Treatment and prevention of age-related macular degeneration using a CETP inhibitor

Abstract

This invention relates to methods and compositions useful in subjects with age-related macular degeneration, in particular dry age-related macular degeneration. It has been demonstrated that the CETP inhibitor obicetrapib increases the plasma level of pre-beta-1 HDL, as well as total plasma lutein, zeaxanthin and tocopherol. More in particular, it has been found that the levels of these lipophilic anti-oxidants are also particularly elevated in pre-beta-1 HDL, which can pass the BrM and reach the retina with relative ease. These constitute particularly strong support for the treatment of AMD using a CETP inhibitor. Thus, broadly stated, the present invention concerns the use of CETP inhibitors in the treatment of age related macular degeneration.

Description

[0001] TREATMENT AND PREVENTION OF AGE-RELATED MACULAR DEGENERATION USING A CETP INHIBITOR

[0002] Field of the Invention

[0003] This invention relates to methods and compositions useful in subjects with age- related macular degeneration, in particular dry age-related macular degeneration. The methods involve administration of a CETP-inhibitor.

[0004] Background of the Invention

[0005] Age-related macular degeneration (“AMD”) is a disease characterized by progressive degenerative abnormalities in the macula, a small area in the central portion of the retina. AMD is characteristically a disease of the elderly and is the leading cause of blindness in individuals >50 years of age in developed countries. In the United States, it is estimated that approximately 6% of individuals 65-74 years of age, and 20% of those older than 75 years of age, are affected with AMD. Because of increasing life expectancy in developed and developing countries, the elderly fraction of the general population is expected to increase at the greatest rate in coming decades. In the absence of adequate prevention or treatment measures, the number of cases of AMD with visual loss is expected to grow in parallel with the aging population.

[0006] AMD is classified into one of two general subgroups; the non-neovascular (“dry”) form of the disease (“dry AMD”) and the neovascular form of the disease (“wet AMD”).

[0007] Dry AMD is more prevalent, accounting for approximately 90% of all AMD cases. In dry AMD the light-sensitive cells in the macula slowly break down, generally one eye at a time. The loss of vision in this condition is usually slow and gradual. With continued progression over multiple years, dry AMD may ultimately result in atrophy of the central retina and central vision loss.

[0008] Wet AMD, is less prevalent. Wet AMD is more likely to cause sudden, often substantial, loss of central vision. Wet AMD happens when abnormal blood vessels start to grow beneath the retina. They leak fluid and blood — hence the name wet AMD — and can create a large blind spot in the centre of the visual field.

[0009] Dry AMD is a major cause of moderate and severe loss of central vision. It is bilateral in most patients. Its exact cause is unknown, although both genetic and environmental factors are thought to play a role. In dry AMD, thinning of the retinal pigment epithelial cells (RPE) in the macula develops, along with other age-related changes to the adjacent retinal tissue layers. Dry AMD is characterized by infiltration and disruption of the photoreceptor-rich, central part of the retina, by focal or diffuse lipoprotein-rich deposits called drusen (yellow crystalline deposits that develop within the macula). These drusen form either under the neurosensory retina called sub- retinal drusenoid deposits or under the retinal pigment epithelium (RPE). The RPE is a monolayer of polarized epithelial cells serving as the interface between the neural retina and the choroid, the main blood supply to the outer layer of the retina. The basement membrane of RPE cells form Bruch’s membrane (BrM), a pentalaminar structure consisting of the endothelial cells of the choriocapillaris and the matrix, which fills the space between the RPE and BrM.

[0010] When the condition is severe, dry AMD results in marked thinning and / or atrophy of the macula, resulting from the loss of the RPE and associated capillaries (choriocapillaris). This collective phenotype in late stage dry AMD is termed geographic atrophy (“GA”). The progressive degeneration of light-sensitive photoreceptor cells in GA leads to severe visual loss in affected eyes. In addition, dry AMD can progress to the wet form of the disease.

[0011] In aging retinae, it is believed that the depletion of endogenous and exogenous antioxidants represents a critical driver in exacerbating degenerative mechanisms. In fact, there is substantial evidence in favour of the protective association, between greater dietary consumption of carotenoids, increased lutein and zeaxanthin concentrations in serum, and AMD prevention. Several AMD trials also demonstrated remarkable improvements in objective measurement of macular function, following supplementation with xanthophyll carotenoids for twelve months or more. In fact, several reports indicate that the improvements in central retinal function were positively correlated with MPOD augmentation.

[0012] The Age-Related Eye Disease Study (AREDS) and AREDS 2 are considered to be among the most influential large-scale clinical trials highlighting the relationship between dietary antioxidants and the risk of AMD progression. Reports indicate that regular consumption of the AREDS micronutrient formula may reduce the risk of late AMD progression by up to 25% during a five-year follow-up with at risk patients.

[0013] All in all, there is substantial evidence that the long-term treatment with carotenoids, in particular lutein and zeaxanthin, promotes enhanced retinal function in patients with AMD, by increasing macular pigment concentrations. To date, such dietary modifications remain the mainstay of therapeutic strategies to potentially delay or prevent both the development and progression of AMD.

[0014] Although dry AMD is the most common form of the disease and a major cause of visual impairment in the (elderly) population, currently no approved therapy exists. The absence of treatment options for dry AMD represents an area of urgent unmet medical need, and a major public health concern for the rapidly increasing elderly population.

[0015] Summary of the Invention

[0016] The present invention, generally speaking, provides methods of treating AMD and symptoms / conditions associated therewith using inhibitors of cholesterylester transfer protein (CETP).

[0017] New analyses of samples from the OCEAN trial (NCT04770389, “Randomized Study of Obicetrapib, optionally combined with Ezetimibe”) have now demonstrated (see examples herein below) that the CETP inhibitor obicetrapib increased the plasma level of pre-beta1 HDL, as well as total plasma lutein, zeaxanthin and tocopherol. More in particular, it has been found that the levels of these lipophilic anti-oxidants are also particularly elevated in pre-beta1 HDL, which observation is highly significant, given that pre-beta1 HDL is the HDL form most likely to pass BrM and reach the retina. The findings that treatment with obicetrapib increases, in particular, pre-beta1 HDL-carried antioxidants (lutein, zeaxanthin and alpha-tocopherol), therefore constitute particularly strong support for the treatment of AMD using obicetrapib.

[0018] Hence, a first 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 age- related macular degeneration, preferably a subject suffering from or at risk of suffering from dry age-related macular degeneration, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of a CETP-inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof. A further aspect of the invention concerns a method for treating, preventing or slowing down the progression of age-related macular degeneration in a subject, preferably dry age-related macular degeneration, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor, preferably Obicetrapib or a pharmaceutically acceptable salt thereof.

[0019] In a further aspect, the invention provides a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising said CETP inhibitor, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from age-related macular degeneration, preferably a subject suffering from or at risk of suffering from dry age-related macular degeneration, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor. A further aspect of the invention provides a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising said CETP inhibitor, for use in a method for treating, preventing or slowing down the progression of age-related macular degeneration in a subject, preferably dry age-related macular degeneration, said method comprising the administration to said subject of (a pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor.

[0020] Yet, a further aspect of the invention concerns the use of a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from age-related macular degeneration, preferably a subject suffering from or at risk of suffering from dry age-related macular degeneration, said method comprising the administration to said subject of (the pharmaceutical composition comprising) a therapeutically effective amount of the CETP inhibitor. A further aspect of the invention provides the use of a CETP-inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for treating, preventing or slowing down the progression of age-related macular degeneration, preferably dry age-related macular degeneration, in a subject, said method comprising the administration to said subject of (the pharmaceutical composition comprising) a therapeutically effective amount of the CETP-inhibitor.

[0021] Other aspects of the invention concern pharmaceutical compositions, preferably in unit dosage form, comprising a CETP inhibitor selected from the group consisting of Obicetrapib and pharmaceutically acceptable salts thereof, and kits comprising a package containing a plurality of one or more of such pharmaceutical unit dosage forms as well as a leaflet containing printed instructions to repeatedly selfadminister said unit dosage forms in order to treat and / or prevent age-related macular degeneration, especially dry age-related macular degeneration.

[0022] 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.

[0023] Definitions

[0024] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

[0025] The terms “subject” or “individual” are used interchangeably and refer to an animal to be treated, including but not limited to humans and non-human primates; rodents, including rats and mice; bovines; equines; ovines; felines; and canines.

[0026] The term “patient” refers to a human subject.

[0027] 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.

[0028] The phrase “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, condition, or disorder, is sufficient to effect treatment of the disease, condition, or disorder.

[0029] The term “pharmaceutically acceptable salt” refers to a salt that is acceptable for administration to a subject. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. The term “salt(s)” as used herein encompass hydrate salt(s). Other examples of pharmaceutically acceptable salts include anions of the compounds of the present disclosure compounded with a suitable cation.

[0030] Other interpretational conventions

[0031] 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.

[0032] In this disclosure, “comprises”, “comprising”, “containing”, “having”, “includes”, “including” and linguistic variants thereof have the meaning normally ascribed to them in (U.S. and / or European) Patent law, permitting the presence of additional components beyond those explicitly recited.

[0033] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.

[0034] 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 (i.e. , 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.

[0035] 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.

[0036] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures of R-enantiomer and S- enantiomer, and enantio-enriched stereomeric mixtures comprising of R- and S- enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0037] Detailed description of the Invention

[0038] CETP Inhibitors

[0039] The present invention, in one aspect, concerns the use of certain CETP inhibitors in the treatment of age related macular degeneration. The term CETP inhibitors refers to a class of compounds that have the capability of inhibiting cholesterylester transfer protein (CETP). Whenever the term ‘CETP inhibitor’ is used herein in general, it refers to the respective compounds in their free base form as well as to any pharmaceutically acceptable derivative thereof, including, in particular, any pharmaceutically acceptable salt, solvate, hydrate, enantiomer, polymorph, etc.

[0040] In accordance with the invention, the CETP inhibitor is obicetrapib or a pharmaceutically acceptable salt thereof.

[0041] “Obicetrapib”, formerly known as TA-8995, is the international non-proprietary name (INN) of the compound with IUPAC name (2R,4S){[3,5Bis(trifluoromethyl)benzyl]-[5(3-carboxypropoxy)pyrimidin-2-yl] amino}- 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester, and according to the following formula (V)

[0042]

[0043] (V).

[0044] 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.

[0045] In certain preferred embodiments of the invention, the CETP inhibitor is a salt form of obicetrapib, more particularly an amorphous obicetrapib calcium salt, in particular, amorphous obicetrapib hemicalcium. More detailed information containing said salts, including methods of their preparation are is provided herein below.

[0046] Pharmaceutical compositions

[0047] In preferred embodiments of the present invention, the CETP inhibitor is provided in the form of or contained in a pharmaceutical composition. As mentioned herein before, an aspect of the invention relates to said pharmaceutical compositions.

[0048] As used herein, the term "pharmaceutical composition" refers to a composition comprising the CETP inhibitor, typically obicetrapib or a pharmaceutically acceptable salt thereof and one or more additional, non-toxic, ingredients, in particular one or more pharmaceutically acceptable carriers and / or excipients, which composition typically is in a form suitable for administration to a (human) subject, through any route of administration, and which composition is physiologically tolerated upon such administration.

[0049] In a preferred embodiment, the composition comprises one or more carriers and / or excipients. As is known by those of average skill in the art, the appropriate choice of excipients is dependent on multiple factors, including the physicochemical properties of the API, the preferred pharmaceutical form, the preferred route of administration, the desired rate of release, etc. The compositions of the invention can be formulated for a variety of routes of administration, oral administration being particularly preferred. It is within the purview of those of average skill in the art to conceive and develop suitable formulations, relying on the common general knowledge as reflected in text books such as Remington’s Pharmaceutical Sciences (Meade Publishing Co., Easton, Pa., 20thEd., 2000), the entire disclosure of which is herein incorporated by reference, and routine development efforts.

[0050] In accordance with the various aspects of the invention, the composition is preferably provided in unit dosage form. The term “unit dosage form” refers to a physically discrete unit suitable as a unitary dosage for human subjects, each unit containing a predetermined quantity of active material, calculated and / or determined to produce the desired therapeutic effect in association with any suitable pharmaceutical carrier(s) and / or excipient(s). Exemplary, non-limiting unit dosage forms include a tablet, caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, gelcap as well as any metered volume of a solution, suspension, syrup or elixir or the like, which may be contained, for instance in a vial, syringe, applicator device, sachet, spray, micropump etc. In accordance with particularly preferred embodiments of the invention, the unit dosage form, is a unit dosage form that is suitable for oral administration. Most preferably, it is a solid unit dosage form, such as a tablet for oral ingestion.

[0051] In accordance with various aspects of the invention, the composition is preferably provided in a unit dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of at least 0.5 mg, preferably at least 1 mg, at least 1 .5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg or at least 10 mg,. Furthermore, in accordance with the various aspects of the invention, the composition is preferably provided in a unit dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof 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, 10 mg or less, 7.5 mg or less, 5 mg or less, 4 mg or less, 3 mg or less or 2.5 mg or less.

[0052] In accordance with the various aspects of the invention, the composition is preferably provided in a unit dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose within the range of 0.5-100 mg, 1-50 mg, 1 ,5-50 mg, 2-25 mg or 2.5-10 mg, e.g. about 2.5 mg, about 5 mg or about 10 mg. In certain preferred embodiments, the composition is provided in a unit dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of 0.5, 1 , 1.5, 2,

[0053] 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11 , 11.5, 12, 12.5, 13,

[0054] 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20 mg. In certain particularly preferred embodiments, the composition is provided in a unit dosage form comprising obicetrapib or a pharmaceutically acceptable salt thereof in a dose of 1 ,

[0055] 2.5, 5, 7.5, 10, 12.5 or 15 mg.

[0056] In certain embodiments of the invention, the pharmaceutical composition further comprises one or more antioxidants, preferably one or more lipophilic antioxidants, more preferably one or more antioxidants selected from the group consisting of tocopherols and carotenoids. More preferably, the pharmaceutical composition comprises one or more antioxidants selected from the group consisting of vitamin E, especially alpha Tocopherol, and xantophylls, especially lutein and zeaxanthin. Most preferably the pharmaceutical composition comprises one or more lipophilic antioxidants selected from the group consisting of alpha Tocopherol , lutein and zeaxanthin.

[0057] Embodiments are envisaged wherein the composition is a fixed dose combination product comprising the CETP inhibitor, and one or more lipophilic antioxidants.

[0058] Hence, the invention provides compositions as defined herein, provided in unit dosage form, comprising said one or more antioxidants, typically in amounts ranging from 1 to 1000 mg.

[0059] In some embodiments, the amount of each antioxidant present in the unit dosage form is at least 50 %, at least 75 %, at least 80 %, at least 85 %, at least 90 %, at least 95 %, at least 97 %, at least 98 % or at least 99 % and / or less than 200 %, less than 150 %, less than 125 %, less than 120 %, less than 115 %, less than 110 %, less than 105 %, less than 103 % , less than 102 % or less than 101 % of the Recommended Dietary Allowances (RDAs), such as the U.S. RDAs established by the (U.S.) national institute of health (‘NIH’), which, currently, use an RDA for alphatocopherol of 15 mg (daily); an RDA for lutein of 10 mg (daily); and an RDA for zeaxanthin of 2 mg (daily).

[0060] In some embodiments, the amount of each lipophilic antioxidant present in the unit dosage form is at least 50 %, at least 75 %, at least 80 %, at least 85 %, at least 90 %, at least 95 %, at least 97 %, at least 98 % or at least 99 % and / or less than 200 %, less than 150 %, less than 125 %, less than 120 %, less than 115 %, less than 110 %, less than 105 %, less than 103 %, less than 102 % or less than 101 % of the highest (daily) dose that is safe and recommended / approved for the treatment of AMD. Currently, treatment guidelines, such as the guidelines published by the American Academy of Ophthalmology, based on the AREDS 2 study, recommend daily dosages of 400 III of alpha tocopherol (a-tocopherol), 2 mg of zeaxanthin and 10 mg of lutein, for patients suffering from dry AMD.

[0061] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising Lutein at an amount of 1 -100 mg, 2-75 mg, 3-50 mg, 4-25 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg or 20 mg, more preferably about 5 mg, 10 mg, 15 mg or 20 mg, most preferably about 10 mg.

[0062] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising Zeaxanthin or a salt thereof at an amount of 0.5-100 mg, 1 -50 mg or 1.5-25 mg, e.g. 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, more preferably about 0.5 mg, 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg or 5 mg, most preferably about 2 mg.

[0063] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha-tocopherol at an amount of 1-100 international units (IU), 2-90 IU, 5-80 IU, 100-700 IU, 10-60 IU , e.g. 15, 17.5, 20, 22.4, 22.5, or 25 III, more preferably about 22.4 IU.

[0064] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha-tocopherol at an amount of 0,5-70 mg, 1 -60 mg, 3-50 mg, 5-40 mg, 10-40 mg , e.g. 10, 12.5, 15, 17.5 or 20 mg, more preferably about 15 mg.

[0065] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha Tocopherol or a salt thereof at an amount of 10- 1000 international units (IU), 20-900 IU, 50-800 IU, 100-700 IU, 200-600 IU , e.g. 200, 300, 400, 500 or 600 IU, more preferably about 200, 400 or 600 IU, most preferably about 400 IU.

[0066] In some embodiments, the invention provides compositions as defined herein, in unit dosage form, comprising alpha-tocopherol at an amount of 5-700 mg, 10-600 mg, 30-500 mg, 50-400 mg, 100-400 mg, e.g. about 134 mg, about 200 mg, about 268 mg, about 335 mg or about 400 mg, most preferably about 134 mg, about 268 mg or about 400 mg, most preferably about 268 mg. In some specific embodiments, the pharmaceutical composition in unit dosage form or solid dosage form, such as the tablet, comprises 0.5 mg, 1 mg, 2 mg, 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 or pharmaceutically acceptable salt thereof. In more specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 2,5 mg of obicetrapib as the calcium salt. In other specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 5 mg of obicetrapib as the calcium salt. In other specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 10 mg of obicetrapib as the calcium salt. In specific embodiments, the excipients present in the tablet cores are microcrystalline cellulose, mannitol, sodium starch glycollate, colloidal silicon dioxide, and magnesium stearate. In specific embodiments, a commercially available film-coating formula (Opadry II white, ex Colorcon) is applied to the cores.

[0067] In preferred embodiments, obicetrapib is present in the compositions and dosage forms as amorphous obicetrapib, and in particularly preferred embodiments, as amorphous obicetrapib hemicalcium.

[0068] Methods of treatment

[0069] In one aspect, the present invention relates to methods of treating a subject with AMD, especially dry AMD, comprising administering to the subject the CETP inhibitor, as described herein. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse progression of dry AMD. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse one or more symptoms of dry AMD, including, but not limited to, visual distortions, reduced central vision, need for greater luminance, difficulty adapting to low luminance, increased blurriness, and decreased color intensity or brightness. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse one or more of tissue- or cellular-level changes that is associated with dry AMD, including, but not limited to, thinning of the RPE cells in the macula, formation of drusen under the RPE, and thinning and / or atrophy of the macula.

[0070] In one aspect, the present invention relates to methods of reversing loss of visual acuity in a subject with dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may increase the best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0071] In one aspect, the present invention relates to methods of slowing or inhibiting loss of visual acuity in a subject with dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may slow or inhibit the decrease in best corrected visual acuity (measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0072] In one aspect, the present invention relates to methods of reversing loss of low luminance visual acuity in a subject with dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may increase the low luminance best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0073] In one aspect, the present invention relates to methods of reducing the rate of formation of drusen in a subject, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the rate of formation of drusen as compared to that in a subject who is not administered the CETP inhibitor.

[0074] In one aspect, the present invention relates to methods of reversing the formation of drusen in a subject, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reverse the formation of drusen as compared to that in a subject who is not administered the CETP inhibitor.

[0075] In one aspect, the present invention relates to methods of reducing the amount of drusen in a subject, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the amount of drusen as compared to that in a subject who is not administered the CETP inhibitor.

[0076] In one aspect, the present invention relates to methods of reducing the formation of drusen in a subject, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the formation of drusen as compared to that in a subject who is not administered the CETP inhibitor. In some embodiments, the measurement using ETDRS letters may be as described in Early Treatment Diabetic Retinopathy Study Research Group (ETDRS), Manual of Operations, Baltimore: ETDRS Coordinating Center, University of Maryland. Available from: National Technical Information Service, 5285 Port Royal Road, Springfield, Va. 22161 ; Accession No. PB8S 223006 / AS; Ferris et al., Am J Ophthalmol 94:91-96, 1982. In some embodiments, the vision testing uses a chart from http: / / www.nei. nih.gov / photo / keyword. asp?conditions=Eye+Charts&match=all, e.g., ETDRS visual acuity Chart 1 , 2 and / or R.

[0077] In one aspect, the present invention relates to methods of treating a subject with Geographic atrophy (GA) secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse progression of GA. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse one or more symptoms of GA secondary to dry AMD, including, but not limited to, reduced or loss of central vision, loss of visual acuity, and reduced or inability to read. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse one or more of tissue- or cellular-level changes that is associated with GA secondary to dry AMD, including, but not limited to, growth of GA lesions, rate of growth or change in GA lesions, and the formation of drusen under the RPE.

[0078] In one aspect, the present invention relates to methods of treating a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse progression of GA. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse one or more symptoms of GA secondary to AMD, including, but not limited to, reduced or loss of central vision, loss of visual acuity, and reduced or inability to read. In some embodiments, administration of the CETP inhibitor may reduce, inhibit, slow, and / or reverse one or more of tissue- or cellular-level changes that is associated with GA secondary to AMD, including, but not limited to, growth of GA lesions, rate of growth or change in GA lesions, and the formation of drusen under the RPE.

