 05 / 064WK@40 / 75 OBI + EZE Anhydrous +small EZEexposed HydratePrototype 2 condition 1 A4459 / 05 / 07 Initial OBI + EZE AnhydrousTablet A4459 / 05 / 072WK@60 / 75 OBI + EZE AnhydrouspackA4459 / 05 / 073WK@50 / 75 OBI + EZE Anhydrous +small EZEexposed HydrateA4459 / 05 / 074WK@40 / 75 OBI + EZE Anhydrous +small EZEexposed HydratePrototype condition 2 A4459 / 05 / 08 Initial OBI + EZE AnhydrousTablet A4459 / 05 / 082WK@60 / 75 OBI + EZE AnhydrouspackA4459 / 05 / 083WK@50 / 75 OBI + EZE Anhydrous +small EZEexposed HydrateA4459 / 05 / 084WK@40 / 75 OBI + EZE Anhydrous +small EZEexposed Hydrate8.4. Example 2: Fixed dose combination for 10 mg ezetimibe and 10 mg obicetrapib tablets (small scale batch ~500 g)

[0324] The details of the prototype formulations manufactured in this set of experiments are summarised in Table 11 and Table 12. A key amendment in the formulation composition was the increment of dose strength of obicetrapib (free acid) from 5.0 mg to 10.0 mg.8.4.1. High shear granulation and fluid bed drying

[0325] These trials were executed as small-scale batches (500 g batch size) according to process condition 2. However, batch A4459 / 16 / 02 (known as “prototype C scale-up”) was executed at 2 Kg batch size scale.

[0326] The powders were sieved manually, loaded into the granulation bowl and mixed for 5 mins. The granulation solution was sprayed at the required spray rate and wet massing was conducted prior to drying the material in a fluid bed drier. The inlet air temperature and the airvolume was adjusted as required to fluidise the granule that was dried until its LOD was equal or lower than the initial LOD. The granules were characterised as for content uniformity of APIs, LOD (soon after milling), sieve analysis, TBD and XRPD. The granule batch A4459 / 13 / 01 (prototype A) and batch A4459 / 16 / 02 (prototype C scale-up) were divided in two aliquots to manufacture the final blends required to generate the 150 mg tablet and the 200 mg tablet.8.4.2. Preparation of the final blend, tableting and coating

[0327] The final blend was prepared by weighing accurately the extra-granular excipients to manufacture tablets with the required composition. The excipients were manually sieved and a bin of suitable volume was used for mixing. The lubricant (MgSt) was sieved separately, added to the bowl and mixed. A single punch compression machine was used to generate a compression profile and manufacture a small-scale batch of tablets. The friability, disintegration time, hardness, appearance and thickness of the tablets was monitored throughout processing. The tablets were tested for discriminating dissolution, ezetimibe USP tablet dissolution method and XRPD.

[0328] Three selected tablet batches (prototype B, prototype C scale-up and prototype C scale-up 200) were coated using a 20% w / w Opadry AMB II white aqueous suspension. The coating process parameters as well as the weight gain of the tablets were monitored throughout processing. The coated tablets were tested for XRPD, discriminating dissolution for obicetrapib, ezetimibe USP tablet dissolution method and ezetimibe USP tablet dissolution method with 75 rpm paddle speed.

[0329] All the intermediates of production and the final drug product were stored in double LDPE bags closed with cable ties and transferred into a thermosealed aluminium bag containing silica.Table 11: Composition (%w / w) of granule and tablet of small scale 10 mg ezetimibe 10 mg obicetrapibPrototypePrototype A Prototype B Prototype C Prototype A200DI D2CoatedGranule Tablet Granule Tablet Granule Tablet Granule Granule Granule Tablet tabletTable 11: Composition (%w / w) of granule and tablet of small scale 10 mg ezetimibe 10 mg obicetrapibA / / 44591301 A / / 44591602Ezetimibe 6.981 6 A / / 44591401. A / / 44591603667 6.981 6.667 6.667 6.981 6.667 6.981 6.981 6.981 5.000 Obicetrapib 7.162 6.840 7.162 6.840 6.840 7.162 6.840 7.162 7.162 7.162 5.130 Avicel PH 20.935 19.993 21 A / / 44591302.982 20.993 20.993 21.982 20.993 21.982 21.982 20.935 14.99557.592 55.000 57. A / / 44591902592 55.000 55.000 57.592 55.000 57.592 57.592 57.592 41.250 PharmatoseKollidon 30 1.047 1.000 1.047 1.000 1.000 1.047 1.000 1.047 1.047 1.047 0.750(in)* (in)* (in)* ( A / / i44591402n) A / / 44591701* (in)* (in)* (in)* (out)* (out)* (in)* (in)* Glycolys 4.189 4.000 4.189 4.000 4.000 4.189 4.000 4.189 4.189 4.189 3.000 Kolliphor 2.094 2.000 1.047 1.000 1.000 1.047 1.000 1.047 1.047 2.094 1.500A / / 44591901MilliQ 20.000+ N / A 20.000 N / A N / A 20.000 20.000A / / 44591801 N / A 20.000 5.000 ** N / A water * 5.000 + 5.000 + +100.000 95.500 100.000 95.500 95.500 100.000 95.500 100.000 100.000 100.000 71.625 Total A / / 44591303N / A N / A N / A N / A N / A N / A N / A N / A N / A N / A 10.437 Avicel PHA / / 44591702 N / A N / A N / A N / A N / A N / A N / A N / A N / A N / A 10.438 PharmatoseA / / 44591403 Kollidon 30 N / A N / A N / A N / A N / A N / A N / A N / A N / A N / A 3.000 N / A 4.000 N / A 4.000 4.000 N / A 4.000 N / A N / A N / A 4.000 GlycolysA / / 44591802 N / A 0.500 N / A 0.500 0.500 N / A 0.500 N / A N / A N / A 0.500 Ligamed A / / 44591304Opadry N / A N / A N / A N / A 3.000 N / A N / A N / A N / A N / A N / A 100.000 100.000 100.000 100.000 103.000 100.000 100.000 100.000 100.000 100.000 100.000 TotalA / / 44591602 * Water does not appear in the tablet; in = material added as a dry powder, out = material solubilised in the water for A / / 44591305granulation; ** Lower quantity added due to an issue with the equipmentA / / 44591803A / / 44591301Table 12 Composition (%w / w) of granule and tablet of 10 mg ezetimibe and 10 mg obicetrapib A / / 44591903 Prototype C (2% A / / 44591404 Scale-up Prototype C Prototype D Prototype C scale-up 200 w / w SLS)Coated Coated Granule Tablet Granule Tablet Granule Tablet Granule Tablet tablet tablet6.981 6.632 6.632 6.981 6.667 6.981 6.667 6.981 5.000 5.000 Ezetimibe7.162 6.804 6.804 7.162 6.840 7.162 6.840 7.162 5.130 5.130 Obicetrapib21.982 20.883 20.883 20.935 19.993 21.982 20.993 21.982 15.745 15.745 Avicel PH57.592 54.712 54.712 57.592 55.000 57.592 55.000 57.592 41.250 41.250 PharmatoseTable 12 Composition (%w / w) of granule and tablet of 10 mg ezetimibe and 10 mg obicetrapib Kollidon 30 1.047 0.995 0.995 1.047 1.000 (in)* 1.047 1.000 1.047 0.750 0.750 Glycolys 4.189 3.980 3.980 4.189 4.000 4.189 4.000 4.189 3.000 3.000 Kolliphor 1.047 0.995 0.995 2.094 2.000 (in)* 1.047 1.000 1.047 0.750 0.750 MilliQ water 20.000 N / A N / A 20.000 N / A 20.000 + N / A 20.000 + N / A N / A + 5.000 + 5.000Total 100.000 95.001 95.001 100.000 95.500 100.000 95.500 100.000 71.625 71.625 Avicel PH N / A N / A N / A N / A N / A N / A N / A N / A 10.437 10.437 Pharmatose N / A N / A N / A N / A N / A N / A N / A N / A 10.438 10.438 Kollidon 30 N / A N / A N / A N / A N / A N / A N / A N / A 3.000 3.000 Glycolys N / A 4.000 4.000 N / A 4.000 N / A 4.000 N / A 4.000 4.000 Ligamed N / A 1.000 1.000 N / A 0.500 N / A 0.500 N / A 0.500 0.500 Opadry N / A N / A 3.000 N / A N / A N / A N / A N / A N / A 3.000 Total 100.000 100.001 103.001 100.000 100.000 100.000 100.000 100.000 100.000 103.000* Water does not appear in the tablet; in = material added as a dry powder, out = material solubilised in the water for granulation8.4.3. Results:These granulation trials were conducted successfully. Overall, the granules presented a PSD similar to that of batch A4459 / 08 / 01 (prototype 4) and showed a relatively large quantity of fine particles (Figure 18). In comparison to batch A4459 / 08 / 02 (prototype 4, condition 2), the tablet batches presented comparable time of disintegration and higher hardness and lower friability values for similar compression forces. The tablets did not present any critical defects (e.g., capping, lamination). The coated tablets presented a smooth and white surface without any visual cosmetic defects upon close inspection.8.4.4. Granules characterization8.4.4. I. Chemical characterization analysis

[0330] The granules were tested for homogeneity of both obicetrapib and ezetimibe, results are reported in Table 13. Analysis were performed on n=6 except for scale up batch performed with n=10.Table 13: Granule uniformity of 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes A4459 / 13 / 01 A4459 / 13 / 02 A4459 / 13 / 03 A4459 / 16 / 02 A4459 / 17 / 01 A4459 / 17 / 02 Prototype A Prototype B Prototype C Prototype C PrototypeScale-up C2% SLS Prototype D Ezeti Obi Ezetim Obi Ezetim Obi Ezetim Obi Ezetim Obi Ezetim Obimibe cetr ibe cetr ibe cetr ibe cetr ibe cetr ibe cetrTable 13: Granule uniformity of 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes (%C1 apib (%Clai apib (%Clai apib (%Clai apib (%Clai apib (%Clai apib aim) (%c m) (%c m) (%c m) (%c m) (%c m) (%c laim laim laim laim laim laim ) ) ) ) ) ) Sam 100. 102.105.6 101.2 97.8 104.0 99.1 102.3 98.4 106.6 103.6 98.6 #1 1 1Sam 100. 100. 101.103.2 97.9 100.4 96.1 105.3 102.8 106.2 103.8 99.0 #2 3 2 4Sam 100. 100. 100.106.2 99.6 95.5 105.2 103.2 98.9 104.3 104.4 99.5 #3 8 5 1Sam 101. 100.100.3 94.5 97.3 92.6 106.4 101.8 98.0 102.1 98.0 105.1 #4 5 0 Sam102.1 96.4 97.9 93.5 104.9 99.9 102.2 98.6 99.6 95.7 103.4 98.3 #5Sam 100. 100.105.1 99.4 99.7 95.8 105.0 101.6 97.9 100.0 96.3 105.4 #6 1 7 Sam- - - - - - 100.8 97.5 - - - - #7Sam- - - - - - 101.1 97.2 - - - - #8Sam- - - - - - 100.8 97.0 - - - - #9Sam- - - - - - 100.2 96.7 - - - - #10Mea 100.103.8 98.2 99.3 95.2 105.1 101.7 98.0 103.1 98.9 104.3 99.4 n 2RSD2.2 2.47 1.5 2.0 0.7 0.8 0.9 3.4 3.0 2.7 0.8 0.9%Physical properties characterization

[0331] XRPD data of the development prototypes are summarized in Table 14. EZE hydrate can be observed in samples before the granulation process or during the granulation. However, the amount of EZE hydrate detected appears always to be very limited.Table 14: XRPD data summary 10 mg ezetimibe and 10 mg (free acid) obicetrapib development prototypes Sample Batch ID XRPDPrototype A Blend OBI + EZE AnhydrousPrototype A Wet Granules A4459 / 13 / 01 OBI + EZE Anhydrous + some EZE Hydrate Prototype A Dry Granules OBI + EZE Anhydrous + some EZE Hydrate Prototype B Blend OBI + EZE AnhydrousPrototype B Wet Granules A4459 / 13 / 02 OBI + EZE Anhydrous +small EZE Hydrate Prototype B Dry Granules OBI + EZE Anhydrous +small EZE Hydrate Prototype C Blend OBI + EZE AnhydrousPrototype C Wet Granules A4459 / 13 / 03 OBI + EZE Anhydrous +small EZE Hydrate Prototype C Dry Granules OBI + EZE AnhydrousPrototype C Scale-up Blend OBI + EZE Anhydrous +small EZE Hydrate Prototype C Scale-up Wet Granules OBI + EZE Anhydrous +small EZE Hydrate A4459 / 16 / 02Prototype C Scale-up Dry Granules OBI + EZE AnhydrousPrototype C 2% SLS Blend OBI + EZE AnhydrousPrototype C 2% SLS Wet Granules A4459 / 17 / 01 OBI + EZE Anhydrous +small EZE Hydrate Prototype C 2% SLS Dry Granules OBI + EZE Anhydrous +small EZE Hydrate Prototype D Blend OBI + EZE Anhydrous +small EZE Hydrate Prototype D Wet Granules A4459 / 17 / 02 OBI + EZE Anhydrous +small EZE HydratePrototype D Dry Granules OBI + EZE AnhydrousTablets characterizationChemical characterization Analysis

[0332] Results for the characterization of the small scale batches are reported in Table 15.Prototypes were tested for dissolution. The dissolution results for obicetrapib showed similar profiles for all the prototypes tested with small differences deemed to be analytical variability. For ezetimibe most promising results were obtained for prototypes D and C which obtained promising results with prototypes C meeting the USP specification of Q=80+5 at 30 minutes, on three vessel. This most promising prototypes were also characterized with USP dissolution method conditions for ezetimibe at the higher paddle speed of 75 rpm. This was due since it was highlighted that the USP method, developed for a lighter tablet comparing to the developed fixed dose combination, appeared to be overdiscriminating for tablets with target weight up to 200 mg. The results showed profiles consistent with that currently commercialized formulation.Table 15: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) _Manufacturing lot A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 number 4 / 01 4 / 04 4 / 02 4 / 03 6 / 03 8 / 03 8 / 01 8 / 02 Prototype Prototy Prototy Prototy Prototy Prototy Prototy Prototy Prototy pe A pe A pe B pe C pe C pe C pe C pe D 200 scale-up scale-up 2% SLS200Test Method Result Result Result Result Result Result Result Result DissolutionObicetrapib5 min 52 75 74 58 72 58 8046Average (47 - (68 - (71 - (53 - (70 - (51 - (77 - (43 - (Min 63) 73) 64) 86)50) 54) 81) 75)Max)10 min 83 99 102 88 93 91 10085Average (82 - (96 - (101 - (85 - (93 - (87 - (98 - (Min Discrimin (83 - 84) 101) 102) 90) 93) 93) 104) 88)Max) ating15 min method at 96 103 106 96 98 97 103 pH 6.80.2 95Average (95 - (102 - (105 - (95 - (97 - (94 - (101 - (Min %w / v of (95 - 97) 104) 108) 97) 100) 100) 106) Max) Tween 96)80, 5030 min rpm 109 104 109 103 104 102 105107Average (107 - (103 - (107 - (102 - (102 - (101 - (101 - paddle (107 - (Min 110) 105) 105) 105) 104) 108) speed and 108) 111)Max) 900 mL45 min vessel 109 103 108 103 104 100 102109Average volume (109 - (100 - (106 - (102 - (102 - (99 - (101 - (108 - (Min 110) 104) 109) 104) 105) 102) 104)109)Max)60 min 109 101 107 103 103 99 102108Average (108 - (100 - (105 - (103 - (103 - (98 - (100 - (107 - (Min 110) 103) 108) 103) 104) 100) 104)108)Max)70 min 108 101 106 102 103 98 101106Average (107 - (99 - (105 - (102 - (103 - (97 - (100 - (106 - (Min 107) 108) 103) 107) 103) 104) 99) 103) Max)Dissolut Dissolutiion onEzetimi methodbe based on(n=3) USP15 min method 41 44 67 76 73 68 68 79 Average condition(40 - (41 - (65 - (75 - (70 - (65 - (66 - (74 - (Min s at pH69) 70) 86) Max) 4.5, 50 43) 45) 76) 76) 71)30 min rpm58 55 82 86 86 79 79 8 Average paddle 8(55 - (52 - (8(Min speed and 0 - (85 - (84 - (79 - (77 - (84 - 60) 84) 88) 87) 80Max) 500 mL 57) 81) ) 94)Table 15: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) _Manufacturing lot A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 A4459 / 1 number 4 / 01 4 / 04 4 / 02 4 / 03 6 / 03 8 / 03 8 / 01 8 / 02 45 min vessel 67 66 88 92 92 84 84 90 Average volume (64 - (62 - (86 - (90 - (92 - (82 - (82 - (87 - (Min69) 89) 94) 93) 86) 84)Max) 67) 95) 60 min73 73 92 95 95 86 86 92 Average (71 - (69 - (90 - (93 - (93 - (84 - (85 - (90 - (Min77) 94) 97) 97) 88) 88) 96) Max) 76)70 min83 84 102 106 102 98 97 102 Average (80 - (101 - (105 - (102 - (98 - (96 - (100 - (Min (80 - 86) 87) 103) 106) 102) 98) 98) 104) Max)DissolutionEzetimibe(n=3)15 min Dissoluti 87 86 89 88 94 Average on(Min - - - (85 - (84 - (88 - (86 - (93 - method 89) 88) 89) 90) 96) Max) based on30 min USP 100 96 96 97 101 Average method - - - (98 - (93 - (95 - (96 - (99 - (Min condition 101) 98) 97) 99) 103) Max) s at pH45 min 4.5, 75r 104 99 99 100 103 Average pm- - - (102 - (97 - (99 - (99 - (101 - (Min paddle106) 101) 99) 101) 105) Max) speed and60 min 500 mL106 101 101 101 103 Average vessel- - - (105 - (99 - (100 - (100 - (101 - (Min volume108) 102) 101) 102) 105) Max)70 min108 104 103 102 104 Average - - - (106 - (102 - (102 - (101 - (101 - (Min109) 106) 103) 104) 105)Max)Physical properties characterization

[0333] All the tablets of small scale prototypes produced presented small amount of EZE hydrate with exception of the Prototype C and C scale up 200mg batches as reported in Table 16.Table 16: XRPD data summary of small scale tablets prototype batchesSample Batch ID XRPDTablet Prototype A A4459 / 14 / 01 OBI + EZE Anhydrous +small EZE HydrateTablet Prototype A 200mg A4459 / 14 / 04 OBI + EZE Anhydrous +small EZE HydrateTablet Prototype B A4459 / 14 / 02 OBI + EZE Anhydrous +small EZE HydrateTablet Prototype C A4459 / 14 / 03 OBI + EZE AnhydrousTablet Prototype C scale up A4459 / 16 / 03 OBI + EZE AnhydrousTablet Prototype C scale up A4459 / 18 / 03 OBI + EZE Anhydrous +small EZE Hydrate200mgTablet Prototype C 2% SLS A4459 / 18 / 01 OBI + EZE Anhydrous +small EZE HydrateTablet Prototype D A4459 / 18 / 02 OBI + EZE Anhydrous +small EZE HydrateStress Stability

