Arginine salts of obicetrapib

Abstract

Obicetrapib L-arginine salts and processes for preparing such obicetrapib L-arginine salts are provided for herein as well as obicetrapib L-arginine salts made by such processes. Further provided are pharmaceutical compositions comprising such obicetrapib L-arginine salts and one or more pharmaceutically acceptable excipients. In addition, methods of treating diseases with pharmaceutical compositions comprising such obicetrapib L-arginine salts are provided.

Description

ARGININE SALTS OF OBICETRAPIB1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 741,340, filed January 02, 2025; U.S. Provisional Application No. 63 / 741,352, filed January 02, 2025; U.S. Provisional Application No. 63 / 846,867, filed July 18, 2025; and U.S. Provisional Application No. 63 / 853,347, filed July 29, 2025; which are hereby incorporated by reference in their entirety.2. BACKGROUND OF THE INVENTION

[0002] Prospective epidemiological studies have shown a strong association between low density lipoprotein-cholesterol (LDL-C) levels and cardiovascular disease (CVD) risk. The application of statin therapy to decrease these atherogenic LDL-C levels has resulted in a marked reduction of CVD-related morbidity and mortality: every 1 mmol / L decrease in LDL-C results in an estimated 22% reduction of CVD events and a 10% reduction of all-cause mortality.Notwithstanding these impressive benefits, a large residual disease burden persists that has a large impact on both individual patients as well as on global healthcare costs. Novel therapeutics are required to reduce further this residual CVD risk in patients.

[0003] One route which reduces LDL-C and elevates high-density lipoprotein cholesterol (HDL-C) levels is to inhibit Cholesterol Ester Transfer Protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (Apo B)-containing particles (mainly LDL and very low density lipoprotein VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of that in VLDL. Hence, CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic Apo B fraction.

[0004] Clinical studies have shown that obicetrapib also known as ((27?,45)-4-{[3,5 bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester), or a pharmaceuticallyacceptable salt thereof is a potent CETP- inhibitor. The structure of obicetrapib is set forth in Formula (I) below:

[0005] The preparation of obicetrapib is disclosed, for example, in U.S. Patent Number 7,872,126. Example 177 teaches the formation of obicetrapib, which, as seen in Formula (I), is a free acid. 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 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 in that there are only half as many calcium atoms as obicetrapib anions in a neutral amorphous obicetrapib calcium salt molecule.

[0006] The molecular formula of amorphous obicetrapib hemicalcium 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 term amorphous obicetrapib hemicalcium means that each obicetrapib moiety portion of the salt i s not Formula (I) (i.e., obicetrapib) but Formula (I) minus a proton. 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.

[0007] Compared to other known CETP -inhibitors, only a relatively low dose of obicetrapib is needed to reach near complete CETP inhibition. Typically, repeated daily dosages (once a day) as low as 2.5 mg of the compound of obicetrapib have proven to be already sufficient to reach near complete CETP inhibition. These are considerably lower dosages than had to be used for other CETP -inhibitors. Moreover, clinical studies have also shown that obicetrapib is welltolerated and that it does not lead to serious side effects. Obicetrapib free acid is the active moiety of obicetrapib hemicalcium.

[0008] While processes have been described for the manufacture of obicetrapib (see, e.g., WO 2005 / 095409A2 and U.S. Patent Nos. 7,872,126 and 8,158,640, Examples 1 and 177-180; WO 2007 / 116922 Al and US Patent No. 8,084,611; and WO 2016 / 024858 and U.S. Patent No.10,112,904) the prior art cited herein produces an unfavorable solid form. These references are incorporated herein by reference in their entirety.

[0009] The prior art teaches the formation of one developable solid form of obicetrapib, obicetrapib hemicalcium in U.S. Patent No. 12,006,305. The ‘305 patent describes amorphous obicetrapib hemicalcium. This reference is incorporated herein by reference in its entirety.

[0010] In addition, many of the previously described processes have relatively low yield and are not particularly suitable for carrying out on an industrial scale. Thus, there is a need for improved solid forms of obicetrapib and alternative processes for the manufacture of obicetrapib and pharmaceutically acceptable salts thereof with an improved yield, purity, and stability.

[0011] Disclosed herein are arginine salts of obicetrapib, processes for making such arginine salts, pharmaceutical compositions comprising such arginine salts and one or more pharmaceutically acceptable excipients. Methods of treating patients with arginine salts of obicetrapib and / or pharmaceutically compositions comprising same are also disclosed.3. SUMMARY OF THE INVENTION

[0012] In many aspects of the disclosure, arginine, such as L-arginine, salts of obicetrapib are provided.

[0013] In further aspects of the disclosure, pharmaceutical compositions comprising an arginine salt of obicetrapib and one or more pharmaceutically acceptable excipients, are provided.