[0079] In one aspect, the present invention relates to methods of reducing the rate of GA growth in a subject with GA secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the rate of GA growth by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%, as compared to that in a subject who is not administered the CETP inhibitor.

[0080] In one aspect, the present invention relates to methods of reducing the rate of GA growth in a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the rate of GA growth by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%, as compared to that in a subject who is not administered the CETP inhibitor.

[0081] In one aspect, the present invention relates to methods of reducing the rate of change in GA area in a subject with GA secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the rate of change in GA area by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%, as compared to that in a subject who is not administered the CETP inhibitor.

[0082] In one aspect, the present invention relates to methods of reducing the rate of change in GA area in a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may reduce the rate of change in GA area by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%, as compared to that in a subject who is not administered the CETP inhibitor.

[0083] In one aspect, the present invention relates to methods of slowing or inhibiting the progression of dry AMD in a subject, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor may slow or inhibit the progression of one or more symptoms of dry AMD, including, but not limited to, visual distortions, reduced central vision, need for greater luminance, difficulty adapting to low luminance, increased blurriness, and decreased color intensity or brightness. In some embodiments, administration of the CETP inhibitor may slow or inhibit the progression of one or more of tissue- or cellular-level changes that are associated with dry AMD, including, but not limited to, thinning of the RPE cells in the macula, formation of drusen under the RPE, and thinning and / or atrophy of the macula.

[0084] In one aspect, the present invention relates to methods of slowing or inhibiting the progression of GA in a subject, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor may slow or inhibit the progression of one or more symptoms of GA secondary to dry AMD or AMD, including, but not limited to, reduced or loss of central vision, loss of visual acuity, and reduced or inability to read. In some embodiments, administration of the CETP inhibitor may slow or inhibit the progression of one or more of tissue- or cellular-level changes that are associated with GA secondary to dry AMD or AMD, including, but not limited to, growth of GA lesions, rate of growth or change in GA lesions, and the formation of drusen under the RPE.

[0085] In one aspect, the present invention relates to methods of slowing or inhibiting loss of visual acuity in a subject with GA secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may slow or inhibit the decrease in best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0086] In one aspect, the present invention relates to methods of slowing or inhibiting loss of visual acuity in a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may slow or inhibit the decrease in best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0087] In one aspect, the present invention relates to methods of reversing loss of visual acuity in a subject with GA secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may increase the best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor. In one aspect, the present invention relates to methods of reversing loss of visual acuity in a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may increase the best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0088] In one aspect, the present invention relates to methods of slowing or inhibiting loss of low luminance visual acuity in a subject with dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may slow or inhibit the decrease in low luminance best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0089] In one aspect, the present invention relates to methods of slowing or inhibiting loss of low luminance visual acuity in a subject with GA secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may slow or inhibit the decrease in low luminance best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0090] In one aspect, the present invention relates to methods of slowing or inhibiting loss of low luminance visual acuity in a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may slow or inhibit the decrease in low luminance best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0091] In one aspect, the present invention relates to methods of reversing loss of low luminance visual acuity in a subject with GA secondary to dry AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may increase the low luminance best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0092] In one aspect, the present invention relates to methods of reversing loss of low luminance visual acuity in a subject with GA secondary to AMD, comprising administering to the subject the CETP inhibitor as described herein. In some embodiments, administration of the CETP inhibitor to the subject may increase the low luminance best corrected visual acuity (measured using ETDRS letters), as compared to that in a subject who is not administered the CETP inhibitor.

[0093] Any or all of the therapeutic effects or indications as described herein can typically be measured between baseline, which is defined as the day at which the treatment with the CETP inhibitor is started, and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months.

[0094] In some embodiments, the methods described herein may further comprise identifying the subject to be treated, such as by determining whether the subject has dry AMD, has GA secondary to dry AMD, or has GA secondary to AMD.

[0095] In some embodiments, the subject may be a mammal, which includes, but is not limited to, a human, monkey, cow, hog, sheep, horse, dog, cat, rabbit, rat, and mouse. In certain embodiments, the subject is a human.

[0096] In some embodiments, the subject may be treatment-naive, e.g., was not previously treated for the dry AMD, GA secondary to dry AMD, or GA secondary to AMD.

[0097] As will be apparent to those skilled in the art, based on the present teachings, methods of the invention, in accordance with some embodiments, further comprise the concurrent treatment with ezetimibe. To this end, ezetimibe 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.

[0098] Administration and Dosage

[0099] In various embodiments, the CETP inhibitor is administered orally and the methods as defined herein before comprise the oral administration of the CETP inhibitor.

[0100] In typical embodiments, the CETP inhibitor is administered as a tablet for oral administration. As defined herein before, in accordance with the invention, the CETP inhibitor is obicetrapib or a pharmaceutically acceptable salt thereof.

[0101] In various embodiments, the dose of obicetrapib or pharmaceutically acceptable salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD). In some embodiments, the dose of the CETP inhibitor is 5-20 mg by mouth per day (5-20 mg po QD). In some embodiments, the dose of the CETP inhibitor is 10-20 mg by mouth per day (10-20 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2.5-15 mg by mouth per day (2.5-15 mg po QD). In some embodiments, the dose of the CETP inhibitor is 5-10 mg by mouth per day (5-10 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 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 mg po QD, 5.5 mg po QD, 6 mg po QD, 6.5 mg po QD, 7 mg po QD, 7.5 mg po QD, 8 mg po QD, 8.5 mg po QD, 9 mg po QD, 9.5 mg po QD, 10 mg po QD, 10.5 mg po QD, 11 mg po QD, 1 1 .5 mg po QD, 12 mg po QD, 12.5 mg po QD, 13 mg po QD, 13.5 mg po QD, 14 mg po QD, 14.5 mg po QD, 15 mg po QD, 15.5 mg po QD, 16 mg po QD, 16.5 mg po QD, 17 mg po QD, 17.5 mg po QD, 18 mg po QD, 18.5 mg po QD, 19 mg po QD, 19.5 mg po QD, or 20 mg po QD. In some embodiments, the dose of the CETP inhibitor is equipotent to 5-20 mg of obicetrapib by mouth per day (5-20 mg po QD).

[0102] In various embodiments, the dose of obicetrapib or pharmaceutically acceptable salt thereof is 0.5-25 mg by mouth per day (0.5-25 mg po QD). In some embodiments, the dose of the CETP inhibitor is 1 -20 mg by mouth per day (1 -20 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2.5-15 mg by mouth per day (2.5-15 mg po QD). In some embodiments, the dose of the CETP inhibitor is 1 -10 mg by mouth per day (1 -10 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2,5-10 mg by mouth per day (2.5-10 mg po QD). In some embodiments, the dose of the CETP inhibitor is 2.5-5 mg by mouth per day (2,5-5 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 0.5 mg po QD, 1 .0 mg po QD, 1 .5 mg po QD, 2.0 mg po QD or 2.5 mg po QD.

[0103] In some specific embodiments, the dose of obicetrapib or a pharmaceutically acceptable salt thereof is 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,

[0104] 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,

[0105] 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,

[0106] 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.

[0107] 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,

[0108] 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,

[0109] 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,

[0110] 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,

[0111] 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,

[0112] 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,

[0113] 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,

[0114] 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg po QD.

[0115] In some specific embodiments, the dose of obicetrapib or a pharmaceutically acceptable salt thereof is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6

[0116] 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1 , 5.2, 5.3, 5.4, 5.5,

[0117] 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4,

[0118] 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3,

[0119] 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0 mg po QD.

[0120] In some specific embodiments, the daily dose of obicetrapib or a pharmaceutically acceptable salt thereof is 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6,

[0121] 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 ,

[0122] 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

[0123] 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 ,

[0124] 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,

[0125] 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 ,

[0126] 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,

[0127] 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 ,

[0128] 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,

[0129] 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 ,

[0130] 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,

[0131] 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 ,

[0132] 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,

[0133] 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, or 30.0 mg.

[0134] In some specific embodiments, the daily dose of obicetrapib or a pharmaceutically acceptable salt thereof is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3,

[0135] 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1 ,

[0136] 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,

[0137] 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9,

[0138] 9.0, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0 mg.

[0139] In various embodiments, the CETP inhibitor is a salt of obicetrapib that is administered at a dose that is equipotent to a certain dose of obicetrapib, administered via the same route. As used herein, the term “equipotent” typically means equally potent or equally capable of producing a pharmacologic effect of certain intensity. It is also common in the art to refer to amounts of a given compound ‘equivalent’ to a specified amount of a reference compound. For example, if the composition comprises a salt of obicetrapib the amount of said salt to be administered and / or to be incorporated into a unit dose form needs to be adjusted to take account of the molecular weight difference between the free base and salt form. For instance, in expressing dose amounts in the label and / or product information of authorized medicinal products comprising a salt form of an active compound that can also be used in free base form, it is customary practice to specify the dose of the free base to which the dose of the salt as used is equivalent. In this context, the term ‘equipotent’ is deemed synonymous to the term ‘equivalent’. In accordance with certain preferred embodiments of the invention the term ‘equipotent’, as used herein, denotes that the salt of obicetrapib is given at a dose containing the same mole amount of obicetrapib as the recited dose of the free base.

[0140] In various embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 2.5-25 mg po QD of obicetrapib, 5-20 mg po QD of obicetrapib, 10-20 mg po QD of obicetrapib, 2.5-15 mg po QD of obicetrapib, or 5-10 mg po QD of obicetrapib. In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 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 mg po QD, 5.5 mg po QD, 6 mg po QD, 6.5 mg po QD, 7 mg po QD, 7.5 mg po QD, 8 mg po QD, 8.5 mg po QD, 9 mg po QD, 9.5 mg po QD, 10 mg po QD, 10.5 mg po QD, 11 mg po QD, 11.5 mg po QD, 12 mg po QD, 12.5 mg po QD, 13 mg po QD, 13.5 mg po QD, 14 mg po QD, 14.5 mg po QD, 15 mg po QD, 15.5 mg po QD, 16 mg po QD, 16.5 mg po QD, 17 mg po QD, 17.5 mg po QD, 18 mg po QD, 18.5 mg po QD, 19 mg po QD, 19.5 mg po QD, or 20 mg po QD of obicetrapib.

[0141] In various embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 0.5-25 mg po QD, 1 -20 mg po QD, 2.5-15 mg po QD, 1-10 mg po QD, 2.5-10 mg po QD, 2,5-5 mg po QD, 0.5 mg po QD, 1.0 mg po QD, 1.5 mg po QD, 2.0 mg po QD or 2.5 mg po QD of obicetrapib..

[0142] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8,

[0143] 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,

[0144] 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,

[0145] 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,

[0146] 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,

[0147] 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,

[0148] 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,

[0149] 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,

[0150] 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,

[0151] 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,

[0152] 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,

[0153] 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,

[0154] 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,

[0155] 28.9, 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg po QD of obicetrapib.

[0156] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the (oral) dose is equipotent to 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1 .3, 1 .4, 1 .5, 1 .6,

[0157] I .7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5,

[0158] 3.6 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1 , 5.2, 5.3, 5.4,

[0159] 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3,

[0160] 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2,

[0161] 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0 mg po QD of obicetrapib.

[0162] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the daily dose is equipotent to 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9,

[0163] I I .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,

[0164] 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,

[0165] 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,

[0166] 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,

[0167] 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.

[0168] 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,

[0169] 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,

[0170] 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,

[0171] 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,

[0172] 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,

[0173] 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,

[0174] 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg of obicetrapib.

[0175] In some specific embodiments, the CETP inhibitor is a salt of obicetrapib and the daily dose is equipotent to 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5,

[0176] 3.6 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5,1 , 5.2, 5.3, 5.4,

[0177] 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3,

[0178] 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2,

[0179] 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0 mg of obicetrapib.

[0180] In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and total daily dose defined herein, is administered as a plurality of divided doses.

[0181] In various embodiments, obicetrapib is administered as a tablet. In some embodiments, the tablet comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of obicetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains obicetrapib as the calcium salt. In particular embodiments, the tablet contains 5 mg obicetrapib as a calcium salt.

[0182] In various embodiments, obicetrapib is administered as a tablet. In some embodiments, the tablet comprises 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of obicetrapib or pharmaceutically acceptable salt thereof.

[0183] In specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 2.5 mg of obicetrapib as the calcium salt.

[0184] In other specific embodiments, tablets are round, 6 mm in diameter, white film- coated tablets, containing 5 mg of obicetrapib as the calcium salt.

[0185] In other specific embodiments, tablets are round, 6 mm in diameter, white film- coated tablets, containing 10 mg of obicetrapib as the calcium salt.

[0186] In specific embodiments, the excipients present in the tablet cores are microcrystalline cellulose, mannitol, sodium starch glycollate, colloidal silicon dioxide, and magnesium stearate. In specific embodiments, a commercially available filmcoating formula (Opadry II white, ex Colorcon) is applied to the cores. In various embodiments, the CETP inhibitor is 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.

[0187] 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 CoA 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.

[0188] In various embodiments, the CETP inhibitor is administered in an amount effective to increase levels of total pre-beta1 HDL in blood as compared to the level prior to commencement of treatment. In typical embodiments, blood levels of pre- betal HDL are measured in plasma. In preferred embodiments, the CETP inhibitor is administered in an amount effective to increase plasma levels of pre-beta1 HDL.

[0189] In certain 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 the CETP inhibitor, to the subject, at a dose and frequency effective to increase a subject’s total plasma levels of lutein and / or to increase a subject’s total plasma levels of zeaxanthin and / or to increase a subject’s total plasma levels of tocopherol and / or increase the total level of HDL-carried antioxidants, typically to values within the ranges recited herein elsewhere.

[0190] As will be apparent to those skilled in the art, based on the present teachings, methods of the invention, in accordance with some embodiments, further comprise the concurrent treatment with ezetimibe. 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. In preferred embodiments, obicetrapib is administered as amorphous obicetrapib, and in particularly preferred embodiments, as amorphous obicetrapib hemicalcium.

[0191] In certain embodiments, the methods of the invention further comprises the concurrent treatment with one or more antioxidants, preferably one or more lipophilic antioxidants, more preferably one or more lipophilic antioxidants selected from the group consisting of tocopherols and carotenoids. More preferably, the methods of the invention further comprises the concurrent treatment with one or more antioxidants selected from the group consisting of vitamin E, especially alpha Tocopherol, and xantophylls, especially lutein and zeaxanthin. Most preferably the methods of the invention further comprises the concurrent treatment with one or more lipophilic antioxidants selected from the group consisting of alpha Tocopherol, lutein and zeaxanthin.

[0192] In a preferred embodiment of the invention, methods as defined herein are provided, wherein the one or more lipophilic antioxidant is administered orally, preferably once, twice or three times a day, more preferably once daily.

[0193] In preferred embodiments of the invention, the frequency and administration intervals of the CETP inhibitor and the antioxidant are equal, more preferably each is administered once daily, still more preferably at the same time of the day, sequentially or concurrently. The CETP inhibitor and (each of) the lipophilic antioxidants may be administered as separate unit dosage forms. In embodiments of the invention, the CETP inhibitor and one or more of the lipophilic antioxidants may be administered in the form of the fixed dose combination product as defined herein.

[0194] In preferred embodiments, the methods of the invention comprise the oral administration of a lipophilic antioxidant at a daily dosage of 1000-1 mg, 750-5 mg 500-10 mg, 250-25 mg or 100-50.

[0195] In some embodiments, the methods of the invention comprise the oral administration of lutein at a daily dosage of 1-100 mg, 2-75 mg, 3-50 mg, 4-25 mg, e.g. about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg or about 20 mg, most preferably about 5 mg, about 10 mg, about 15 mg or about 20 mg, most preferably about 10 mg.

[0196] In some embodiments, the methods of the invention comprise the oral administration of Zeaxanthin at a daily dosage of 0.5-100 mg, 1 -50 mg or 1 .5-25 mg, e.g. about 1 mg, about 1 .5 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg, most preferably about 0.5 mg, about 1 mg, about 1 .5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg or about 5 mg; or a salt, solvate or co-crystal of Zeaxanthin, in the equipotent dosage, most preferably about 2 mg.

[0197] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol at a daily dosage of 1 -100 international units (III), 2-90 IU, 5-80 IU, 100-700 IU, 10-60 IU , e.g. 15, 17.5, 20, 22.4, 22.5, or 25 IU, more preferably about 22.4 IU.

[0198] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol at a daily dosage of 0,5-70 mg, 1-60 mg, 3-50 mg, 5-40 mg, 10-40 mg , e.g. 10, 12.5, 15, 17.5 or 20 mg, more preferably about 15 mg.

[0199] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol at a daily dosage of 10-1000 international units (IU), 20-900 IU, 50-800 IU, 100-700 IU, 200-600 IU, e.g. about 200 IU, about 300 IU, about 400 IU, about 500 IU or about 600 IU, most preferably about 200 IU, about 400 IU or about 600 IU.

[0200] In some embodiments, the methods of the invention comprise the oral administration of alpha-tocopherol at a daily dosage of 5-700 mg, 10-600 mg, 30-500 mg, 50-400 mg, 100-400 mg, e.g. about 134 mg, about 200 mg, about 268 mg, about 335 mg or about 400 mg, most preferably about 134 mg, about 268 mg or about 400 mg.

[0201] Biomarkers

[0202] In various embodiments of the invention, the methods are effective in and / or intended for increasing the plasma level of pre-beta1 HDL. More in particular, the methods are effective in and / or intended for increasing plasma level of pre-beta1 HDL, at least 5%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably at least 10%, at least 12.5%, at least 15%, at least 17.5%, or at least 20%. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of pre-beta1 HDL, with at least 2.5 pg / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 2.5 pg / mL, at least 5 pg / mL, at least 7.5 pg / mL, at least 10 pg / mL, at least 12.5 pg / mL, at least 15 pg / mL, at least 17.5 pg / mL, at least 20 pg / mL, or at least 22.5 pg / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of pre-beta1 HDL, to a level above 110 pg / mL, preferably above 112.5 pg / mL, above 115 pg / mL, above 120 pg / mL, above 125 pg / mL or above 130 pg / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of pre-beta1 HDL, to a level above 55 pg / mL, preferably above 67.5 pg / mL, above 70 pg / mL, above 72.5 pg / mL or above 75 pg / mL.

[0203] In various embodiments of the invention, the methods are effective in and / or intended for increasing the plasma level of lutein. More in particular, the methods are effective in and / or intended for increasing the plasma level of lutein, at least 2.5%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably at least 5%, at least 7.5%, at least 10%, at least 12.5%, or at least 15%. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of lutein, with at least 2.5 ng / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 5 ng / mL, at least 10 ng / mL, at least 12.5 ng / mL, at least 15 ng / mL, at least 17.5 ng / mL, at least 20 ng / mL, at least 22.5 ng / mL, or at least 25 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of lutein, to a level above 100 ng / mL, preferably above 110 ng / mL, above 120 ng / mL, above 130 ng / mL, above 140 ng / mL, above 150 ng / mL, above 160 ng / mL, above 170 ng / mL, or above 180 ng / mL.

[0204] In further embodiments, the methods are effective in and / or intended for increasing the plasma level of lutein from baseline, with at least 27.5 ng / mL, at least 30 ng / mL at least 32.5 ng / mL, at least 35 ng / mL, at least 37.5 ng / mL or at least 40 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of lutein, to a level above 190 ng / mL or above 200 ng / mL.

[0205] In various embodiments of the invention, the methods are effective in and / or intended for increasing the level of lutein carried by HDL and / or Pre-beta1 HDL. More in particular, the methods are effective in and / or intended for increasing the level of lutein carried by HDL and / or Pre-beta1 HDL, at least 2.5%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably at least 5%, at least 7.5%, at least 10%, at least 12.5%, or at least 15%. In further embodiments, the methods are effective in and / or intended for increasing the level of lutein carried by HDL and / or Pre-beta1 HDL, with at least 2.5 ng / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 5 ng / mL, at least 10 ng / mL, at least 12.5 ng / mL, at least 15 ng / mL, at least 17.5 ng / mL, at least 20 ng / mL, at least 22.5 ng / mL, or at least 25 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the level of lutein carried by HDL and / or Pre-beta1 HDL, to a level above 50 ng / mL, preferably above 60 ng / mL, above 70 ng / mL, above 90 ng / mL, above 100 ng / mL, above 110 ng / mL, above 120 ng / mL, above 130 ng / mL, above 140 ng / ml or above 150 ng / mL.

[0206] In various embodiments of the invention, the methods are effective in and / or intended for increasing the plasma level of zeaxanthin. More in particular, the methods are effective in and / or intended for increasing the plasma level of zeaxanthin, at least 2.5%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably at least 5%, at least 7.5%, at least 10%, at least 12.5%, or at least 15%. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of zeaxanthin, with at least 1 ng / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 1 .5 ng / mL, at least 2 ng / mL, at least 2.5 ng / mL, at least 3 ng / mL, at least 3.5 ng / mL, at least 4 ng / mL, at least 4.5 ng / mL, or at least 5 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of zeaxanthin, to a level above 20 ng / mL, preferably above 22.5 ng / mL, above 25 ng / mL, above 27.5 ng / mL, above 30 ng / mL, above 32.5 ng / mL, above 35 ng / mL, above 37.5 ng / mL, above 40 ng / mL, above 42.5 ng / mL, or above 45 ng / mL.