[0334] Based on the process tableting parameters and dissolution data, the following tablet prototypes were selected to assess the feasibility of the coating process:A4459 / 16 / 03 (150 mg / tab, prototype C scale-up)A4459 / 18 / 03 (200 mg / tab prototype C scale-up / 200mg),and subsequently set down for stability a stress stability study with the following design. Results are reported in Table 17 and Table 18.Table 17: Stress stability study designStorage Conditions Time (weeks)T / RH Type 0 2 3 425°C / 60%RH Long-term (T) - (T)40°C / 75%RH uncovered Stress (T) T - T40°C / 75%RH closed Accelerated T (T) - (T)40°C / 75%RH closed withStress (T) (T) - (T)desiccantKey:T= Tested for appearance, assay & related substances, Content Uniformity (only at initial) discriminating dissolution, water content by KF, and form check by XRPD(T)= Optional testingTable 18: Results for assay, water content and visual appearance of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) prototype C 200 and prototype C scale-up stress stability Prototype Time point - Storage Assay of Assay of Water AppearanceNo. conditions Ezetimibe Obicetrapib content (visual)(% Claim) (% Claim) (% w / w)Prototype White roundInitial 99.1 101.2 5.1C 200 tabletBN 2 weeks - 40°C / 75%RH 99.4 100.7 7.3 No testedexposedTable 18: Results for assay, water content and visual appearance of small scale 10mg ezetimibeand 10 mg obicetrapib (free acid) prototype C 200 and prototype C scale-up stress stability A4459 / 19 / 4 weeks - 40°C / 75%RH99.6 100.8 7.1 White round03 exposed tablet4 weeks - 40°C / 75%RH100.3 100.5 4.3 No testedpacked4 weeks - 40°C / 75%RHWhite roundpacked 100.6 100.6 3.7tabletWith dessiccantPrototype Initial 97.3 98.4 4.9C scale up 2 weeks - 40°C / 75%RH White roundBN 97.6 98.8 6.6exposed tabletA4459 / 19 / 4 weeks - 40°C / 75%RH02 97.5 98.6 6.8 No testedexposed4 weeks - 40°C / 75%RH98.4 98.4 4.3 White roundpacked tablet4 weeks - 40°C / 75%RHpacked 98.3 98.3 3.6 No testedWith dessiccantTable 19Table 19: Results for impurities profile of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid)_ _ prototype C 200 and prototype C scale-up stress stability _Batch Time Obicetrapib related impurities Ezetimibe related impurities point - IMP_R FRO MON Total IMP_R EZETIMI EZETIMI Total Storage RT L O-BN impurit RT BE BE impurit condition 0.94 (% FREE ies 0.79 CYCLIC KETONE ies (> s (% a / a) a / a) (% (% a / a) (% a / a) (% a / a) (% a / a) 0.05) a / a) (% a / a) Initial 0.08 0.07 0.18 0.33 0.05 N. D. 0.05 0.10 2 weeks - 40°C / 75%0.08 0.07 0.16 0.31 0.05 0.22 0.07 0.33 RHexposed4 weeks - 40°C / 75%0.08 0.06 0.16 0.31 0.05 0.52 0.08 0.65 Prototype RHC 200 exposedBN 4 weeks - A4459 / 19 40°C / 75% / 03 0.06 0.05 0.17 0.28 0.04 N. D 0.05 0.05 RHpacked4 weeks - 40°C / 75%RH0.06 0.05 0.17 0.28 0.04 N. D 0.05 0.05 packedWithdesiccantInitial 0.09 0.07 0.18 0.33 0.05 N. D. 0.05 0.10 PrototypeC scale 2 weeks - 40°C / 75%up 0.08 0.07 0.16 0.31 0.05 0.09 0.06 0.19 BN RHexposedA4459 / 19 4 weeks - / 02 40°C / 75%0.06 0.06 0.17 0.29 0.05 0.22 0.06 0.32 RHexposed4 weeks - 40°C / 75%0.06 0.05 0.17 0.28 0.05 N. D. 0.05 0.10 RHpacked4 weeks - 40°C / 75%RH0.06 0.05 0.17 0.28 0.05 N. D. 0.05 0.10 packedWithdesiccantN. D. = Not DetectedTable 20: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib_ (free acid) prototype C 200 and prototype C scale-up stress stability _ Manufacturing lotPrototype C 200 BN A4459 / 19 / 03 Prototype C scale up BN A4459 / 19 / 02 numberPrototype Initi 2 weeks - 4 weeks - 4 weeks - Initi 2 weeks - 4 weeks - 4 weeks - al 40°C / 75 40°C / 75 40°C / 75 al 40°C / 75 40°C / 75 40°C / 75 %RH %RH %RH %RH %RH %RH exposed packed packed exposed packed packed with with desiccant desiccant Test Method Res Result Result Result Res Result Result Result ult ultObicetr (n=6 (n=6) (n=6) (n=6) (n=6 (n=6) (n=6) (n=6) apib ) )5 min 68 60 73 77 68 69 59 72 Average (67 (55 - 64) (67 - 76) (70 - 81) (65 (66 - 72) (35 -69) (69 - 76) (MinMax) 71) 73)10 min 80 85 95 88 89 84 88 87 Average Discrimin (78 (83 - 87) (93 - 97) (83 - 91) (86 (81 - 87) (81 - 92) (84 -91) (Min atingMax) method at 83) 93)pH 6.80.215 min 88 90 100 94 94 89 94 95 %w / v ofAverage (84 (89 - 91) (98 - (90 - 97) (87 - 93) (91 - 97) (92 - 98)Tween 80, (91(Min 102)50 rpmMax) 90) 98)paddle30 min speed and 95 98 105 100 100 94 101 100 Average 900 mL (93 (96 - 99) (102 - (97 - (95 (91 - 99) (96 - (96 - (Min vessel 110) 103) 106) 103) Max) volume 96) 105)45 min 99 100 104 100 101 96 100 99 Average (97 (98 - (101 - (97 - (97 (93 - (96 - (96 - (Min 101) 107) 103) 101) 105) 102) Max) 101) 105)60 min 102 100 102 100 102 96 99 98 Average (100 (98 - (101 - (97 - (97 (94 - (96 - (96 - (Min 102) 104) 102) 100) 103) 101)Max) 104) 104)Table 20: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib _ (free acid) prototype C 200 and prototype C scale-up stress stability _ Manufacturing lotPrototype C 200 BN A4459 / 19 / 03 Prototype C scale up BN A4459 / 19 / 02 number70 min 104 102 102 102 103 99 100 99 Average (102 (100 - (101 - (101 - (99 (98 - (98 - (97 - (Min 103) 104) 103) 101) 103) 101) Max) 107) 106)Prototype Initi 2 weeks - 4 weeks - 4 weeks - Initi 2 weeks - 4 weeks - 4 weeks - al 40°C / 75 40°C / 75 40°C / 75% al 40°C / 75 40°C / 75 40°C / 75% %RH %RH RH with %RH %RH RH with exposed packed desiccant exposed packed desiccant Ezetimi (n=3 (n=3be ) )15 min 69 68Average (59 (63(Min DissolutioMax) n method 75) 71)30 min based on 78 74Average USP (76 (68(Min methodMax) conditions 81) 77)45 min at pH 4.5, 81 76Average 50 rpm (79 (69(Min paddleMax) speed and 83) 79)60 min 500 mL 82 77Average vessel (80 (70(Min volumeMax) 84) 80)70 min 96 92Average (94 (90(MinMax) 100) 93)Ezetimi (n=3 (n=6) (n=6) (n=6) (n=3 (n=6) (n=6) (n=6) be ) )15 min Dissolutio 86 83Average n method (84 79 86 82 (80 76 84 83 (Min (78 - 81) (84 - 87) (80 - 84) (73 - 78) (83 - 86) (81 - 87) based onMax) USP 89) 85)30 min method 94 90Average conditions (92 90 95 91 (87 88 93 91 (Min at pH 4.5, (89 - 91) (94 - 95) (87 - 93) (84 - 90) (92 - 95) (89 - 94) Max) 75 rpm 97) 93)paddle 45 min 97 93Average speed and (95 95 98 94 (89 93 97 94 (Min 500 mL (94 - 96) (97 - 99) (90 - 97) (90 - 95) (96 - 97) (92 - 96) Max) vessel 99) 96)60 min volume 98 96(n= 3) 99Average (96 98 969 - (91 96 98 96 ( 8(Min (97 - 98) (92 - 99) (93 - 98) (95 - 99) (94 - 99)101)Max) 101) 99)Table 20: Results of the dissolution characterization of small scale 10mg ezetimibe and 10 mg obicetrapib (free acid) prototype C 200 and prototype C scale-up stress stability Manufacturing lot Prototype C scale up BN A4459 / 19 / 02Prototype C 200 BN A4459 / 19 / 03number70 min 102 99100 102 101 100 100 99 Average (101 (96(100 - (101 - (98 - (97 - (100 - (98 - (Min100) 103) 102) 101) 101) 101)Max) 103) 102)Physical properties characterization

[0335] XRPD data of samples placed on stress stability are summarized in Table 21. Both prototype tablets present ezetimibe hydrate when exposed at 40°C / 75%RH condition at 2WK, however once packaged the polymorphic conversion does not happen up to 4WK storage.Table 21 XRPD data summary of prototype C 200 and scale up placed on stress stabilitySample Batch ID XRPDTablet Prototype C scale up Initial A4459 / 19 / 02 OBI + EZE Anhydrous2WK @40 / 75 exposed OBI + EZE Anhydrous +small EZE Hydrate4WK 40 / 75 exposed OBI + EZE Anhydrous +small EZE Hydrate4 WK 40 / 75 packaged OBI + EZE Anhydrous4 WK 40 / 75 packaged with OBI + EZE AnhydrousdesiccantTablet Prototype C 200mg Initial A4459 / 19 / 03 OBI + EZE Anhydrous2WK @40 / 75 exposed OBI + EZE Anhydrous +small EZE Hydrate4WK 40 / 75 exposed OBI + EZE Anhydrous +small EZE Hydrate4 WK 40 / 75 packaged OBI + EZE Anhydrous4 WK 40 / 75 packaged with OBI + EZE Anhydrousdesiccant8.5. Example 3: Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by co-granulation of drug substances / active ingredients (FDC1) (small scale batch ~ 500 g)8.5.1. High shear granulation, drying, preparation of final blend and tableting

[0336] Three compositions (Composition 1 batch A4459 / 20 / 02, Composition 2 batch A4459 / 20 / 03 and Composition 3 batch A4459 / 20 / 04) were prepared as summarised in Table 22. The prototype formulation composition selected for these compositions was that of “prototype C” (e.g. granule batch A4459 / 13 / 03). The preparation and characterization (LOD and XRPD) of the granules are described in the previous sections (small-scale manufactures). The granules were tested for content uniformity, LOD, sieve analysis, TBD and XRPD. The blend for tableting and the compression profile and manufacture of a small batch of tablets at 150 mg tablet weight was performed as described in the previous example. The tablets were tested forcontent uniformity, XRPD, dissolution and water content by KF. All the intermediates of production and the final drug product were stored as described in the previous sections.Table 22: Composition (% w / w) of granule and tablet for the FDC1 composition Composition #1 Composition #2 Composition #3A4459 / 23 / 0 A4459 / 23 / 0 A4459 / 20 / 0 A4459 / 23 / 0 A4459 / 20 / 02 A4459 / 20 / 03Component 2 3 4 4Granule Tablet Granule Tablet Granule Tablet (%, w / w) (%, w / w) (%, w / w) (%, w / w) (%, w / w) (%, w / w)Intra-gr anularEzetimibe 6.981 6.667 6.981 6.667 6.981 6.667 Obicetrapib 7.162 6.840 7.162 6.840 7.162 6.840 Avicel PH 101 21.982 20.993 21.982 20.993 21.982 20.993 Pharmatose 20057.592 55.000 57.592 55.000 57.592 55.000 MKollidon 30 1.047 1.000 1.047 1.000 1.047 1.000 Glycolys 4.189 4.000 4.189 4.000 4.189 4.000 Kolliphor SLS 1.047 1.000 1.047 1.000 1.047 1.00020.000 + 20.000 + up to visualMilliQ water* N / A N / A N / A 5.000 5.000 (30.000)Total Granule 100.000 95.500 100.000 95.500 100.000 95.500Extra-granularGlycolys N / A 4.000 N / A 4.000 N / A 4.000 Ligamed MF-2-V N / A 0.500 N / A 0.500 N / A 0.500 Total tablet N / A 100.000 N / A 100.000 N / A 100.000* Water does not appear in the final product. All excipients for granulation added as a dry powderResultsThe high shear granulation was conducted successfully. The drying step was conducted without any issues and, after 15 minutes drying the LOD of the granules was lower than the initial LOD. In general, the and the granules presented a relatively large quantity of fine particles despite the increase of the impeller speed (composition 1) (Figure 26), the time of wet massing (composition 2) or the quantity of granulating agent (composition 3). The tablet friability, time of disintegration, thickness and hardness were found to be similar among these tablet batches.Granules chemical characterizationThe granules were tested for homogeneity, and obicetrapib and ezetimibe were found to be homogeneously dispersed.Physical properties characterization

[0337] XRPD data of the Blend / granules prototypes FDC1 approach are summarized in Table 23. Eze hydrate appears only in the wet granules samples. All the three prototypes present similar flowability.Table 23: XRPD data summary of granules from FDC1 compositionsSample Batch ID XRPDPrototype 1 Blend before granulation A4459 / 20 / 02 OBI + EZE AnhydrousPrototype 1 Wet Granules OBI + EZE Anhydrous +smallEZE HydratePrototype 1 Final dry Granules OBI + EZE AnhydrousPrototype 2 Blend before granulation A4459 / 20 / 03 OBI + EZE AnhydrousPrototype 2 Wet Granules OBI + EZE Anhydrous +smallEZE HydratePrototype 2 Final dry Granules OBI + EZE AnhydrousPrototype 3 Blend before granulation A4459 / 20 / 04 OBI + EZE AnhydrousPrototype 3 Wet Granules OBI + EZE Anhydrous +smallEZE HydratePrototype 3 Final dry Granules OBI + EZE AnhydrousTablets chemical characterization

[0338] Results of the chemical characterization of the FDC 1 tablets are reported in Table 24. The results of the analytical characterization did not show any significant differences between the three compositions.Table 24: Results of the chemical characterization of FDC1 compositionsManufacturing lot number A4459 / 23 / 02 A4459 / 23 / 03 A4459 / 23 / 04 Prototype Composition Composition Composition #1: prototype C, #2: prototype C, #3: prototype C, Test Method Result Result Result Assay HPLCObicetrapib (%claim) 2730 100.1 97.6 99.2 Ezetimibe (%claim) 2731 99.9 99.7 99.7 Impurities HPLCIMP RRT0.94 (% claim) 2730 0.06 0.06 0.06 FROL(% claim) 2730 0.05 0.06 0.05 MONO-BN FREE(% claim) 2730 0.17 0.16 0.17 Total impurities of Obicetrapib > 2730 0.28 0.28 0.280.05%EzetimibeKetone (% a / a) 2731 < QL (0.05%) < QL (0.05%) < QL (0.05%) Ezetimibe tetrahydropyran analog 2731 N. D. N. D. N. D.(%a / a)Total impurities of Ezetimibe > 2731 < QL (0.05%) < QL (0.05%) < QL (0.05%) 0.05%Uniformity of dosage units USP <905>Table 24: Results of the chemical characterization of FDC1 compositionsManufacturing lot number A4459 / 23 / 02 A4459 / 23 / 03 A4459 / 23 / 04 Obicetrapib Ph. Eur. 2.9.40 or Average % Average % Average %JP 6.02 by UNIC / Claim: 99.7 Claim: 98.5 Claim: 99.3 1190 Range % Range % Range % Claim:Claim: (94.0- Claim: (97.1 - (97.6 -100.5) 102.4) 99.2) AV = 2.3 AV = 5.5 AV = 1.8Ezetimibe Average % Average % Average %Claim: 102.6 Claim: 101.5 Claim: 101.6 Range % Range % Range % Claim: (96.8 - Claim: (100.3 - Claim: (100.0 - 105.6) 102.2) 103.1) AV = 7.0 AV = 1.5 AV = 2.5 Dissolution Obicetrapib5 min Average 74 77 80 (Min Max) (72 - 76) (74 - 79) (77 - 83) 10 min Average 94 95 95 (Min Max) Discriminating (90 - 97) (92 - 97) (94 - 96) 15 min Average method at pH 98 99 99 (Min Max) 6.80.2 %w / v of (95 - 102) (98 - 101) (98 - 99) 30 min Average Tween 80, 50 rpm 103 104 100 (Min Max) paddle speed and (99 - 106) (103 - 106) (102 - 106) 45 min Average 900 mL vessel 103 104 100 (Min Max) volume (100 - 105) (103 - 107) (102 - 101) 60 min Average 103 103 100 (Min Max) (101 - 107) (102 - 105) (100 - 100) 70 min Average 104 103 100 (Min Max) (102 - 108) (102 - 104) (99 - 101) Dissolution Ezetimibe15 min Average 86 88 90 (Min Max) Dissolution (83 - 88) (86 - 89) (86 - 92) 30 min Average method based on 100 100 102 (Min Max) USP method (97 - 102) (98 - 102) (99 - 104) conditions at pH45 min Average 4.5, 75 rpm 105 104 106 (Min Max) (102 - 107) (102 - 105) (104 - 107) paddle speed and60 min Average 500 mL vessel 107 106 107 (Min Max) volume (105 - 109) (105 - 107) (106 - 109) 70 min Average 109 108 108 (Min Max) (107 - 111) (107 - 108) (107 - 109)Water content KF 4.6 % w / w 4.6 % w / w 4.6 % w / w Physical properties characterization

[0339] XRPD data of the Tablets from FDC1 compositions are summarized in Table 25. There is no presence of Eze hydrate in all samples.Table 25: XRPD data summary of granules of FDC1 compositionsSample Batch ID XRPD3Composition 1 Tablet A4459 / 23 / 02 OBI + EZE AnhydrousComposition 2 Tablet A4459 / 23 / 03 OBI + EZE AnhydrousComposition 3 Tablet A4459 / 23 / 04 OBI + EZE Anhydrous8.6. Example 4: Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by granulation of ezetimibe and addition of obicetrapib in the extragranule (FDC2)8.6.1. High shear granulation and dryingA / 44592