[0014] In still further aspects of the disclosure, methods of treatment using said arginine salts of obicetrapib or pharmaceutically acceptable compositions thereof are provided.

[0015] In additional aspects of the disclosure, methods of making arginine salts of obicetrapib are provided.4. BRIEF DESCRIPTION OF FIGURES

[0016] FIG. 1 is an x-ray powder diffraction pattern of obicetrapib free acid.

[0017] FIG. 2 is an x-ray powder diffraction pattern of the result of spray drying the obicetrapib hydrochloride of Example 2.

[0018] FIG. 3 is an x-ray powder diffraction pattern of obicetrapib L-arginine.

[0019] FIG. 3 A is an mDSC thermogram of obicetrapib L-arginine.

[0020] FIG. 4 is an x-ray powder diffraction pattern of obicetrapib L-arginine.5. DETAILED DESCRIPTION

[0021] In many embodiments, salts of obicetrapib are provided. In many such embodiments, arginine salts of obicetrapib, such as L-arginine and amorphous obicetrapib L-arginine are provided. The chemical structure of obicetrapib L-arginine is shown below.

[0022] Examples of making L-arginine are set forth in Examples 3 and 4. FIG. 3 and FIG. 4 are x-ray powder diffractions of obicetrapib L-arginine prepared in accordance with said Examples which show the obicetrapib L-arginine to be amorphous.

[0023] Obicetrapib L-arginine may be made by treating a solution of obicetrapib free acid in a suitable solvent such as MTBE along with L-arginine and water and / or ethanol to form the salt. An antisolvent such as heptane may be added, followed by cooling and the salt may be dried and filtered to provide solid and dried obicetrapib L-arginine.

[0024] In these and other embodiments of the disclosure, pharmaceutical compositions comprising obicetrapib arginine, including obicetrapib L-arginine and / or amorphous obicetrapib L-arginine are provided. Such pharmaceutical compositions may be in the form of solid oral dosage forms. Solid dosage formulations may be in the form of a tablet or a capsule for oral administration, for example. The concentration of obicetrapib, based on obicetrapib free acidequivalent may range from 1% to 25% in many embodiments. Such solid dosage formulations may be administered to a patient daily.

[0025] In these and other embodiments, the solid dosage formulations may further comprise one or more pharmaceutically acceptable excipients. As used herein a “pharmaceutically acceptable excipient” is an excipient used to make a pharmaceutical composition such as a finished dosage form. Exemplary finished dosage forms include oral dosage forms such as tablets and capsules.

[0026] Such pharmaceutically acceptable excipients include but are not limited to one or more binders, fillers (also known as diluents), surfactants, disintegrants, coloring agents, glidant, opacifiers, lubricants, chelating agents, pH modifiers, or plasticizers. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See “The Handbook of Pharmaceutical Excipients”, 9th edition, Rowe et al., Eds., American Pharmaceuticals Association (2020); and “Remington: The Science and Practice of Pharmacy”, 22nd edition, Gennaro, Ed., Lippincott Williams & Wilkins (2013).

[0027] The one or more binders used in the pharmaceutical compositions may be, for example, 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, or bentonites.

[0028] The pharmaceutical composition may also comprise one or more disintegrants such as cross-linked polyvinylpyrrolidone, croscarmellose sodium, calcium carboxyl methylcellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, sodium starch glycolate, or pregelatinized starch.

[0029] The one or more filler (also known as diluents) used in the pharmaceutical compositions may include 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.

[0030] The pharmaceutical compositions 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 processoror dip coating. Alternatively, coating may also be performed using a 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. Plasticizers may be present in the film coating and may be selected from, for example, polyethylene glycol and the like.

[0031] Glidants present in the pharmaceutical compositions may be selected from, for example, silicon dioxide, talc, magnesium stearate and the like.

[0032] Lubricants present in the pharmaceutical compositions may be, for example, fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and / or palmitic acid and the like.

[0033] The pH modifiers which may be present in the pharmaceutical compositions may be selected from, for example, sodium carbonate, sodium hydrogen carbonate, calcium phosphate, calcium carbonate, and the like.Methods of Treatment for Cardiovascular Disease

[0034] The present disclosure further provides for methods of treating subjects suffering from or having an increased risk of developing a cardiovascular disease, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to said subjects, optionally in combination with a therapeutically effective amount of ezetimibe or other lipid-modifying therapy.

[0035] In some embodiments, the method comprises administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to subjects with atherosclerotic cardiovasculardisease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies.

[0036] Obicetrapib and methods for treating subjects with ASCVD and / or HeFH are described in WO 2025 / 059594, the disclosure of which is incorporated herein by reference in its entirety.

[0037] In certain embodiments, the subject’s baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is > 100 mg / dL.

[0038] In certain embodiments, the subject’s baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is > 70 mg / dL to < 100 mg / dL with at least one of the following risk enhancers:• recent MI• type 2 diabetes mellitus• fasting triglycerides (TG) > 150 mg / dL• fasting Lp(a) > 30 mg / dL• fasting HDL-C < 40 mg / dL.