[0207] In further embodiments, the methods are effective in and / or intended for increasing the plasma level of zeaxanthin from baseline, with at least 7.5 ng / mL, at least 10 ng / mL at least 12.5 ng / mL, at least 15 ng / mL, at least 17.5 ng / mL or at least 20 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of zeaxanthin, to a level above 47.5 ng / mL or above 50 ng / mL.

[0208] In various embodiments of the invention, the methods are effective in and / or intended for increasing the level of zeaxanthin carried by HDL and / or Pre-beta1 HDL. More in particular, the methods are effective in and / or intended for increasing the level of zeaxanthin carried by HDL and / or Pre-beta1 HDL, at least 10%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably at least 20 %, at least 30%, at least 40%, at least 50%, or at least 60%. In further embodiments, the methods are effective in and / or intended for increasing the level of zeaxanthin carried by HDL and / or Pre-beta1 HDL, with at least 1 ng / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 2 ng / mL, at least 3 ng / mL, at least 4 ng / mL, at least 5 ng / mL, at least 6 ng / mL, at least 7 ng / mL, at least 8 ng / mL, at least 9 ng / mL, or at least 10 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the level of zeaxanthin carried by HDL and / or Pre-beta1 HDL, to a level above 15 ng / mL, preferably above 17.5 ng / mL, above 2 ng / mL, above 22.5 ng / mL, above 25 ng / mL, above 27.5 ng / mL or above 30 ng / mL.

[0209] In various embodiments of the invention, the methods are effective in and / or intended for increasing the level of HDL alpha tocopherol. More in particular, the methods are effective in and / or intended for increasing level of HDL alpha tocopherol, with at least 5%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably with at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%. In further embodiments, the methods are effective in and / or intended for increasing the level of HDL alpha tocopherol, with at least 250 ng / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 500 ng / mL, at least 750 ng / mL, at least 1000 ng / mL, at least 1250 ng / mL, at least 1500 ng / ml, at least 1750 ng / ml, at least 2000 ng / ml, at least 2250 ng / ml or at least 2500 ng / ml. In further embodiments, the methods are effective in and / or intended for increasing level of HDL alpha tocopherol, to a level above 5000 ng / mL, preferably above 5250 ng / mL, above 5500 ng / mL, above 5750 ng / mL, above 6000 ng / mL above 6250 ng / mL, above 6500 ng / mL, above 6750 ng / mL, above 7000 ng / mL, above 7250 ng / mL or above 7500 ng / mL.

[0210] In further embodiments, the methods are effective in and / or intended for increasing the plasma level of alpha tocopherol from baseline, with at least 2750 ng / ml, at least 3000 ng / ml, at least 3250 ng / ml at least 3500 ng / mL. In further embodiments, the methods are effective in and / or intended for increasing the plasma level of alpha tocopherol, to a level above 7750 ng / mL or above 8000 ng / mL.

[0211] In various embodiments of the invention, the methods are effective in and / or intended for increasing the level of alpha tocopherol carried by HDL and / or Pre-beta1 HDL. More in particular, the methods are effective in and / or intended for increasing the level of alpha tocopherol carried by HDL and / or Pre-beta1 HDL, with at least 5%, from baseline, wherein baseline is defined as start of treatment with the CETP inhibitor, more preferably with at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%. In further embodiments, the methods are effective in and / or intended for increasing the level of alpha tocopherol Pre-beta1 HDL, with at least 250 ng / mL, from baseline, wherein baseline is defined as start of the treatment with the CETP inhibitor, more preferably at least 500 ng / mL, at least 750 ng / mL, at least 1000 ng / mL, at least 1250 ng / mL, at least 1500 ng / ml, at least 1750 ng / ml, at least 2000 ng / ml, at least 2250 ng / ml or at least 2500 ng / ml. In further embodiments, the methods are effective in and / or intended for increasing the level of alpha tocopherol carried by HDL and / or Pre-beta1 HDL, to a level above 5000 ng / mL, preferably above 5250 ng / mL, above 5500 ng / mL, above 5750 ng / mL, above 6000 ng / mL above 6250 ng / mL, above 6500 ng / mL, above 6750 ng / mL, above 7000 ng / mL above 7250 ng / mL or above 7500 ng / mL.

[0212] Pharmaceutical Kits

[0213] 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 form is a unit dosage form comprising the CETP inhibitor, such as the unit dosage forms described herein elsewhere, 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 AMD, in particular dry AMD, and / or any symptom associated with (dry) AMD, as defined herein.

[0214] 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 comprising the CETP inhibitor, such as the unit dosage forms described herein elsewhere, 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 the CETP inhibitor 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 a CETP inhibitor 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 the CETP inhibitor and ezetimibe.

[0215] In accordance with embodiments of the invention, the pharmaceutical kit comprises a first plurality of solid unit dosage forms comprising the CETP inhibitor, such as the unit dosage forms comprising the CETP inhibitor described herein elsewhere, and a second plurality of solid unit dosage forms comprising one or more lipophilic antioxidants, such as the unit dosage forms comprising one or more lipophilic antioxidants described herein elsewhere. Preferably the one or more lipophilic antioxidants is / are selected from the group consisting of alpha Tocopherol, lutein and zeaxanthin. 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 comprising one or more lipophilic antioxidants, 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.

[0216] 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 the therapeutic 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 AMD, in particular dry AMD.

[0217] The amorphous calcium salt form of obicetrapib

[0218] In certain preferred embodiments of the invention, obicetrapib, as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib, more particularly an amorphous obicetrapib calcium salt, in particular, amorphous obicetrapib hemicalcium.

[0219] The amorphous obicetrapib hemicalcium of the disclosure is different from and can be distinguished from the crystalline obicetrapib hemicalcium disclosed in U.S. Patent Number 7,872,126. A common technique used to distinguish crystalline from amorphous materials is x-ray powder diffraction. However, this technique has limitations, especially when the crystalline material is disordered. In the case of amorphous obicetrapib hemicalcium, x-ray powder diffraction patterns of two different lots of amorphous obicetrapib hemicalcium are provided in Figure 25 and Figure 26. These patterns have the familiar “halo” type features that are associated with amorphous materials. The x-ray powder diffraction pattern from Figure 26 has peaks at about 3.4°26, about 7.0°26, and about 9.2°26. Similarly, another sample of Figure 27 has x-ray powder diffraction peaks also at about 3.4°26, about 7.0°26, and about 9.2°26. The x-ray powder diffraction patterns of any of Figure 25 or Figure 26 or Figure 27 may be used to characterize amorphous obicetrapib hemicalcium, provided, however, occasionally, a sharp higher angle peak is present, such as at about 31.7°26 is found (such as in Figure 26), and that peak, when present, is due to sodium chloride. In Figure 27, in another sample of amorphous obicetrapib hemicalcium, peaks at about 3.4°26, about 7.0°26, and about 9.2°26 were identified. The peak at about 5.6°26 in Figure 27 was determined to be due to Kapton foil, which was used in the measurement setup as explained in Example 3.20. The x-ray powder pattern of crystalline obicetrapib hemicalcium as prepared in Example 3.16 is shown in Figure 30. It too exhibits halo-like behavior which, for a crystalline compound, may be indicative of disorder.

[0220] Example 3.18, Example 3.19, Example 3.20, and Example 3.21 set forth various x-ray powder diffraction procedures. The procedure of Example 3.18 was generally used to collect the data set forth in Figures 25, 30, 31 , and 32; Example 3.19 was generally used for Figure 26; Example 3.20 was used generally used for Figure 27; and Example 3.21 was generally used for Figures 41 , 42, and 43 (with Figure 43 being for Compound 1 D rather than crystalline obicetrapib HCI).

[0221] The use of the term “amorphous” in “amorphous obicetrapib hemicalcium” does not mean that the material has no order whatsoever. As shown by the presence of peaks in the x-ray powder diffraction pattern, there is still some order in the sample. Thus, as used herein, the term “amorphous” in “amorphous obicetrapib hemicalcium” does not mean that the x-ray powder diffraction pattern must contain purely an amorphous halo (but may contain halo-like features). Rather, it means that there is disorder, but the amorphous phase is distinguishable from the crystalline phase as discussed below.

[0222] Another technique which may be used to distinguish crystalline materials from amorphous materials is polarized light microscopy (“PLM”). In PLM, a material is viewed through polarized light, and by viewing the material through cross-polarizers, one can differentiate between materials that are anisotropic (e.g., crystals) or isotropic (e.g., amorphous compounds). Anisotropic materials, when exposed to polarized light through cross polarizers, exhibit birefringence which manifests itself by exhibiting color change through cross polarizers. Isotropic materials, on the other hand, do not show birefringence and exhibit no color change when exposed to polarized light.

[0223] In Figure 33, amorphous obicetrapib hemicalcium was analyzed by polarized light microscopy as set forth in Example 3.17. As Figure 33 shows, the materials under study do not birefringe indicating that the material is amorphous. By comparison, Figure 34 is a polarized light micrograph of crystalline obicetrapib hemicalcium made in accordance with Example 3.16. Notably, the particles shown in Figure 34 (which is in black and white) exhibits a much brighter contrast. In the corresponding color version, that figure is multicolored. Thus, Figure 34 indicates crystallinity. In addition, the crystals in Figure 34 are larger than the particles provided in the amorphous obicetrapib hemicalcium polarized light micrograph of Figure 33. Accordingly, PLM and / or the lack of birefringence can be used to characterize amorphous obicetrapib hemicalcium.

[0224] Other techniques can further be used to distinguish amorphous obicetrapib hemicalcium from crystalline obicetrapib hemicalcium, and therefore can be used to characterize amorphous obicetrapib hemicalcium. One such technique is modulated differential scanning calorimetry also referred to as “mDSC.” The difference in the amount of heat necessary to increase the temperature of a sample, as compared to a reference, is measured as a function of temperature and may be measured using modulated Differential Scanning Calorimetry (mDSC). In an mDSC thermogram, one can also measure a glass transition temperature which can be used to characterize an amorphous material. In Figure 36, for which the procedure is described in Example 3.25, the mDSC thermogram of amorphous obicetrapib hemicalcium was measured using an open sample holder allowing for volatile gases to escape during a measurement. In Figure 36, the opening was done by piercing a lid on the pan so as to create a pinhole. A glass transition temperature of about 110°C was recorded for this sample.

[0225] With respect to thermal measurements, the term “about” generally refers to a variability of plus or minus 1 °C. By comparison, crystalline obicetrapib hemicalcium has a higher glass transition temperature under the same conditions, and three measurements in Figure 38 indicate a range between about 118°C and about 125.5°C. In some embodiments, the glass transition temperature of amorphous obicetrapib hemicalcium is between about 109°C and 112°C when measured with a pinhole. In one sample, at Example 3.26, the glass transition temperature of amorphous obicetrapib hemicalcium was found to be about 111 °C (111.32°C at the midpoint) and is shown in Figure 37. The onset was measured to be about 102°C (101.62°C) and the endpoint about 118°C (117.58°C)

[0226] The glass transition temperature of amorphous obicetrapib hemicalcium may also be measured using mDSC with a closed pan. The type of sample preparation may affect the measured glass transition temperature. In such cases, the glass transition temperature decreases to temperatures of less than about 100°C and in particular between about 70°C and about 92°C depending on humidity.

[0227] Other thermal techniques may also be used to analyze and characterize amorphous obicetrapib hemicalcium such as thermogravimetric analysis (TGA). Figure 35 is a thermogravimetric analysis thermogram of amorphous obicetrapib hemicalcium showing a weight loss of less than 1 % when heated to about 200°C. Such weight losses may be, for example, between about 0.8% and about 0.95% including between about 0.84% and about 0.92%. In Figure 35, the weight loss was determined to be about 0.85%. This particular material was found to have a water content of about 1 .5%. In some embodiments, the water content of may be higher and include a range from about 0% to about 5% water by weight, including up to about 4% by weight, up to about 3% by weight, and between about 0.5% and 1 .5% by weight.

[0228] Solid-state13C-NMR spectroscopy is another technique which may be used to characterize amorphous materials. Figure 39 shows a solid-state13C-NMR spectrum of both crystalline and amorphous obicetrapib hemicalcium with Figure 40 and Figure 41 showing the crystalline and amorphous obicetrapib hemicalcium separately. There are at least two differences in the spectra. The crystalline phase has a peak at about 22.1 ppm and which not present in the amorphous phase. In addition, a peak at about 29.5 ppm in the crystalline phase is pronounced while not nearly so in the amorphous phase. Thus, the absence of a solid-state13C-NMR peak at about 22.1 ppm and / or the absence of a pronounced peak at about 29.5 ppm may be used to characterize amorphous obicetrapib hemicalcium. In addition, a solid-state13C-NMR spectrum substantially the same as that of Figure 41 may be used to characterize amorphous obicetrapib hemicalcium. The absence of a peak in this context does not mean there is necessarily no intensity of, for example, 22.1 ppm or 29.5 ppm, but rather the intensity is not pronounced as it is in the crystalline obicetrapib hemicalcium13C-NMR spectrum.

[0229] The properties of crystalline materials also typically differ from those of amorphous materials. Thermodynamically, crystalline materials are more physically stable than amorphous materials. Accordingly, there is a thermodynamic driving force to convert amorphous compounds into crystalline ones. Under accelerated stress conditions, if there would be a physical conversion of solid form, one would therefore generally expect it to be from amorphous to crystalline. However, with obicetrapib hemicalcium, the reverse is the case.

[0230] Figure 30 is a plot of x-ray powder diffraction pattern taken of crystalline obicetrapib hemicalcium, and Figure 31 is a plot of x-ray powder diffraction patterns taken of crystalline obicetrapib hemicalcium under stress conditions. In Figure 31 , there are four diffraction patterns shown based on stability study set forth in Example 3.27. Pattern 1 is an x-ray powder diffraction pattern of a sample of amorphous obicetrapib hemicalcium. Pattern 2 is the x-ray powder diffraction pattern of a sample of crystalline obicetrapib hemicalcium. In pattern 3, the sample of crystalline obicetrapib hemicalcium was exposed to 70°C at 75% relative humidity for one day. As can be seen from pattern 3, the x-ray powder diffraction pattern shows the near total loss of crystallinity in that day. After 7 days under the same conditions, the result remains the same as seen in pattern 4. A similar experiment was performed on amorphous obicetrapib hemicalcium shown in Figure 32. Pattern 1 was taken before the sample was placed on stability. Exposing that material to the same 70°C and 75% relative humidity conditions did not trigger a crystallization and the material remained amorphous after 7 days (pattern 2) and 14 days (pattern 3). Thus, these experiments suggest, contrary to what one would expect, that the amorphous form of obicetrapib hemicalcium is more stable than crystalline obicetrapib hemicalcium. In some embodiments of the disclosure, provided herein is stable amorphous obicetrapib hemicalcium. In these embodiments, the amorphous obicetrapib hemicalcium is more physically stable than crystalline obicetrapib hemicalcium under typical pharmaceutical use and processing conditions.

[0231] While not wishing to be bound by theory, it is possible that the kinetics here are such that the amorphous phase is kinetically stabilized with respect to the thermodynamically more stable crystalline phase at least under pharmaceutically relevant processing and use conditions. The result of this stability profile is that amorphous obicetrapib hemicalcium is more suitable for pharmaceutical development and use than the corresponding crystalline phases. Despite being more physically resilient, amorphous obicetrapib hemicalcium is more soluble than the highly insoluble crystalline obicetrapib hemicalcium.

[0232] Solubility is especially challenging with obicetrapib. At 20°C, for example, the solubility of obicetrapib has been measured to be substantially less than 0.1 mg / mL in water. It would be desirable to have a solid form of obicetrapib that would deliver a larger amount of obicetrapib.

[0233] While solubility is a thermodynamic quantity of a material, one can measure the kinetic solubility of a material without necessarily reaching thermodynamic equilibrium. Such measurements provide the solubility under metastable conditions and provide information, for example, of the amount of material undergoing dissolution as a function of time.

[0234] The amorphous form has a higher kinetic solubility and dissolution rate than the crystalline form (and by extension obicetrapib itself). Both crystalline and amorphous obicetrapib hemicalcium kinetic solubility determinations were made in biorelevant media at different pHs, namely at about 5.0 (FeSSIF conditions) and at pH of about 6.5 (FaSSIF) conditions as set forth in Example 3.28.

[0235] Table W shows the measured solubility of two different batches of amorphous obicetrapib hemicalcium versus crystalline obicetrapib hemicalcium over the course of 2 hours in FeSSIF media at 37°C. In both cases, the amorphous obicetrapib hemicalcium had a higher concentration in solution than the corresponding crystalline material for all time points measured. The concentrations in Table W are those of obicetrapib (i.e. , the free acid). Table W - Kinetic Solubility of Crystalline and Amorphous Obicetrapib Hemicalciumin FeSSIF (pH 5.0) at 37°C

[0236] Table X shows a similar experiment at 37°C but in FaSSIF media at a pH of 6.5. As with Table W, in both batches, the amorphous obicetrapib hemicalcium had a higher concentration in solution than the corresponding crystalline material for all time points measured. The concentrations in Table X are those of obicetrapib (i.e. , the free acid).

[0237] Table X - Kinetic Solubility of Crystalline and Amorphous Obicetrapib Hemicalcium in FaSSIF (pH 6.5) at 37°C

[0238] Because amorphous obicetrapib hemicalcium dissolves faster than the corresponding crystalline phase, more drug is available for immediate use and potentially higher bioavailability in the amorphous phase than in the crystalline phase.

[0239] Amorphous obicetrapib hemicalcium is also advantageous because, unlike many amorphous organic compounds, it does not readily pick up moisture. When exposed to relative humidities approaching 90%, moisture uptake has been measured to be typically less than about 5% for example. This lack of hygroscopicity is favorable because it does not require any special handling or storage conditions. Other drawbacks commonly associated with manufacturing and using amorphous materials are similarly not present. For example, amorphous materials are often challenging to make chemically pure. Here, however, amorphous obicetrapib hemicalcium can be made routinely with chemical purities of 99.9% or higher.

[0240] In some embodiments of the disclosure, there is provided substantially pure amorphous obicetrapib hemicalcium. In these and other embodiments, the chemical purity of substantially pure amorphous obicetrapib hemicalcium is 99.9% or greater.

[0241] In many aspects of the disclosure, there is provided a method of preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium, wherein the method comprises: treating obicetrapib with an acid to form a salt, solvate, or composition; isolating the resulting salt, solvate or composition; and treating that salt, solvate, or composition with a calcium source to create an amorphous obicetrapib calcium salt, such as amorphous obicetrapib hemicalcium. The resulting salt can then be isolated.

[0242] Examples of calcium sources include calcium salts such as halogenated calcium salts and soluble calcium salts. In many embodiments, the calcium source is calcium chloride.

[0243] The preparation of an amorphous salt of obicetrapib calcium such as amorphous obicetrapib hemicalcium has been found to occur when there is an intermediate salt, solvate or composition (such composition comprising the corresponding acid used to make a salt). Treating obicetrapib directly with a calcium base such as calcium hydroxide has not been found to be a viable way of making an amorphous salt of obicetrapib calcium due to either low solubility, the weakness of the bases available or both. Rather, it has been found that by deploying an intermediate salt, such as a sodium salt, the preparation of amorphous obicetrapib hemicalcium is viable. However, even with a sodium salt, it is preferable for purity and yield purposes to utilize an additional salt or salt-type exchange (such as with the use of a composition or solvate rather than an actual salt) in connection with the sodium salt of obicetrapib. In particular, the use of the salt, solvate, or composition enables the production of a highly pure amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium.

[0244] Exemplary salts that may be made as an intermediate include those from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methylsulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, or a teoclate. When the intermediate is a solvate or a composition, then the corresponding acids may be used or present. In addition, when a solvate, the intermediate may further include a solvent such as an organic solvent or water, in which case the solvate would be a hydrate. One such organic solvent is CPME (cyclopentyl methyl ether).

[0245] In some embodiments, the intermediate is a solvate of an acid. In these and other embodiments, the intermediate is a solvate of an acid and an organic solvent. In some particular embodiments, the intermediate is a solvate comprising an acid and a solvent. In some of these embodiments, the acid is hydrochloric acid and a solvent is CPME.

[0246] In many aspects of the disclosure, the disclosure includes methods for preparing amorphous obicetrapib calcium salts, such as amorphous obicetrapib hemicalcium. The disclosure further includes amorphous obicetrapib calcium salts, including amorphous obicetrapib hemicalcium, so prepared. In one such preparation, an intermediate referred to herein as crystalline obicetrapib HCI is used in the processes for preparing amorphous obicetrapib calcium, such as amorphous obicetrapib hemicalcium.

[0247] In many aspects of the disclosure, amorphous obicetrapib hemicalcium is prepared via a chemical synthesis where an intermediate is used denoted by Formula

[0248] (IH).

[0249] Where y varies such that the mass percent of HCI varies from 0.01 % to 8% by weight and is believed to further include an associated organic solvent such as by way of a solvate. In some embodiments, y varies from 0.002 to 1 .5. In some embodiments,

[0250] SUBSTITUTE SHEET (RULE 26) y varies from 0.3 to 1. In some embodiments, y varies from 0.4 to 0.6, including between 0.5 and 0.6. In some embodiments, Formula (IH), as a solvate, is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents which may form solvates include toluene and heptane.

[0251] Obicetrapib HCI as typically prepared herein is crystalline. Further, the term crystalline obicetrapib HCI may include CPME as a solvate when CPME is used in the preparation of crystalline obicetrapib HCI. In Formula (IH), the solvate is of an organic solvent and in many embodiments, that solvent is CPME. In some embodiments, the disclosure provides for compositions comprising crystalline obicetrapib HCI.

[0252] Formula (IH) is referred to as obicetrapib HCI and when crystalline, it is referred to as crystalline obicetrapib HCI.