[0340] Three compositions were prepared as summarised in Table 26. The excipients contained / 001in the granule were the same of those used for the manufacture of the granule for the FDC1 approach. The formulation composition of these granules reflected that of FDC1 granuleA / 44592“prototype C”. The method of h / 301igh shear granulation, granule drying, and milling was described in the previous sections. The granules were tested for content uniformity (ezetimibe only), sieve A / 44592analysis, TBD and XRPD. / 7111 _ _Table 26: Composition (% w / w) of granule, tablet and coated tablet of FDC2 compositionsA / 44592Prototype 1 Prototype 2 Prototype 3 / 501m < < A / 445921C / 601Tabl Tab Tab A / 44592Component et let let Tablcoat coa coa Granule Tablet Granule et G A / 44592ranule Tableted ted ted (%, w / w) (%, w / w) (%, w / w) (%, (%, w / 502 / w) (%, w / w)(%, (%, (%, w / w)w / w w / w w / w A / 44592) ) ) Intra-granule / 6024.34 4.3 4.3 Ezetimibe 7.692 4.348 7.692 4.348 7.692 4.3488 48 48 Avicel PH 13.3 13.34 13. 13.23.614 13.347 23.614 23.614 13.347101 47 7 347 347 Pharmatos 34.9 34.91 34. 34.61.771 34.914 61.771 61.771 34.914e 200 M 14 4 914 9140.65 0.6 0.6 Kollidon 30 1.154 0.652 1.154 0.652 1.154 0.6522 52 52 2.60 2.6 2.6 Glycolys 4.615 2.608 4.615 2.608 4.615 2.6088 08 08 Kolliphor 0.65 0.6 0.61.154 0.652 1.154 0.652 1.154 0.652SLS 2 52 52Table 26: Composition (% w / w) of granule, tablet and coated tablet of FDC2 compositionsPrototype 1 Prototype 2 Prototype 3A / 44592 / 001 Tabl Tab Tab Component et let let Tablcoat coa coa Granule A / 44592 Tablet Granule et Granule Tableted ted ted (%, w / w) (%, w / 301 / w) (%, w / w) (%, (%, w / w) (%, w / w)(%, (%, (%,w / w)w / w w / w w / w A / 44592) / 701 _ _ ) ) MilliQ20+5 N / A N / A 20+5 N / A N / A 20+5 N / A N / A water* A / 44592Total 56.5 / 501 56.52 56. 56.100.000 56.521 100.000 100.000 56.521 Granule 21 1 521 521Extra-granule A / 445924.46 / 601 4.4 4.4 Obicetrapib N / A 4.461 N / A 4.461 N / A 4.4611 A / 44592 61 61 Avicel PH 25.9 23.11 23. 22.N / A 25.974 N / A A / 4459 N / A 22.757200 74 8 118 2 757 Pearlitol 200 10.0 8.9 / 502 8.7N / A 10.000 N / A 8.900 N / A 8.761SD 00 00 612.17 5.0 A / 44592 5.0 Glycolys N / A 2.174 N / A 5.000 N / A 5.0004 00 / 602 00 0.43 1.0 1.0 Aerosil 200 N / A 0.435 N / A 1.000 N / A 1.0005 00 A / 44592 00_ _ Ligamed 0.43 1.0 1.5N / A 0.435 N / A 1.000 N / A 1.500MF-2-V 5 00 00 Opadry 3.00 3.0 3.0N / A N / A N / A N / A N / A N / A AMBII 0 00 00103. 100.0 103 103 Total tablet N / A 100.000 N / A N / A 100.000000 00.00.00*Water does not appear in the final product. All excipients for granulation added as a dry powder8.6.2. Preparation of final blend, tableting and coating

[0341] The components of the extra-granular formulation are listed below:- ObicetrapibPlastic filler (Avicel PH 200)Brittle filler (Pearlitol 200 SD)- Disintegrant (Glycolys)- Glydant (Aerosil 200)- Lubricant (Ligamed MF-2-V)

[0342] The final blend was prepared by weighing accurately and sieving the extra-granular components (excipients and API). The excipients and the granule were loaded in a bin of suitable volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the bin and mixed.

[0343] For the generation of a compression profile and the manufacture of a small batch of tablets, a single punch compression machine (EK0) equipped with an 9.0 mm round punch (R=l 1) was used. The target tablet weight was 230 mg and, throughout the process, the tablet friability, disintegration time, hardness, appearance end thickness was monitored as well as the individual tablet weight and the tablet weight of ten tablets.

[0344] The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.

[0345] The tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension at the required target weight increase (target weight increase 3% w / w, limits 2% w / w - 4% w / w). The coating suspension and the method of coating was described in the previous section. The coating parameters as well as the weight gain of the tablets was monitored throughout processing. The coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.

[0346] All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed.Results

[0347] The high shear granulation of the FDC2 compositions was conducted successfully. The drying step was conducted without any issues and, after ca. 16 minutes drying, the LOD of the granules was lower than the initial LOD. The granules showed a relatively large quantity of fine particles (Figure 29). The values of disintegration time and thickness were similar among FDC2 tablet batches.Granules chemical characterization

[0348] A4459 / 20 / 01 blend was tested for homogeneity of both obicetrapib and ezetimibe, and was found to be homogeneously dispersed. Results for other two granules were not collected. Tablets chemical characterization

[0349] Chemical characterization of the protoype 1 of FDC 2 tablets results are reported in Table 27 and Table 28. The results of the analytical characterization did not show any significant differences between the three prototypes of FDC2.Table 27: Results of the analytical characterization of FDC2 - UncoatedManufacturing lot number A4459 / 23 / 01 A4459 / 26 / 01 A4459 / 26 / 02 Prototype Prototype 1 Prototype 2 Prototype 3 Test Method Result Result Result Assay HPLCObicetrapib (%claim) 2730 97.6 96.8 95.6 Ezetimibe (%claim) 2731 102.1 102.7 101.0 Impurities HPLCIMP RRT0.94 (% claim) 2730 0.06 0.06 0.05FROL(% claim) 2730 0.05 0.05 0.05MONO-BN FREE(% 2730 0.19 0.16 0.16claim)Total impurities of 2730 0.31 0.27 0.26 Obicetrapib > 0.05%Ezetimibe□Ketone (%a / a) 2731 0.05 0.05 0.05 Ezetimibe tetrahydropyran 2731 N. D. N. D. N. D.analog (%a / a)Total impurities of 2731 0.05 0.05 0.05 Ezetimibe > 0.05%Uniformity of dosage unitsObicetrapib Average % Average % Average %Claim: 97.6 Claim: 96.7 Claim: 96.4 USP <905> Range % Claim: Range % Claim: Range % Claim:(95.5-100.3) (96.1 -97.4) (95.2 -98.2) Ph. Eur. 2.9.40 orAV = 4.9 AV = 2.9 AV = 4.7JP 6.02 by UNIC / Ezetimibe 1190 Average % Average % Average %Claim: 101.7 Claim: 102.3 Claim: 101.1 Range % Claim: Range % Claim: Range % Claim: (100.6 - 103.1) (101.0 - 103.2) (99.3 -103.1) AV = 2.2 AV = 2.6 AV = 2.9Dissolution ObicetrapibTable 27: Results of the analytical characterization of FDC2 - UncoatedManufacturing lot number A4459 / 23 / 01 A4459 / 26 / 01 A4459 / 26 / 02 5 min Average Discriminating 56 56 55 (Min Max) method at pH 6.80.2 (51 -62) (51 -61) (50 - 57) 10 min Average %w / v of Tween 80, 80 78 77 (Min Max) 50 rpm paddle (73 - 86) (74 - 79) (76 - 78) 15 min Average speed and 900 mL 86 86 83 (Min Max) vessel volume (77 - 92) (84 - 89) (82 - 86) 30 min Average 89 91 91 (Min Max) (81 - 97) (89 - 92) (87 - 93) 45 min Average 89 91 91 (Min Max) (80 - 96) (88 - 92) (88 - 93) 60 min Average 88 91 90 (Min Max) (80 - 95) (89 - 92) (88 - 92) 70 min Average 98 97 96 (Min Max) (95 - 100) (96 - 89) (95 - 97) Dissolution Ezetimibe15 min Average 68- - (Min Max) Dissolution method (61 -71)30 min Average based on USP 76- - (Min Max) method conditions (70 - 79)45 min Average at pH 4.5, 50 rpm 79- - (Min Max) paddle speed and (74 - 81)60 min Average 500 mL vessel 80(Min M volume - - ax) (75 - 83)70 min Average 101- - (Min Max) (100 - 101)Dissolution Ezetimibe15 min Average 88 85 82 (Min Max) Dissolution method (85 - 94) (81 - 88) (76 - 88) 30 min Average based on USP 94 94 90 (Min Max) method conditions (92 - 101) (90 - 96) (84 - 97) 45 min Average at pH 4.5, 75 rpm 97 97 93 (Min Max) paddle speed and (94 - 103) (93 - 100) (87 - 101) 60 min Average 500 mL vessel 98 98 94 (Min Max) volume (95 - 104) (94 - 101) (88 - 102) 70 min Average 103 102 101 (Min Max) (102 - 105) (101 - 104) (99 - 103)Water content KF 4.4 % w / w 4.3 % w / w 4.0 % w / wTable 28: Results of the analytical characterization of FDC2- CoatedManufacturing lot number A4459 / 27 / 01 A4459 / 27 / 02 A4459 / 27 / 03 Prototype Prototype 1 - Prototype 2 Prototype 3Coated Coated Coated Test Method Result Result Result Assay HPLCObicetrapib (%claim) 2730 95.9 96.4 95.0 Ezetimibe (%claim) 2731 102.1 102.6 101.0 Impurities HPLCIMP RRT0.94 (% claim) 2730 0.06 0.06 0.06 FROL(% claim) 2730 0.05 0.05 0.05MONO-BN FREE(% claim) 2730 0.16 0.16 0.16Table 28: Results of the analytical characterization of FDC2- CoatedManufacturing lot number A4459 / 27 / 01 A4459 / 27 / 02 A4459 / 27 / 03 Total impurities of Obicetrapib > 2730 0.27 0.27 0.27 0.05%Ezetimibe□Ketone (% a / a) 2731 < QL (0.05 %) < QL (0.05 %) < QL (0.05 %) Ezetimibe tetrahydropyran analog 2731 N. D. N. D. N. D.(%a / a)Total impurities of Ezetimibe > 2731 < QL (0.05 %) < QL (0.05 %) < QL (0.05 %) 0.05%Uniformity of dosage unitsObicetrapib Average % Average % Average % Claim: 97.0 Claim: 96.4 Claim: 95.2 Range % Range % Range % Claim: Claim: (94.0- Claim: (95.4 - (93.2 -96.1) USP <905>99.1) 97.8) AV = 5.5 Ph. Eur. 2.9.40 orAV = 6.1 AV = 4.0JP 6.02 by UNIC / Ezetimibe 1190 Average % Average % Average % Claim: 101.2 Claim: 101.9 Claim: 101.0 Range % Range % Range % Claim: (99.6 - Claim: (100.7 - Claim: (99.6 - 102.5) 102.9) 102.3) AV = 2.2 AV = 2.2 AV= 1.7 Dissolution Obicetrapib5 min Average 58 59 57 (Min Max) (43 - 66) (51 -63) (52 -61) 10 min Average 83 79 85 (Min Max) Discriminating (76 - 86) (77 - 83) (82 - 87) 15 min Average method at pH 6.8 88 84 90 (Min Max) + 0.2 %w / v of (84 - 91) (82 - 90) (87 - 93) 30 min Average Tween 80, 50 rpm 94 90 96 (Min Max) paddle speed and (91 - 96) (87 - 97) (92 - 101) 45 min Average 900 mL vessel 95 90 95 (Min Max) volume (91 - 99) (88 - 98) (91 - 102) 60 min Average 95 90 94 (Min Max) (91 - 102) (90 - 98) (91 - 100) 70 min Average 103 97 98 (Min Max) (100 - 104) (95 - 98) (97 - 99) Dissolution Obicetrapib15 min Average 89 90 90 (Min Max) Discriminating (87 - 91) (88 - 92) (87 - 93) 30 min Average method at pH 95 95 95 (Min Max) 6.8+ 0.2 %w / v of (94 - 96) (94 - 97) (92 - 97) 45 min Average Tween 80, 75 rpm 96 96 96 (Min Max) paddle speed and (95 - 98) (95 - 97) (94 - 97) 60 min Average 1000 mL vessel 97 96 96 (Min Max) volume (96 - 98) (95 - 97) (94 - 97) 70 min Average 98 96 96 (Min Max) (95 - 100) (94 - 98) (95 - 98) Dissolution EzetimibeDissolution15 min Average 82 84 85 (Min Max) method based on (76 - 89) (78 - 90) (76 - 88) USP method30 min Average 92 92 92conditions at pH(Min Max) 4.5, 75 rpm (85 - 101) (87 - 97) (86 - 95) 45 min Average paddle speed and 94 95 95(Min Max) (87 - 102) (90 - 100) (89 - 98)Table 28: Results of the analytical characterization of FDC2- CoatedManufacturing lot number A4459 / 27 / 01 A4459 / 27 / 02 A4459 / 27 / 03 60 min Average 500 mL vessel 95 96 96 (Min Max) volume (88 - 103) (92 - 101) (90 - 99) 70 min Average 102 103 102 (Min Max) (101 - 104) (102 - 104) (102 - 103)Water content KF 4.0 % w / w 4.1 % w / w 4.0 % w / wPhysical Properties characterization

[0350] XRPD data of the Blend / granules from FDC2 compositions are summarized in Table 29. XRPD data of the tablets from FDC2 approach are summarized in Table 30. There was a presence of small amount of Eze hydrate in prototype 1.Table 29: XRPD data summary of granules from FDC2 compositionsSample Batch ID XRPDPrototype 1 Final dry A4459 / 20 / 01 OBI + EZE Anhydrous + small amount of EZE Granules hydratePrototype 2 Final dry A4459 / 25 / 01 OBI + EZE AnhydrousGranulesPrototype 3 Final dry A4459 / 25 / 02 OBI + EZE AnhydrousGranulesTable 30: XRPD data summary of tablets from FDC2 compositionsSample Batch ID XRPDPrototype 1 Tablet uncoated- A4459 / 23 / 01 / - OBI + EZE Anhydrous + small amount ofcoated A4459 / 27 / 01 EZE hydratePrototype 2 Tablet uncoated- A4459 / 26 / 01- OBI + EZE Anhydrouscoated A4459 / 27 / 02Prototype 3 Tablet uncoated- A4459 / 26 / 02 - OBI + EZE Anhydrouscoated A4459 / 27 / 03Stress Stability

[0351] Prototype 2 coated tablet was selected for the stress stability study with the following designTable 31: Stress stability study designStorage Conditions Time (weeks)T / RH Type 0 2 3 425°C / 60%RH Long-term (T) - (T)40°C / 75%RH uncovered Stress (T) T T - T40°C / 75%RH closed Accelerated (T) - (T)Key:T= Tested for appearance, assay & related substances, discriminating dissolution, water content by KF, and form check by XRPD(T)= Optional testing

[0352] Results are reported in Table 66, Table 67 and Table 68.Table 32: Results for assay, water content and visual appearance of prototype 2 FDC2 stressstability _ _ _ _ _ _Prototype Time point - Storage Assay of Assay of Water AppearanceNo. conditions Ezetimibe Obicetrapib content (visual)(% Claim) (% Claim) (% w / w)Prototype 2 White roundInitial 102.7 96.4 4.1BN tabletA4459 / 28 / 02 2 weeks - 40°C / 75%RH 101.2 95.8 4.6 White roundtabletsexposed4 weeks - 40°C / 75%RH 102.1 94.6 5.1 White roundtabletexposed4 weeks - 101.4 96.0 3.1 Not tested40°C / 75%RH packedTable 33: Results for impurities profile of prototype 2 FDC2 stress stabilityObicetrapib related impurities Ezetimibe related impuritiesMOTime NOTotal IMP_ FR IMPpoint - IMP_ EZETI EZETBN Total IRR impuriT OL impuri RRT RRT MIBE MIBE Batch Storage FRE ties (> 0.94 (% 0.73 0.79 CYCLI ties KETON conditio E 0.05) (% (% (% (% E clai C ns (% (% claim) m) claim) a / a) a / a) (% a / a) (% a / a) claim a / a))0.06 0.05 0.16 0.27 N. D. 0.04 N. D 0.04 < QL Initial2 weeks40°C / 75 0.06 0.05 0.16 0.26 N. D. 0.05 N. D. 0.06 0.11 %RHexposedPrototyp 4 weekse 2 BNA4459 / 2 40°C / 75 0.05 0.05 0.16 0.26 N. D. 0.05 0.06 0.07 0.18 8 / 02 %RHexposed4 weeks< QL40°C / 75 0.06 0.06 0.16 0.28 0.03 0.05 0.07 0.12 (0.05%%RH )packedN. D. = Not DetectedTable 34: Results of the dissolution characterization of prototype 2 FDC2 stress stability Manufacturing lot number Prototype 2 BN A4459 / 28 / 02Time point and storage Initial 2 weeks - 4 weeks - 4 weeks - 40°C / 75%RH 40°C / 75%RH 40°C / 75%RH conditionsexposed exposed packedTest Method Result Result ResultObicetrapib. (“=6) _ (n=6) _Table 34: Results of the dissolution characterization of prototype 2 FDC2 stress stability Manufacturing lot number Prototype 2 BN A4459 / 28 / 025 min Discriminating 5951 57 52 Average method at pH (51 - (45 - 53) (55 -65) (47 - 57) (Min Max) 6.80.2 %w / v of 63)10 min Tween 80, 50 79A rpm paddle speed 71 77 80 verage (77 - (68 - 74) (74 - 81) ( (Min Max) and 900 mL 78 - 83)83)15 min vessel volume 8478 83 88 Averag (82 - (76 - 81) (80 - 88) (87 - 89) (Min Max) 90)30 min 9086 89 94 Average (87 - (84 - 89) (86 - 93) (91 - 96) (Min Max) 97)45 min 9087 89 93 Average (88 - (85 - 89) (87 - 92) (87 - 92) (Min Max) 98)60 min 9087 89 91 Average (90 - (84 - 90) (88 - 93) (88 - 93) (Min Max) 98)70 min 9797 97 97 Average (95 - (95 - 97) (96 - 98) (96 - 98) (Min Max) 98)Time point and storage Initial 2 weeks - 4 weeks - 4 weeks - conditions 40°C / 75%RH 40°C / 75%RH 40°C / 75%RH exposed exposed packed Ezetimibe (n=6) (n=6). (n=6> (n=6) 15 min 8469 72 78 Average (78 - (66 - 73) (66 - 76) (64 - 87) (Min Max) 90)30 min Dissolution 92method based o 81 86 90 Average n (87 - (77 - 84) (81 - 90(Min Max) USP method ) (79 - 98)97)conditions at pH45 min 4.5, 75 rpm 9586 92 94 Average (90 - paddle speed (83 - 89) (87 - 96) (85 - 101) (Min Max) and 500 mL 100)60 min vessel volume 9689 96 96 Average (n= 3) (92 - (86 - 91) (90 - 101) (88 - 102) (Min Max) 101)70 min 10399 102 103 Average (102 - (97 - 100) (100 - 104) (101 - 106)(Min Max) 104)8.7. Example 5: Fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib by granulation of obicetrapib and addition of ezetimib in the extragranule (FDC3)

[0353] Prototype compositions were prepared as summarised in Table 35. The method of granulation was as per process condition 2 as described above. The method of high shear granulation, granule drying, and milling was described in the previous sections. The granules were tested for content uniformity (obicetrapib only), sieve analysis, TBD and XRPD.Table 35: Composition (% w / w) of the granule, tablet and coated tablet of the FDC3 composition Component Granule (%, w / w) Tablet (%, w / w) Tablet (mg) Coated Tablet (%, w / w)Intra-granuleObicetrapib 7.89 4.46 10.26 10.26Avicel PH 101 23.614 13.347 30.7 30.7 Pharmatose 200 M 61.573 34.802 80.04 80.04 Kollidone 30 1.154 0.652 1.5 1.5Glycolys 4.615 2.608 6 6Kolliphor SLS 1.154 0.652 1.5 1.5Purified Water* 30 N / A N / A N / ATotal Granule 100 56.521 130 130Extra-granuleEzetimib N / A 4.438 10 10Avicel PH 200 N / A 23.23 53.43 53.43 Pearlitol 200 SD** N / A 8.9 20.47 20.47 Glycolys N / A 5 11.5 11.5Aerosil 200** N / A 1 2.3 2.3Ligamed MF-2-V N / A 1 2.3 2.3Opadry AMB II N / A N / A 6.9Total Tablet 100 230 236.9** or lactose ***optional8.7.1. Preparation of final blend, tableting and coating

[0354] The final blend was prepared by weighing accurately and sieving the extra-granular components (excipients and API). The excipients and the granule were loaded in a bin of suitable volume and blended using a Pharmatech mixer. Then, the lubricant (MgSt) was added to the bin and mixed.