[0039] In certain embodiments, the subjects have not achieved adequate lipid lowering on a high-intensity statin (HIS) regimen. In specific embodiments, the HIS is 20 or 40 mg rosuvastatin per day. In specific embodiments, the HIS is 40 or 80 mg of atorvastatin per day.

[0040] In various embodiments, the therapeutically effective amount of obicetrapib in (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients with an obicetrapib free acid equivalent in the amount of 2.5 - 10 mg per day. In certain embodiments, the therapeutically effective amount of obicetrapib free acid equivalent of the present disclosure is obicetrapib in the amount of 2.5, 5.0, 7.5, or 10 mg per day. In specific embodiments, the therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is 10 mg obicetrapib free acid equivalent per day.

[0041] In various embodiments, the (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical compositioncomprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in combination with maximally tolerated lipid-modifying therapy.

[0042] In some embodiments, the maximally tolerated lipid-modifying therapy comprises a statin. In certain embodiments, the subject is co-administered a HIS regimen.

[0043] In some embodiments, the maximally tolerated lipid-modifying therapy comprises ezetimibe. In certain embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients of the present disclosure is administered in combination with ezetimibe. In specific embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is administered with the free acid equivalent of 10 mg of obicetrapib in combination with 10 mg ezetimibe.

[0044] In specific embodiments, the (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered as a fixed dose combination with ezetimibe.

[0045] In specific embodiments of the method of the present disclosure, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are present in fixed dose combinations with 10 mg ezetimibe, and are administered on top of maximally tolerated lipid-modifying therapy to subjects with heterozygous familial hypercholesterolemia (HeFH) and / or Atherosclerotic Cardiovascular Disease (ASCVD) or Multiple ASCVD Risk Factors.

[0046] Obicetrapib and ezetimibe combination treatment and fixed dose pharmaceutical compositions thereof are described in WO 2024 / 042061, the disclosure of which is incorporated herein by reference in its entirety.

[0047] In various embodiments of the methods of the present disclosure, a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is administered to lower serum LDL-C as compared to baseline (level prior to first administration of obicetrapib), lower non-HDL-C as compared to baseline, lower ApoB as compared to baseline, raise HDL-C levels as compared to baseline, and / or lower Lp(a) as compared to baseline. In certain embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is administered to lower serum LDL-C to < 100 mg / dL and in some embodiments, to lower serum LDL-C to 70 mg / dL or less.

[0048] In certain embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount and for a time sufficient to achieve one or more of the following: lower serum LDL-C as compared to baseline (level prior to first administration of obicetrapib), lower non-HDL-C as compared to baseline, lower ApoB as compared to baseline, raise HDL-C levels as compared to baseline, and / or lower Lp(a) as compared to baseline.

[0049] In certain embodiments, the method reduces the incidence of major adverse cardiovascular (MACE) in subjects with HeFH and / or ASCVD who are not adequately controlled by their lipid-modifying therapies are provided.

[0050] In certain embodiments, the method reduces one or more of death, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization.

[0051] In specific embodiments, the method reduces death. In specific embodiments, the method reduces non-fatal myocardial infarction. In specific embodiments, the method reducesnon-fatal stroke. In specific embodiments, the method reduces the need for coronary revascularization.

[0052] In some embodiments, methods reduce the incidence of MACE in 3 -composite MACE. In some embodiments, the composite consists of coronary heart disease death, nonfatal myocardial infarction and coronary revascularization.

[0053] In some embodiments, the methods reduce the incidence of MACE in 4-compose MACE. In some embodiments, the composite consists of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke and coronary revascularization.

[0054] In some embodiments the subject is at least 30, 35, 40, 45, 50, 55, 60, 65, or 70 years old.

[0055] In some embodiments, obicetrapib is administered in combination with concomitant lipid-modifying therapies. In some embodiments, those concomitant lipid modifying therapies include administration of at least one of statins, high intensity statins, PCSK9 inhibitors, and ezetimibe.

[0056] In some embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is administered to a subject on maximally tolerated lipid-modifying therapy who has atherosclerotic cardiovascular disease (ASCVD) as evidenced by having at least one feature in Group A and / or Group B below:A. Imaging evidence of vascular diseaseThis is defined as having one of the following on prior clinically indicated vascular imaging:1) Angiographic evidence of coronary artery disease (invasive or CCTA) with a visual diameter stenosis <50% in at least one major epicardial coronary artery 2) Angiographic evidence (invasive or CCTA derived) of coronary artery disease with a visual diameter stenosis >50% in at least one major epicardial coronary artery but fractional flow reserve 0.83) Carotid artery stenosis >50%B. Having established clinically manifest ASCVDThis is defined as having one of the following:1) History of myocardial infarction (MI)2) History of ischemic stroke3) Previous percutaneous coronary intervention (PCI)4) Previous carotid artery revascularization5) Documentation of a resting ankle-brachial index <0.856) Previous revascularization of an iliac, femoral, or popliteal artery or lower extremity amputation due to peripheral artery disease