[0253] Without being bound by theory, it is believed that crystalline HCI obicetrapib is a mixed salt solvate. It has been found that when CPME is used to deliver HCI in the reaction to create Formula (IH), the chloride content of Formula (IH) ranges between about 2.5% and 3.0% by weight which is below what one would expect for a neutral salt - namely about 4.8% by weight.

[0254] In many embodiments, when CPME is so used, it is found in the material when crystallized. When CPME is used in the reaction to deliver dry HCI and is thus found in the crystallized material, the resulting crystalline Formula (IH) material is referred to as crystalline obicetrapib HCI, those x-ray powder diffraction pattern are seen in Figure 42. An advantage of using crystalline obicetrapib HCI as an intermediate is that the resulting amorphous obicetrapib hemicalcium has a chemical purity which is routinely 99.9% pure or greater. Chemical purity is the quantitative representation of whether other chemical entities other than the compound being measured are present. For example, a chemical purity of 99.9% amorphous obicetrapib hemicalcium means that not more than 0.1 % of the compounds in a sample of amorphous obicetrapib hemicalcium are other entities. Physical purity refers to the amount of other solid forms of the same compound present which, in the case of amorphous obicetrapib hemicalcium, the other solid form being crystalline obicetrapib hemicalcium. The disclosure herein provides for amorphous obicetrapib hemicalcium which is physically pure meaning it is free or substantially free of crystalline obicetrapib hemicalcium. Unless otherwise stated herein, the purity measurements provided herein are measurements of chemical purity. HCI obicetrapib, as used herein, is not limited to crystalline obicetrapib HCI. Indeed, upon desolvation, crystalline obicetrapib HCI may become amorphous.

[0255] Upon stress, crystalline obicetrapib HCI loses its crystallinity. In Figure 42, pattern 2 reflects crystalline obicetrapib HCI subject to a mild drying treatment whereby surface solvent was removed and it can be seen that this compound is crystalline. By comparison, the sample whose x-ray powder diffraction was measured in pattern 1 was subject to a stronger drying treatment at 48 hours at 55°C at a pressure of 2mbar. As is apparent, this drying changed the material from crystalline to amorphous, likely due to loss of HCI and a desolvation of CPME.

[0256] 1H-NMR spectroscopy, for example, was used to show the presence of CPME in the top pattern, but was substantially absent in the lower, amorphous pattern. The amorphous pattern, therefore, represents HCI obicetrapib which is not crystalline obicetrapib. It may be obicetrapib, but is believed to have HCI associated with the obicetrapib as a solvate and thus is HCI obicetrapib, but with a lower chloride content than typically found in the ranges found for crystalline obicetrapib HCI. In some embodiments, that chloride content is less than 0.1 % by weight such as between about 0.01 % and 0.1 % by weight.

[0257] Crystalline obicetrapib HCI may be characterized by an x-ray powder diffraction pattern comprising a peak at about 9.8°29. In some embodiments, crystalline obicetrapib HCI may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 8.1 °20, about 9.8°20, about 13.8°20, about 16.7°20, or about 19.5°20. Table Y provides illustrative peaks which may be present in crystalline obicetrapib HCI. In some embodiments, crystalline obicetrapib HCI may be characterized by an x-ray powder diffraction pattern substantially the same as that in Figure 43, although it is believed that the material analyzed in Figure 43 was measured in such a way that a peak between about 4.3°20 and about 4.7°20 was not measured. Table Y

[0258] Another intermediate used in the preparation of obicetrapib is that of Formula

[0259] (VI) wherein Y1 is a protecting group (e.g., as described herein); An- is an anion; and n is an integer from 1 -3.

[0260] In one embodiment, the compound of Formula (VI) is a mesylate salt where n is 1 , Y1 is t-butyl, and has the structure of Compound 1 D:

[0261] A1H-NMR spectrum of Compound 1 D (in solution) can be found in Figure 45. Crystalline Compound 1 D may be characterized by an x-ray powder diffraction pattern comprising one or more peaks at about 5.2°20 or about 9.1 °20. In some embodiments, crystalline Compound 1 D may be characterized by an x-ray powder diffraction pattern

[0262] 42

[0263] SUBSTITUTE SHEET (RULE 26) comprising one or more peaks at about 5.2°20, about 9.1 °20, about 15.9°20, about 16.5°20, about 17.2°20, about 18.6°20, and about 19.2°20. Table Z provides illustrative peaks which may be present in crystalline Compound 1 D (with the peak at about 5.2°20 not measured due to instrument limitations in reflection mode). In some embodiments, crystalline Compound 1 D may be characterized by an x-ray powder diffraction pattern substantially the same as Figure 44.

[0264] Table Z

[0265] Crystalline compounds such as crystalline Compound 1 D and a crystalline obicetrapib HCI, for example, may be characterized by x-ray powder diffraction. An x- ray powder diffraction pattern is an x-y graph with °20 (diffraction angle) on the x-axis and intensity on the y-axis. The peaks are usually represented and referred to by their position on the x-axis rather than the intensity of peaks on the y-axis because peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is not typically used to characterize solid forms. The data from x-ray powder diffraction may be used in multiple ways to characterize crystalline forms. For example, the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline obicetrapib HCI compound or a crystalline Compound 1 D. A smaller subset of such data, however, may also be, and typically is, suitable for characterizing such compounds. For example, a collection of one or more peaks from such a pattern may be used to so characterize these compounds. When the phrase “one or more peaks” of a list of peaks from an x-ray powder diffraction pattern are provided, what is generally meant is that any combination of the peaks listed may be used for characterization. Further, the fact that other peaks are present in the x-ray powder diffraction pattern, generally does not negate or otherwise limit that characterization.

[0266] In addition to the variability in peak intensity, there may also be variability in the position of peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of peaks for purposes of characterization. Such variability in the position of peaks along the x-axis may derive from several sources (e.g., sample preparation, particle size, moisture content, solvent content, instrument parameters, data analysis software, and sample orientation). For example, samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms, and different x-ray instruments may operate using different parameters and these may lead to slightly different diffraction patterns from the same crystalline solid. Due to such sources of variability, it is common to recite x-ray diffraction peaks using the word “about” prior to the peak value in °20. For purposes of data reported herein, that value is generally ±O.2°20 are intended to be reported with such a variability whenever disclosed herein whether the word “about” is present or not. Variability may, in some instances, be higher depending on instrumentation conditions including how well instruments are maintained.

[0267] In some embodiments, crystalline Compound 1 D may be further characterized by an x-ray powder diffraction pattern substantially the same as the x-ray powder pattern as that of Figure 44.

[0268] In certain preferred embodiments of the invention, obicetrapib, as contained in the present pharmaceutical compositions, as used in the present methods, as contained in the unit dosage forms (comprised in the pharmaceutical kit), etc., is a salt form of obicetrapib described by one or more of the following non-limiting clauses: Clause 1 . An amorphous calcium salt of obicetrapib.

[0269] Clause 2. Amorphous obicetrapib hemicalcium.

[0270] Clause 3. Stable amorphous obicetrapib hemicalcium.

[0271] Clause 4. Substantially pure amorphous obicetrapib hemicalcium.

[0272] Clause 5. The amorphous obicetrapib hemicalcium salt of clauses 2-4, substantially free of any crystalline salt of obicetrapib hemicalcium.

[0273] Clause 6. The amorphous obicetrapib hemicalcium of clauses 2-5, having an x-ray powder diffraction pattern substantially the same as that of Figure 25. Clause 7. The amorphous obicetrapib hemicalcium of clauses 2-5, having an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°20, about 7.O°20, and about 9.2°20.

[0274] Clause 8. The amorphous obicetrapib hemicalcium of clauses 2-7, wherein the amorphous obicetrapib hemicalcium does not birefringe.

[0275] Clause 9. The amorphous obicetrapib hemicalcium of clauses 2-8, having a glass transition temperature at a value between about 107°C and about 112°C.

[0276] Clause 10. The amorphous obicetrapib hemicalcium of clause 9, wherein the glass transition temperature is measured with modulated differential scanning calorimetry.

[0277] Clause 11. The amorphous obicetrapib hemicalcium of clause 10, wherein the measurement with modulated differential scanning calorimetry uses a sample pan which is open.

[0278] Clause 12. The amorphous obicetrapib hemicalcium of clause 11 , wherein the opening is a pinhole.

[0279] Clause 13. The amorphous obicetrapib hemicalcium of clauses 8-12, wherein the glass transition temperature is at a value between about 110°C and about 112°C.

[0280] Clause 14. The amorphous obicetrapib hemicalcium of clauses 2-13, having a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan.

[0281] Clause 15. The amorphous obicetrapib hemicalcium of clause 14, having a glass transition temperature at a value between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan.

[0282] Clause 16. The amorphous obicetrapib hemicalcium of clauses 2-15, having a loss in weight of less than about 1 % when heated to about 200°C.

[0283] Clause 17. The amorphous obicetrapib hemicalcium of clause 16, wherein the weight loss is between about 0.8% and about 0.95%.

[0284] Clause 18. The amorphous obicetrapib hemicalcium of clause 17, wherein the weight loss is between about 0.84% and about 0.92%.

[0285] Clause 19. The amorphous obicetrapib hemicalcium of clauses 2-18, having a water content of less than about 5%.

[0286] Clause 20. The amorphous obicetrapib hemicalcium of clause 19, having a water content of less than about 4%.

[0287] Clause 21. The amorphous obicetrapib hemicalcium of clause 20, having a water content of less than about 3%. Clause 22. The amorphous obicetrapib hemicalcium of clause 19, having a water content of between about 0.5% and about 1 .5%.

[0288] Clause 23. The amorphous obicetrapib hemicalcium of clauses 2-22, in a bulk form or formulated composition having a particle size distribution wherein about 90% of the particles have a diameter of about 15 microns or less.

[0289] Clause 24. The amorphous obicetrapib hemicalcium of clause 23, wherein about 90% of the particles have a diameter of between about 6 microns and about 15 microns.

[0290] Clause 25. The amorphous obicetrapib hemicalcium of clause 24, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 14 microns or less.

[0291] Clause 26. The amorphous obicetrapib hemicalcium of clause 25, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 13 microns or less.

[0292] Clause 27. The amorphous obicetrapib hemicalcium of clause 26, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 12 microns or less.

[0293] Clause 28. The amorphous obicetrapib hemicalcium of clause 27, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 11 microns or less.

[0294] Clause 29. The amorphous obicetrapib hemicalcium of clause 28, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 10 microns or less.

[0295] Clause 30. The amorphous obicetrapib hemicalcium of clause 29, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 9 microns or less.

[0296] Clause 31. The amorphous obicetrapib hemicalcium of clause 30, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 8 microns or less.

[0297] Clause 32. The amorphous obicetrapib hemicalcium of clause 31 , having a particle size distribution wherein about 90% or more of the particles have a diameter of about 7 microns or less.

[0298] Clause 33. The amorphous obicetrapib hemicalcium of clause 32, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 6 microns or less. Clause 34. The amorphous obicetrapib hemicalcium of clause 33, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 5 microns or less.

[0299] Clause 35. The amorphous obicetrapib hemicalcium of clause 34, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 4 microns or less.

[0300] Clause 36. The amorphous obicetrapib hemicalcium of clause 35, having a particle size distribution wherein about 90% or more of the particles have a diameter of about 3 microns or less.

[0301] Clause 37. The amorphous obicetrapib hemicalcium of clauses 2-36, in a bulk form or formulated composition having a particle size distribution wherein about 50% of the particles have a diameter of about 5 microns or less.

[0302] Clause 38. The amorphous obicetrapib hemicalcium of clause 37, having a particle size distribution wherein about 50% of the particles have a diameter of about 4 microns or less.

[0303] Clause 39. The amorphous obicetrapib hemicalcium of clause 38, having a particle size distribution wherein about 50% of the particles have a diameter of about 3 microns or less.

[0304] Clause 40. The amorphous obicetrapib hemicalcium of clauses 2-39, in a bulk form or formulated composition having a particle size distribution wherein about 10% of the particles have a diameter of about 2 microns or less.

[0305] Clause 41. The amorphous obicetrapib hemicalcium of clauses 2-40, having a chemical purity of at least 98.0%.

[0306] Clause 42. The amorphous obicetrapib hemicalcium of clause 41 , having a chemical purity of at least 99.0%.

[0307] Clause 43. The amorphous obicetrapib hemicalcium of clause 42, having a chemical purity of at least 99.5%.

[0308] Clause 44. The amorphous obicetrapib hemicalcium of clause 43, having a chemical purity of at least 99.6%.

[0309] Clause 45. The amorphous obicetrapib hemicalcium of clause 44, having a chemical purity of at least 99.7%.

[0310] Clause 46. The amorphous obicetrapib hemicalcium of clause 45, having a chemical purity of at least 99.8%. Clause 47. The amorphous obicetrapib hemicalcium of clause 46, having a chemical purity of at least 99.9%.

[0311] Clause 48. The amorphous obicetrapib hemicalcium of clauses 2-47, having a solid- state13C-NMR spectrum substantially the same as that of Figure 41 .

[0312] Clause 49. The amorphous obicetrapib hemicalcium of clauses 2-48, having a solid- state13C-NMR spectrum where no peak is present at about 22.1 ppm.

[0313] Clause 50. The amorphous obicetrapib hemicalcium of clauses 2-49, having a solid- state13C-NMR spectrum where no peak is present at about 29.5 ppm.

[0314] Clause 51. Unmilled amorphous obicetrapib hemicalcium.

[0315] Clause 52. Milled amorphous obicetrapib hemicalcium.

[0316] Clause 53. The amorphous obicetrapib hemicalcium of clauses 2-50, wherein the amorphous obicetrapib hemicalcium has been milled.

[0317] Clause 54. The amorphous obicetrapib hemicalcium of clauses 2-50 or 53, wherein the amorphous obicetrapib hemicalcium has been jet milled.

[0318] Clause 55. The amorphous obicetrapib hemicalcium of clauses 2-50 or 53-54 wherein the amorphous obicetrapib hemicalcium has been spray dried.

[0319] In many aspects of the disclosure, there is provided a method of preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium, wherein the method comprises: treating obicetrapib with HCI to obtain crystalline obicetrapib HCI; isolating crystalline obicetrapib HCI; preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium, from the crystalline obicetrapib HCI isolated in step (ii); and isolating an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium.

[0320] In other aspects of the disclosure, there is provided a method of preparing obicetrapib wherein the method comprises: preparing a compound of Formula (IV), by coupling a compound of Formula (II) or a salt thereof, with a compound of Formula (III); where X1 is a leaving group and Y1 is a protecting group; preparing a carbamate of Formula (V) from the compound of Formula (IV) and isolating as a solid salt form of Formula (VI): where Y1 is a protecting group, An- is an anion and wherein n is an integer from 1-3; optionally desalting the compound of Formula (VI) and alkylating with a compound of Formula (VII) to provide a compound of Formula (VIII): where, X2 is a leaving group, Y1 is a protecting group; and converting the compound of Formula (VIII) to obicetrapib, wherein the reaction steps (a)-(d) are performed in an organic solvent, compounds (IV), (V) and (VIII) are optionally not isolated from the organic solvent, and wherein the process does not need to comprise chromatography.

[0321] 49

[0322] SUBSTITUTE SHEET (RULE 26) The reactions in steps (a)-(d) of the subject method are performed in a solvent, and intermediate compounds of Formulae (IV), (V) and (VIII) do not need to be isolated from their respective solvents if they are to be processed further to end products. This means that any solvent swap between reaction steps (x) and (x+1 ) takes places by evaporating at least part of the solvent used in step (x) and by gradually adding the solvent of step (x+1 ), such that the compound remains in solution during the solvent swap. The intermediate compound of Formula (VI) may be isolated from the solvent as a salt in solid form, such that it can be washed to remove impurities. This isolation step ensures sufficient purity of downstream products. The subject process does not need to comprise purification steps using chromatography, such as column chromatography to achieve the chemical purity levels described herein.

[0323] Method of Preparing an Amorphous Calcium Salt, such as Amorphous Obicetrapib Hemicalcium - Steps (i)-(ii) from Aspects (i)-(iv)

[0324] In some embodiments of the method of preparing an amorphous calcium salt of obicetrapib such as amorphous obicetrapib hemicalcium, the method includes step (i), treating obicetrapib with HCI in an organic solvent to obtain crystalline obicetrapib HCI.

[0325] In some embodiments, crystalline obicetrapib HCI has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more.

[0326] In some embodiments, the HCI in step (i) is in a suitable solvent. Such solvent may be an aqueous solvent or an organic solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of a solvent and an anti-solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1 ,4- dioxane, 1 ,2-diflurobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane.

[0327] In some embodiments, the HCI has sufficient solubility in the anti-solvent such that it can be used as a suitable solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (i) further comprises toluene. In some embodiments, toluene is the majority component of the organic solvent.

[0328] In some embodiments, step (i) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35°C and 40°C under agitation, adding dry HCI in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, then adding further n-heptane as an anti-solvent. At this point, a small portion of the reaction mixture can optionally be extracted, cooled to a temperature of between 10°C and 15°C, to obtain a slurry of crystals of crystalline obicetrapib HCI in a mixture of cyclopentyl methyl ether and n- heptane (referred to herein as a “seed crystal slurry”). Optionally, all or a portion of the seed crystal slurry of crystalline obicetrapib HCI can then be added back to the reaction mixture. The seeds assist with nucleation but are not required. The resulting reaction mixture is then cooled to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HCI from the system under agitation. In some embodiments, the crystalline obicetrapib HCI is crystallized over a period of 12 hours or more, with subsequent filtration (e.g., through a filter dryer), one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some cases, a wet filter cake of crystalline obicetrapib HCI is dried in vacuo in steps using temperatures of 25°C-30°C, 30°C-40°C, 40°C- 50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0329] In some embodiments, the method of preparing crystalline obicetrapib HCI comprises the addition of seed crystals (e.g., as a seed crystal slurry). The seed crystals of an HCI compound can be formed as a slurry by following step (i) as set out above and after addition of dry HCI in cyclopentyl methyl ether and anti-solvent n- heptane, extracting a small portion of the reaction mixture, cooling to a temperature between 10°C and 15°C, to provide a slurry of crystals of crystalline obicetrapib HCI in cyclopentyl methyl ether and n-heptane.

[0330] Accordingly, in one embodiment, step (i) comprises providing crystalline obicetrapib HCI in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35°C and 45°C under agitation, adding dry HCI in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, addition of further n-heptane as anti-solvent, and the optional addition of seed crystals of an HCI compound (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HCI from the system under agitation. In some embodiments, the crystalline obicetrapib HCI is crystallized over a period of 12 hours or more, with subsequent filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some embodiments, crystalline obicetrapib HCI is dried in vacuo. In some embodiments, crystalline obicetrapib HCI is subjected to drying in a vacuum drying cabinet at 25 mbar pressure and at a temperature of 55°C for 10 hours or more. In some embodiments, after the drying procedure, the crystalline obicetrapib HCI includes less than 0.1 weight percent residual cyclopentyl methyl ether.

[0331] In some embodiments, step (i) comprises providing the solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent used in step (d) (such as toluene), less than 1 weight percent of n-heptane based on weight of solution, addition of n-heptane, raising the temperature to 35°C to 45°C under agitation, adding dry HCI in cyclopentyl methyl ether and raising the temperature again to 50°C to 55°C, addition of further n- heptane as anti-solvent, optional addition of seed crystals of a crystalline obicetrapib HCI (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 10°C and 15°C, followed by crystallizing crystalline obicetrapib HCI from the system under agitation, such as during a period of at least 12 hours, with subsequent filtration, one or more washing steps with a mixture of cyclopentyl methyl ether and n-heptane, and drying, such as in vacuo. In some embodiments, the amount of toluene is substantially greater.

[0332] In some embodiments the crystalline obicetrapib HCI from step (i) is isolated in step (ii). In some embodiments, the isolated crystalline obicetrapib HCI has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, 99.7%, or even more.

[0333] Another embodiment of the disclosure concerns the crystalline obicetrapib HCI, obtained by or obtainable by the process as defined herein.

[0334] Still another embodiment of the disclosure is directed to HCI obicetrapib, including crystalline obicetrapib HCI.

[0335] In some embodiments, the crystalline obicetrapib HCI is stored at controlled room temperature and under a nitrogen atmosphere and is protected from moisture to prevent the formation of an amorphous solid such as from desolvation. Method of Preparing an Amorphous Calcium Salt of Obicetrapib, such as Amorphous Obicetrapib Hemicalcium - Steps (iii)-(iv) from Aspects (i)-(iv)

[0336] In some embodiments of the method of preparing an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium, the method includes step (iii)-(iv), preparing an amorphous calcium salt of obicetrapib from crystalline obicetrapib HCI isolated in step (ii), and isolating an amorphous calcium salt of obicetrapib, such as amorphous obicetrapib hemicalcium.

[0337] In some embodiments of the method of isolating an amorphous calcium salt of obicetrapib according to step (iv), the amorphous calcium salt of obicetrapib is in the form of amorphous obicetrapib hemicalcium:

[0338] In some embodiments of the method of preparing obicetrapib, step (iii) includes the following steps:

[0339] (iii-1 ) converting crystalline obicetrapib HCI of step (ii) to provide obicetrapib in an organic solvent;

[0340] (iii-2) treating obicetrapib in the organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and

[0341] 53

[0342] SUBSTITUTE SHEET (RULE 26) (iii-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemicalcium; wherein the compounds in steps (iii-1 ) and (iii-2) are not isolated.