[0355] For the generation of a compression profile and the manufacture of a small batch of tablets, a single punch compression machine was used. The target tablet weight was 230 mg and, throughout the process, the tablet friability, disintegration time, hardness, appearance end thickness was monitored as well as the individual tablet weight and the tablet weight of ten tablets. The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.

[0356] The tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension at the required target weight increase. The coating suspension and the method of coating was described in the previous section. The coating parameters as well as the weight gain of the tablets was monitored throughout processing. The coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.

[0357] All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed.8.8. Example 6: fixed dose combination of 10 mg ezetimibe and 10 mg obicetrapib as a bilayer tablet by individual granulation of obicetrapib and ezetimib followed by compression (FDC4)

[0358] Prototype compositions were prepared as summarised in Table 36. The method of granulation of ezetimibe was same as described above for FDC1 and of obicetrapib was same as described above for FDC3. The method of high shear granulation, granule drying, and milling was same described in the previous section for FDC1. The granules were then fed via two hoppers into the compression machine. The first granule was used to fill the die followed by a light compression. The second granule was then filled followed by compression as per the method explained in previous examples. The individual granules were tested for content uniformity (obicetrapib or ezetimibe), sieve analysis, TBD and XRPD. The granules were compressed to form a tablet as per the methods described above. The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.Table 36: Composition (% w / w) of the granule, tablet and coated tablet of the FDC4 composition Componen FDC4 (obicetrapib granule) FDC4 (ezetimibe granule) t Granul Tablet Bi- Coated Final Granul Tablet Bi- Tablet Final e (%,w / w laye Tablet Bie (%,w / w laye (%,w / w Bi(%,w / w ) r (%,w / w layer (%,w / w ) r ) layer ) (mg) ) Table ) (mg) Table t (mg) t (mg) Intra-granuleEzetimibe N / A N / A N / A 7.692 10 10 Obicetrapi 7.89 10.2 10.26 N / A N / A N / A b 6Avicel PH 23.614 30.7 30.7 23.614 30.7 30.7 101Pharmatos 61.573 80.0 80.04 61.771 80.3 80.3 e 200 M 4Kollidon 1.154 1.5 1.5 1.154 1.5 1.5 30Glycolys 4.615 6 6 4.615 6 6 Kolliphor 1.154 1.5 1.5 1.154 1.5 1.5 SLSPurified 30 N / A N / A 30 N / A N / A Water*Total 100 130 130 100 130 130 GranuleExtra-granule for each bilayerGlycolys N / A 5.5 5.5 N / A 5.5 5.5Table 36: Composition (% w / w) of the granule, tablet and coated tablet of the FDC4 com position Aerosil 200 N / A N / A N / A N / A N / A N / A Ligamed N / A 1.4 1.4 N / A 1.4 1.4 MF-2-VIndividual N / A 136. N / A 136.Bilayer 9 9Total N / A 273.8TabletCoating of 273.8 mg bi-layer tabletsOpadry N / A N / A 3 8.2AMB II*purified water is a granulating agent and does not feature in any of the final formulations

[0359] The tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension at the required target weight increase. The coating suspension and the method of coating was described in the previous section. The coating parameters as well as the weight gain of the tablets was monitored throughout processing. The coated tablets were tested for XRPD, dissolution, appearance, content uniformity and water content by KF.All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed.8.9. Example 7: Scale-up of FDC1 and FDC2 compositions8.9.1. High shear granulation, drying, final blend, tableting and coating

[0360] The API and excipients were dispensed accurately, sieved and added to the granulation bowl according to the approach detailed in the FDC1 and FDC2 formulation approaches above. The parameters of granulation for both the FDC1 and FDC2 approach were identical. The granules were tested for content uniformity (only for the FDC1 approach), LOD, sieve analysis, TBD and XRPD.

[0361] The final blend of the FDC1 and FDC2 compositions were prepared to manufacture tablets whose batch number and composition is detailed in Table 37. The components of the extra-granule were manually sieved and loaded in a bin of suitable volume. The granule was mixed with the extra-granular materials using a Pharmatech mixer. Then, the FDC2 blend was tested for content uniformity.Table 37: Composition (% w / w) of granule, tablet and coated tablet of FDC1 and FDC2 scale-up trials Component Scale-Up - FDC2 Scale-Up FDC1A4459 / 29 / 04 A4459 / 29 / 05 A4459 / 29 / 01 A4459 / 29 / 02 Table TableGranule t Coated tablet Granule t Coated Tablet (%, w / w) (%, (%, w / w) (%, w / w) (%, (%, w / w) w / w) w / w)Intra-gr anularEzetimibe 7.692 4.348 4.348 7.018 6.667 6.667 Obicetrapib N / A N / A N / A 7.200 6.840 6.840 Avicel PH23.614 13.347 13.347 21.950 20.853 20.853 101Pharmatose61.771 34.914 34.914 57.516 54.640 54.640 200 MKollidon 30 1.154 0.652 0.652 1.053 1.000 1.000 Glycolys 4.615 2.608 2.608 4.210 4.000 4.000 Kolliphor1.154 0.652 0.652 1.053 1.000 1.000 SLSPurified 20.000 + 5.000 20.000 + 5.000N / A N / A N / A N / A Water* + 5.000 + 5.000Total100.000 56.521 56.521 100.000 95.000 95.000 GranuleExtra-granularObicetrapib N / A 4.461 4.461 N / A N / A N / A Avicel PHN / A 23.118 23.118 N / A N / A N / A 200Pearlitol 200N / A 8.900 8.900 N / A N / A N / A SDGlycolys N / A 5.000 5.000 N / A 4.000 4.000 Aerosil 200 N / A 1.000 1.000 N / A N / A N / A LigamedN / A 1.000 1.000 N / A 1.000 1.000 MF-2-VOpadryN / A N / A 3.000 N / A N / A 3.000 AMB II100.00 100.00Total Tablet N / A 103.000 N / A 103.000 0 0* Water does not appear in the final product. The excipient used in the granulation were added as a dry powder

[0362] For the generation of a compression profile and for the tableting exercise the use of rotary press machines was assessed. The friability, disintegration time, hardness, thickness and appearance of the tablets as well as the individual tablet weight and the tablet weight of ten tablets was monitored during the tableting exercise. The tablets were tested for content uniformity (stratified samples: start, middle and end of production), XRPD, dissolution and water content by KF.

[0363] The tablets were coated using a 20% w / w Opadry AMB II white aqueous suspension at the required target weight increase (target weight increase 3% w / w, limits 2% w / w - 4% w / w). The coating suspension and the method of coating was described in the previous section. The coating parameters as well as the weight gain of the tablets was monitored throughout processing. The coated tablets were tested for XRPD, dissolution, appearance, assay and impurities, and water content by KF.

[0364] All the intermediates of production and the final drug product were stored in double LDPE bags with silica and transferred into an aluminium bag that was thermosealed.Results

[0365] The high shear granulation of the scale-up batches was conducted successfully. The granules presented similar values of PSD by sieve analysis and a large quantity of fines (Figure 37). These PSD values were comparable to those found in the previous trials (e.g. batch A4459 / 16 / 02 as a reference for the FDC1 scale-up batch and batch A4459 / 25 / 01 as a reference for the FDC2 scale-up batch). Despite this similarity of PSD data, the flowability of the scale-up batches improved in comparison to that of the reference batches according to the value of the Hauser ratio. These tablets presented disintegration time shorter than 5 mins and friability lower than 0.2%. The coating process was performed without any critical issues and the appearance of the coated tablets for both formulation approaches was suitable since the surface of the tablets was smooth.Granules chemical characterization

[0366] The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe and were found to be homogeneously dispersed. Dissolution of both obicetrapib and ezetimibe and impurities profile of ezetimibe, results reported in Table 38, Figure 38, Figure 39 and Figure 40.Table 38: Granule and final blend impurities profile and dissolution result for scale up batches Manufacturing lot number A4459 / 29 / 01 A4459 / 29 / 05 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) Test Method Result Result Impurities HPLCIMP RRT0.79 (% a / a) 2731 < QL (0.05%) 0.05 Ezetimibe□Ketone (% a / a) 2731 0.05 0.05 Ezetimibe tetrahydropyran analog 2731 N. D. N. D.(%a / a)Total impurities of Ezetimibe > 2731 0.05 0.100.05%Dissolution Obicetrapib5 min Average 85- (Min Max) (78 - 95)10 min Average 93- (Min Max) (90 - 95)15 min Average Discriminating method at 96- (Min Max) pH 6.80.2 %w / v of (94 - 98)30 min Average Tween 80, 50 rpm paddle 97- (Min Max) speed and 900 mL vessel (95 - 99)45 min Average volume 98(Min Max) (95 - 100) - 60 min Average 97- (Min Max) (94 - 99)70 min Average 97- (Min Max) (94 - 99)Dissolution Ezetimibe15 min Average 89 90 (Min Max) (87 - 94) (87 - 91) 30 min Average Dissolution method 94 99 (Min Max) based on USP method (91 - 99) (96 - 101) 45 min Average conditions at pH 4.5, 75 94 101 (Min Max) rpm paddle speed and (91 - 100) (98 - 103) 60 min Average 500 mL vessel volume 95 102 (Min Max) (92 - 100) (99 - 105) 70 min Average 95 105(Min Max) (93 - 100) (102 - 106) Tablets chemical characterization

[0367] Chemical characterization of the scale up batches uncoated tablets results are reported in Table 39. Dissolution results on uncoated tablets at different compression forces are reported in Table 40, Table 41, Table 42 and Table 43. Results for coated tablets are reported in Table 42.Physical properties characterization

[0368] XRPD data of the Granules / T ablets from Scale up batches are summarized in Table 43. All the batches tested showed the absence of EZE hydrate.IllTable 39: Results of the analytical characterization of scale up batches - UncoatedManufacturing lot number A4459 / 29 / 02 A4459 / 29 / 05 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) Test Method Result ResultUniformity of dosage unitsObicetrapib Average % Claim: 99.3 Average % Claim: 97.0USP <905> Range % Claim: (98.0- Range % Claim: (94.0 - Ph. Eur. 2.9.40 100.1) 99.1)or AV = 1.6 AV = 6.1 Ezetimibe JP 6.02 by Average % Claim: Average % Claim: 96.4UNIC / 102.5 Range % Claim: (95.4 - 1190 Range % Claim: (100.3 97.8)- 103.9) AV = 4.0AV = 3.2Water content KF 4.6 % w / w 4.3 % w / wTable 40: Ezetimibe dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) at different compression forcesTablet at 4.5KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 93.0 93.8 93.5 93.9 95.4 95.5 94.2 1.1 30 102.4 101.8 101.2 101.3 103.4 103.6 102.3 1.0 45 104.9 103.6 103.5 103.4 105.3 105.5 104.4 0.9 60 104.7 103.7 103.8 104.1 105.7 105.4 104.6 0.8 70 105.2 104.0 104.6 104.5 105.9 105.7 105.0 0.7Tablet at 12.5KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 85.0 84.8 86.7 87.9 88.7 90.2 94.2 2.4 30 99.7 99.4 98.8 101.7 99.8 102.3 102.3 1.4 45 103.0 103.5 102.4 104.8 103.3 105.5 104.4 1.1 60 105.0 105.1 104.6 106.6 104.3 106.5 104.6 0.9 70 105.2 105.6 105.1 106.8 105.2 107.7 105.0 1.0Tablet at 18.5KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 80.5 82.5 87.4 88.1 85.6 87.1 87.2 2.4 30 99.0 99.3 101.1 101.8 100.5 101.4 100.3 1.4 45 103.5 104.7 106.0 106.5 104.2 107.3 105.4 1.4 60 104.8 105.2 106.7 107.9 105.3 107.4 106.2 1.270 106.6 106.5 107.9 108.4 106.8 108.6 107.4 0.9Table 41: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) at different compression forcesTablet at 4,5KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSDTable 41: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 02 (FDC1) at different compression forces5 60.8 61.0 73.4 74.6 72.6 73.5 69.3 9.4 10 94.1 96.0 98.1 97.3 91.5 95.4 95.4 2.5 15 101.0 103.0 102.6 100.5 96.8 99.0 100.5 2.3 30 102.3 103.3 103.6 102.6 98.5 100.2 101.7 1.9 45 99.1 101.1 101.2 100.9 97.8 98.2 99.7 1.5 60 99.7 99.6 100.0 98.8 97.1 97.6 98.8 1.2 70 104.6 96.9 100.1 99.8 98.4 97.4 99.5 2.8Tablet at 12,5KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 31.7 33.0 41.0 43.4 45.6 43.4 39.7 14.8 10 74.2 76.8 78.9 81.6 83.1 80.1 79.1 4.1 15 95.3 90.8 93.0 94.0 94.0 93.5 93.4 1.6 30 103.5 98.8 104.1 99.2 99.4 98.6 100.6 2.5 45 100.5 98.7 101.7 98.0 97.7 98.8 99.2 1.6 60 100.5 100.1 101.1 96.9 98.9 99.3 99.5 1.5 70 97.9 97.7 100.9 98.0 98.6 98.7 98.7 1.2Tablet at 12,5KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 31.7 33.0 41.0 43.4 45.6 43.4 39.7 14.8 10 74.2 76.8 78.9 81.6 83.1 80.1 79.1 4.1 15 95.3 90.8 93.0 94.0 94.0 93.5 93.4 1.6 30 103.5 98.8 104.1 99.2 99.4 98.6 100.6 2.5 45 100.5 98.7 101.7 98.0 97.7 98.8 99.2 1.6 60 100.5 100.1 101.1 96.9 98.9 99.3 99.5 1.5 70 97.9 97.7 100.9 98.0 98.6 98.7 98.7 1.2Table 42: Ezetimibe dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) at different compression forcesTablet at 5 KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 80.4 81.5 88.9 80.3 85.6 84.0 83.4 4.1 30 91.2 90.7 98.5 89.3 94.5 92.4 92.8 3.6 45 95.2 94.5 102.2 92.5 97.8 95.9 96.3 3.5 60 96.9 96.1 103.4 94.1 99.1 97.2 97.8 3.3 70 104.2 103.9 104.9 99.0 104.0 103.1 103.2 2.1Tablet at 10 KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 81.9 79.2 82.9 82.9 79.6 76.2 80.5 3.3 30 92.3 89.4 94.5 93.2 91.4 87.5 91.4 2.8 45 96.6 94.0 98.8 96.8 95.4 92.2 95.6 2.4 60 98.3 95.6 100.9 98.9 98.1 93.9 97.6 2.6 70 101.2 102.0 103.7 103.0 102.5 101.4 102.3 0.9Tablet at 20 KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 15 62.8 64.5 73.0 73.0 79.6 68.4 70.2 8.9 30 84.4 84.4 89.1 87.8 92.5 87.8 87.7 3.5 45 90.1 90.8 95.0 93.1 96.7 92.4 93.0 2.7 60 93.1 94.1 97.8 96.1 98.8 95.7 95.9 2.270 102.7 102.6 102.9 104.0 104.8 102.2 103.2 1.0Table 43: Obicetrapib dissolution results for scale-up batch A4459 / 29 / 05 (FDC2) at different compression forcesTablet at 5 KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 57.7 60.1 64.5 64.5 65.1 74.2 64.3 8.8 10 78.4 77.5 80.1 78.4 79.2 88.2 80.3 4.9 15 83.7 82.0 83.3 81.9 82.7 90.6 84.0 3.9 30 86.7 84.4 86.3 83.5 85.6 92.7 86.5 3.8 45 88.1 85.5 89.7 83.8 92.2 92.5 88.6 4.0 60 88.2 85.8 89.8 84.1 87.3 93.9 88.2 3.9 70 94.8 93.9 93.9 90.5 94.5 96.2 94.0 2.0Tablet at 10 KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 56.5 56.6 62.2 62.0 66.0 70.2 62.2 8.6 10 75.1 75.0 75.8 76.1 78.4 81.9 77.0 3.4 15 81.7 79.2 80.6 80.7 87.3 86.8 82.7 4.2 30 87.9 85.1 84.2 84.2 92.4 88.9 87.1 3.7 45 88.1 87.7 85.9 85.3 93.8 89.4 88.4 3.5 60 89.5 88.7 86.4 86.5 94.6 90.5 89.4 3.4 70 94.5 94.4 94.1 94.4 95.3 95.5 94.7 0.6Tablet at 20 KNTime (min) Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Mean % Release % RSD 5 56.5 56.6 62.2 62.0 66.0 70.2 62.2 8.6 10 75.1 75.0 75.8 76.1 78.4 81.9 77.0 3.4 15 81.7 79.2 80.6 80.7 87.3 86.8 82.7 4.2 30 87.9 85.1 84.2 84.2 92.4 88.9 87.1 3.7 45 88.1 87.7 85.9 85.3 93.8 89.4 88.4 3.5 60 89.5 88.7 86.4 86.5 94.6 90.5 89.4 3.470 94.5 94.4 94.1 94.4 95.3 95.5 94.7 0.6Table 44: Results of the analytical characterization of scale up batches 10mg ezetimibe 10 mg obicetrapib - CoatedManufacturing lot number A4459 / 29 / 03 A4459 / 29 / 06 Prototype FDC 2FDC 1 CoatedCoatedTest Method Result Result Appearance Visual White round coated White round coated tablets tabletsAssay HPLCObicetrapib (%claim) 2730 98.3 96.9Ezetimibe (%claim) 2731 101.3 101.6Impurities HPLCIMP RRT0.94 (% claim) 2730 0.06 0.06FROL(% claim) 2730 0.07 0.06MONO-BN FREE(% claim) 2730 0.16 0.16Total impurities of Obicetrapib > 2730 0.29 0.280.05%IMP RRT0.79 (% a / a) 2731 0.05 0.05Ezetimibe□Ketone (%a / a) 2731 0.05 0.05Ezetimibe tetrahydropyran analog 2731 N. D. N. D.(%a / a)Table 44: Results of the analytical characterization of scale up batches 10mg ezetimibe 10 mg obicetrapib - CoatedManufacturing lot number A4459 / 29 / 03 A4459 / 29 / 06Total impurities of Ezetimibe > 2731 0.10 0.100.05%Dissolution Obicetrapib5 min Average 53 60(Min Max) (38 -60) (56 - 66) 10 min Average 89 84(Min Max) Discriminating (84 - 93) (80 - 90) 15 min Average method at pH 100 90(Min Max) 6.80.2 %w / v of (97 - 106) (87 - 97)Tween 80, 5030 min Average 108 98rpm paddle(Min Max) (103 - 112) (95 - 103)speed and 90045 min Average mL vessel 106 98(Min Max) volume (103 - 111) (95 - 102) 60 min Average 103 97(Min Max) (101 - 106) (94 - 102) 70 min Average 102 98(Min Max) (101 - 104) (96 - 101) Dissolution Ezetimibe15 min Average 87 84(Min Max) Dissolution (75 - 91) (76 - 87) 30 min Average method based on 100 94(Min Max) USP method (98 - 101) (87 - 98)conditions at pH45 min Average 4.5, 75 rpm 103 98(Min Max) (102 - 105) (92 - 101)paddle speed60 min Average and 500 mL 104 99(Min Max) vessel volume (103 - 106) (94 - 102) 70 min Average 106 104 (Min Max) (105 - 107) (102 - 106)Water content KF 4.5 % w / w 4.2 % w / wTable 45: XRPD data summary of granules / tablets from scale up batchSample Batch ID XRPDFDC1 ( INTRA-INTRA) Granules A4459 / 29 / 01 OBI + EZEAnhydrousFDC1 (INTRA-INTRA) Tablet uncoated - A4459 / 29 / 02 - A4459 / 29 / 03 OBI + EZEcoated AnhydrousFDC2 (INTRA-EXTRA) Granules A4459 / 29 / 04 OBI + EZEAnhydrousFDC2 (INTRA- EXTRA) Tablet uncoated A4459 / 29 / 05- A4459 / 29 / 06 OBI + EZE- coated Anhydrous8.10. Example 8: Technical batches of FDC1 and FDC2 compositions