[0057] In certain embodiments, administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show statistically significant improvement (reduction from baseline) as compared to placebo in one or more of (i) total non-calcified coronary atherosclerotic plaque volume (NCPV), (ii) NCPV in the most diseased coronary segment (NCPVMD), (iii) reduction in low attenuation plaque volume, (iv) reduction in calcified plaque volume, (v) reduction in perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries), (vi) reduction in FAI score age- and gender-matched population centile.

[0058] In specific embodiments, the equivalent of 10 mg obicetrapib free acid is administered per day. In certain embodiments, the equivalent of 10 mg obicetrapib free acid is administered per day in combination with 10 mg of ezetimibe. In specific embodiments, the equivalent of 10 mg obicetrapib is administered per day in fixed dose combination with 10 mg of ezetimibe.What is meant by the term “equivalent of 10 mg obicetrapib” is, for example, that if any obicetrapib arginine salt of the disclosure were to be dosed, the corresponding amount of the obicetrapib free acid in that dosage form would be 10 mg.

[0059] In some embodiments, the subject is a hypo-responder to high-intensity statin (HIS) therapy, and is further receiving concomitant statin therapy.

[0060] In some embodiments, the cardiovascular disease is atherosclerotic cardiovascular disease (ASCVD).

[0061] In some embodiments, there is provided methods for treating subjects suffering from or having an increased risk of developing a cardiovascular disease comprising administering apharmaceutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients in combination with an HMG CoA reductase inhibitor (statin). In some embodiments, the HMG CoA reductase inhibitor is atorvastatin or rosuvastatin, or a pharmaceutically acceptable salt thereof.Methods of Treatment for Neurodegenerative Disease

[0062] Also provided herein are methods for treating or slowing the progression of a neurodegenerative disease in a subject who has or is at risk of developing such a neurodegenerative disease. The method comprises administering a pharmaceutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients of the present disclosure to said subject.

[0063] In some embodiments, the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0064] In various embodiments, methods are provided for attenuating increase in plasma phosphorylated Tau 217 (p-Tau217) in the plasma of a subject in need thereof, comprising administering to the subject a deuterated derivative of obicetrapib, in an amount effective to attenuate increase in p-Tau217 in the plasma of the subject determined prior to the first administration of the deuterated derivative of obicetrapib.

[0065] In certain embodiments, methods are provided for attenuating increase in plasma phosphorylated Tau 217 (p-Tau217) in a subject in need thereof compared to the increase in plasma p-Tau217 of said subject observed at 12 months of non-obicetrapib therapy, the method comprising orally administering (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients of the present disclosure, in an amount effective to attenuate increase in p-Tau217 in the plasma of the subject determined prior to the first administration of the obicetrapib.

[0066] In some embodiments, there is provided a method of treating or slowing the progression of Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of an (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients. In certain embodiments, the subject has at least one ApoE4 allele. In specific embodiments, the subject has one ApoE4 allele. In specific embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has no evidence of cognitive impairment prior to first administration of obicetrapib. In some embodiments, the subject has mild cognitive impairment (MCI) prior to first administration of obicetrapib.

[0067] In various embodiments, methods are provided for reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, comprising administering to the subject (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients. In certain embodiments, the subject has at least one ApoE4 allele. In specific embodiments, the subject has one ApoE4 allele. In specific embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has no evidence of cognitive impairment prior to first administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients. In some embodiments, the subject has mild cognitive impairment (MCI) prior to first administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an argininesalt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients.

[0068] In some embodiments, there is provided a method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, comprising administering to the patient (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients in an amount effective to reduce ApoE4 concentration in the CNS. In certain embodiments, the subject has at least one ApoE4 allele. In specific embodiments, the subject has one ApoE4 allele. In specific embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has no evidence of cognitive impairment prior to first administration of obicetrapib. In some embodiments, the subject has mild cognitive impairment (MCI) prior to first administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients.

[0069] In various embodiments of the method, the method comprises administering (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients of the present disclosure in a fixed dose combination with ezetimibe, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises 5 to 20 mg ezetimibe.Methods of Treatment for Metabolic Disease

[0070] In some embodiments, there is provided a method for treating subjects suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia comprising administering a pharmaceutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphousobicetrapib L-arginine, and one or more pharmaceutically acceptable excipients and a pharmaceutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject is partially or completely intolerant to statins.