[0343] Accordingly, in some embodiments step, (iii-1 ) comprises the following steps:

[0344] (aa) providing crystalline obicetrapib HCI, as isolated in step (ii);

[0345] (bb) dissolving crystalline obicetrapib HCI in a mixture of water and isopropyl acetate under agitation. In some embodiments, step (bb) is conducted at a temperature between 15°C and 25°C;

[0346] (cc) allowing phase separation and subjecting the resulting organic phase to one or more subsequent washing steps with water, wherein each washing step is followed by separating off the aqueous phase, resulting in a washed organic phase; and

[0347] (dd) performing two or more distillations on the washed organic phase resulting from step (cc) at a temperature of 50°C or lower (such as 30°C or lower), with intermediate additions of ethanol, to obtain a solution of obicetrapib in ethanol.

[0348] In some embodiments step, (iii-2) comprises the following steps:

[0349] (ee) adding an aqueous NaOH solution to the solution obtained in step (dd) and agitating the resulting mixture, such as at a temperature between 20°C and 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib; and (ff) optionally filtering the solution obtained in step (ee).

[0350] In some embodiments step, (iii-3) comprises the following steps:

[0351] (gg) preparing a CaCI2 solution by adding deionized water to CaCI2 under agitation, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes;

[0352] (hh) cooling the CaCI2 solution obtained in step (gg) to a temperature from 8°C to 12°C and adding via a filter to the solution obtained in step (ff) or (ee) under agitation at said temperature;

[0353] (ii) stirring the slurry resulting from step (hh) for about 1 to about 10 hours. In some embodiments of step (ii), the stirring is conducted at a temperature between 8°C and 12°C;

[0354] (jj) isolating the solids from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the isolating is conducted at a temperature between 8°C and 12°C; (kk) washing the filtration residue obtained in step (jj) with water in one or more washing steps. In some embodiments of step (kk), the washing is conducted at a temperature between 8°C and 12°C; and

[0355] (II) drying the washed residue obtained in step (kk), such as in vacuo at a temperature from 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain amorphous obicetrapib hemicalcium (also sometimes referred to herein as compound 3).

[0356] In some embodiments, amorphous obicetrapib hemicalcium is submitted to a subsequent reworking procedure. In some embodiments, amorphous obicetrapib hemicalcium is further reworked by dissolving in ethanol (such as twice the weight of ethanol relative to amorphous obicetrapib hemicalcium) at a temperature of 25°C to 50°C, followed by cooling to 10°C to 15°C, followed by filtering into a mixture of aqueous calcium chloride solution and ethyl acetate, also cooled to 10°C to 15°C, followed by filtering, washing with water and drying in vacuo at 45°C or less for 20 hours or more.

[0357] In some embodiments of step (iv), amorphous obicetrapib hemicalcium is isolated with a purity of 95% or more, such as a purity of 95.5% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98% or more, 98.5% or more, 99% or more, 99.1 % or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.

[0358] In some embodiments, amorphous obicetrapib hemicalcium is subjected to a milling process. In some embodiments, the milling process is adapted (e.g., parameters such as feed rate, venturi pressure and mill pressure are adapted) to allow production of micronized amorphous obicetrapib hemicalcium.

[0359] Method of Preparing Obicetrapib - Step (a) from Aspects (a) - (d)

[0360] In step (a) of the process for preparing obicetrapib according to the present disclosure, the compound of Formula (II), or a salt thereof, is coupled with a compound of Formula (III) to provide a compound of Formula (IV) (where X1 is a leaving group and Y1 is protecting group, e.g., as described herein).

[0361] Step (a) of the subject method, starts with a compound of Formula (II) (2R,4S)-4- amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline), or a salt thereof:

[0362] The compound of Formula (II) can for example be obtained using a process as disclosed in WO2016 / 024858A1 or in WO2007 / 116922A1 , both of which are incorporated herein by reference in their entirety. In some embodiments the compound of Formula (II) can be obtained from a corresponding salt that is stable and can be obtained in pure and solid form. The solid form can be amorphous or crystalline. In some embodiments, the compound of Formula (II) is obtained from a corresponding crystalline salt.

[0363] In some embodiments, the compound of Formula (II) provided in step (a) is a salt of the Formula (HA) or (I I B): wherein Am- is an anion and n is an integer from 1-3.

[0364] In some embodiments, the compound of Formula (II) provided in step (a) is a salt of Formula (HA). In some embodiments, the compound of Formula (HA) is used directly in the coupling reaction with the compound of Formula (HI) without performing a desalting step.

[0365] In some embodiments, the compound of Formula (II) provided in step (a) is a salt of Formula (I IB). In some embodiments, the compound of Formula (I IB) is used

[0366] 56

[0367] SUBSTITUTE SHEET (RULE 26) directly in the coupling reaction with the compound of Formula (III) without performing a desalting step.

[0368] In some embodiments, the compound of Formula (II) in step (a) is obtained from a salt of Formula (HA) or (I IB). In some embodiments, the following steps are carried out before the coupling reaction of step (a):

[0369] (pre-a1 ) providing a compound of Formula (HA) or (HB):

[0370] (pre-a2) desalting the compound of Formula (HA) or (HB) to obtain the compound of Formula (II), wherein the reaction in step (pre-a2) is performed in an organic solvent, the compound of Formula (II) is not isolated from the organic solvent, and the process does not comprise chromatography.

[0371] In some embodiments, the compound of Formula (II) in step (a) is obtained from a salt of Formula (HA). In some embodiments, the compound of Formula (II) in step (a) is obtained from a salt of Formula (HB).

[0372] In some embodiments the salts of Formula (HA) or (HB), are chosen from salts with an anion Am- selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methylsulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate.

[0373] In some embodiments the salts of Formula (HA) or (HB), are chosen from salts with an anion Am- selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0374] In some embodiments the salts of Formula (HA) or (HB), are chosen from salts with an anion Am- selected from chloride, bromide, bitartrate, and mesylate.

[0375] 57

[0376] SUBSTITUTE SHEET (RULE 26) In some embodiments of the salts of Formula (HA) or ( 11 B), m is 1 .

[0377] In some embodiments the salt is of Formula (HA), and the anion Am- is mesylate, where m is 1 . The mesylate (MSA) salt (also referred to herein as compound 1A, shown below) can be obtained via a process as disclosed in WO2016 / 024858A1 or in WO2007 / 116922A1 , the disclosures of which are incorporated herein by reference in their entirety.

[0378] In some embodiments, the desalting of a compound of Formula (HA) or (HB) in step (pre-a2) is performed in a mixture of an aqueous sodium hydroxide solution and an organic solvent chosen from toluene, dichloromethane, cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, chlorobenzene and combinations thereof, followed by heating the mixture then cooling the mixture, and allowing the system to phase separate, and separating off the aqueous phase. In some embodiments, the solvent is toluene. In some embodiments the reaction mixture is heated to a temperature between 45°C and 60°C, then cooled to a temperature between 15°C and 40°C.

[0379] In some embodiments, the organic phase obtained after separating off the aqueous phase is subjected to one or more aqueous washing steps wherein each aqueous washing step is followed by separating off the aqueous phase, such as one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and subsequently one or more washing steps with deionized water, again followed by separating off the aqueous phase. The resulting washed organic phase is then optionally subjected to distillation to reduce the water content to below 1000 ppm, based on the weight of the solution. Alternatively, in some embodiments, a small amount of water remains in the organic phase with the compound of Formula (II) and the subsequent coupling with a compound of Formula (HI) proceeds in the presence of this small amount of water.

[0380] 58

[0381] SUBSTITUTE SHEET (RULE 26) In some embodiments the desalting reaction in step (pre-2a) is performed on the mesylate salt (Compound 1A) in a mixture of an aqueous sodium hydroxide solution and toluene, at a temperature between 45°C and 60°C, followed by cooling the mixture to a temperature between 15°C and 25°C, allowing the system to phase separate, and separating off the aqueous phase. The toluene phase obtained after separating off the aqueous phase is then optionally subjected to one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and subsequently one or more washing steps with deionized water, again followed by separating off the aqueous phase, after which the resulting washed toluene phase is subjected to distillation at a temperature between 50°C and 65°C under reduced pressure to reduce the water content to below 1000 ppm, based on the weight of the total amount of the solution. Alternatively, a small amount of water remains in the toluene with the compound of Formula (II) and the subsequent coupling reaction with a compound of Formula (III) proceeds in the presence of this small amount of water.

[0382] As outlined above, in step (a) the compound of Formula (II), or a salt thereof (e.g., compound of Formula (HA) or (IIB), such as the mesylate salt 1A), is coupled with a compound of Formula (III) to provide a compound of Formula (IV). In some embodiments, this process is carried out in an organic solvent.

[0383] The coupling partner of Formula (III) in step (a) includes a leaving group (X1 ). It will be understood that any convenient leaving group may find use in the present disclosure for X1 . In some embodiments, the leaving group (X1 ) in the compound of Formula (III) is selected from a halogen, a carbamate, and a substituted sulfonyloxy group. In some embodiments, the leaving group (X1 ) in the compound of Formula (III) is a sulfonyloxy group selected from a methanesulfonyloxy, p-toluenesulfonyloxy or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group (X1 ) is a carbamate. In some embodiments, the leaving group (X1 ) is a halogen. In certain embodiments, the halogen is chloride. The coupling partner of Formula (III) in step (a) also includes a protecting group (Y1 ). The term “protecting group” refers to any group which when bound to a functional group such as a carboxylic acid moiety of the compounds (including intermediates thereof) prevents reactions from occurring at the functional group and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group e.g., the carboxylic acid moiety. The particular removable protecting group employed is not critical and examples of carboxylic acid protecting groups include conventional substituents such as t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1 ,1 -diethylallyl esters, 2,2,2-trifluro ethyl esters, phenyl esters, 4-methoxybenzyl esters, silyl esters, ortho esters, esters of 2,6-disubstituted phenols (e.g., 2,6-dimethylphenol) and any other groups that can be introduced chemically onto a carboxylic acid group or like functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. It will be understood that any convenient protecting group (e.g., ester group) for a carboxylic acid moiety may find use in the present disclosure forY1 , and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis, 4th Ed., by T. W. Greene and P. G. M. Wuts (John Wiley & Sons, New York, 1999), in Protecting Group Chemistry, 1st Ed., by Jeremy Robertson (Oxford University Press, 2000); and in March's Advanced Organic chemistry: Reactions Mechanisms, and Structure, 8th Ed., by Michael B. Smith (Wiley- Interscience Publication, 2001 ). In some embodiments, the protecting group (Y1 ) is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group, and a silyl group. In some embodiments, the protecting group (Y1 ) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4-methoxybenzyl ester, a 2,6- disubstituted phenol, and a silyl group. In some embodiments, the protecting group (Y1 ) is a t-butyl group. In some embodiments, the compound of Formula (III) is of the structure 1 B below:

[0384] IB .

[0385] In some embodiments of the coupling reaction of step (a), the solvent is selected from toluene, t-butanol, 1 ,4- dioxane, xylene, N-methyl-2-pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of organic solvent toluene and organic cosolvent t- butanol.

[0386] SUBSTITUTE SHEET (RULE 26) If steps (pre-a1 ) and (pre-a2) are performed before step (a), the compound of Formula (II) is already present in the required solvent, because the same organic solvents are used in steps (pre-a2) and (a) or because of a solvent swap in step (pre- a2). If need be, more organic solvent and for example an organic co-solvent can be added in step (a). As will be appreciated by the skilled person, an organic co-solvent can also be added during a solvent swap in step (pre-a2). In some embodiments, steps (pre-a1 ) and (pre-a2) are performed before step (a) and the compound of Formula (II) is present in toluene.

[0387] The coupling reaction in step (a) typically is a catalyzed reaction. In some embodiments, the reaction is a palladium-catalyzed coupling reaction in the presence of a base. Suitable examples of palladium catalysts are for example tris(dibenzylideneacetone)dipalladium and Pd(ll)acetate. Suitable bases include organic bases (e.g., sodium t-butoxide, and potassium t-butoxide) and inorganic bases (e.g., K3PO4, K3PO4 H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).

[0388] In many embodiments, anhydrous K3PO4 is used as a base. In many such embodiments, the particle size distribution is such that 90% of the particles are smaller than between about 140 and about 307 microns including between about 140 and about 170 microns, including about 160 and about 290 microns, and about 180 and about 220 microns, and about 200 and about 210 microns. In some embodiments, 90% of the particles are less than 205 microns.

[0389] In these and other embodiments, 50% of the particles are between about 35 and about 173 microns or smaller, including between about 35 and about 40 microns.

[0390] In these and other embodiments, 10% of the particles between about 7 and about 74 microns including between about 7 and about 10 microns.

[0391] In some embodiments, the compound of Formula (II) is reacted in step (a) with a compound of Formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base. In some embodiments, the reaction mixture further includes a ligand. In some embodiments, the compound of Formula (HA) or (IIB) is reacted in step (a) with a compound of Formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base. In some embodiments, the reaction mixture further includes a ligand.

[0392] In some embodiments, the desalted compound of Formula (II) is reacted in step (a) with a compound of Formula (III) in the solvent (e.g., an organic solvent), using Pd(l l)acetate, either (S)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl] or rac-BINAP as a ligand. In some embodiments, (S)-BINAP is used as the ligand, and a base selected from sodium t-butoxide, potassium t-butoxide, anhydrous K3PO4, K3PO4 H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH.

[0393] In some embodiments, a salt of Formula (HA) or (I IB) is reacted in step (a) with a compound of Formula (III) in the solvent (e.g., an organic solvent), using Pd(ll)acetate, either (S)-BINAP [(S)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl], (R)- BINAP [(S)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl], or rac-BINAP as a ligand. In some embodiments, (S)-BINAP is used as the ligand, and a base selected from sodium t-butoxide, potassium t-butoxide, anhydrous K3PO4, K3PO4 H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH. In some embodiments, the salt of Formula (HA) is the mesylate salt, Compound 1A.

[0394] In some embodiments, the reaction in step (a) is performed at a temperature from 70°C and 80°C, optionally under a nitrogen atmosphere, for 2 or more hours.

[0395] In some embodiments, the compound of Formula (II) or salt of Formula (HA) is reacted in step (a) with a compound of Formula (HI) wherein X1 is Cl and Y1 is t-butyl, in a mixture of organic solvent toluene and organic co-solvent t-butanol, using Pd(H)acetate as catalyst, (S)-BINAP as a ligand, and anhydrous K3PO4 or K3PO4 H2O as a base, at a temperature between 70°C and 80°C, under a nitrogen atmosphere, for 2 or more hours.

[0396] In some embodiments, the one or more aqueous washing steps comprise one or more washing steps with water, preferably deionized water, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous HCI solution, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and finally one or more washing steps with again deionized water, followed by separating off the aqueous phase.

[0397] If t-butanol is used as an organic co-solvent in step (a), this organic co-solvent is removed from the organic phase during the washing steps.

[0398] If step (a) is performed in an organic solvent different from the solvent used in step (b), the organic solvent used in step (a) is swapped in step (a) with the organic solvent applied in step (b), such that the compound of Formula (IV) remains in solution. In some embodiments wherein the (organic) solvents used in steps (a) and (b) are different, at least part of the (organic) solvent used in step (a) is evaporated, such as by using distillation at reduced pressure, and the organic solvent of step (b) is added, such that the compound of Formula (IV) remains in solution during the solvent swap. This process can be performed by continuously evaporating the (organic) solvent used in step (a) and by continuously adding the organic solvent of step (b), for example until the amount of the (organic) solvent used in step (a), based on the total amount of solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the (organic) solvent used in step (a) and subsequently adding part of the organic solvent used in step (b), for example until the amount of the (organic) solvent used in step (a), based on the total amount of solvent, is below a certain threshold value.

[0399] In some embodiments, the solvent used in step (a) is a mixture of organic solvent toluene and organic co-solvent t-butanol. The t-butanol is removed from the organic phase comprising the compound of Formula (IV) during the washing steps.

[0400] In some embodiments of step (a), the remaining organic solvent toluene is swapped with acetonitrile by distilling off in two or more steps, at a temperature between 50°C and 65°C under reduced pressure, part of the toluene with intermediate addition of acetonitrile, in an amount to obtain a solvent mixture with less than about 20 weight percent toluene, based on the combined weight of the solvents, such that the compound of Formula (IV) remains in solution. In some embodiments of the compound of Formula (IV), Y1 is t-butyl.

[0401] Method of Preparing Obicetrapib - Step (b) from Aspects (a) - (d)

[0402] In step (b) of the method for preparing a compound of Formula (I) according to the disclosure, the compound of Formula (IV) is converted to the carbamate of Formula (V) in an organic solvent, and subsequently isolated as a solid salt of Formula (VI) (where Y1 is a protecting group, e.g., as described herein).

[0403] (V) (VI)

[0404] In some embodiments, the organic solvent used in step (b) is selected from acetonitrile, chlorobenzene, toluene, N-methyl-2-pyrrolidone, xylene, 1 ,4-dioxane, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, t- butyl methyl ether, and combinations thereof. In some embodiments, the organic solvent is acetonitrile or a mixture of chlorobenzene and dichloromethane.

[0405] As explained hereinbefore, the compound of Formula (IV) is already provided in step (a) in the organic solvent used in step (b), either because the same organic solvents are used in steps (a) and (b) or because of a solvent swap in step (a). In some embodiments of the compounds of Formulae (IV), (V) and (VI), Y1 is t-butyl.

[0406] In some embodiments, the organic solvent used in step (b) is a mixture of acetonitrile toluene, with less than about 20 weight percent toluene, based on the combined weight of the organic solvents.

[0407] In some embodiments, the conversion of the compound of Formula (IV) to the corresponding carbamate with Formula (V) in step (b) is performed in acetonitrile with less than about 20 weight percent toluene, based on the combined weight of the organic solvents, with an excess ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C.

[0408] If step (b) is performed in an organic solvent different from the organic solvent used in step (c), the organic solvent used in step (b) is swapped in step (b) with the

[0409] 64

[0410] SUBSTITUTE SHEET (RULE 26) organic solvent applied in step (c), such that the compound of Formula (V) remains in solution.

[0411] In some embodiments where the organic solvents used in steps (b) and (c) are different, at least part of the organic solvent used in step (b) is evaporated, such as by distillation at reduced pressure, and the organic solvent of step (c) is added, such that the compound of Formula (V) remains in solution during the organic solvent swap. This process can be performed by continuously evaporating the organic solvent used in step (b) and by continuously adding the organic solvent of step (c), for example until the amount of the organic solvent used in step (b), based on the total amount of organic solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (b) and subsequently adding part of the organic solvent used in step (c), for example until the amount of the organic solvent used in step (b), based on the total amount of organic solvent, is below a certain threshold value.

[0412] The resulting mixture is preferably subjected to one or more treatments with an aqueous sodium chloride and / or HCI solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution, followed by separating off the aqueous phase.

[0413] In some embodiments, the conversion of the compound of Formula (IV) to the corresponding carbamate with Formula (V) in step (b) is performed in acetonitrile with an excess of ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20oC, and this solvent is swapped in step (b) with isopropyl acetate by distilling off in two or more steps, at a temperature of 6O0C or less under reduced pressure, part of the acetonitrile with intermediate addition of isopropyl acetate, in an amount to obtain a solution of the compound of Formula (V) in isopropyl acetate, wherein the solution may be subjected to one or more treatments with an aqueous NaCI / HCI solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution, followed by separating off the aqueous phase.

[0414] Next, the compound of Formula (V) dissolved in an organic solvent is converted to a corresponding salt according to Formula (VI), wherein An- is an anion and n is an integer from 1 -3. The solid form of the salt according to Formula (VI) is then isolated as a solid form. In some embodiments, the salt of Formula (VI) is chosen from salts with an anion An- selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate and mesylate), a sulfate (e.g., methylsulfate), a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate.

[0415] In some embodiments, the salt of Formula (VI) is chosen from salts with an anion An- selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0416] In some embodiments, the salt of Formula (VI) is chosen from salt with an anion An- selected from chloride, bromide, bitartrate, and mesylate.

[0417] In some embodiments, the salt from of Formula (VI) is the mesylate salt including the crystalline mesylate salt thereof, Compound 1 D:

[0418] In some embodiments, of the salt of Formula (VI), n is 1.

[0419] The organic solvent used in the conversion of Formula (V) to (VI) is not particularly limited, but in some embodiments is selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof. In some embodiments, isopropyl acetate or a mixture comprising dichloromethane, n-heptane and isopropyl alcohol, such as a mixture of chlorobenzene, dichloromethane, n-heptane and isopropyl alcohol is used. It is noted that, the compound of Formula (V) is already provided in organic solvent owing to the solvent swap described herein before.

[0420] Accordingly, in some embodiments, the organic solvent used in the conversion of compound of Formula (V) to its corresponding salt of Formula (VI) selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, with less than about 20 weight percent toluene and

[0421] 66

[0422] SUBSTITUTE SHEET (RULE 26) less than about 7 weight percent acetonitrile, based on the combined weight of the solvents. In some embodiments, the solvent is a mixture of isopropyl acetate, toluene and acetonitrile, with less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile, based on the combined weight of the solvents.

[0423] In some embodiments, it is preferred to add an organic co-solvent different from the organic solvent already used in step (b). Exemplary organic co-solvents are selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, such as methyl t-butyl ether. As will be appreciated by the skilled person, the need and advantages of using an organic co-solvent depend on the particular organic solvent already used in step (b). In certain cases, the use of a co-solvent can be dispensed with.

[0424] In some embodiments, the organic solvent for the conversion of a compound of Formula (V) to its corresponding salt of Formula (VI) comprises isopropyl acetate and methyl t-butyl ether as an organic co-solvent.