[0369] The batch numbers and compositions of the granules, tablets and coated tablets of the technical manufactures of the FDC1 and FDC2 formulations are detailed in Table 49.Table 49: Composition (% w / w) of the granule, tablet and coated tablet of the FDC1 and FDC2 technical batchesFDC2 (ezeetimibe intra - obicetrapib extra) FDC1 (ezetimibe intra - obicetrapib intra) A4459 / 30 A4459 / 30A4459 / 31 / 01 A4459 / 31 / 02 / 01 / 02CoateCoat Coat Component d Table Tablet Tabl ed Tablet Tabl ed Granule Table Granule t (%, et table (%, et table (%, w / w) t (%, w / w) (%,w / w) (mg) t w / w) (mg) t (%, w / w) (mg) (mg) w / w)Intra-granule10.0 10.0 Ezetimibe 7.692 4.348 4.348 10.00 7.018 6.667 6.667 10.000 010.2 Obicetrapib N / A N / A N / A N / A N / A 7.200 6.840 6.840 10.26630.7 13.34 31.2 20.85 Avicel PH 101 23.614 13.347 30.70 21.950 20.853 31.280 7 8 3 Pharmatose 80.3 34.91 81.9 54.6461.771 34.914 80.30 57.516 54.640 81.96 200 M 0 4 6 0 Kollidon 30 1.154 0.652 1.50 0.652 1.50 1.053 1.000 1.50 1.000 1.50 Glycolys 4.615 2.608 6.00 2.608 6.00 4.210 4.000 6.00 4.000 6.00 Kolliphor SLS 1.154 0.652 1.50 0.652 1.50 1.053 1.000 1.50 1.000 1.50 Purified30.000 N / A N / A N / A N / A 30.000 N / A N / A N / A N / A Water130. 56.52 130.0 142. 95.00 142.5 Total Granule 100.000 56.521 100.000 95.00000 1 0 50 0 0 Extra-granule10.2Obicetrapib N / A 4.461 4.461 10.26 N / A N / A N / A N / A N / A 653.1 23.11Avicel PH 200 N / A 23.118 53.17 N / A N / A N / A N / A N / A 7 8Pearlitol 200 20.4N / A 8.900 8.900 20.47 N / A N / A N / A N / A N / A SD 711.5Glycolys N / A 5.000 5.000 11.50 N / A 4.000 6.00 4.000 6.000Aerosil 200 N / A 1.000 2.30 1.000 2.30 N / A N / A N / A N / A N / ALigamed MF- N / A 1.000 2.30 1.000 2.30 N / A 1.000 1.50 1.000 1.50 2-VOpadry AMBN / A N / A N / A 3.000 6.90 N / A N / A N / A 3.000 4.50 II100.00 230. 103.0 236.9 100.00 150. 103.0 154.5 Total Tablet N / A N / A0 00 00 0 0 00 00 0High shear granulation and drying

[0370] The components of the FDC1 granule (batch A4459 / 30 / 02) and FDC2 granule (batch A4459 / 30 / 01) were sieved manually and added to the granulation bowl. For both FDC1 and FDC2 compositions, the batch size of the granule was 2 kg, and, identical processing condition of granulation were used. The physical mixture was blended for 5 mins at 220 rpm and a LOD testing was executed. The granulating agent (purified water) was sprayed and, following spraying, 1 min wet massing was conducted. A sample for XRPD and LOD was taken. Then, the granule was dried using a fluid bed drier. The drying step was concluded as the LOD of the granule was equal or lower than the initial LOD or below 3% (w / w). The granules were tested for content uniformity (only for FDC1), PSD, LOD, sieve analysis, TBD and XRPD.Final Blend and tableting

[0371] The method of preparation of the final blend was described in the previous section (scale-up batches). The FDC2 blend was tested for content uniformity.

[0372] For the generation of a compression profile and for the tableting campaign, a rotary press machine was used. To manufacture FDC1 tablets (150 mg target tablet weight), a 7.0 mm diameter punch was used whereas, for FDC2 tablets (230.0 mg tablet weight) an 8.5 mm diameter punch. The friability, disintegration time, hardness, thickness and appearance of the tablets as well as the individual tablet weight and the tablet weight of ten tablets was monitored during tableting. The tablets were tested for content uniformity (stratified sample: start, middle and end of production), XRPD, dissolution and water content by KF.Coating

[0373] The coating suspension was prepared at 20% (w / w) solid content by adding the required quantity of Opadry to water under stirring. The suspension was mixed for no less than 45 minutes and its visual homogeneity confirmed. Then, the spray rate of the coating suspensionwas measured. The coating suspension was kept under stirring all the time. The weight gain of the tablets was monitored throughout the manufacture and spraying was stopped as the required target gain (3% w / w, 2% w / w - 4% w / w limits) was achieved. The coated tablets were visually inspected and tested for XRPD, dissolution, appearance, content uniformity, and water content by KF.

[0374] All the intermediates of production and the final drug product were stored in the stability chambers with following packaging:• 60mL High Density Polyethylene (HDPE) induction sealed and closed with child resistant cap. The fill count for tablets is 20;• 60mL High Density Polyethylene (HDPE) induction sealed with 2g of desiccant canister and closed with child resistant cap. The fill count for tablets is 20.ResultsTechnical batches of FDC1 and FDC2 compositions

[0375] The high shear granulation of the technical batches was conducted successfully and no issues occurred during the process. The powder consumption was comparable to that observed in the scale-up batches. The drying process was executed within 45 mins as the LOD of the granule was lower than 3%. The granules showed similar PSD values and the quantity of fine particles was relatively large (e.g. the quantity of particles smaller than 125 pm was ca. 70 % - 73 %) (Figure 45). No relevant differences were observed in comparison to the scale-up batches.

[0376] In comparison to the FDC2 scale-up batch (batch A4459 / 29 / 06), the FDC2 technical batch presented harder tablets for similar levels of compression force albeit, the time of disintegration between these batches was very similar for a given value of tablet hardness.Granules chemical characterization

[0377] The granule and the final blend were tested for homogeneity of both obicetrapib and ezetimibe, and were found to be homogeneously dispersed.Tablets chemical characterization

[0378] Chemical characterization of the technical batches coated tablets results are reported in Table 50. The tablets showed a suitable level of quality with the % claims within the typical acceptance criterion for clinical phases (i.e. 90.0 - 110.0 %). The results of the contentuniformity test met the pharmacopoeia requirement of AV < 15.0. Dissolution met the proposed specification for Q=75% at 45 minutes (Figure 46 and Figure 47).Table 50: Results of the analytical characterization of technical batches - CoatedManufacturing lot number A4459 / 31 / 02 A4459 / 31 / 01 Prototype FDC 1 (intra-Intra) FDC 2 (intra-Extra) Test Method Result Result Appearance Visual White round coated White round coated tablet tabletAssay HPLCObicetrapib (%claim) 2730 96.8 94.3Ezetimibe (%claim) 2731 100.8 100.7Impurities HPLCIMP RRT0.93 (% claim) 2730 0.07 < QL (0.05 %)IMP RRT0.94 (% claim) 2730 N. D 0.05FROL(% claim) 2730 0.11 0.06MONO-BN FREE(% claim) 2730 0.15 0.16Total impurities of Obicetrapib > 2730 0.33 0.260.05%IMP RRT0.73 (% a / a) 2731 N. D. N. D.IMP RRT0.79 (% a / a) 2731 O.05 < QL (0.05 %) Ezetimibe□Ketone (%a / a) 2731 0.05 0.05Ezetimibe tetrahydropyran analog 2731 N. D. N. D.(%a / a)Total impurities of Ezetimibe > 2731 0.10 0.050.05%Uniformity of dosage unitsObicetrapib Average % Claim: 98.3 Average % Claim: 96.1Range % Claim: (97.1 Range % Claim: (93.9 USP <905> - 100.4) - 99.0)Ph. Eur. 2.9.40 or AV = 2.4 AV = 4.0 Ezetimibe JP 6.02 by UNIC / Average % Claim: Average % Claim: 99.21190 100.8 Range % Claim: (97.7 - Range % Claim: (99.3 - 101.5)101.5) AV = 2.7AV = 2.4Dissolution Obicetrapib15 min Average 90 85(Min Max) (89 - 92) (82 - 86) 30 min Average Medium pH 6.8+ 96 93(Min Max) 0.2 %w / v of Tween (94 - 97) (92 - 94) 45 min Average 80, 75 rpm paddle 97 95(Min Max) speed and 1000 mL (95 - 98) (93 - 96) 60 min Average vessel volume 97 95(Min Max) (96 - 98) (94 - 97) 70 min Average 97 96(Min Max) (96 - 98) (94 - 97) Dissolution Ezetimibe Dissolution method15 min Average based on USP 84 81(Min Max) method conditions (82 - 87) (72 - 83) 30 min Average at pH 4.5, 75 rpm 96 92(Min Max) paddle speed and (93 - 99) (88 - 94)Table 50: Results of the analytical characterization of technical batches - CoatedManufacturing lot number A4459 / 31 / 02 A4459 / 31 / 0145 min Average 500 mL vessel 99 96 (Min Max) volume (97 - 103) (95 - 97) 60 min Average 102 98 (Min Max) (99 - 105) (97 - 99) 70 min Average 104 102 (Min Max) (101 - 107) (101 - 104)Water content KF 4.0 % w / w 3.7 % w / w Physical properties characterization

[0379] XRPD data of the Granules / T ablets from Technical Batches are summarized in Table 51. All the batches tested showed the absence of EZE hydrate with exception of the granules from the FDC2 formulation. However, the hydrate form disappears in the coated tablet. Both batches of Granules show similar flowability. PSD data of granules are reported in Table 52 and in Figure 48. Batches show similar bi-modal curves.Table 51: XRPD data summary of granules / tablets from technical batchesSample Batch ID XRPDFDC2 ( INTRA-EXTRA) Granules A4459 / 30 / 01 OBI + EZE Anhydrous + small amount EZE hydrateFDC2 (INTRA- EXTRA) Tablet coated A4459 / 31 / 01 OBI + EZE AnhydrousFDC1 (INTRA-INTRA) Granules A4459 / 30 / 02 OBI + EZE AnhydrousFDC1 (INTRA- INTRA) Tablet coated A4459 / 31 / 02 OBI + EZE AnhydrousTable 52: PSD data summary of granules from technical batchesDvl0( xlO) Dv50 Dv90 Span(x50) (x90)Granules FDC2 38.70 87.20 184.73 1.67A4459 / 30 / 01Granules FDC1 34.17 82.42 275.71 2.92A4459 / 30 / 02Stability studies