[0071] In some embodiments there is provided a method for treating 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 heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD) comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients and a pharmaceutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0072] Also provided herein are methods for treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0073] Pharmaceutical compositions comprising obicetrapib and at least one SGLT2 inhibitor are described in WO 2023 / 129595 and WO 2024 / 226537, the disclosures of which are incorporated herein by reference in their entireties.

[0074] In some embodiments there is provided a method for treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapibL-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients and a therapeutically effective amount of an least one SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.Methods of Treatment for Atherosclerotic Disease

[0075] Also provided herein, are methods of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof comprising administering (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients such subjects.

[0076] In one embodiment, there is provided a method of treating heterozygous familial hypercholesterolemia (HeFH) in a subject in need thereof comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients such subjects.

[0077] In some embodiments, there is provided a method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, comprising orally administering an HDL-elevating amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to the subject. Optionally, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is co-administered with at least one liposoluble antioxidant.

[0078] In some embodiments, there is provided a method of improving atherosclerotic plaque characteristics in a subject with ASCVD comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphousobicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients. Optionally, the obicetrapib arginine salt of the disclosure is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, there is provided a method of reducing coronary artery inflammation in a subject with ASCVD comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients. Optionally, the obicetrapib arginine salt of the disclosure is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments of any of the methods described herein, the effective dosage amount of an arginine salt of obicetrapib is formulated in a pharmaceutical composition as disclosed herein.Dosing

[0081] In some embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered to the subject.

[0082] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered orally. In some embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in a solid dosage form.

[0083] In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet further comprises a film coating. In typical embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered as tablets for oral administration. In various embodiments, the dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is 2.5-40 mg obicetrapib free acid equivalent by mouth per day (2.5-40 mg po QD). In some embodiments, the dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is 5-40 mg of obicetrapib free acid equivalent by mouth per day (5-40 mg po QD). In some embodiments, the dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is 10-40 mg of obicetrapib free acid equivalent by mouth per day (10-40 mg po QD).

[0084] In some specific embodiments, the dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is an obicetrapib free acid equivalent in the amount of 2.5 mg po QD, 3.0 mg po QD, 3.5 mg po QD, 4.0 mg po QD, 4.5 mg po QD, 5.0 mg po QD, 5.5 mg po QD, 6.0 mg po QD, 6.5 mg po QD, 7.0 mg po QD, 7.5 mg po QD, 8.0 mg po QD, 8.5 mg po QD, 9.0 mg po QD, 9.5 mg po QD, 10.0 mg po QD, 10.5 mg po QD, 11.0 mg po QD, 11.5 mg po QD, 12.0 mg po QD, 12.5 mg po QD, 13.0 mg po QD, 13.5 mg po QD, 14.0 mg po QD, 14.5 mg po QD, 15.0 mg po QD, 15.5 mg po QD, 16.0 mg po QD, 16.5 mg po QD, 17.0 mg po QD, 17.5 mg po QD, 18.0 mg po QD, 18.5 mg po QD, 19.0 mg po QD, 19.5 mg po QD, 20.0 mg po QD, 20.5 mg po QD, 21.0 mg po QD, 21.5mg po QD, 22.0 mg po QD, 22.5 mg po QD, 23.0 mg po QD, 23.5 mg po QD, 24.0 mg po QD, 24.5 mg po QD, 25.0 mg po QD, 25.5 mg po QD, 26.0 mg po QD, 26.5 mg po QD, 27.0 mg po QD, 27.5 mg po QD, 28.0 mg po QD, 28.5 mg po QD, 29.0 mg po QD, 29.5 mg po QD, 30.0 mg po QD, 30.5 mg po QD, 31.0 mg po QD, 31.5 mg po QD, 32.0 mg po QD, 32.5 mg po QD, 33.0 mg po QD, 33.5 mg po QD, 34.0 mg po QD, 34.5 mg po QD, 35.0 mg po QD, 35.5 mg po QD, 36.0 mg po QD, 36.5 mg po QD, 37.0 mg po QD, 37.5 mg po QD, 38.0 mg po QD, 38.5 mg po QD, 39.0 mg po QD, 39.5 mg po QD, or 40.0 mg po QD.