[0425] Subsequently, an acid is added to form the salts of Formula (VI) defined supra. In some embodiments the acid is selected from ditartartic acid, sulfuric acids, sulfonic acids, hydrogen bromide and hydrogen chloride. In some embodiments, the acid is methanesulfonic acid. In embodiments wherein the salt of Formula (VI) can be obtained in crystalline form, part of the acid needed to form the salt of Formula (VI) can be added before the crystallization and part during the crystallization.

[0426] The solid form of the salt of Formula (VI) is isolated by crystallization if the salt of Formula (VI) can be obtained in crystalline form, filtration, one or more optional washing steps of the filtration residue, and drying.

[0427] In some embodiments, the compound of Formula (V) is converted to the corresponding mesylate salt according to Formula (VI) with methanesulfonic acid in an organic solvent mixture of isopropyl acetate and methyl t-butyl ether with less than about 20 weight percent toluene and less than 7 weight percent acetonitrile, based on the combined weight of the organic solvents, followed by crystallizing the mesylate salt according to Compound 1 D from the organic solvent, with subsequent filtration, one or more optional washing steps of the filtration residue, and drying.

[0428] In some embodiments wherein the salt according to Formula (VI) can be obtained in crystalline form, crystallization is induced by adding seed crystals of the salt according to Formula (VI). In some embodiments, wherein the salt according to Formula (VI) can be obtained in crystalline form, crystallizing the salt according to Formula (VI) and obtaining the crystalline form of the salt according to Formula (VI) is performed by adding the acid needed to form the salts, by agitating the resulting mixture for more than 60 minutes at a temperature from 20°C to 25°C, by allowing crystallization under agitation at a temperature between 15°C and 25°C for more than 120 minutes, followed by subjecting the resulting slurry to vacuum filtration, wherein the filtration residue is washed one or more times with the same organic solvent that is used to crystallize the salt according to Formula (VI) from, and by vacuum drying the crystalline form of the salt according to Formula (VI).

[0429] In an embodiment, the invention concerns the salt according to Formula (VI), wherein An- is an anion, wherein n is an integer from 1-3. In some embodiments, the compound is the crystalline mesylate (MSA) salt of Formula (VI) (e.g., Compound 1 D as described herein).

[0430] In some embodiments, crystallizing the mesylate salt of Formula (VI) from an organic solvent mixture of isopropyl acetate and methyl t-butyl ether and obtaining the crystalline form of the mesylate salt according to Compound 1 D is performed by adding methanesulfonic acid needed to form the salt, agitating the resulting mixture for more than 60 minutes at a temperature between 15°C and 25°C (e.g., 20°C), then allowing crystallization under agitation at a temperature between 15°C and 25°C for more than 120 minutes. The resulting slurry is subjected to vacuum filtration, wherein the filtration residue is washed one or more times with a mixture of isopropyl acetate and methyl t-butyl ether, and dried under vacuum to provide a crystalline form of the mesylate salt according to Compound 1 D.

[0431] In some embodiments, the compound of Formula (VI) is obtained in a yield of at least 70%, based on the number of moles of the compound of Formula (II). In some embodiments, the compound of Formula (VI) is obtained with a purity of 99% or more, such as a purity of 99.1 % or more, 99.2% or more, 99.3% or more, 99.5% or more, or even more. Method of Preparing Obicetrapib - Step (c) from Aspects (a) - (d)

[0432] In step (c) of the process according to the present disclosure, the isolated salt of Formula (VI), or the desalted derivative thereof (e.g., the compound according to Formula (V)), is alkylated with a compound of Formula (VII) to provide a compound of Formula (VIII): where, X2 is a leaving group and Y1 is a protecting group (e.g., as described herein).

[0433] In some embodiments of step (c), the isolated solid form of the salt according to Formula (VI), such as a crystalline form of the salt according to Formula (VI) (such as the crystalline mesylate salt, Compound 1 D), is reacted directly with a compound of Formula (VII) in an organic solvent, to form a compound of Formula (VIII) (i.e., without a desalting step).

[0434] In some embodiments of step (c), the isolated solid form of the salt according to Formula (VI), such as a crystalline form of the salt according to Formula (VI) (such as the crystalline mesylate salt, Compound 1 D), is desalted and reacted with a compound of Formula (VII) in an organic solvent, to form a compound of Formula (VIII). Desalting the compound of Formula (VI) results in a compound according to Formula (V).

[0435] When the compound of Formula (VI) is subjected to a desalting step, the desalting process and the subsequent reaction with a compound of Formula (V) are performed in the same organic solvent. In some embodiments, the organic solvent is selected from xylene, n-hexane, toluene, heptanes (mix of isomers), n-heptane, dichloromethane, chlorobenzene, and combinations thereof. In some embodiments, the organic solvent is toluene or n-heptane.

[0436] 69

[0437] SUBSTITUTE SHEET (RULE 26) In some embodiments, step (c) is carried out in the presence of a base. In some embodiments, step (c) is carried out in the presence of a solid-liquid phase-transfer catalyst.

[0438] In some embodiments, the base is selected from alkali metal hydrides, alkali metal hydroxides, alkali earth metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and amines. In some embodiments, the base is chosen from alkali metal alkoxides. In some embodiments, the base is sodium t- pentoxide or a mixture of sodium t-butoxide, and potassium t-butoxide.

[0439] In some embodiments, the solid-liquid phase-transfer catalyst is selected from t- butylammonium hydrogensulfate, tetra-n-butylammonium bromide, tetra-n- butylammonium iodide, a crown ether, and combinations thereof. In some embodiments, the catalyst is t-butylammonium hydrogensulfate.

[0440] In some embodiments, the reaction of the compound of Formula (V) or (VI) with the compound of Formula (VII) is performed at a temperature between 0°C and 25°C (such as from 5°C to 20°C).

[0441] The coupling partner of Formula (VII) in step (c) includes a leaving group X2. It will be understood that any convenient leaving group may find use in the present disclosure for X2. In some embodiments, the leaving group X2 in the compound of Formula (VII) is selected from a halogen, and a substituted sulfonyloxy group. In some embodiments, the leaving group X2 in the compound of Formula (VII) is a substituted sulfonyloxy group selected from a methanesulfonyloxy, p-toluenesulfonyloxy or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group X2 is a halogen. In certain embodiments, the halogen is bromide. In some embodiments, the compound of Formula (VII) is of the structure 1 E below.

[0442] In some embodiments, the desalting of the compound of Formula (VI) and the subsequent reaction with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of a base and a catalyst at a temperature from 5°C to 25°C. In some embodiments, the desalting of the compound of Formula (VI) and the subsequent reaction with a compound of Formula (VII) in step (c) is

[0443] SUBSTITUTE SHEET (RULE 26) performed in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogensulfate as a catalyst at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours. In some embodiments of the compound of Formula (VI), Y1 is t-butyl.

[0444] In some embodiments, the alkylation of a compound of Formula (VI) (i.e., without an additional desalting step) with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of a base and a catalyst at a temperature from 5°C to 25°C. In some embodiments, the alkylation of a compound of Formula (VI) with a compound of Formula (VII) in step (c) is performed in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t- butylammonium hydrogensulfate as a catalyst at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.

[0445] In some embodiments, step (c) includes providing crystalline 1 D, desalting this compound and reacting the desalted compound with a compound of Formula (VII) wherein X2 is Br in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.

[0446] In some embodiments, step (c) includes reacting crystalline 1 D with a compound of Formula (VII) wherein X2 is Br in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.

[0447] In some embodiments of step (c), the base is the last reagent added to the reaction mixture. Without being bound to any particular theory, the inventors have discovered that by adding the base as the last reagent, the number of equivalents of both the base and the compound of Formula (VII) used in the reaction mixture can be reduced. A reduction in the number of equivalents of the compound of Formula (VII) can in turn reduce the risk of carryover of Formula (VII) related impurities to the final product.

[0448] Accordingly, step (c) results in the production of a compound of Formula (VIII) in an organic solvent. In some embodiments of the compound of Formula (VIII), Y1 is t-butyl. In some embodiments, this reaction mixture is subjected in step (c) to one or more aqueous washing steps to remove impurities, followed by separating off the aqueous phase, and optionally one or more filtration steps, to obtain a washed reaction mixture comprising the compound of Formula (VIII) in the organic solvent. In some embodiments, the reaction mixture comprising the compound of Formula (VIII) in the organic solvent is concentrated by distilling off part of the organic phase to obtain a concentrated reaction mixture comprising the compound of Formula (VIII) in the organic solvent. In some embodiments, the organic solvent comprises from 30 to 40 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture. In some embodiments, the organic solvent comprises 34 to 37 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.

[0449] The one or more aqueous washing steps, the optionally one or more filtration steps, and the concentration step are preferably combined such that a washed and concentrated reaction mixture comprising the compound of Formula (VIII) in the organic solvent is obtained. In some cases, the organic solvent includes from 30 to 40 weight percent of the compound of Formula (VIII). In some embodiments, the organic solvent includes from 34 to 37 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.

[0450] In some embodiments, the one or more aqueous washing steps comprise one or more washing steps with an aqueous acetic acid solution.

[0451] In some embodiments, the reaction mixture comprising the compound of Formula (VIII) in toluene as an organic solvent is subjected in step (c) to one or more aqueous washing steps with an aqueous acetic acid solution followed by separating off the aqueous phase, and subsequently by distilling off part of the toluene, typically at a temperature from 75°C to 90°C under reduced pressure, to obtain a washed and concentrated reaction mixture comprising the compound of Formula (VIII) in toluene with from 30 to 40 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture. In some embodiments, the concentrated mixture includes from 34 to 37 weight percent of the compound of Formula (VIII) based on the weight of the reaction mixture.

[0452] If step (c) is performed in an organic solvent different from the organic solvent used in step (d), the organic solvent used in step (c) is swapped in step (c) with the organic solvent applied in step (d) such that the compound of Formula (VIII) remains in solution.

[0453] In some embodiments, wherein the organic solvents used in steps (c) and (d) are different, at least part of the organic solvent used in step (c) is evaporated, preferably using distillation at reduced pressure, and the organic solvent of step (d) is added, such that the compound of Formula (VIII) remains in solution during the organic solvent swap. This process can be performed by continuously evaporating the organic solvent used in step (c) and by continuously adding the organic solvent of step (d), for example until the amount of the organic solvent used in step (c), based on the total amount of organic solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (c) and subsequently adding part of the organic solvent used in step (d), for example until the amount of the organic solvent used in step (c), based on the total amount of organic solvent, is below a certain threshold value.

[0454] Method of Preparing a Compound of Formula (I) - Step (d) from Aspects (a) - (d)

[0455] In step (d) of the process according to the present disclosure, the compound of Formula (VIII) is converted to obicetrapib in a first organic solvent (where Y1 is a protecting group, e.g., as described herein).

[0456] The selection of the first organic solvent used in step (d) is not particularly limited.

[0457] In some embodiments, the first organic solvent is not an ether or an ester. In some embodiments, the first organic solvent is toluene or a mixture of n-heptane and acetic acid. As explained hereinbefore, the compound of Formula (VIII) is already provided in step (c) in the first solvent used in step (d), either because the same organic solvents are used in steps (c) and (d) or because of a solvent swap in step (c). Accordingly, in some embodiments, the first organic solvent as defined hereinbefore with from 30 to 40 weight percent of the compound of Formula (VIII), such as from 34 to 37 weight percent, based on the weight of the reaction mixture, is provided in step (d).

[0458] SUBSTITUTE SHEET (RULE 26) In some embodiments, toluene as a first organic solvent with from 30 to 40 weight percent of the compound of Formula (VIII), such as from 34 to 37 weight percent, based on the weight of the reaction mixture, is provided in step (d).

[0459] Any convenient protecting group for a carboxylic acid, such as an ester moiety, may find use as Y1 in the compound of Formula (VIII). As disclosed herein, the selection of an appropriate protecting group for a carboxylic acid can be readily determined by one skilled in the art. In some embodiments of Formula (VIII), the protecting group (Y1 ) is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group, and a silyl group. In some embodiments of Formula (VIII), the protecting group (Y1 ) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4- methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group. In some embodiments of the compound of Formula (VIII), the protecting group Y1 is t-butyl. In some embodiments, the conversion of the compound of Formula (VIII) to obicetrapib is performed by contacting the compound of Formula (VIII) in the first organic solvent, such as toluene or a mixture of n-heptane and acetic acid, with acetic acid (AcOH) and dry HCI under agitation. In some embodiments, the reaction mixture is heated to a temperature between 40°C and 55°C and the resulting mixture is maintained at this temperature under agitation for at least 3 hours.

[0460] Obicetrapib can be isolated from the resulting mixture using techniques known to the skilled person.

[0461] In some embodiments, the resulting mixture comprising obicetrapib, is subjected in step (d) to one or more aqueous washing steps. In some embodiments, the one or more aqueous washing steps in step (d) are performed as follows: (AA) the reaction mixture comprising obicetrapib is cooled to a temperature between 15°C and 25°C, and subsequently a mixture of n-heptane, acetonitrile and water is added followed by agitating the resulting mixture for more than 15 minutes at this temperature;

[0462] (BB) the system obtained in step (AA) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;

[0463] (CC) a mixture of n-heptane, acetonitrile, toluene and water is added to the aqueous phase obtained in step (BB), followed by agitating the resulting system for more than 15 minutes at a temperature between 15°C and 25°C; (DD) the system obtained in step (CC) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;

[0464] (EE) the organic phase obtained in step (BB) and the organic phase obtained in step (DD) are combined, water is added, and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C;

[0465] (FF) the system obtained in step (EE) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;

[0466] (GG) water is added to the organic phase obtained in step (FF) and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C; (HH) the system obtained in step (GG) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;

[0467] (II) an aqueous solution of sodium citrate tribasic dihydrate is added to the organic phase obtained in step (HH) followed by agitating the resulting mixture for more than 15 minutes at a temperature between 15°C and 25°C;

[0468] (JJ) the system obtained in step (II) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;

[0469] (KK) water is added to the organic phase obtained in step (JJ) and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C; and

[0470] (LL) the system obtained in step (KK) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated.

[0471] Steps (AA) to (LL) in this embodiment result in a washed compound of Formula (I) in an organic solvent mixture comprising n-heptane, acetonitrile and the first organic solvent. In some embodiments the first solvent is toluene.

[0472] In some embodiments, wherein the first organic solvent does not already mainly consist of cyclopentyl methyl ether, the organic solvent mixture is swapped in a subsequent step (MM) with CPME such that obicetrapib remains in solution.

[0473] Hence, in some embodiments, step (LL) is followed by step (MM) wherein at least part of the solvents in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation at reduced pressure, and wherein cyclopentyl methyl ether is added, such that obicetrapib remains in solution during the solvent swap. In some embodiments, the process results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent based on the weight of the solution. In some embodiments, the concentration of obicetrapib in cyclopentyl methyl ether is from 33 and 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent, and less than 1 weight percent of n-heptane based on the weight of the solution.

[0474] This process can be performed by continuously evaporating the solvents in the organic solvent mixture obtained in step (LL) and by continuously adding cyclopentyl methyl ether, for example until the amount of specific solvents in the organic solvent mixture, based on the total amount of organic solvents, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the solvents in the organic solvent mixture obtained in step (LL) and by subsequently adding cyclopentyl methyl ether, for example until the amount of specific solvents in the organic solvent mixture, based on the total amount of solvent, is below a certain threshold value.

[0475] In some embodiments, the first organic solvent is toluene, step (LL) is followed by step (MM) wherein at least part of the n-heptane, acetonitrile and toluene in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation at a temperature of 45°C or lower and at reduced pressure (in-vacuo), with intermediate additions of cyclopentyl methyl ether, such that obicetrapib remains in solution during the solvent swap, resulting in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent. In some embodiments, the concentration of obicetrapib in cyclopentyl methyl is from 33 to 37 weight percent based on the weight of the solution, with less than 0.5 weight percent of toluene, less than 0.5 weight percent of acetonitrile and less than 2.7 weight percent of n-heptane.

[0476] Method of Preparing a Crystalline obicetrapib HCI- Steps (e)-(f) in addition to Aspects (a) ~ (d)

[0477] In some embodiments of the subject method, step (d) is followed by step (e)- (f), wherein obicetrapib is treated with HCI such as in a suitable solvent. Such solvent may be an aqueous solvent or an organic solvent. In some embodiments, the use of an organic solvent provides crystalline obicetrapib HCI.

[0478] In some embodiments, the organic solvent used in step (e) comprises a mixture of a solvent and an anti-solvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl- tetrahydrofuran, dichloromethane, 1 ,4-dioxane, 1 ,2-diflurobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane. In some embodiments, the HCI has sufficient solubility in the anti-solvent such that it can be used as a suitable solvent. In some embodiments, the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (e) further comprises toluene.

[0479] In some embodiments, step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35°C and 40°C under agitation, adding dry HCI in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, then adding further n-heptane as an anti-solvent. At this point, a small portion of the reaction mixture can be extracted, cooled to a temperature of between 10°C and 15°C, to obtain a slurry of crystals of crystalline obicetrapib HCI in a mixture cyclopentyl methyl ether and n-heptane (referred to herein as a “seed crystal slurry”). Optionally, all or a portion of the seed crystal slurry of crystalline obicetrapib HCI can then be added as seed crystals back to the reaction mixture. The seeds assist with nucleation but are not required and thus the process described herein can be done without seeding. The resulting reaction mixture is then cooled to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HCI from the system under agitation. In some embodiments, the crystalline obicetrapib HCI is crystallized over a period of 12 hours or more, with subsequent filtration (e.g., through a filter dryer), one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some cases, a wet filter cake of crystalline obicetrapib HCI is dried in vacuo in steps using temperatures of 25°C-30°C, 30°C-40°C, 40°C- 50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0480] Accordingly, in some embodiments, the method of preparing crystalline obicetrapib HCI comprises the addition of seed crystals (e.g., as a seed crystal slurry). The seed crystals of crystalline obicetrapib HCI can be formed as a slurry by following step (i) as set out above and after addition of dry HCI in cyclopentyl methyl ether and anti-solvent n-heptane, extracting a small portion of the reaction mixture, cooling to a temperature between 10°C and 15°C, to provide a slurry of crystals of crystalline obicetrapib HCI in cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (e) comprises a mixture of cyclopentyl methyl ether and n-heptane. Accordingly, in one embodiment, step (e) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and n- heptane, raising the temperature to 35°C-45°C under agitation, adding dry HCI in cyclopentyl methyl ether and raising the temperature again to 50°C-55°C, addition of further n-heptane as anti-solvent, the optional addition of seed crystals of crystalline obicetrapib HCI (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HCI from the system under agitation. In some embodiments, the crystalline obicetrapib HCI is crystallized over a period of at least 12 hours, with subsequent filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some embodiments, the crystalline obicetrapib HCI is dried in vacuo. In some embodiments, the crystalline obicetrapib HCI is subjected to drying in a vacuum drying cabinet at 25 mbar pressure and at a temperature of 55°C for 10 hours or more. In some embodiments, after the drying procedure, the crystalline obicetrapib HCI includes less than 0.1 weight percent residual cyclopentyl methyl ether.

[0481] In some embodiments described hereinbefore, step (MM) of step (d) results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent used in step (d), and less than 1 weight percent of n-heptane. In some embodiments described hereinbefore, step (MM) of step (d) results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of toluene, and less than 1 weight percent of n-heptane. These solutions can, after addition of n-heptane, advantageously be used in step (e). As will be appreciated by the skilled person, the n-heptane can also be added in step (d).

[0482] Accordingly, in some embodiments, step (e) comprises providing the solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent used in step (d) (such as toluene), and less than 1 weight percent of n-heptane, addition of n-heptane, raising the temperature to 35°C to 45°C under agitation, adding dry HCI in cyclopentyl methyl ether and raising the temperature again to 50°C to 55°C, addition of further n-heptane as anti-solvent, the optional addition of seed crystals of crystalline obicetrapib HCI (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HCI from the system under agitation, such as during a period of at least 12 hours, with subsequent filtration, one or more washing steps with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some cases, a wet filter cake of crystalline obicetrapib HCI is dried in vacuo in steps using temperatures of 25°C- 30°C, 30°C-40°C, 40°C-50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0483] In some embodiments, step (f) comprises the following steps:

[0484] (aa) providing crystalline obicetrapib HCI;

[0485] (bb) dissolving the crystalline obicetrapib HCI in ethanol under agitation. In some embodiments at a temperature between 15°C and 25°C;

[0486] (cc) adding an aqueous NaOH solution to the solution obtained in step (bb) and agitating the resulting mixture, such as at a temperature from 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt obicetrapib;

[0487] (dd) optionally filtering the solution obtained in step (cc);

[0488] (ee) preparing a CaCI2 solution by adding deionized water to CaCI2 under agitation, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes;

[0489] (ff) cooling the CaCI2 solution obtained in step (ee) to a temperature between 8°C and 12oC and adding via a filter to the solution obtained in step (dd) (or (cc)) under agitation at said temperature;

[0490] (gg) stirring the slurry resulting from step (ff) for about 1 to about 10 hours. In some embodiments the slurry is stirred at a temperature between 8°C and 12°C;

[0491] (hh) isolating the solids from the slurry obtained in step (gg) by filtration. In some embodiments the isolating is conducted at a temperature between 8°C and 12°C;

[0492] (ii) washing the filtration residue obtained in step (hh) with water in one or more washing steps. In some embodiments the washing is conducted at a temperature between 8°C and 12°C; and

[0493] (jj) drying the washed residue obtained in step (ii), such as in vacuo at a temperature between 40°C and 50°C for more than 16 hours (such as 200 hours or more), to obtain amorphous obicetrapib hemicalcium. In some embodiments of the subject method, crystalline obicetrapib HCI is isolated in step (f) with a purity of 98% or more, such as 98.5% or more, 99% or more 99.5% or more, or even more.