[0380] A summary of physicochemical analysis of technical batches after three months of storage for FDC2 composition is provided in Table 53 (without desiccant) and Table 54 (with desiccant), and for FDC1 composition in Table 55 (without desiccant) and Table 56 (with desiccant).Table 53: Long-term and accelerated storage stability results for FDC2 technical batch no. A4459 / 31 / 01 (without desiccant) _Storage Time Appearan. / Co OBICETRA DIASTEREOISO ETHYL FROL MONOConditio (Mont lour PIB (TA- MER Amount ESTER Amount BN n hs) APP / 1001 8995) HPLC / 2730 (% Amount HPLC / 2 FREE (Individual) Amount claim) HPLC / 2 730 (% Amount HPLC / 2730 (Mean) 730 (% claim) HPLC / 2 (% claim) claim) (Mean) 730 (% (Mean) (Mean) claim)(Mean) Specificat N / A White to off- NGT 0.3 NGT 0.3 NGT 0.3 ion white round 90.0-110.0 % NGT 0.3 % claim% claim % claim % claim coated tablet claimInitial 0 White round 94.3 <0.05 <0.05 0.06 0.16 coated tablet25°C / 60% 1 White round 96.7 <0.05 <0.05 0.07 0.16 RH coated tabletPackaged 3 White round 95.5 <0.05 <0.05 0.07 0.16 coated tablet30°C / 65% 1 White round 95.6 <0.05 <0.05 0.07 0.16 RH coated tabletPackaged40°C / 75% 1 White round 95.5 <0.05 <0.05 0.07 0.16 RH coated tabletPackaged 3 White round 95.3 <0.05 <0.05 0.07 0.16coated tabletTable 53 (Contd.)Storage Time IMP_RRT0. IMP_RRT0. Total EZETIMI EZETIMI EZETIMI Condition (Month 93 Amount 94 Amount degradatio BE BE BE s) HPLC / 2730 HPLC / 2730 n products Amount CYCLIC KETONE (% claim) (% claim) equal / great HPLC / 273 Amount Amount (Mean) (Mean) er than 1 (% HPLC / 273 HPLC / 2730.05% claim) 1 (% 1 (% claim (% (Mean) claim) claim) claim) (Mean) (Mean) (Mean)Specificati N / A NGT 0.3 % NGT 0.3 % NGT 2.0 % 90.0-110.0 NGT 0.5 % NGT 0.5 % on claim claim claim % claim claim claim Initial 0 <0.05 0.05 0.26 100.7 <0.05 0.05 25°C / 60% 1 <0.05 <0.05 0.23 103.0 <0.05 0.05 RH 3 <0.05 0.06 0.29 103.2 <0.05 <0.05 Packaged30°C / 65% 1 <0.05 <0.05 0.23 102.2 <0.05 0.05 RHPackaged40°C / 75% 1 <0.05 <0.05 0.23 101.6 <0.05 0.06 RH 3 <0.05 0.07 0.30 103.1 <0.05 0.05PackagedTable 53 (contd.)Storage Time IMP RRT IMP RRT IMP RRT Total Time Time Conditio (Mont 0.73 0.79 3.11 degradati point(min) point(min) n hs) Amount Amount Amount on 15 15HPLC / 273 HPLC / 273 HPLC / 273 products OBICETRA OBICETRA 1 (% 1 (%claim) 1 (%claim) greater / eq PIB (TA- PIB (TA- claim) (Mean) (Mean) ual than 8995) 8995) (Mean) 0.05% DISS / 1295 DISS / 1295 claim (% claim) (% claim) (Mean) (Mean) (Range) Specificat N / A NGT 0.5 % NGT 0.5 % NGT 0.5 % NGT 2.0ion claim claim claim % claim Report result Report result Initial 0 <0.05 <0.05 - 0.05 85 82 - 86 25°C / 60% 1 <0.05 0.05 <0.05 0.10 85 80 - 91 RH 3 <0.05 0.05 <0.05 0.05 87 85 - 95 Packaged30°C / 65% 1 <0.05 0.05 <0.05 0.10 89 87 - 91 RHPackaged40°C / 75% 1 <0.05 0.05 <0.05 0.10 85 84 - 88 RH 3 <0.05 0.05 <0.05 0.10 85 83 - 88PackagedTable 53 (contd.)Storage Time Time Time Time Time Time Time Conditio (Mont point(min) point(min) point(min) point(min) point(min) point(min) n hs) 30 30 45 45 60 60OBICETR OBICETR OBICETR OBICETR OBICETR OBICETR APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- 8995) 8995) 8995) 8995) 8995) 8995) DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Mean) (Range) (Mean) (Range) (Mean) (Range) Specifica N / A Report result Report result Complies Report result Report result Report result tion with EP,USP, JPwhereQ = 75% at45 minutesInitial 0 93 92 - 94 95 93 - 96 95 94 - 97 25°C / 60 1 98 94 - 104 98 94 - 104 99 95 - 104 % RH 3 96 94 - 98 98 96 - 99 97 96 - 100 Packaged30°C / 65 1 99 97 - 101 99 97 - 101 100 97 - 102 % RHPackaged40°C / 75 1 95 93 - 98 96 94 - 99 97 95 - 100 % RH 3 95 93 - 97 97 95 - 99 97 94 - 98PackagedTable 53 (contd.)Storage Time Time Time Time Time Time Time Condition (Month point(min) point(min) point(min) point(min) point(min) point(min) s) 70 70 15 15 30 30OBICETRA OBICETRA EZETIMI EZETIMI EZETIMI EZETIMI PIB (TA- PIB (TA- BE BE BE BE 8995) 8995) DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1295 DISS / 1295 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Mean) (Range) (Mean) (Range) (Mean) (Range)Specificati N / A Report result Report result Report Report Report Report on result result result result Initial 0 96 94 - 97 81 72 - 83 92 88 - 94 25°C / 60% 1 99 96 - 104 79 65 - 87 95 87 - 101 RH 3 97 96 - 100 85 82 - 88 95 92 - 100 Packaged30°C / 65% 1 100 97 - 102 88 86 - 90 95 93 - 97 RHPackaged40°C / 75% 1 97 95 - 100 80 58 - 88 91 74 - 97 RH 3 97 94 - 99 80 75 - 84 93 90 - 94PackagedTable 53(contd.)Storage Time Time Time Time Time Time Time Condition (Month point(min) point(min) point(min) point(min) point(min) point(min) s) 45 45 60 60 70 70EZETIMI EZETIMI EZETIMI EZETIMI EZETIMI EZETIMI BE BE BE BE BE BE DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Mean) (Range) (Mean) (Range) (Mean) (Range) Specificati N / A Complies Report Report Report Report Report on with EP, result result result result result USP, JPwhereQ = 75% at45 minutesInitial 0 96 95 - 97 98 97 - 99 102 101 - 104 25°C / 60% 1 99 94 - 105 99 96 - 103 106 103 - 108 RH 3 98 95 - 103 100 96 - 105 103 100 - 105 Packaged30°C / 65% 1 98 96 - 101 99 97 - 102 103 100 - 105 RHPackaged40°C / 75% 1 94 79 - 101 97 82 - 102 104 101 - 106 RH 3 98 97 - 101 101 101 - 104 105 102 - 107PackagedTable 53(contd.)Storage Time Water Strength Strength Strength Strength Condition (Months) content RESR / 1001 RESR / 1001 RESR / 1001 RESR / 1001UMID / 1231 (N) (N) (Kp) (Kp) (% w / w) (Mean) (Range) (Mean) (Range) (Mean)Specification N / A Report Report Report Report Results Report Results Results Results ResultsInitial 0 3.7 92 81 - 99 9.36 8.26 - 10.10 25°C / 60% RH 1 3.8 109 98 - 123 11.15 9.99 - 12.54 Packaged 3 4.1 116 104 - 124 11.81 10.61 - 12.64 30°C / 65% RH 1 4.0 109 97 - 128 11.09 9.89 - 13.05 Packaged40°C / 75% RH 1 4.2 100 95 - 105 10.22 9.69 - 10.71Packaged 3 4.8 93 84 - 107 9.45 8.57 - 10.91 N / A: Not ApplicableTable 54: Long-term and accelerated storage stability results for FDC1 technical batch no. A4459 / 31 / 02 (without desiccant) _Storage Time Appearan. / C OBICETR DIASTEREOIS ETHYL FROL MONOConditio (Mont olour APIB (TA- OMER Amount ESTER Amount BN n hs) APP / 1001 8995) HPLC / 2730 (% Amount HPLC / 2 FREE (Individual) Amount claim) HPLC / 2 730 (% Amount HPLC / 2730 (Mean) 730 (% claim) HPLC / 2 (% claim) claim) (Mean) 730 (% (Mean) (Mean) claim)(Mean) Specifica N / A White to off- NGT 0.3 NGT 0.3 NGT 0.3 tion white round 90.0-110.0 NGT 0.3 % claim% claim % claim % claim coated tablet % claimInitial 0 White round 96.7 <0.05 <0.05 0.11 0.15 coated tablet25°C / 60 1 White round 97.7 <0.05 <0.05 0.11 0.16 % RH coated tabletPackaged 3 White round 98.4 <0.05 <0.05 0.11 0.16 coated tablet30°C / 65 1 White round 97.7 <0.05 <0.05 0.11 0.16 % RH coated tabletPackaged40°C / 75 1 White round 97.4 <0.05 <0.05 0.12 0.16 % RH coated tabletPackaged 3 White round 98.2 <0.05 <0.05 0.11 0.16coated tabletTable 54(contd.)Storage Time IMP_RRT0. IMP_RRT0. Total EZETIMI EZETIMI EZETIMI Condition (Month 93 Amount 94 Amount degradatio BE BE BEs) HPLC / 2730 HPLC / 2730 n products Amount CYCLIC KETONE (% claim) (% claim) equal / great HPLC / 273 Amount Amount (Mean) (Mean) er than 1 (% HPLC / 273 HPLC / 2730.05% claim) 1 (% 1 claim (% (Mean) claim) (%claim) claim) (Mean) (Mean) (Mean)Specificati N / A NGT 0.3 % NGT 0.3 % NGT 2.0 % 90.0-110.0 NGT 0.5 % NGT 0.5 % on claim claim claim % claim claim claim Initial 0 0.07 <0.05 0.33 100.8 <0.05 0.05 25°C / 60% 1 0.07 <0.05 0.35 102.6 <0.05 0.05 RH 3 0.06 <0.05 0.33 104.0 <0.05 <0.05 Packaged30°C / 65% 1 0.07 <0.05 0.35 103.1 <0.05 0.05 RHPackaged40°C / 75% 1 0.07 <0.05 0.34 103.6 <0.05 0.05 RH 3 0.07 <0.05 0.34 104.3 <0.05 <0.05PackagedTable 54 (contd.)Storage Time IMP RRT IMP RRT IMP RRT Total Time Time Conditio (Mont 0.73 0.79 3.11 degradati point(min) point(min) n hs) Amount Amount Amount on 15 15HPLC / 273 HPLC / 273 HPLC / 273 products OBICETRA OBICETRA 1 (% 1 (%claim) 1 (%claim) greater / eq PIB (TA- PIB (TA- claim) (Mean) (Mean) ual than 8995) 8995) (Mean) 0.05% DISS / 1295 DISS / 1295 claim (% claim) (% claim) (Mean) (Mean) (Range) Specificat N / A NGT 0.5 % NGT 0.5 % NGT 0.5 % NGT 2.0 %ion claim claim claim claim Report result Report result Initial 0 <0.05 0.05 - 0.10 90 89 - 92 25°C / 60% 1 <0.05 0.05 <0.05 0.10 94 93 - 95 RH 3 <0.05 0.05 <0.05 0.05 91 90 - 95 Packaged30°C / 65% 1 <0.05 0.05 <0.05 0.10 94 93 - 95 RHPackaged40°C / 75% 1 <0.05 0.05 <0.05 0.10 93 91 - 94 RH 3 <0.05 0.05 <0.05 0.05 90 89 - 91PackagedTable 54(contd.)Storage Time Time Time Time Time Time Time Conditio (Mont point(min) point(min) point(min) point(min) point(min) point(min) n hs) 30 30 45 45 60 60OBICETR OBICETR OBICETR OBICETR OBICETR OBICETR APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- 8995) 8995) 8995) 8995) 8995) 8995) DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Mean) (Range) (Mean) (Range) (Mean) (Range) Specifica N / A Report Report Complies Report Report Report tion results results with EP, results results results USP, JPwhereQ = 75% at45 minutesInitial 0 96 94 - 97 97 95 - 98 97 96 - 98 25°C / 60 1 99 97 - 100 99 99 - 100 99 98 - 101 % RH 3 100 97 - 102 101 97 - 108 99 97 - 102 Packaged30°C / 65 1 100 97 - 103 100 98 - 101 100 98 - 101 % RHPackaged40°C / 75 1 99 98 - 100 100 98 - 101 100 98 - 101 % RH 3 99 97 - 101 99 98 - 101 99 98 - 101PackagedTable 54(contd.)Storage Time Time Time Time Time Time Time Condition (Month point(min) point(min) point(min) point(min) point(min) point(min) s) 70 70 15 15 30 30OBICETRA OBICETRA EZETIMI EZETIMI EZETIMI EZETIMI PIB (TA- PIB (TA- BE BE BE BE 8995) 8995) DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1295 DISS / 1295 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Mean) (Range) (Mean) (Range) (Mean) (Range)Specificati N / A Report result Report result Report Report Report Report on result result result result Initial 0 97 96 - 98 84 82 - 87 96 93 - 99 25°C / 60% 1 99 98 - 101 85 73 - 89 98 97 - 100 RH 3 99 96 - 101 89 85 - 91 99 94 - 101 Packaged30°C / 65% 1 100 98 - 101 89 83 - 93 96 91 - 100 RHPackaged40°C / 75% 1 100 99 - 101 90 87 - 91 98 96 - 100 RH 3 99 98 - 101 86 81 - 90 98 92 - 102PackagedTable 54 (contd.)Storage Time Time Time Time Time Time Time Condition (Month point(min) point(min) point(min) point(min) point(min) point(min) s) 45 45 60 60 70 70EZETIMI EZETIMI EZETIMI EZETIMI EZETIMI EZETIMI BE BE BE BE BE BE DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Mean) (Range) (Mean) (Range) (Mean) (Range) Specificati N / A Complies Report Report Report Report Report on with EP, result result result result result USP, JPwhereQ = 75% at45 minutesInitial 0 99 97 - 103 102 99 - 105 104 101 - 107 25°C / 60% 1 104 103 - 105 105 104 - 107 107 105 - 109 RH 3 103 98 - 105 105 100 - 106 106 102 - 107 Packaged30°C / 65% 1 98 94 - 103 101 96 - 105 104 102 - 107 RHPackaged40°C / 75% 1 101 98 - 103 103 100 - 104 105 103 - 107 RH 3 102 96 - 107 104 98 - 108 106 102 - 109PackagedTable 54(contd.)Storage Time Water Strength Strength Strength Strength Condition (Months) content RESR / 1001 RESR / 1001 RESR / 1001 RESR / 1001UMID / 1231 (N) (N) (Kp) (Kp) (% w / w) (Mean) (Range) (Mean) (Range) (Mean)Specification NA Report result Report result Report result Report result Report result Initial 0 4.0 - - - - 25°C / 60% RH 1 4.2 74 70 - 76 7.58 7.14 -7.75 Packaged 3 4.6 70 66 -78 7.17 6.73 -7.95 30°C / 65% RH 1 4.4 73 70 -77 7.46 7.14 -7.85 Packaged40°C / 75% RH 1 4.8 65 61 -69 6.62 6.22 -7.04Packaged 3 5.5 60 57 -63 6.10 5.81 -6.42 N / A: Not ApplicableTable 55: Long-term and accelerated storage condition results for FDC2 technical batch no. A4459 / 31 / 01 (with desiccant)Storage Time Appearan. / Co OBICETRA DIASTEREOISO ETHYL FROL MONOConditio (Mont lour PIB (TA- MER Amount ESTER Amount BN n hs) APP / 1001 8995) HPLC / 2730 (% Amount HPLC / 2 FREE (Individual) Amount claim) HPLC / 2 730 (% Amount HPLC / 2730 (Mean) 730 (% claim) HPLC / 2 (% claim) claim) (Mean) 730 (% (Mean) (Mean) claim)(Mean) Specificat White to off- NGT 0.3 NGT 0.3 NGT 0.3 ion white round 90.0-110.0 % NGT 0.3 % claim% claim % claim % claim coated tablet claimInitial 0 White round 94.3 <0.05 <0.05 0.06 0.16 coated tablet25°C / 60% 3 White round 96.4 <0.05 <0.05 0.07 0.16 RH coated tabletPackaged40°C / 75% 3 White round 96.3 <0.05 <0.05 0.07 0.16 RH coated tabletPackagedTable 55(contd.)Storage Time IMP_RRT0. IMP_RRT0. Total EZETIMI EZETIMI EZETIMI Condition (Month 93 Amount 94 Amount degradatio BE BE BEs) HPLC / 2730 HPLC / 2730 n products Amount CYCLIC KETONE (% claim) (% claim) equal / great HPLC / 273 Amount Amount (Mean) (Mean) er than 1 (% HPLC / 273 HPLC / 2730.05% claim) 1 (% 1 (% claim (% (Mean) claim) claim) claim) (Mean) (Mean) (Mean)Specificati NGT 0.3 % NGT 0.3 % NGT 2.0 % 90.0-110.0 NGT 0.5 % NGT 0.5 % on claim claim claim % claim claim claim Initial 0 <0.05 0.05 0.26 100.7 <0.05 0.05 25°C / 60% 3 <0.05 0.07 0.30 103.5 <0.05 <0.05 RHPackagedStorage Time IMP_RRT0. IMP_RRT0. Total EZETIMI EZETIMI EZETIMI Condition (Month 93 Amount 94 Amount degradatio BE BE BE s) HPLC / 2730 HPLC / 2730 n products Amount CYCLIC KETONE (% claim) (% claim) equal / great HPLC / 273 Amount Amount (Mean) (Mean) er than 1 (% HPLC / 273 HPLC / 2730.05% claim) 1 (% 1 (% claim (% (Mean) claim) claim) claim) (Mean) (Mean) (Mean)Specificati NGT 0.3 % NGT 0.3 % NGT 2.0 % 90.0-110.0 NGT 0.5 % NGT 0.5 % on claim claim claim % claim claim claim 40°C / 75% 3 <0.05 0.06 0.29 104.1 <0.05 <0.05 RHPackagedTable 55(contd.)Storage Time IMP RRT IMP RRT Total Time Time Time Conditio (Mont 0.73 0.79 degradati point(min) point(min) point(min) n hs) Amount Amount on 15 15 30HPLC / 273 HPLC / 273 products OBICETRA OBICETRA OBICETRA 1 1 greater / eq PIB (TA- PIB (TA- PIB (TA- (%claim) (%claim) ual than 8995) 8995) 8995) (Mean) (Mean) 0.05% DISS / 1295 DISS / 1295 DISS / 1295 claim (% claim) (% claim) (% claim) (Mean) (Mean) (Range) (Mean) Specificat NGT 0.5 % NGT 0.5 % NGT 2.0 Report Report Report ion claim claim % claim Results Results Results Initial 0 <0.05 <0.05 0.05 85 82 - 86 93 25°C / 60% 3 <0.05 0.05 0.05 85 83 - 86 93 RHPackaged40°C / 75% 3 <0.05 0.06 0.06 83 82 - 85 92 RHPackagedTable 55(contd.)Storage Time Time Time Time Time Time Time Conditio (Mont point(min) point(min) point(min) point(min) point(min) point(min) n hs) 30 45 45 60 60 70OBICETR OBICETR OBICETR OBICETR OBICETR OBICETR APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- 8995) 8995) 8995) 8995) 8995) 8995) DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Range) (Mean) (Range) (Mean) (Range) (Mean) Specifica Report Complies Report Report Report Report tion Results with EP, Results Results Results Results USP, JPwhereQ = 75% at45 minutesInitial 0 92 - 94 95 93 - 96 95 94 - 97 96 25°C / 60 3 92 - 95 95 93 - 97 95 93 - 97 95 % RHPackaged40°C / 75 3 91 - 93 95 93 - 95 95 93 - 96 95 % RHPackagedTable 55(contd.)Storage Time Time Time Time Time Time Time Condition (Month point(min) 70 point(min) point(min) point(min) point(min) point(min) s) OBICETRAP 15 15 30 30 45IB (TA-8995) EZETIMI EZETIMI EZETIMI EZETIMI EZETIMI DISS / 1295 BE BE BE BE BE (% claim) DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 (Range) (% claim) (% claim) (% claim) (% claim) (% claim)(Mean) (Range) (Mean) (Range) (Mean) Specificati Report Results Report Report Report Report Complies on Results Results Results Results with EP,USP, JP where Q = 75% at 45 minutes Initial 0 94 - 97 81 72 - 83 92 88 - 94 96 25°C / 60% 3 93 - 97 81 60 - 87 95 85 - 99 97 RHPackaged40°C / 75% 3 93 - 96 86 83 - 88 94 91 - 96 96 RHPackagedTable 55(contd.)Storage Time Time Time Time Time Time Water Condition (Month point(min) point(min) point(min) point(min) point(min) content s) 45 60 60 70 70 UMID / 12EZETIMIB EZETIMIB EZETIMIB EZETIMIB EZETIMIB 31 (% E E E E E w / w) DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 (Mean) (% claim) (% claim) (% claim) (% claim) (% claim)(Range) (Mean) (Range) (Mean) (Range)Specificati Report Report Report Report Report Report on Results Results Results Results Results Results Initial 0 95 - 97 98 97 - 99 102 101 - 104 3.7 25°C / 60% 3 89 - 101 99 92 - 103 103 100 - 104 2.9 RHPackaged40°C / 75% 3 93 - 98 98 95 - 100 103 102 - 104 3.3 RHPackagedTable 55 (contd.)Storage Condition Time Strength Strength Strength Strength (Months) RESR / 1001 RESR / 1001 RESR / 1001 RESR / 1001 (N) (N) (Kp) (Kp) (Mean) (Range) (Mean) (Range) Specification Report Results Report Results Report Results Report Results Initial 0 92 81 - 99 9.36 8.26 - 10.10 25°C / 60% RH 3 115 110 - 120 11.70 11.22 - 12.24 Packaged40°C / 75% RH 3 114 102 - 127 11.59 10.40 - 12.95PackagedTable 56: Long-term and accelerated storage condition results for FDC1 technical batch no. A4459 / 31 / 02 (with desiccant)Storage Time Appearan. / Co OBICETRA DIASTEREOISO ETHYL FROL MONOConditio (Mont lour PIB (TA- MER Amount ESTER Amount BN n hs) APP / 1001 8995) HPLC / 2730 (% Amount HPLC / 2 FREE (Individual) Amount claim) HPLC / 2 730 (% Amount HPLC / 2730 (Mean) 730 (% claim) HPLC / 2 (% claim) claim) (Mean) 730 (% (Mean) (Mean) claim)(Mean) Specificat NA White to off- NGT 0.3 NGT 0.3 NGT 0.3 ion white round 90.0-110.0 % NGT 0.3 % claim% claim % claim % claim coated tablet claimInitial 0 White round 96.7 <0.05 <0.05 0.11 0.15 coated tablet25°C / 60% 3 White round 98.0 <0.05 <0.05 0.11 0.16 RH coated tabletPackaged40°C / 75% 3 White round 98.1 <0.05 <0.05 0.11 0.16 RH coated tabletPackagedTable 56(contd.)Storage Time IMP_RRT0. IMP_RRT0. Total EZETIMI EZETIMI EZETIMI Condition (Month 93 Amount 94 Amount degradatio BE BE BE s) HPLC / 2730 HPLC / 2730 n products Amount CYCLIC KETONE (% claim) (% claim) equal / great HPLC / 273 Amount Amount (Mean) (Mean) er than 1 (% HPLC / 273 HPLC / 2730.05% claim) 1 1 claim (% (Mean) (%claim) (%claim) claim) (Mean) (Mean) (Mean)Specificati NGT 0.3 % NGT 0.3 % NGT 2.0 % 90.0-110.0 NGT 0.5 % NGT 0.5 % on claim claim claim % claim claim claim Initial 0 0.07 <0.05 0.33 100.8 <0.05 0.05 25°C / 60% 3 0.06 <0.05 0.34 104.7 <0.05 <0.05 RHPackaged40°C / 75% 3 0.07 <0.05 0.34 105.3 <0.05 <0.05 RHPackagedTable 56(contd.)Storage Time IMP RRT IMP RRT Total Time Time Time Conditio (Mont 0.73 0.79 degradati point(min) point(min) point(min) n hs) Amount Amount on 15 15 30HPLC / 273 HPLC / 273 products OBICETRA OBICETRA OBICETRA 1 1 (% greater / eq PIB (TA- PIB (TA- PIB (TA- (%claim) claim) ual than 8995) 8995) 8995) (Mean) (Mean) 0.05% DISS / 1295 DISS / 1295 DISS / 1295 claim (% claim) (% claim) (% claim) (Mean) (Mean) (Range) (Mean) Specificat NGT 0.5 % NGT 0.5 % NGT 2.0 Report Report Report ion claim claim % claim Results Results ResultsInitial 0 <0.05 0.05 0.10 90 89 - 92 96Storage Time IMP RRT IMP RRT Total Time Time Time Conditio (Mont 0.73 0.79 degradati point(min) point(min) point(min) n hs) Amount Amount on 15 15 30HPLC / 273 HPLC / 273 products OBICETRA OBICETRA OBICETRA 1 1 (% greater / eq PIB (TA- PIB (TA- PIB (TA- (%claim) claim) ual than 8995) 8995) 8995) (Mean) (Mean) 0.05% DISS / 1295 DISS / 1295 DISS / 1295 claim (% claim) (% claim) (% claim) (Mean) (Mean) (Range) (Mean) Specificat NGT 0.5 % NGT 0.5 % NGT 2.0 Report Report Report ion claim claim % claim Results Results Results 25°C / 60% 3 <0.05 0.05 0.05 89 88 - 90 97 RHPackaged40°C / 75% 3 <0.05 0.05 0.05 88 87 - 89 95 RHPackagedTable 56(contd.)Storage Time Time Time Time Time Time Time Conditio (Mont point(min) point(min) point(min) point(min) point(min) point(min) n hs) 30 45 45 60 60 70OBICETR OBICETR OBICETR OBICETR OBICETR OBICETR APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- APIB (TA- 8995) 8995) 8995) 8995) 8995) 8995) DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 DISS / 1295 (% claim) (% claim) (% claim) (% claim) (% claim) (% claim) (Range) (Mean) (Range) (Mean) (Range) (Mean) Specifica Report Complies Report Report Report Report tion Results with EP, Results Results Results Results USP, JPwhereQ = 75% at45 minutesInitial 0 94 - 97 97 95 - 98 97 96 - 98 97 25°C / 60 3 96 - 98 98 97 - 98 98 97 - 98 98 % RHPackaged40°C / 75 3 94 - 97 96 95 - 97 96 95 - 98 96 % RHPackagedTable 56(contd.)Storage Time Time Time Time Time Time Time Condition (Month point(min) 70 point(min) point(min) point(min) point(min) point(min) s) OBICETRAP 15 15 30 30 45IB (TA-8995) EZETIMI EZETIMI EZETIMI EZETIMI EZETIMI DISS / 1295 BE BE BE BE BE (% claim) DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 (Range) (% claim) (% claim) (% claim) (% claim) (% claim)(Mean) (Range) (Mean) (Range) (Mean) Specificati Report Results Report Report Report Report Complies on Results Results Results Results with EP,USP, JP where Q = 75% at 45 minutes Initial 0 96 - 98 84 82 - 87 96 93 - 99 99 25°C / 60% 3 97 - 99 92 90 - 94 100 98 - 102 104 RHPackaged40°C / 75% 3 95 - 97 90 87 - 92 102 98 - 104 105 RHPackagedTable 56(contd.)Storage Time Time Time Time Time Time Water Condition (Month point(min) point(min) point(min) point(min) point(min) content s) 45 60 60 70 70 UMID / 12EZETIMIB EZETIMIB EZETIMIB EZETIMIB EZETIMIB 31 (% E E E E E w / w) DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 DISS / 1298 (Mean) (% claim) (% claim) (% claim) (% claim) (% claim)(Range) (Mean) (Range) (Mean) (Range)Specificati Report Report Report Report Report Report on Results Results Results Results Results Results Initial 0 97 - 103 102 99 - 105 104 101 - 107 4.0 25°C / 60% 3 102 - 105 106 104 - 107 108 106 - 109 3.5 RHPackaged40°C / 75% 3 102 - 109 107 103 - 109 107 105 - 110 3.7 RHPackagedTable 56 (contd.)Storage Condition Time Strength Strength Strength Strength (Months) RESR / 1001 RESR / 1001 RESR / 1001 RESR / 1001 (N) (N) (Kp) (Kp) (Mean) (Range) (Mean) (Range) Specification NA Report Results Report Results Report Results Report Results Initial 0 - - - - 25°C / 60% RH 3 77 69 - 84 7.89 7.04 - 8.57 Packaged40°C / 75% RH 3 77 69 - 82 7.86 7.04 - 8.36PackagedN / A: Not Applicable8.11. Example 9: Study to evaluate the comparative bioavailability of two fixed- dose combination formulations of obicetrapib / ezetimibe 10 mg / 10 mg (FDC1 and FDC2) with obicetrapib, 10 mg co-administered with ezetimibe, 10 mg in healthy adult subjects under fasted conditions8.11.1. Study design