[0085] In some specific embodiments, the dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is an obicetrapib free acid equivalent in the amount of 2.5 mg po QD, 3.0 mg po QD, 3.5 mg po QD, 4.0 mg po QD, 4.5 mg po QD, 5.0 mg po QD, 5.5 mg po QD, 6.0 mg po QD, 6.5 mg po QD, 7.0 mg po QD, 7.5 mg po QD, 8.0 mg po QD, 8.5 mg po QD, 9.0 mg po QD, 9.5 mg po QD, 10.0 mg po QD, 10.5 mg po QD, 11.0 mg po QD, 11.5 mg po QD, 12.0 mg po QD, 12.5 mg po QD, 13.0 mg po QD, 13.5 mg po QD, 14.0 mg po QD, 14.5 mg po QD, 15.0 mg po QD, 15.5 mg po QD, 16.0 mg po QD, 16.5 mg po QD, 17.0 mg po QD, 17.5 mg po QD, 18.0 mg po QD, 18.5 mg po QD, 19.0 mg po QD, 19.5 mg po QD, 20.0 mg po QD, 20.5 mg po QD, 21.0 mg po QD, 21.5 mg po QD, 22.0 mg po QD, 22.5 mg po QD, 23.0 mg po QD, 23.5 mg po QD, 24.0 mg po QD, 24.5 mg po QD, 25.0 mg po QD, 25.5 mg po QD, 26.0 mg po QD, 26.5 mg po QD, 27.0 mg po QD, 27.5 mg po QD, 28.0 mg po QD, 28.5 mg po QD, 29.0 mg po QD, 29.5 mg po QD, 30.0 mg po QD, 30.5 mg po QD, 31.0 mg po QD, 31.5 mg po QD, 32.0 mg po QD, 32.5 mg po QD, 33.0 mg po QD, 33.5 mg po QD, 34.0 mg po QD, 34.5 mg po QD, 35.0 mg po QD, 35.5 mg po QD, 36.0 mg po QD, 36.5 mg po QD, 37.0 mg po QD, 37.5 mg po QD, 38.0 mg po QD, 38.5 mg po QD, 39.0 mg po QD, 39.5 mg po QD, or 40.0 mg po QD.

[0086] In some specific embodiments, the dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is an obicetrapib free acid equivalent in the amount of 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4,12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg po QD.

[0087] In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and is administered as a plurality of divided doses.

[0088] In some specific embodiments, the daily dose of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is an obicetrapib free acid equivalent in the amount of 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6,22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg per day. In some embodiments, the dose is provided in a plurality of doses.

[0089] In some embodiments, the tablet comprises (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is the equivalent of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg of obicetrapib free acid.

[0090] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered once daily for at least 8 weeks, at least 6 months, at least 12 months, at least 24 months, or at least 36 months.

[0091] In some embodiments, the subject does not have cardiovascular disease. In some embodiments, the subject is not being treated for cardiovascular disease. In some embodiments, the subject is not concurrently undergoing treatment with one or more HMG Co A reductase inhibitors (statins). In some embodiments, the subject is not concurrently being treated with one or more statins selected from the group atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin or their salts thereof.

[0092] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising anarginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to increase levels of ApoAI in CSF.

[0093] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to decrease levels of ApoE4 in CSF.

[0094] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to decrease levels of ApoJ (clusterin) in CSF.

[0095] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to increase levels of lutein in CSF of the subject.

[0096] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to increase levels of a-tocopherol in CSF of the subject.

[0097] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to increase levels of zeaxanthin in CSF of the subject.

[0098] In various embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to increase levels of total ApoE-HDL in blood as compared to the level prior to commencement of treatment. In typical embodiments, blood levels of ApoE-HDL are measured in plasma. In preferred embodiments, (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients are administered in an amount effective to increase plasma levels of ApoE-HDL in particles lacking ApoC3 and / or percentage of plasma HDL-ApoE in HDL particles lacking ApoC3.6. EXAMPLESExample 1 - Obicetrapib free acid

[0099] A solution of 100g of amorphous obicetrapib hemicalcium (amorphous obicetrapib hemicalcium may be prepared as set forth in U. S. Patent No. 12,006,305) in dichloromethane (lOv, 1000 mL) was prepared at 20-25°C with stirring until fully dissolved. Aqueous HC1 (2 N, 30 equiv. relative to the calcium salt) was added in one portion with efficient agitation, and the biphasic mixture was stirred overnight at 20-25 °C. The layers were separated, and the organic phase was washed with water (3 x 5 vol) until the pH of the organic phase was > 5. The organic phase was then washed with saturated aqueous NaCl (1 x 5 vol), dried over anhydrous Mg2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford an oil, which was converted to a solid foam by applying repeated vacuum / vent cycles. Yield: 93.9 g. HPLC purity: 99.9%. FIG. 1 is an x-ray powder diffraction pattern of obicetrapib free acid.Example 2 - Obicetrapib free acid

[0100] Obicetrapib hydrochloride Form A may be prepared as disclosed in U.S. Patent No. 12,006,305.