[0494] Another embodiment of the disclosure concerns the crystalline obicetrapib HCI obtained by or obtainable by the process as defined herein.

[0495] Still another embodiment of the disclosure is directed to crystalline obicetrapib HCI.

[0496] In some embodiments, crystalline obicetrapib HCI is stored at controlled room temperature and under a nitrogen atmosphere and is protected from moisture to prevent the formation of an amorphous solid, because crystalline obicetrapib HCI including crystalline obicetrapib HCI is hygroscopic.

[0497] Method of Preparing Amorphous Obicetrapib Hemicalcium Steps (q)-(h) in Addition to Aspects (a) to (f)

[0498] In some embodiments of the subject method, step (f) is followed by steps (g)- (h), wherein the crystalline obicetrapib HCI is converted to amorphous obicetrapib hemicalcium (Formula IB):

[0499] In some embodiments step (g), the preparation of amorphous obicetrapib hemicalcium includes steps (g1 )-(g3) as set out below:

[0500] (g1 ) converting crystalline obicetrapib HCI of step (f) to obicetrapib in an organic solvent;

[0501] (g2) treating obicetrapib in the organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and

[0502] (g3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemicalcium;

[0503] SUBSTITUTE SHEET (RULE 26) wherein the compounds in steps (g1 ) and (g2) are not isolated.

[0504] Accordingly, in some embodiments step, (g1 ) comprises the following steps:

[0505] (aa) providing crystalline obicetrapib HCI as defined or obtained in step (f);

[0506] (bb) dissolving crystalline obicetrapib HCI in a mixture of water and isopropyl acetate under agitation. In some embodiments, step (bb) is conducted at a temperature between 15°C and 25°C;

[0507] (cc) allowing phase separation and subjecting the resulting organic phase to one or more subsequent washing steps with water, wherein each washing step is followed by separating off the aqueous phase, resulting in a washed organic phase; and

[0508] (dd) performing two or more distillations on the washed organic phase resulting from step (cc) at a temperature of 50°C or lower (such as 30°C or lower), with intermediate additions of ethanol, to obtain a solution of the compound of obicetrapib in ethanol. In some embodiments step, (g2) comprises the following steps:

[0509] (ee) adding an aqueous NaOH solution to the solution obtained in step (dd) and agitating the resulting mixture, such as at a temperature between 20°C and 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib; and

[0510] (ff) optionally filtering the solution obtained in step (ee).

[0511] In some embodiments step, (g3) comprises the following steps:

[0512] (gg) preparing a CaCI2 solution by adding deionized water to CaCI2 under agitation, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes;

[0513] (hh) cooling the CaCI2 solution obtained in step (gg) to a temperature from 8°C to 12°C and adding via a filter to the solution obtained in step (ff) or (ee) under agitation at said temperature;

[0514] (ii) stirring the slurry resulting from step (hh) for about 1 to 10 hours. In some embodiments of step (ii), the stirring is conducted at a temperature between 8°C and 12°C;

[0515] (jj) isolating the solids from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the isolating is conducted at a temperature between 8°C and 12°C;

[0516] (kk) washing the filtration residue obtained in step (jj) with water in one or more washing steps. In some embodiments of step (kk), the washing is conducted at a temperature between 8°C and 12°C; and (II) drying the washed residue obtained in step (kk), such as in vacuo at a temperature from 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain the amorphous obicetrapib hemicalcium (also sometimes referred to herein as compound 3).

[0517] In some embodiments, step (g) comprises the following steps:

[0518] (aa) providing crystalline obicetrapib HCI, as defined or obtained in step (f);

[0519] (bb) dissolving crystalline obicetrapib HCI in ethanol under agitation. In some embodiments at a temperature between 15°C and 25°C;

[0520] (cc) adding an aqueous NaOH solution to the solution obtained in step (bb) and agitating the resulting mixture, such as at a temperature from 20°C to 25°C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib;

[0521] (dd) optionally filtering the solution obtained in step (cc);

[0522] (ee) preparing a CaCI2 solution by adding deionized water to CaCI2 under agitation, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes;

[0523] (ff) cooling the CaCI2 solution obtained in step (ee) to a temperature between 8°C and 12oC and adding via a filter to the solution obtained in step (dd) or (cc) under agitation at said temperature;

[0524] (gg) stirring the slurry resulting from step (ff) for about 1 to 10 hours. In some embodiments the slurry is stirred at a temperature between 8°C and 12°C;

[0525] (hh) isolating the solids from the slurry obtained in step (gg) by filtration. In some embodiments the isolating is conducted at a temperature between 8°C and 12°C;

[0526] (ii) washing the filtration residue obtained in step (hh) with water in one or more washing steps. In some embodiments the washing is conducted at a temperature between 8°C and 12°C; and

[0527] (jj) drying the washed residue obtained in step (ii), such as in vacuo at a temperature between 40°C and 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain the amorphous hemicalcium- salt of Formula (IB).

[0528] In some embodiments, amorphous obicetrapib hemicalcium is stored sealed at a temperature of less than 30°C and protected from light.

[0529] In some embodiments, amorphous obicetrapib hemicalcium is submitted to a subsequent reworking procedure. In some embodiments, amorphous obicetrapib hemicalcium is further reworked by dissolving in ethanol (such as twice the weight of ethanol relative to amorphous obicetrapib hemicalcium at a temperature of 25°C to 50°C, followed by cooling to 10°C to 15°C, followed by filtering into a mixture of aqueous calcium chloride solution and ethyl acetate, also cooled to 10°C to 15°C, followed by filtering, washing with water and drying in vacuo at 45°C or less for 20 hours or more.

[0530] In many embodiments of the disclosure, amorphous obicetrapib hemicalcium is processed to achieve a particle size distribution. In many embodiments such processing is by milling. Examples of milling include hammer milling, ball milling, and jet milling. In other embodiments, spray drying may be used to achieve a particle size distribution. Thus, in some embodiments, of the disclosure, spray-dried amorphous obicetrapib hemicalcium is provided. An example of jet-milled amorphous obicetrapib hemicalcium is provided in Example 3.14.

[0531] In many embodiments of the disclosure, unmilled amorphous obicetrapib hemicalcium is provided. In many embodiments of the disclosure, milled amorphous obicetrapib hemicalcium is provided.

[0532] In many embodiments, the particle size distribution of amorphous obicetrapib hemicalcium is such that 90% of the particles have a diameter of about 15 microns or less. In these and other embodiments, 90% of the particles have a diameter of about 14 microns or less, 13 microns or less, 12 microns or less, 11 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, 5 microns or less, 4 microns or less, or 3 microns or less.

[0533] In some embodiments, 90% of the particles have a diameter between about 6 microns and 15 microns.

[0534] In these and other embodiments, the particle size distribution of amorphous obicetrapib hemicalcium is such that 50% of the particles have a diameter of about 5 microns or less, such as, for example, 4 microns or less or 3 microns or less.

[0535] In these and other embodiments, the particle size distribution of amorphous obicetrapib hemicalcium is such that 10% of the particles have a diameter of about 2 microns or less.

[0536] Amorphous obicetrapib hemicalcium of the disclosure can be made with high chemical purity according to the processes of the disclosure. Such levels of purity include greater than 98.0 % pure such as greater than 98.1 %, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1 %, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or more. The highest level of purities such as greater than 99.8% or 99.9% pure are more readily achieved with processes where crystalline obicetrapib HCI is used as an intermediate.

[0537] As summarized above, also provided herein are amorphous calcium salts of obicetrapib including amorphous obicetrapib hemicalcium. New intermediates for use in the synthesis of obicetrapib and salts thereof are also provided.

[0538] Thus, the subject method has been described by reference to certain embodiments discussed above. It will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those of skill in the art.

[0539] Other Aspects of the Present Invention

[0540] In some embodiments, the present invention relates to the CETP inhibitor as described herein for use in treating a subject with dry AMD; treating a subject with GA secondary to dry AMD; treating a subject with GA secondary to AMD; reducing the rate of GA growth in a subject with GA secondary to dry AMD; reducing the rate of GA growth in a subject with GA secondary to AMD reducing the rate of change in GA area in a subject with GA secondary to dry AMD; reducing the rate of change in GA area in a subject with GA secondary to AMD; slowing or inhibiting the progression of dry AMD in a subject in need thereof; slowing or inhibiting the progression of GA in a subject in need thereof, slowing or inhibiting loss of visual acuity in a subject with dry AMD; slowing or inhibiting loss of visual acuity in a subject with GA secondary to dry AMD; slowing or inhibiting loss of visual acuity in a subject with GA secondary to AMD; reversing loss of visual acuity in a subject with dry AMD; reversing loss of visual acuity in a subject with GA secondary to dry AMD; reversing loss of visual acuity in a subject with GA secondary to AMD; slowing or inhibiting loss of low luminance visual acuity in a subject with dry AMD; slowing or inhibiting loss of low luminance visual acuity in a subject with GA secondary to dry AMD; slowing or inhibiting loss of low luminance visual acuity in a subject with GA secondary to AMD; reversing loss of low luminance visual acuity in a subject with dry AMD; reversing loss of low luminance visual acuity in a subject with GA secondary to dry AMD; reversing loss of low luminance visual acuity in a subject with GA secondary to AMD; reducing the formation of drusen in a subject; reducing the rate of formation of drusen in a subject; reversing the formation of drusen in a subject; or reducing the amount of drusen in a subject. Such uses are performed in accordance with the methods of the present invention described herein. In some embodiments, the present invention relates to uses of the CETP inhibitor as described herein to treat a subject with dry AMID; to treat a subject with GA secondary to dry AMD; to treat a subject with GA secondary to AMD; to reduce the rate of GA growth in a subject with GA secondary to dry AMD; to reduce the rate of GA growth in a subject with GA secondary to AMD; to reduce the rate of change in GA area in a subject with GA secondary to dry AMD; to reduce the rate of change in GA area in a subject with GA secondary to AMD; to slow or inhibit the progression of dry AMD in a subject in need thereof; to slow or inhibit the progression of GA in a subject in need thereof; to slow or inhibit the loss of visual acuity in a subject with dry AMD; to slow or inhibit the loss of visual acuity in a subject with GA secondary to dry AMD; to slow or inhibit the loss of visual acuity in a subject with GA secondary to AMD; to reverse the loss of visual acuity in a subject with dry AMD; to reverse the loss of visual acuity in a subject with GA secondary to dry AMD; to reverse the loss of visual acuity in a subject with GA secondary to AMD; to slow or inhibit the loss of low luminance visual acuity in a subject with dry AMD; to slow or inhibit the loss of low luminance visual acuity in a subject with GA secondary to dry AMD; to slow or inhibit the loss of low luminance visual acuity in a subject with GA secondary to AMD; to reverse the loss of low luminance visual acuity in a subject with dry AMD; to reverse the loss of low luminance visual acuity in a subject with GA secondary to dry AMD; to reverse the loss of low luminance visual acuity in a subject with GA secondary to AMD; to reduce the formation of drusen in a subject; to reduce the rate of formation of drusen in a subject; to reverse the formation of drusen in a subject; or to reduce the amount of drusen in a subject. Such uses are performed in accordance with the methods of the present invention described herein.

[0541] In some embodiments, the present invention relates to the use of the CETP inhibitor in the manufacture of a medicament for treating a subject with dry AMD; treating a subject with GA secondary to dry AMD; treating a subject with GA secondary to AMD; reducing the rate of GA growth in a subject with GA secondary to dry AMD; reducing the rate of GA growth in a subject with GA secondary to AMD; reducing the rate of change in GA area in a subject with GA secondary to dry AMD; reducing the rate of change in GA area in a subject with GA secondary to AMD; slowing or inhibiting the progression of dry AMD in a subject in need thereof, slowing or inhibiting the progression of GA in a subject in need thereof; slowing or inhibiting loss of visual acuity in a subject with dry AMD; slowing or inhibiting loss of visual acuity in a subject with GA secondary to dry AMD; slowing or inhibiting loss of visual acuity in a subject with GA secondary to AMD; reversing loss of visual acuity in a subject with dry AMD; reversing loss of visual acuity in a subject with GA secondary to dry AMD; reversing loss of visual acuity in a subject with GA secondary to AMD; slowing or inhibiting loss of low luminance visual acuity in a subject with dry AMD; slowing or inhibiting loss of low luminance visual acuity in a subject with GA secondary to dry AMD; slowing or inhibiting loss of low luminance visual acuity in a subject with GA secondary to AMD; reversing loss of low luminance visual acuity in a subject with dry AMD; reversing loss of low luminance visual acuity in a subject with GA secondary to dry AMD; reversing loss of low luminance visual acuity in a subject with GA secondary to AMD; reducing the formation of drusen in a subject; reducing the rate of formation of drusen in a subject; reversing the formation of drusen in a subject; or reducing the amount of drusen in a subject. These uses of the medicament are performed in accordance with the methods of the present invention described herein.

[0542] Description of the Figures

[0543] Figure 1 : Alpha-Tocopherol in plasma at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject. Data are presented in box and whisker diagrams; the boxes correspond to the interquartile range (IQR). The line in the middle of the box is plotted at the median. The whiskers indicate the range of the data within 1 .5 X IQR with outliers indicated as circles. The paired t-test was used to determine the p values. * p < 0.05, ** p < 0.01 , *** p < 0.001 .

[0544] Figure 2: Alpha-Tocopherol in HDL at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0545] Figure 3: Lutein in plasma at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment , obtained by subtracting baseline values from treated values for each subject.

[0546] Figure 4: Lutein in HDL at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0547] Figure 5: Zeaxanthin in plasma at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0548] Figure 6: Zeaxanthin in HDL at baseline and after treatment (OCEAN study), in placebo (A) and treatment with obicetrapib (B), ezetimibe (C) and obicetrapib+ezetimibe combination (D). Panel E shows the effect of each treatment, obtained by subtracting baseline values from treated values for each subject.

[0549] Figure 7: HDL vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0550] Figure 8: triglycerides vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0551] Figure 9: Plasma tocopherol vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0552] Figure 10: Tocopherol in HDL vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0553] Figure 11 : Plasma Zeaxanthin vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0554] Figure 12: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0555] Figure 13: Tocopherol in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0556] Figure 14: Plasma Zeaxanthin vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0557] Figure 15: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0558] Figure 16: Plasma tocopherol vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0559] Figure 17: Tocopherol in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0560] Figure 18: Tocopherol in non-HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study). Figure 19: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0561] Figure 20: Pre-beta1 HDL plasma levels at baseline (V2) and after treatment (V4) in placebo group (ROSE2 study).

[0562] Figure 21 : Pre-beta1 HDL plasma levels at baseline (V2) and after treatment (V4) in obicetrapib treatment group (ROSE2 study).

[0563] Figure 22: Plasma tocopherol vs. Pre-beta1 HDL at baseline in all participants (ROSE2 study).

[0564] Figure 23: Plasma tocopherol vs. Pre-beta1 HDL at baseline in the obicetrapib treatment group (ROSE2 study).

[0565] Figure 24: Plasma tocopherol vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (ROSE2 study).

[0566] Figure 25 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0567] Figure 26 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0568] Figure 27 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0569] Figure 28 is an infrared spectrum of amorphous obicetrapib hemicalcium.

[0570] Figure 29 is a1H-NMR spectrum of amorphous obicetrapib hemicalcium.

[0571] Figure 30 is an x-ray powder diffraction pattern of crystalline obicetrapib hemicalcium.

[0572] Figure 31 is an x-ray powder diffraction pattern stackplot from a stability study of crystalline obicetrapib hemicalcium.

[0573] Figure 32 is an x-ray powder diffraction pattern stackplot from a stability study of amorphous obicetrapib hemicalcium.

[0574] Figure 33 is a polarized light micrograph of amorphous obicetrapib hemicalcium.

[0575] Figure 34 is a polarized light micrograph of crystalline obicetrapib hemicalcium.

[0576] Figure 35 is a thermogravimetric analysis plot of amorphous obicetrapib hemicalcium.

[0577] Figure 36 is a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium. Figure 37 a modulated differential scanning calorimetry thermogram (with pinhole) of amorphous obicetrapib hemicalcium.

[0578] Figure 38 is a modulated differential scanning calorimetry thermogram (with pinhole) of crystalline obicetrapib hemicalcium.

[0579] Figure 39 is a solid-state13C-NMR spectrum of amorphous and crystalline obicetrapib hemicalcium.

[0580] Figure 40 is a solid-state13C-NMR spectrum of crystalline obicetrapib hemicalcium.

[0581] Figure 41 is a solid-state13C-NMR spectrum of amorphous obicetrapib hemicalcium.

[0582] Figure 42 is an x-ray powder diffraction pattern of crystalline obicetrapib HCI and at least partially desolvated crystalline obicetrapib HCI.

[0583] Figure 43 is an x-ray powder diffraction pattern of crystalline obicetrapib HCI.

[0584] Figure 44 is an x-ray powder diffraction pattern of crystalline Compound 1 D.

[0585] Figure 45 is1H-NMR spectrum of Compound 1 D.

[0586] Figure 46: Plasma alpha tocopherol concentrations before and after treatment (NCT05421078) with placebo (A), 2.5 mg obicetrapib (B), 5 mg obicetrapib (C) and 10 mg obicetrapib (D).

[0587] Figure 47: Plasma lutein concentrations before and after treatment (NCT05421078) with placebo (A), 2.5 mg obicetrapib (B), 5 mg obicetrapib (C) and 10 mg obicetrapib (D).

[0588] Figure 48: Plasma zeaxanthin concentrations before and after treatment (NCT05421078) with placebo (A), 2.5 mg obicetrapib (B), 5 mg obicetrapib (C) and 10 mg obicetrapib (D).

[0589] FIG. 49 shows the percent change from baseline in mean lutein concentration in total plasma, high-density lipoprotein (HDL) fraction, and non-HDL fraction, before and after 8-week treatment with 5 mg obicetrapib as further described in Example 1 (P<0.05).

[0590] Examples

[0591] Example 1: phase 2 clinical trial (OCEAN; NCT04770389)

[0592] OCEAN (NCT04770389) was designed as a placebo-controlled, double-blind, randomized, phase 2 study in participants with mild dyslipidemia to evaluate the efficacy, safety, and tolerability of obicetrapib and ezetimibe combination therapy. The screening period for this study will take up to 2 weeks. Following the screening period, eligible patients will be randomized to placebo, 5 mg obicetrapib + 10 mg ezetimibe; 5 mg obicetrapib + placebo ezetimibe; or placebo obicetrapib + 10 mg ezetimibe for an 8 week treatment period. After the treatment period, patients will continue for a 4 week safety follow-up and a 8 week PK follow-up. The primary endpoint was percent change in LDL-C after 8 weeks of treatment, and secondary endpoints are percent change in apoB, HDL-C, and non-HDL-C.

[0593] In addition, the effects of treatment on lipophilic antioxidants (Lutein, zeaxanthin and alpha-tocopherol) were assessed by determining the plasma levels of these lipophilic antioxidants, as well as the levels at which they are carried in HDL and pre- betal HDL in particular, before and after treatment.

[0594] The results of the Lipophilic antioxidants measurements of the samples obtained at baseline and after treatment are summarized in table 1 below. Surprisingly, Obicetrapib treatment alone raised plasma lutein by 37.3% (p<0.04) and the obicetrapib plus ezetimibe combination by 31.1 % (p<0.042). Changes in lutein were more dramatic in the HDL fraction (73.5% and (p<0.023) and 90.2% (p<0.008)) for the same groups. Obicetrapib treatment alone raised plasma zeaxanthin by 57.1 % (p<0.026) and the obicetrapib plus ezetimibe combination by 33.4% (p<0.037). As observed for lutein the changes in zeaxanthin were more dramatic in the HDL fraction (88.2% and (p<0.013) and 74.9% (p<0.006)) for the same groups. Interestingly, HDL alpha tocopherol was significantly raised in the obicetrapib group (89.1 >% (p<0.010)) and obicetrapib plus ezetimibe group (71.3% (p<0.001 )).

[0595] Samples were measured in reflection mode using an Al sample holder without any further preparation (i.e. , grinding). The detector measures over the entire angle range from approx. 2°29 to 120° 20 simultaneously; in the case of HCI obicetrapib, discernible signals useful for phase identification are seen up to approx. 45°20. The temperature in the diffractometer is typically around 30 °C during measurements. Table 1. Lipophilic antioxidants measured at baseline and after treatment

[0596] Table 2 below shows the results of the Pre-beta1 HDL analyses. Further results of antioxidant analyses are presented as figures 1 -19. Table 2: Pre-beta1 HDL (Ocean trial samples)

[0597] Significant increases in Lutein, Zeaxanthin and Tocopherols were measured in the HDL fractions of the obicetrapib and obicetrapib plus ezetimibe treated subjects. Obicetrapib and obicetrapib plus ezetimibe also increased the plasma level of pre- betal HDL, as well as lutein, zeaxanthin and tocopherol carried by pre-beta1 HDL.

[0598] Example 2: phase 2b clinical trial (ROSE2; NCT05266586)

[0599] ROSE2 (NCT05266586) was designed as a placebo-controlled, double-blind, randomized phase 2 study to evaluate the efficacy, safety and tolerability of obicetrapib 10 mg in combination with ezetimibe 10 mg as an adjunct to high-intensity statin therapy. A total of 119 patients were randomized to receive combination therapy, obicetrapib 10 mg or placebo for an 84-day treatment period. The primary efficacy endpoint was the percent change from Day 1 to Day 84 in LDL-C for the combination treatment group compared to the placebo group and was met. Patients treated with the combination of obicetrapib and ezetimibe achieved a median reduction in LDL-C of 59%, as compared to patients treated with placebo, who achieved a median reduction in LDL-C of 6%. Overall, the combination of obicetrapib and ezetimibe was observed to be well-tolerated, with a safety profile observed to be comparable to placebo.