[0381] This was an open-label, single-dose, randomized, three-treatment, three-period, six-sequence crossover study comparing the two test products and coadministration of the reference products under fasted conditions. In each of the study periods, the subjects received either Treatment T1

[0382] (1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC1 tablet [Formulation #1]), Treatment T2 ( lx obicetrapib, 10 mg and ezetimibe, 10 mg FDC2 tablet [Formulation #2]), or Treatment R (1 X obicetrapib tablet, 10 mg co-administered with 1 x ZETIA® (ezetimibe) tablet, 10 mg) following an overnight fast of at least 10 hours. The order of administration followed a six sequence randomization schedule. Blood samples were collected at pre-dose and at intervals over 336 hours after dosing in each study period. Subjects were confined at the clinical facility from at least 10 horns before dosing until 24 hours after dosing in each study period and returned to the clinical facility for the 48-, 72-, 96-, 144-, 192-, 240-, and 336-hour post-dose blood sample collections. The interval between doses were at least 49 days.

[0383] The plasma concentrations of obicetrapib, ezetimibe and its metabolite, ezetimibe glucuronide were measured by fully validated analytical methods. Statistical analysis using average bioequivalence methodology were performed to evaluate the bioavailability of each of the test formulations relative to that of the coadministration of the reference products.8.11.2. Selection of study population

[0384] The subject population included 36 healthy, non -tobacco-, non-nicotine-using, adult male andf emale subjects.8.11.3. Treatment administration

[0385] The subjects received Treatment Tl, Treatment T2, or Treatment R according to a three treatment, three-period, six-sequence randomization schedule (Table 57) under direct observation following an overnight fast of at least 10 hours.• Treatment T1: 1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #1)• Treatment T2: 1 x obicetrapib, 10 mg and ezetimibe, 10 mg FDC Tablet (Formulation #2) • TreatmentR: 1 X obicetrapib Tablet, 10 mg co-administered with 1 XZETIA® (ezetimibe) Tablet, 10 mgTable 57Sequence Period 1 Period 2 Period 31 T1 T2 R2 T2 T1 R3 R T1 T24 T1 T2 R5 T2 T1 R6 R T1 T2

[0386] Each dose was administered with 240 mL of room temperature water. Subjects were instructed to swallow the tablet(s) whole without chewing or biting.Sample Collection, Handling and Bioanalytical PlansSample Size• 4 mL collections (K2EDTA vacutainers) for analysis of obicetrapib• 4 mL collections (K2EDTA vacutainers) for analysis of ezetimibe and ezetimibe glucuronideCollection TimesPre-dose samples were collected within 60 minutes before dosing. All times are relative to the dosing minute.For analysis of obicetrapib: Pre-dose (0-hour) and at 0.50,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0*, 96.0*, 144.0*, 192.0*, 240.0* and 336.0* hours postdose (*return sample)For analysis of ezetimibe and ezetimibe glucuronide: Pre-dose (0-hour) and at 0.25, 0.50, 0.75,1.0, 1.333, 1.667, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, 12.0, 16.0, 20.0, 24.0, 48.0*, 72.0* and 96.0* hours post-dose (*return sample)Total number of collections per period / per subject: 49Total blood volume per subject: The total volume of blood collected for pharmacokinetic sampling was approximately 588 mL.

[0387] Sample Processing for analysis of obicetrapib: Blood samples were collected in room temperature 4 mL K2EDTA vacutainers. After collection, the samples were mixed by gently inverting the tube several (i.e., 8-10) times and placed in an ice / water bath. The samples were then placed in the centrifuge and spin at 3000 rpm for 10 minutes at 4°C. The resulting plasma was separated into two aliquots (at least 1.0 mL in Aliquot 1 and remainder in aliquot 2) and transferred into polypropylene sample storage tubes and stored at -70°C (± 10°C) until ready for shipment to the bioanalytical laboratory. The plasma aliquots were placed in the freezer within 30 minutes after sample collection. After collection until placement in the freezer, blood / plasma samples were kept cooled in an ice / water bath.

[0388] Sample Processing for analysis of ezetimibe and ezetimibe glucuronide: Blood samples were collected in room temperature 4 mL K2EDT A vacutainers. After collection, the samples were mixed gently by inverting the tube several (at least 8) times and placed in an ice / water bath. The samples were then placed in the centrifuge and spin at 3000 rpm for 10 minutes at 4°C. The resulting plasma was separated into two aliquots (at least 1.0 mL in Aliquot 1 and remainder in Aliquot 2) and transferred into polypropylene sample storage tubes (e.g., Sarstedt #60.546) and stored at -70°C (or colder) until ready for shipment to the bioanalytical laboratory. After collection until placement in the freezer, blood / plasma samples were kept cooled in an ice / water bath.Pharmacokinetic analysis

[0389] For all treatments, the following pharmacokinetic parameters were calculated for obicetrapib, ezetimibe and its metabohte, ezetimibe glucuronide.Primary PK parameters

[0390] Cmax: Maximum measured plasma concentration.

[0391] AUCo-t: Area under the plasma concentration versus time curve from time zero to the last measurable plasma concentration, as calculated by linear trapezoidal method.

[0392] AUCo-«>: Area under the plasma concentration versus time curve from time zero to infinity where AUCo-co = AUCo-t + Ct / z. Ct is the last measurable concentration and Az is the terminal disposition rate constant.Secondary PK parameters

[0393] Tmax: Time of the maximum measured plasma concentration. If the maximum value occured at more than one time point, Tmax is defined as the first time point with this value.

[0394] kz: Apparent first-order terminal disposition rate constant. This parameter was calculated from the negative of the slope of the dataset with the best -fit least-squares linear regression analysis of the terminal in-linear concentration-time data. The number of data points (3 or more) in the terminal phase (not including Cmax) was included in the final regression analysis for an evaluable kz was determined from the dataset that has the highest adjusted Rsquared (R2) value of 0.7 or more. kz was considered non-evaluable if (1) the last three terminal points were used to determine kz and either the middle or the last point was higher than the preceding point or (2) the resulting adjusted R2value was less than 0.7.

[0395] An evaluable kz was considered not reliable and not reportable if the resulting apparent first-order terminal half-life (t 1 / 2,) value was longer than the time interval over which kz was estimated. If the resulting 11 / 2, value was longer than the time interval over which kz was determined, an interval that was longer than the estimated 11 / 2, was explored. The interval with the next highest adjusted R2value was chosen and the decrease in the adjusted R2value was assessed to determine if a reliable estimation of the kz was possible. If kz was deemed not reliable then no 11 / 2, and AUCo-co values were reported for that dataset.

[0396] 11 / 2: The first-order terminal disposition half-life was calculated as ln(2) / kzData set for analysis and statistical methods

[0397] Linear and semi -logarithmic graphs of the concentration -time profiles for each subject were provided, using the actual times of sample collections. Actual sample collection time were used for calculating the pharmacokinetic parameters. Plasma concentration data from all evaluable subjects with no significant protocol deviation(s) were used for estimation of Cmax and / or AUCs from at least two periods of the study, one of which includes Treatment R.

[0398] PK parameters from any subject who experienced emesis within two times the median Tmax of obicetrapib or ezetimibe, respectively, calculated from the observed data of the specific treatment arm were excluded from the statistical analysis for the respective analyte.

[0399] Analyses of Variance was performed on In-transformed AUCo-t, AUCo-co, and Cmax using an analysis of variance model (ANOVA). The ANOVA was conducted separately forTreatment T1 versus Treatment R analysis and for Treatment T2 versus Treatment R analysis, using an incomplete block design. Treatment T2 was excluded from ANOVA for comparison of Treatments T1 versus R and Treatment T1 was excluded from ANOVA for comparison of Treatments T2 versus R.

[0400] Confidence intervals (90%) on the geometric mean ratios (obtained from logarithmic transformed data) for AUCo-t, AUCo-co and Cmax for the comparison of each of the FDC formulations (T1 and T2) to Treatment R was constructed to test two one-sided hypotheses at the a = 0.05 level of significance.Results

[0401] Confidence intervals (90%) on the geometric mean ratios for AUCo-t, AUCo-co and Cmax for obicetrapib, ezetimibe and ezetimibe glucoronide (from T1 and T2 for formulation #1 as well as formulation #2) were found to be within a range of 75%-125%, preferably 80%-125%, and more preferably 90%-l 10% of AUCo-t, AUCo-co and Cmax of obicetrapib, ezetimibe and ezetimibe glucoronide, respectively. The test formulations #1 and #2 were found to be bioequivalent with reference treatment arm (R). The adverse events observed with T1 or T2 arm of the treatment were statistically not significantly different from the R arm.8.12. Example 10: phase 2B clinical trial (ROSE2; NCT05266586)8.12.1. Introduction and Background Information

[0402] Dyslipidemias are disorders of lipoprotein metabolism, including lipoprotein overproduction or deficiency, which may be manifested by elevation of the levels of the serum total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-C) and triglyceride (TG) concentrations, and a decrease in the levels of high-density lipoprotein (HDL) cholesterol (HDL-C) concentration. These disorders are generally diagnosed by measuring the serum lipids and classified by the pattern of elevation / reduction in the lipid / lipoprotein fractions. Dyslipidemia itself does not generally cause any symptoms, but it can lead to symptomatic vascular disease including coronary artery disease and peripheral arterial disease. It is acknowledged that while there are a number of genetic and lifestyle factors which contribute to the development of vascular disease, dyslipidemia is 1 of the most prominent risk factors and normalization of the lipid profile has been a major target in cardiovascular (CV) protection strategies.

[0403] Statins are generally the drug of first choice in treating dyslipidemia. Statins are considered as the most potent, most effective, and best tolerated drugs for reducing LDL-C levels. Many patients, despite treatment with high-intensity statin therapy, do not achieve acceptable levels of LDL-C with statins alone.

[0404] There is a need for chronic therapies which will robustly reduce elevated LDL-C levels when used adjunctive to high-intensity statin therapy.8.12.1.1. Cholesteryl Ester Transfer Protein Inhibitors

[0405] Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver and adipose tissue. It circulates in the blood, bound primarily to HDL-C, and is involved in the transfer of cholesteryl esters and TG between lipoproteins. In particular, it mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB) -containing particles, eg, very low-density lipoprotein and LDL-C, in exchange for TG. As a result, cholesteryl ester from HDL can be taken up by the liver through scavenger receptor class B type 1; this action also leads to decreased HDL-C and ultimately to increased LDL-C.

[0406] Inhibition of CETP activity reduces ApoB and LDL-C and increases HDL-C. CETP-inhibiting therapies were originally developed based on the premise that increasing HDL-C levels would prevent CV events. However, clinical study results and Mendelian randomization data have revealed that these effects are caused by changes in the concentration of ApoB-containing particles (including LDL particles) rather than changes in the HDL-Clevels.Therefore, the LDL-C and ApoB-lowering effects, which arise from CETP inhibition and occur through upregulation of the LDL receptor, will benefit patients with elevated LDL-C and increased CV risk.

[0407] Ference and colleagues have recently investigated the association between changes in LDL-C levels (and other lipoproteins) and the risk of CV events related to variants in the CETP gene alone and in combination with variants in the 3 -hydroxy-3 -methylglutaryl-coenzyme A reductase (HMGCR) gene.