[0101] About 4 g of obicetrapib HC1 Form A was dissolved in 20 mL acetone and spray dried on a Procept 4M8-TriX spray dryer. The inlet temperature was reduced from an initial 150°C to 140°C. The inlet gas flow rate was 0.3 m3 / min. The nozzle gas pressure was 1.0 bar. The sample injection pump speed was 100 rpm, and the cyclone gas pressure was raised from an initial 0.5 bar to 0.75 bar to an eventual 1.0 bar. The resulting material was dried in a vacuum desiccatorfor four days, and the yield was 73.1%. FIG. 2 is an x-ray powder diffraction pattern of the resulting material (obicetrapib free acid). Energy dispersive x-ray spectroscopy detected no chlorine.Example 3 - Obicetrapib L-arginine

[0102] A reactor (Rl) is charged with obicetrapib free acid made in general accordance with Example 1 (1.0 eq.) followed by L-arginine (about 0.9 to 1.0). MTBE (4 vol.) and water (0.2 vol.) are then added to Rl. The resulting mixture is stirred at about 25°C when a clear solution is obtained. In a separate reactor (R2), heptane (30 vol.) is charged, and the contents are cooled to about 0°C. The clear solution from Rl is then transferred to R2 slowly while maintaining the temperature at about 0°C. After completion of the transfer, the mixture in R2 is stirred at about 0°C for about 10 to 16 hours. The resulting solids are isolated by filtration to afford a wet cake, which is washed with heptane or MTBE / heptane and dried at 30°C for 18 hours to provide obicetrapib L-arginine salt as a white solid. 1H-NMR (400 MHz, DMSO-d6) 5 ppm 0.61 - 0.89 (m, 4 H) 1.14 - 1.32 (m, 5 H) 1.39 - 1.76 (m, 7 H) 1.84 (quin, J=6.63 Hz, 2 H) 2.03 - 2.14 (m, 2 H) 2.21 - 2.36 (m, 1 H) 2.96 - 3.13 (m, 2 H) 3.18 - 3.31 (m, 1 H) 3.95 (brt, J=6.57 Hz, 2 H) 4.05 - 4.25 (m, 2 H) 4.25 - 4.40 (m, 1 H) 4.73 (br d, J=16.51 Hz, 1 H) 5.29 (br d, J=16.88 Hz, 1 H) 5.66 - 5.79 (m, 1 H) 6.90 (s, 1 H) 7.48 - 7.71 (m, 2 H) 7.89 - 8.09 (m, 3 H) 8.12 - 8.32 (m, 2 H).

[0103] FIG. 3 is an x-ray powder diffraction pattern of obicetrapib L-arginine. FIG. 3 A is an mDSC thermogram of obicetrapib L-arginine made in general accordance with Example 3.Example 4 - Obicetrapib L-arginine

[0104] 100.1 mg of obicetrapib free acid (Example 2) and 26.7 mg of L-arginine were combined.1 mL of ethanol was added. The sample was stirred briefly, resulting in a thin suspension. The sample was sonicated briefly, but no significant changes were observed. After stirring for 4 hours at room temperature, the sample was observed to be a clear solution. 1 mL of heptane was added, and no significant changes were observed. The sample was left to stir at room temperature for 3 days, resulting in a clear solution. The sample was uncapped for evaporation at room temperature. After 2 days of evaporation, the sample formed a slightly yellow gum on the bottom of the vial. Heptane was added, and the sample was sonicated. A slightly hazy liquidphase formed along with the gum. The sample was stirred at room temperature overnight and formed a clear liquid phase above the gum / gel on the bottom of the vial. Methyl tert-butyl ether was added, and the sample was sonicated before being stirred at room temperature. The resulting yellow gum with a clear liquid phase was placed under a stream of nitrogen for evaporation. After 4 days, off-white solids formed on the sides of the vial.FIG. 4 is an x-ray powder diffraction pattern of obicetrapib L-arginine.7. EMBODIMENTS

[0105] The disclosure can further be described by the non-limiting embodiments as set forth below.

[0106] Embodiment 1. Obicetrapib arginine.

[0107] Embodiment 2. The obicetrapib arginine of Embodiment 1, wherein the obicetrapib arginine is obicetrapib L-arginine.

[0108] Embodiment 3. The obicetrapib arginine of Embodiment 1, wherein the obicetrapib arginine is amorphous obicetrapib L-arginine.

[0109] Embodiment 4. Amorphous obicetrapib L-arginine.

[0110] Embodiment 5. The amorphous obicetrapib L-arginine of Embodiment 4, having an x-ray powder diffraction pattern substantially the same as that of FIG. 3.[OHl] Embodiment 6. The amorphous obicetrapib L-arginine of Embodiment 4, having an x-ray powder diffraction pattern substantially the same as that of FIG. 4.

[0112] Embodiment 7. A pharmaceutical composition comprising obicetrapib arginine of any one of Embodiments 1 to 6, and one or more pharmaceutically acceptable excipients.

[0113] Embodiment 8. The pharmaceutical composition of any one of Embodiments 1 to 7 made by (a) direct compression or (b) dry granulation followed by encapsulation or tablet compression.

[0114] Embodiment 9. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients thereof to the subject.

[0115] Embodiment 10. The method of Embodiment 9, further comprising administration of an HMG CoA reductase inhibitor.

[0116] Embodiment 11. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients thereof to the subject.