[0408] The results of these Mendelian randomization analyses demonstrate that treatment with a CETP inhibitor has the potential to effectively reduce the risk of CV events. Both genetic and therapeutic inhibition of CETP leads to quantitatively concordant changes in LDL-C and ApoB levels. A further Mendelian randomization analysis concluded that the clinical benefit

[0409] of lower LDL-C levels per unit difference may specifically be related to the absolute reduction in ApoB-containing lipoprotein particles.8.12.1.2. Obicetrapib (TA-8995)

[0410] Obicetrapib (TA-8995) is a selective CETP inhibitor. Inhibition of CETP by obicetrapib blocks the transfer of cholesteryl ester from non -atherogenic HDL particles to particles in lipoprotein fractions (including LDL) that cause atherosclerosis and reduces the concentration of cholesterol in LDL, as well as other atherogenic lipoproteins. Obicetrapib also has several additional compound-specific activities that are hypothesized to be beneficial in patients. In a recent study, obicetrapib treatment not only reduced the number of ApoB-containing particles that constitute LDL-C, it also increased apolipoprotein E (ApoE), which led to the removal of cholesterol via the liver and also reduced lipoprotein (a) (Lp[a]).5 Finally, obicetrapib not only potently increases HDL-C and the concentration of apolipoprotein Al (ApoAl)-containing lipoproteins but has been demonstrated to be a potent inducer of cholesterol efflux, which is the main driver of reverse cholesterol transport. This effect is considered important because it is expected to reduce established atheroma burden.8.12.1.3. Clinical Development of Obicetrapib

[0411] Both single ascending dose (TA-8995-01) and multiple ascending dose (TA-8995-02) studies of obicetrapib have been conducted in healthy volunteers. A formal, thorough QT / QTc study (TA-8995-04) demonstrated that obicetrapib has no effect on the QTcF. A drug-drug interaction study (TA-8995-05) showed no significant effect of obicetrapib on P-glycoprotein activity, but showed that obicetrapib is a mild inducer of cytochrome P450 3A4. A mass balance study in healthy males concluded that obicetrapib is steadily absorbed, and the principal route of excretion was in the feces (TA-8995-07). Finally, bioequivalence between obicetrapib capsule and tablet formulations was investigated (TA-8995-08).

[0412] The first patient study conducted was a Phase 2 clinical study (TA-8995-03) in Denmark and The Netherlands where the aim was to evaluate the optimal dose of obicetrapib alone and in combination with statins in patients with mild dyslipidemia. This study concluded that a 10 mg daily dose of obicetrapib therapy resulted in an LDL-C reduction of 45.4%, an HDL-C increase of 179.0%, an ApoAl increase of 63.4%, and a significant increase of HDL-C efflux capacity.

[0413] Furthermore, given on top of atorvastatin 20 mg, obicetrapib 10 mg resulted in an additional 50.3% reduction in LDL-C. A second patient study (TA-8995-06) showed a statistically significant reduction in Lp(a) levels following 12 weeks of obicetrapib treatment.

[0414] Two Phase 2 studies of obicetrapib (TA-8995-303 and TA-8995-201) are currently nearing completion. The first study, TA-8995-303, is evaluating the LDL-lowering effects of obicetrapib 5 mg in combination with ezetimibe 10 mg in participants with mild dyslipidemia. The second study, TA-8995-201, is evaluating the LDL-lowering effects of obicetrapib (both 5 mg and 10 mg) as an adjunct to high intensity statin therapy in participants with dyslipidemia who are on high-intensity statins. Two Phase 3 studies of obicetrapib 10 mg investigating the treatment of elevated LDL-C levels in participants with established atherosclerotic CV disease (ASCVD), as well as heterozygous familial hypercholesterolemia, are currently in development. One study (TA-8995-301) will include participants on maximally tolerated lipid-lowering therapy, including maximally tolerated doses of statins with an LDL-C inclusion criterion of >100 mg / dL. The other study (TA-8995-302) will also include participants who are on maximally tolerated lipid-lowering therapy, including maximally tolerated doses of statins with an LDL-C inclusion criterion of >70 mg / dL and <100 mg / dL. Together, these 2 pivotal studies will evaluate the effects of obicetrapib 10 mg in populations requiring further LDL-C reduction across a range of baseline LDL-C values relevant to contemporary clinical practice.

[0415] A third Phase 3 study (TA-8995-304) will investigate the effect of obicetrapib 10 mg on clinical outcomes (ie, major adverse CV events, including CV death, non -fatal myocardial infarction, non-fatal stroke, or non-elective coronary revascularization).8.12.1.4. Rationale

[0416] Chronic LDL-C elevation leads to progressive accumulation of arterial atherosclerotic lesions that require long-term management. While lifestyle changes are the primary intervention, these measures seldom reduce plasma LDL-C by more than 15%, and pharmacologic treatments are required to adequately treat hyperlipidemia.

[0417] Statins are considered as first-line therapy for reducing LDL-C levels. However, despite lipid lowering therapy with statins, many patients are unable to achieve acceptable levels of LDL-C.

[0418] Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are one alternative to statins. However, there are several limitations with these therapies, including high costs, limited long-term outcome data relative to statins, and muscle-related events. In addition, because PCSK9 inhibitors are injectable, this poses a less attractive option for patients who prefer oral medications.

[0419] Accordingly, there remains an unmet need for therapies to effectively reduce elevated LDL-C levels and CV risk at an acceptable cost, a convenient dosage form, and a more favorable safety profile to encourage long-term use and patient compliance. Obicetrapib, an oral CETP inhibitor, has demonstrated safety and efficacy in the reduction of LDL-C, in addition to other beneficial effects. The combination of obicetrapib and ezetimibe, an oral cholesterol absorption inhibitor, could be a valuable alternative to a PCSK9 inhibitor in patients who require additional LDL-C lowering despite high-intensity statin therapy.7.12.1.4.1. Rationale for Obicetrapib and Ezetimibe Combination Therapy

[0420] Ezetimibe selectively inhibits intestinal cholesterol absorption. Ezetimibe used as monotherapy for patients with hypercholesterolemia significantly reduces serum LDL-C levels, as evidenced by a meta-analysis of 8 randomized, double-blind, placebo-controlled studies, with a statistically significant mean reduction in LDL-C of 18.58% compared with placebo. Ezetimibe in combination with statin therapy further reduces LDL-C levels. A meta-analysis of 27 studies, including more than 21,000 patients, demonstrated a 15.1% greater reduction in LDL-C in patients treated with statin and ezetimibe in combination compared with statin alone. The IMPROVE-IT study, in which simvastatin 40 mg daily was compared with a combination of simvastatin 40 mg plus ezetimibe 10 mg in 18,144 patients with acute coronary syndrome, demonstrated a modest but statistically significant further reduction in future CV events (a 2% absolute risk reduction over 7 years) in the combination group compared with statins alone. These large long-term studies have also demonstrated an excellent safety profile for ezetimibe. Importantly, additional Mendelian randomization studies have revealed that the CETP inhibitor HMGCR inhibitor interaction does not occur when a CETP inhibitor is combined with ezetimibe.

[0421] A Phase 2 study is currently underway evaluating the LDL-lowering effects of obicetrapib 5 mg in combination with ezetimibe 10 mg in participants with mild dyslipidemia and no prior CV events (TA-8995-303).

[0422] To evaluate the potential of a higher dose of obicetrapib in combination with ezetimibe to augment reduction in LDL-C and ApoB, this study will evaluate the effect of obicetrapib 10 mg in combination with ezetimibe 10 mg in participants currently receiving high-intensity statin therapy (atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg) as part of their guideline-directed medical therapy.7.12.1.4.1.2 Dose Selection Rationale for Obicetrapib

[0423] In clinical studies in healthy volunteers, obicetrapib was generally well tolerated in single doses up to 150 mg and multiple doses up to 25 mg / day for 21 days. In clinical studies in patients, obicetrapib was also well tolerated after daily dosing of 10 mg for 12 weeks, both alone and in combination with 2 different statins. Near maximal effects were observed with the 10 mg obicetrapib dose. At this dose level, CETP activity and concentrations were reduced, HDL-C levels were increased, and LDL-C levels were decreased. There were no dose-related adverse events (AEs) identified and no clinically significant changes in vital signs, electrocardiograms (ECGs), or hematology or biochemistry parameters in any clinical studies. A statistically significant reduction in Lp(a) levels from baseline was also observed at the 10 mg obicetrapib dose level. Therefore, the present study will utilize a dose of 10 mg obicetrapib in participants with ASCVD who are not adequately controlled despite maximally tolerated lipid-modifying therapies.8.12.1.5. Risk / Benefit

[0424] The primary pharmacology in in vitro, ex vivo, and in vivo studies have demonstrated that obicetrapib has the ability to inhibit CETP, decrease LDL-C levels, increase HDL-C levels, and importantly, reduce the number of atherogenic ApoB -containing particles in a way that is useful in the treatment of dyslipidemia.

[0425] The safety pharmacology studies have demonstrated that obicetrapib has no adverse effect on critical physiological systems (eg, central nervous system, respiratory system, gastric emptying, urinary tract, and steroidal hormonal production [including aldosterone levels]) at doses up to 300 mg / kg in rats.

[0426] In clinical studies in patients, obicetrapib was also well tolerated after daily dosing of 10 mg for 12 weeks, both alone and in combination with 2 different statins. There were no dose-related AEs identified and no clinically significant changes in vital signs, ECGs, or hematology or biochemistry parameters in any clinical studies.9. Study Objectives9.1. Primary Objective

[0427] The primary objective of this study is to evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg combination therapy compared with placebo, when used as an adjunct to high-intensity statin therapy, on LDL-C at Day 84.9.2. Secondary Objectives

[0428] The secondary objectives of this study include the following, in hierarchical order:• To evaluate the effect of obicetrapib 10 mg monotherapy compared with placebo, when used as an adjunct to high-intensity statin therapy, on LDL-C at Day 84;• To evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg combination therapy compared with placebo, when used as an adjunct to high-intensity statin therapy, on ApoB at Day 84; and• To evaluate the effect of obicetrapib 10 mg monotherapy compared with placebo, when used as an adjunct to high-intensity statin therapy, on ApoB at Day 84.9.3. Exploratory Objectives

[0429] The exploratory objectives of this study include the following:• To evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg combination therapy and obicetrapib 10 mg monotherapy, when used as an adjunct to high -intensity statin therapy, on non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), HDL-C, TG, ApoE, Lp(a), and HDL-ApoE at Day 84;• To evaluate the effect of obicetrapib 10 mg + ezetimibe 10 mg combination therapy and obicetrapib 10 mg monotherapy, when used as an adjunct to high -intensity statin therapy, on the proportion of participants achieving predefined LDL-C targets at Day 84;• To assess the mean trough plasma levels of obicetrapib 10 mg + ezetimibe 10 mg combination therapy and obicetrapib 10 mg monotherapy at steady state on Days 28, 84, and 112; and• To evaluate the safety and tolerability profiles of obicetrapib 10 mg + ezetimibe 10 mg combination therapy and obicetrapib 10 mg monotherapy, when used as an adjunct to high- intensity statin therapy, assessed by clinical laboratory values and incidence of AEs.10. STUDY DESCRIPTION10.1. Summary of Study DesignThis study will be a placebo-controlled, double-blind, randomized, Phase 2 study to evaluate the efficacy, safety, and tolerability of obicetrapib 10 mg, both in combination with ezetimibe 10 mg and as monotherapy, as an adjunct to high -intensity statin therapy. This study will take place at approximately 20 sites in the United States.10.1.1. Screening Period

[0430] At the Screening Visit, participants will be required to sign an informed consent form (ICF) before any study -related procedures are performed. After signing the ICF, participants will be assessed for study eligibility.10.1.2. Treatment Period

[0431] Up to 2 weeks after the Screening Visit, participants will return to the site on Day 1 (Visit 2) and confirm study eligibility before being randomized and beginning treatment.Approximately 114 eligible participants (38 participants per treatment group) will be randomized in a 1:1:1 ratio to 1 of the following treatment groups:• Combination therapy: Obicetrapib 10 mg + ezetimibe 10 mg (administered as one 10 mg obicetrapib tablet and one 10 mg ezetimibe capsule);• Obicetrapib monotherapy: Obicetrapib 10 mg (administered as one 10 mg obicetrapib tablet and 1 placebo capsule); or• Placebo (administered as 1 placebo tablet and 1 placebo capsule).

[0432] During the 12-week Treatment Period, the assigned study drugs will be administered by the participants orally with water, once daily on Day 1 to Day 84 at approximately the same time each morning. Participants will return to the site on Day 28 (±2 days), Day 84 (±2 days), and Day 112 (±2 days) for efficacy, safety, and pharmacokinetic (PK) assessments. Participants, Investigators, the Clinical Research Organization (CRO), and the Sponsor will be blinded to all lipid results from Day 1 (Visit 2) for the first participant until all enrolled participants completethe Day 84 (End of Treatment) visit or are withdrawn from the study, in order to protect blinding to treatment assignment.10.1.3. Safety Follow-Up Period

[0433] Participants will return to the site for a Safety Follow-up Visit (Visit 5) approximately 4 weeks after the end of the Treatment Period for safety and PK assessments.10.1.4. Coronavirus Disease 2019 Contingency Measures

[0434] In cases of COVID-19 limitations, it is the Investigator’s responsibility to assure the safety of participants. If necessary, the Sponsor will implement and document mitigation strategies. At the Investigator’s discretion, the study visit(s) can be conducted in-clinic or virtually. If conducted virtually, the visit will include alternative methods for safety, efficacy, and distribution / collection of study drug, including but not limited to phone / video contact, alternative location for biologic...

Claims

WHAT IS CLAIMED:

1. A fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, for use in a method of synergistically lowering LDL-C plasma levels in a subject in need thereof, said method comprising the administration of the fixed dose pharmaceutical composition.

2. A fixed dose pharmaceutical composition for use according to claim 1, wherein the subject is a subject suffering from heterozygous familial hypercholesterolaemia (HeFH), mixed dyslipidemia, or established atherosclerotic cardiovascular disease (ASCVD).

3. A fixed dose pharmaceutical composition for use according to claim 1, wherein the subject is a subject suffering from non-familial hypercholesterolaemia.

4. A fixed dose pharmaceutical composition for use according to any one of claims 1-3, wherein the subject is unable to reach an LDL-C plasma level of < 70 mg / dL with the maximum tolerated dose of a statin in addition to ezetimibe.

5. A fixed dose pharmaceutical composition for use according to any one of claims 1-3, wherein the subject is a subject that is intolerant to statins or for whom statins are contraindicated, and is unable to reach an LDL-C plasma level of < 70 mg / dL with ezetimibe alone.

6. A fixed dose pharmaceutical composition for use according to any one of claims 1-5, wherein the subject is a subject requiring additional lowering of LDL-C as an adjunct to diet and / or to maximally tolerated lipid-lowering therapy other than obicetrapib / ezetimibe combination therapy.

7. A fixed dose pharmaceutical composition for use according to any one of the preceding claims, wherein the method comprises the oral administration of obicetrapib at a daily dose ofabout 10 mg and the oral administration of ezetimibe at a daily dose of about 10 mg, during a period of at least three months.

8. A fixed dose pharmaceutical composition for use according to 7, wherein said method results in a reduction of LDL-C plasma levels of at least 40%, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably at least 45%, most preferably at least 50%.

9. A fixed dose pharmaceutical composition for use according to claim 7, wherein said method results in a reduction of LDL-C plasma levels, with at least 40 mg / dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably at least 45 mg / dL, more preferably at least 50 mg / dL.

10. A fixed dose pharmaceutical composition for use according to claim 7, wherein said method results in a reduction of LDL-C plasma levels to a level below 60 mg / dL, preferably below 55 mg / dL, more preferably below 50 mg / dL.

11. A fixed dose pharmaceutical composition for use according to any one of claims 1-4, wherein the method further comprises the concurrent treatment with a HMG Co A reductase inhibitor.

12. A fixed dose pharmaceutical composition for use according to claim 11, wherein the method comprises the administration of rosuvastatin at a daily dosage of 20 mg or 40 mg or the administration of atorvastatin at a daily dosage of 40 or 80 mg.

13. A fixed dose pharmaceutical composition for use according to any one of the preceding claims 1-12, wherein obicetrapib is present in the form of an amorphous calcium salt of obicetrapib.

14. A fixed dose pharmaceutical composition for use according to claim 13, wherein the amorphous calcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

15. A fixed dose pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients, for use in a method of synergistically slowing the development and / or progression of CVD, more in particular ASCVD, and / or synergistically reducing the risk and / or occurrence of CVD related events, in particular ASCVD related events, in a subject in need thereof, said method comprising the administration of the fixed dose pharmaceutical composition in a subject in need thereof, said method comprising the administration of the fixed dose pharmaceutical composition.

16. A fixed dose pharmaceutical composition for use according to claim 15, wherein the subject is a subject suffering from heterozygous familial hypercholesterolaemia (HeFH), mixed dyslipidemia, or established atherosclerotic cardiovascular disease (ASCVD).

17. A fixed dose pharmaceutical composition for use according to claim 15, wherein the subject is a subject suffering from non-familial hypercholesterolaemia.

18. A fixed dose pharmaceutical composition for use according to any one of claims 15-17, wherein the subject is unable to reach an LDL-C plasma level of < 70 mg / dL with the maximum tolerated dose of a statin in addition to ezetimibe.

19. A fixed dose pharmaceutical composition for use according to any one of claims 15-17, wherein the subject is a subject that is intolerant to statins or for whom statins are contraindicated, and is unable to reach an LDL-C plasma level of < 70 mg / dL with ezetimibe alone.

20. A fixed dose pharmaceutical composition for use according to any one of claims 15-17, wherein the subject is a subject requiring additional lowering of LDL-C as an adjunct to diet and / or to maximally tolerated lipid-lowering therapy other than obicetrapib / ezetimibe combination therapy.

21. A fixed dose pharmaceutical composition for use according to any one of claims 15-20, wherein the method comprises the oral administration of obicetrapib at a daily dose of about 10 mg and the oral administration of ezetimibe at a daily dose of about 10 mg, during a period of at least three months.

22. A fixed dose pharmaceutical composition for use according to 21, wherein said method results in a reduction of LDL-C plasma levels of at least 40%, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably at least 45%, most preferably at least 50%.

23. A fixed dose pharmaceutical composition for use according to claim 21, wherein said method results in a reduction of LDL-C plasma levels, with at least 40 mg / dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe, more preferably at least 45 mg / dL, more preferably at least 50 mg / dL.

24. A fixed dose pharmaceutical composition for use according to claim 21, wherein said method results in a reduction of LDL-C plasma levels to a level below 60 mg / dL, preferably below 55 mg / dL, more preferably below 50 mg / dL.

25. A fixed dose pharmaceutical composition for use according to any one of claims 15-19, wherein the method further comprises the concurrent treatment with a HMG Co A reductase inhibitor.

26. A fixed dose pharmaceutical composition for use according to claim 25, wherein the method comprises the administration of rosuvastatin at a daily dosage of 20 mg or 40 mg or the administration of atorvastatin at a daily dosage of 40 or 80 mg.

27. A fixed dose pharmaceutical composition for use according to any one of the preceding claims 15-26, wherein obicetrapib is present in the form of an amorphous calcium salt of obicetrapib.

28. A fixed dose pharmaceutical composition for use according to claim 27, wherein the amorphous calcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

29. A fixed dose pharmaceutical composition for use according to claims 1-28, wherein said method results in a reduction of sdLDL-C plasma levels of at least 33%, from baseline, wherein baseline is defined as start of the treatment with obicetrapib and ezetimibe.

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