[0117] Embodiment 12. The method of Embodiment 11, where the neurodegenerative disease is Alzheimer's Disease (AD), Lewy Body dementia, vascular or multi-infarct dementia, or frontotemporal dementia (FTD).

[0118] Embodiment 13. A method of treating a subject suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0119] Embodiment 14. A method of treating a subject 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 heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular (CV) disease (ASCVD), the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, and a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt of ezetimibe to the subject.

[0120] Embodiment 15. A method of treating or preventing a metabolic disorder in a subject who has or is at risk of developing a metabolic disorder, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0121] Embodiment 16. A method of treating or preventing a disorder selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cardiovascular disease, atherosclerotic cardiovascular disease, heart failure and chronic kidney disease in a subject who has or is at risk of said disorder, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, and a therapeutically effective amount of at least one SGLT2 inhibitor, or a pharmaceutically acceptable salt of an SGLT2 inhibitor to the subject.

[0122] Embodiment 17. A method of treating heterozygous familial hypercholesterolemia (HeFH) and / or atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to the subject.

[0123] Embodiment 18. A method of reducing or preventing vascular symptoms in a subject with a beta hemoglobinopathy, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt ofobicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to the subject.

[0124] Embodiment 19. The method of Embodiment 18, wherein (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, is co-administered with at least one liposoluble antioxidant.

[0125] Embodiment 20. A method of improving atherosclerotic plaque characteristics in a patient with ASCVD, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to the subject.

[0126] Embodiment 21. The method of Embodiment 20, wherein the (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, is co-administered with a therapeutically effective amount of ezetimibe, or a pharmaceutically acceptable salt thereof.

[0127] Embodiment 22. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising administering to the subject (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients.

[0128] Embodiment 23. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients, in an amount effective to reduce ApoE4 concentration in the CNS.

[0129] Embodiment 24. A method of reducing major adverse cardiovascular events (MACE) in subjects with atherosclerotic cardiovascular disease (ASCVD) and / or heterozygous familial hypercholesterolemia (HeFH) who are not adequately controlled by maximally tolerated lipid-modifying therapies, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients to the subject.

[0130] Embodiment 25. The method of Embodiment 24, wherein (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients is administered at an oral dose of 10 mg per day for at least six months.

[0131] Embodiment 26. The method of Embodiments 24 or 25, wherein the baseline fasting serum LDL-C on maximally tolerated lipid-modifying therapy is >100 mg / dL, and administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients lowers serum LDL-C to less than 100 mg / dL.

[0132] Embodiment 27. The method of any one of Embodiments 24 to 26, wherein administration of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, andone or more pharmaceutically acceptable excipients on top of prior maximally-tolerated lipid modifying therapy is sufficient, after 18 months of treatment, to show reduction from baseline as compared to placebo in one or more of:(i) total non-calcified coronary atherosclerotic plaque volume (NCPV);(ii) NCPV in the most diseased coronary segment (NCPVMD);(iii) low attenuation plaque volume;(iv) calcified plaque volume;(v) perivascular fat attenuation index score measured in all of the left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) (collectively, the principal coronary arteries); and(vi) FAI score age- and gender-matched population centile.

[0133] Embodiment 28. A method of making obicetrapib L-arginine of any one of Embodiments 1 to 6 comprising treating a solution comprising L-arginine in a suitable solvent with L-arginine.

[0134] Embodiment 29. The obicetrapib L-arginine made from the process of Embodiment 28.

Claims

CLAIMS1. Obicetrapib arginine.

2. The obicetrapib arginine of claim 1, wherein the obicetrapib arginine is obicetrapib L- arginine.

3. The obicetrapib arginine of claim 1, wherein the obicetrapib arginine is amorphous obicetrapib L-arginine.

4. The amorphous obicetrapib L-arginine of claim 3, having an x-ray powder diffraction pattern substantially the same as that of FIG. 3.

5. The amorphous obicetrapib L-arginine of claim 3, having an x-ray powder diffraction pattern substantially the same as that of FIG. 4.

6. A pharmaceutical composition comprising obicetrapib arginine of any one of claims 1 to 5, and one or more pharmaceutically acceptable excipients.

7. A method of treating a subject suffering from or having an increased risk of developing a cardiovascular disease, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients thereof to the subject.

8. A method of slowing the progression of a neurodegenerative disease in a subject who is at risk of developing a neurodegenerative disease, the method comprising administering a therapeutically effective amount of (i) an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, or (ii) a pharmaceutical composition comprising an arginine salt of obicetrapib, such as obicetrapib L-arginine and / or amorphous obicetrapib L-arginine, and one or more pharmaceutically acceptable excipients thereof to the subject. Embodiment 28.

9. A method of making obicetrapib L-arginine of any one of claims 1 to 6 comprising treating a solution comprising L-arginine in a suitable solvent with L-arginine.

10. The obicetrapib L-arginine made from the process of claim 9.

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