[0600] Like for the OCEAN study (see example 1 ), effects of treatment on lipophilic antioxidants (Lutein, zeaxanthin and alpha-tocopherol) were assessed by determining the plasma levels of these lipophilic antioxidants, as well as the levels at which they are carried in HDL and pre-beta1 HDL in particular, before and after treatment. Results of these analyses are presented as figures 20-24. As can be derived from the results presented therein, obicetrapib and obicetrapib plus ezetimibe increased the plasma level of pre-beta-1 HDL, as well as the amount of alpha-tocopherol carried by HDL, in particular pre-beta1 HDL. These results are in line with and confirm the findings based from the OCEAN study samples.

[0601] Example 3: synthesis of amorphous obicetrapib hemicalcium

[0602] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein.

[0603]

[0604] Scheme 1

[0605] With reference to Scheme 1 , amorphous obicetrapib hemicalcium (compound 3) was prepared in six chemical steps and three isolations from the mesylate salt of

[0606] (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A), t-butyl-4-(2-chloropyrimidin-5-yloxy)-butyrate (compound 1 B), and 3,5- bis(trifluoromethyl)benzyl bromide (compound 1 E). Compound 1A was coupled with compound 1B through a palladium-catalyzed reaction to produce a solution of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C), which was not isolated but directly reacted with excess ethyl chloroformate in the presence of pyridine to produce (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester, which was isolated as a crystalline mesylate salt (Compound 1 D). The crystalline mesylate salt, Compound 1 D was alkylated with 3,5 bis(trifluoromethyl)benzyl bromide (compound 1 E) under strongly basic conditions to produce a solution of (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-t-butoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-

[0607] SUBSTITUTE SHEET (RULE 26) ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (compound 1 F) in toluene. Compound IF was then subjected to an acidic cleavage of the tert-butyl ester to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]- [5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (compound 1). Compound 1 was then converted to compound 2, which is a solvate of (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (compound 2). Finally, compound 2 was converted to the amorphous hemicalcium salt (compound 3) and milled to the target particle size. Compound 2 is crystalline obicetrapib HCI and compound 3 is amorphous obicetrapib hemicalcium. An FT-IR spectrum of milled amorphous obicetrapib hemicalcium can be found in Figure 28. A solution -state1H- NMR spectrum consistent with chemical structure of obicetrapib hemicalcium can be found at Figure 29. Each of the steps in the manufacturing process for (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (compound 1), the intermediate HCI intermediate (compounds 2), and the corresponding amorphous calcium salt (compound 3) will be described in more detail in Examples 3.1-3.16 below. Examples 3.1 -3.3, 3.5, 3.7, 3.9, 3.11-3.12 describe a method for manufacturing steps in the process for preparing amorphous obicetrapib hemicalcium (compound 3); and Examples 3.4, 3.6, 3.8, 3.10 and 3.13 provide additional methods of preparing the compounds indicated. The methods in these examples sometimes represent more than one batch prepared of the indicated compounds made. Examples 3.14-3.15 describe methods for milling amorphous obicetrapib hemicalcium (compound 3); and Example 3.16 describes a method for preparing crystalline obicetrapib hemicalcium.

[0608] Example 3.1 - Preparation of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-

[0609] SUBSTITUTE SHEET (RULE 26) (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline

[0610] (compound 1A) (62 kg, 182 mol, 1 .00 equiv.) was added to a reaction vessel fitted with a reflux condenser along with toluene (375 L). The resulting slurry was stirred at 52°C and 1 M aqueous sodium hydroxide solution (322 L, 5.2 vol.) was added. The reaction mixture was stirred until all solid was dissolved and then cooled to 20°C. The stirring was halted and the reaction mixture was allowed to split into two phases. The bottom aqueous phase was drained, and an aqueous solution of sodium chloride (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. The stirring was once again halted and the reaction mixture was allowed to split into two phases. The bottom aqueous phase was drained, and deionized water (310 L, 5.0 vol.) was added. The reaction mixture was then stirred at 20°C for 30 minutes. The stirring was once again halted and the rection mixture was allowed to split into two phases. The bottom aqueous phase was separated. The resulting organic solution was then distilled under vacuum at an internal temperature of 65°C or less. Distillation was continued until a final visual volume of 4.0 volumes (250 L) was reached. The reaction vessel was then cooled to 20°C to provide a solution of (2R,4S)-4-amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline (Compound 1A - FREE BASE) in toluene with a small amount of water present. Compound 1A - FREE BASE was not isolated but used directly in Example 3.2.

[0611] Example 3.2 - Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2- yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Compound 1 C)

[0612] Additional toluene (107 L, 1.5 vol.) was added to the reaction vessel (“vessel A”) containing the (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Compound 1A - FREE BASE) in toluene with <1000 ppm water from the previous step. T-Butyl-4-(2-chloropyrimidin-5-yloxy)-butyrate (compound 1 B) (54.6 kg, 200 mol, 1.10 equiv.) was then added to vessel A along with f-BuOH (122 L, 1.55 vol.). The reaction mixture was stirred and sparged with nitrogen. Meanwhile, palladium acetate

[0613] 96

[0614] SUBSTITUTE SHEET (RULE 26) (410 g, 1.8 mol, 1 mol%) was added under nitrogen to a second reaction vessel (“vessel B”). (S)-BINAP (2.48 kg, 4.0 mol, 2.2 mol%) and toluene (107 L, 1.5 vol.) were further added to vessel B and the resulting mixture was stirred to form a red / orange Pd-BINAP solution. The orange / red Pd-BINAP solution of reaction vessel B was transferred to vessel A. K3PO4 (85 kg, 400 mol, 2.20 equiv.) was further added to vessel A and the resulting reaction mixture was heated to an Internal temperature of 72°C and stirred for at least 2 hours. The mixture was then cooled to 20°C, deionized water was carefully added (124 L) and the mixture was stirred for 30 minutes. Stirring was then halted and layers were allowed to split into two phases. The bottom aqueous phase was separated, and an aqueous solution of 1 M HCI was added (123 L) with stirring. After 30 minutes, the stirring was once again stopped and the layers were allowed to split into two phases. The bottom aqueous phase was separated, and an aqueous solution of sodium chloride (326 kg, 5.26 vol.) was added with stirring. After 30 minutes, the stirring was once again stopped and the layers were allowed to split into two phases. The bottom aqueous phase was separated, and deionized water (248 L, 4.0 vol.) was added with stirring. After 30 minutes, the stirring was once again stopped and the layers were allowed to split into two phases. The bottom aqueous phase was separated. The resulting reaction mixture was then treated with ethylenediamine (1 .60 kg, 0.15 equiv.) and stirred at 20°C for 80 minutes. The reaction mixture was then filtered over a charcoal cartridge and the filtrate returned to a clean vessel. Mixture was then distilled under a partial vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation in reactor (155 L) remained, then acetonitrile (394 L, 5.0 vol.) was added. The mixture was then distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation in reactor (155 L), then the contents were cooled to 20°C. The reaction vessel was then charged with acetonitrile (394 L, 5.0 vol. vol., to reach 11 volumes by visual observation (approximately 620 L)) to obtain (2R,4S)-4-[5-(3-t- butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline (compound 1C) dissolved in acetonitrile. Compound 1C was not isolated but used directly in Example 3.3. Example 3.3 - Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2- yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, as a Crystalline Mesylate Salt (Compound 1D)

[0615] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) in acetonitrile (approximately 620 L) was cooled to an internal temperature of <10°C and pyridine (72 L, 900 mol, 4.9 equiv.) was added. Ethyl chloroformate (136 L, 1428 mol, 7.84 equiv.) was then added through an addition funnel while keeping the internal temperature of the reactor contents <10°C. The internal temperature of the reaction mixture was then increased linearly to 20°C over the course of 3.5 hours. The mixture was then distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until approximately 2.50 volumes by visual observation (155 L). Isopropyl acetate (471 L, 6.6 vol.) was then added to the reaction vessel and distillation was continued under vacuum at an internal temperature of 60°C or less until roughly 2.50 volumes remained by visual observation (155 L). Then isopropyl acetate (471 L, 6.6 vol.), 1 M hydrochloric acid (307 L, 5.0 vol.), and 26% aqueous sodium chloride (63 L, 1.2 vol.) were added to the reaction vessel. The resulting mixture was stirred for 30 minutes, then separated into two phases. The bottom aqueous phase was separated, and saturated aqueous sodium bicarbonate solution (132 L, 2.3 vol.) was added. The resulting mixture was stirred for 30 minutes, then separated into two phases. The bottom aqueous phase was separated and the remaining mixture was distilled under vacuum and at 60°C or less to reach a total volume of roughly 4.0 volumes by visual observation (250 L) to obtain (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (corresponding free base of Compound 1 D) in isopropyl acetate based on the weight of the solution.

[0616] Additional isopropyl acetate (86 L, 1 .4 vol.) and methyl t-butylether (MTBE, 593 L, 9.6 vol) were added to (corresponding free base of Compound 1 D) in isopropyl

[0617] 98

[0618] SUBSTITUTE SHEET (RULE 26) acetate and the jacket temperature was set to 20°C. Methanesulfonic acid (MsOH, 17.6 kg, 1.0 equiv. based on mmol of compound (corresponding free base of Compound 1 D) was then added to the reaction mixture over 60 minutes. The resulting slurry was then agitated for 8 hours. The slurry was then filtered under vacuum at 20°C. The solid cake was then washed with 75 / 25 v / v isopropyl acetate (78 L, 1 .1 vol.) and methyl t-butyl ether solution (236 L, 2.8 vol.) then dried under vacuum and at 20°C to obtain isolated (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester, as a crystalline mesylate salt (Compound 1 D) with a yield of 74 %, based on the number of moles of compound 1A. The purity of the crystalline Compound 1 D obtained was > 99 %.

[0619] Example 3.4 - Additional Preparation of Compound 1C and Compound 1D

[0620] The preparation described below was generally used to prepare multiple batches of Compound 1C and Compound 1D. In some preparations, for example, seeding with Compound 1 D was done and others not as further discussed below.

[0621] Pd(OAc)2 and (S)-BINAP were dissolved in toluene and stirred to form the corresponding Pd-BINAP-complex (color change to red) (the “catalyst solution”). Toluene, Compound 1 B, Compound 1A and K3PO4 were added to the reactor and stirred. A target content for water is on the order of 6%. Catalyst solution was added to the reactor mixture, and the reaction mixture was heated up to 70-75 °C and stirred.

[0622] After washing with HCI, brine and water, subsequent phase separation, EDA and toluene were charged and the solution was stirred for approximately 90 min. The solution was passed via a cartridge loaded with activated carbon (Begerow, F-9120) for removing palladium. Afterwards, the solvent was switched from toluene to acetonitrile (MeCN) by distillation to obtain Compound 1 C.

[0623] To the Compound 1C solution, pyridine was added and cooled to lower than 10 °C prior to ethyl chloroformate addition. Ethyl chloroformate was dosed in one or two portions to the Compound 1C solution, while the temperature was controlled to NMT 10 °C. The reaction mixture was then stirred for approximately 1 hour at 17-27°C, converting Compound 1C to the free base of Compound 1 D (Compound 1 D-FB). A solvent switch from acetonitrile to isopropyl acetate (iPrOAc) was done by distillation, and the organic phase was washed with HCI (1 M), brine and aqueous NaHCOs (NaOH may also be used) followed by volume reduction by distillation. To the Compound 1 D-FB solution in iPrOAc, methanesulfonic acid (MsOH) and MTBE was added and stirred. In some cases, previously made seed crystals of Compound 1 D were added, but that is not required. Whether seeds are added or not, crystallization of Compound 1D followed. The solid product was filtered, washed with MTBE / iPrOAc (75 / 25) and dried on a filter.

[0624] Example 3.5 - Preparation of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- tbutoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline- 1-carboxylic acid ethyl ester (Compound 1F)

[0625] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester, as a crystalline mesylate salt (Compound 1 D) (42kg) and toluene (465 kg, 12.7 vol.) was added to a reaction vessel at a temperature of 5°C. Tetrabutylammonium hydrogensulfate (3.5 kg, 0.16 equiv.) and sodium tert-pentoxide (34.5 kg, 4.8 equiv.) were then added and the resulting reaction mixture was stirred for 10 minutes and degassed with nitrogen. 3,5- bis(trifluoromethyl)benzyl bromide (Compound 1 E) (28 kg, 1.41 equiv.) was then added to the reaction mixture and stirring was continued for 6.5 hours at 5°C. The reaction mixture was then treated with 1 N acetic acid solution (320 kg) and allowed to stir for approximately 30 minutes at 20°C. After which time, the stirring was stopped and the mixture was allowed to separate into two phases. The lower aqueous phase was discarded and the reaction mixture was concentrated under vacuum at an internal temperature 60°C or less until approximately 3.3 volumes (137 L) remained, to obtain a solution of 36.8 weight percent (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- tbutoxycarbonylpropoxy) pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline- 1-carboxylic acid ethyl ester (Compound 1 F) in toluene, based on the weight of the solution, 97% yield based on the number of moles of Compound 1 D).

[0626] 100

[0627] SUBSTITUTE SHEET (RULE 26) Example 3.6 - Additional Preparation of Compound 1F

[0628] Compound 1E was charged to a toluene solution containing Compound 1 D and tetrabutylammonium hydrogensulfate. Under cooling, sodium tert-pentoxide in toluene was added. The resulting reaction mixture was quenched with dilute acetic acid. The aqueous layer was separated and the product in the toluene layer was treated with charcoal and concentrated in vacuum (Compound 1 F.)

[0629] Example 3.7 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (Compound 1)

[0630] A solution of 37 wt.% (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- tbutoxycarbonylpropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro- 2Hquinoline- 1 -carboxylic acid ethyl ester (compound 1 F) in toluene (128.4 kg of the 37 wt.% solution, equivalent to 47.5 kg compound 1 F) was diluted to 32wt% with additional toluene and then mixed with acetic acid (253 kg, 5.33 wt.), and 6 M HCI (109.9 kg, 2.32 wt, prepared in situ with 66.1 kg of cone. HCI and 43.8 kg of water). The resulting reaction mixture was vigorously agitated and warmed to 48°C for 3 hours. The reaction mixture was then cooled to 21 °C, then n-heptane (159.8 kg, 3.36 wt.), acetonitrile (73.8 kg, 1.55 wt.) and water (170 kg, 3.58 wt.) were added. The resulting mixture was agitated for 34 minutes and then allowed to separate into two phases. The lower aqueous phase was then further treated with water (90 kg, 1.89 wt.), n-heptane (95 kg, 2.00 wt.), acetonitrile (38 kg, 0.80 wt.) and toluene (42 kg, 0.88 wt.) and once again agitated for 20 minutes before separating the organic phase and discharging the lower aqueous phase. The combined organic phases were then treated with water (240 kg, 5.05 wt.) and agitated for an additional 30 minutes before

[0631] 101

[0632] SUBSTITUTE SHEET (RULE 26) separating into two phases. The lower aqueous phase was discarded and the upper organic phase was treated with 5% w / w sodium citrate tribasic dihydrate (34 kg, 0.72 wt.) and water (205 kg, 4.32 wt.). The resulting mixture was vigorously agitated for 30 minutes and then allowed to separate into two phases before discarding the lower aqueous phase. The remaining organic phase was treated once again with water (240 kg, 5.05 wt.) and agitated for 30 minutes before allowing to separate into two phases and discharging the lower aqueous phase. The organic phase was then concentrated to approximately 3 volumes (approximately 149 L) in-vacuo maintaining an internal temperature of 50°C or less. The reaction mixture was diluted with cyclopentyl methyl ether (CPME, 250 kg, 5.26 wt.) and agitated. The solution was then concentrated to approximately 3 volumes (approximately 165 L) in-vacuo maintaining an internal temperature of 50°C or less. CPME (250 kg, 5.26 wt.) was then added and the mixture concentrated to approximately 2.5 volumes (approximately 124 L) in-vacuo, maintaining an internal temperature of 50°C or less to obtain a solution of 33.7 weight percent of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin- 2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (compound 1 , free base form) in cyclopentyl methyl ether (CMPE) having 1 weight percent toluene, less than 1 weight percent n-heptane, based on the weight of the solution.

[0633] Example 3.8 - Additional Preparation of Compound 1

[0634] Compound 1 F ( in solution in toluene) was mixed with acetic acid and 6 M aq. HCI. The biphasic mixture was intensively stirred at 45 - 50 °C and subsequently cooled to 20 °C. After addition of water, acetonitrile and n-Heptane, the mixture was extracted, and the layers were separated.

[0635] The aqueous layer of the first extraction was diluted with water and extracted with Acetonitrile, n-heptane, and toluene a second time. The two obtained organic extracts were combined. The organic phase was washed with water and 5% sodium citrate solution added so that the pH was > 3.5. A water wash was performed, and the organic layer was treated with activated charcoal. A solvent switch from toluene and n-Heptane to CPME was performed by repeated vacuum distillation and charging CPME to obtain Compound 1. Example 3.9 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester hydrochloride (Compound 2)

[0636] The 33.7 weight percent solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]- [5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (compound 1 , free base form, 115.6 kg, 59.2 mol) in cyclopentyl methyl ether (CPME) from the previous step was added to a clean reaction vessel under nitrogen with a jacket temperature of 22°C. After dilution with CPME (27.8 kg / 0.58 wt.) , n-heptane was then added (54.8 kg, 1.15 wt.) and the internal reaction temperature was increased to 39°C. 3.0 M HCI in CPME (17.6 kg, 0.37 wt.) was then added at a constant rate while maintaining an internal reaction temperature of 39°C. After the addition of HCI was complete, the internal temperature was increased to 52°C. Additional n-heptane was then added (133.2 kg, 2.80 wt.) at a constant rate while maintaining an internal reaction temperature of 51 °C. The reaction mixture was heated to 55°C and then it was cooled to 49°C. An aliquot of the reaction mixture was removed, cooled to 11 °C at a linear cooling rate until a slurry formed containing crystals of compound 2 in CPME / n-heptane (referred to herein as “seed crystal slurry”). A seed crystal slurry of compound 2 (169 g, 0.43 weight percent) in CPME / n-heptane was then added at 49°C and this temperature was held for 105 minutes. The opaque reaction mixture was then cooled to 11 °C over the course of 12 hours at a linear cooling rate. The reaction mixture was then filtered under vacuum at 11 °C to collect the solid wet HCI intermediate (compound 2). A mixture of CPME and n-heptane (56.6 kg CPME, 179 kg n-heptane) was then added to the reaction vessel and cooled to 11 °C. Half the mixture was then poured through the filter dryer as a chromatography wash. The second half was passed through the filter as a slurry wash.

[0637] 103

[0638] SUBSTITUTE SHEET (RULE 26) Compound 2 was not unloaded from the filter dryer but was further purified by recrystallization according to the following procedure.

[0639] Compound 2 in cyclopentyl methyl ether (CPME) (77.6 kg) was added into a filter dryer containing compound 2 and heated to 25°C. The dissolved compound 2 was then transferred to a reaction vessel with a reactor jacket temperature set at 25°C under nitrogen, and the internal temperature was increased to 38°C. 3.1 M HCI in CPME (6.4 kg) was added so that a total of 1 .07 equiv. HCI was achieved based on assay of compound 1 in compound 2 crude and assay of HCI in compound 2 crude. A / -Heptane was then added (139.4 kg and the internal reaction temperature was increased to 51 °C. A seed crystal slurry of compound 2 (291 g, 0.87 weight percent) in CPME / n-heptane was then added at 50°C and this temperature was held for 105 minutes. The opaque reaction slurry was then cooled to 11 °C over 12 hours at a linear cooling rate. The slurry was then filtered under vacuum at 9°C using a filter dryer. 20 vol.% of CPME in n-heptane (57.4 kg CPME, 180 kg n-heptane) was then added to the reaction vessel and cooled to 11 °C. Half the mixture was then poured through the filter dryer as a chromatography wash. The second half was passed through the filter dryer as a slurry wash. The wet filter cake was then dried in vacuo in steps of jacket temperature 25, 35, 46, 54°C to provide compound 2 in 64% yield (from compound 1 F) with 99.6 area% purity and residual solvents 0.3%w CPME and < 0.1 %w n- heptane.

[0640] Example 3.10 - Additional Preparation of Compound 2

[0641] Compound 1 in solution was further diluted with n-Heptane and heated to 40 °C. At this temperature approximately 3 M HCI in CPME (1.1 meq regarding Compound 1 F) were added. The solution was further heated to 48 - 53 °C and a second portion of n-Heptane was charged. The clear solution was cooled to 53 °C for optional seeding with Compound 2 seeding crystals (seeding is optional but preferred in a manufacturing context). If seeded, the solution is desaturated at 53°C and then cooled to 10°C over 12 hours.

[0642] A crystal curing procedure (a repeated heating and cooling cycle procedure) can be performed to improve the color of the resulting filtered Compound 2. The product suspension was filtered, washed once with cooled CPME I n-Heptane (20:80 vol) and once with cooled n-Heptane and then dried in vacuum. Example 3.11 - (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (Compound 3)

[0643] (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2- yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester hydrochloride (compound 2, 35.0 kg, 48.4 mol) was added to isopropyl acetate (IPAC, 214 kg, 6.11 wt.) to an inert reactor and stirred at 22°C to achieve dissolution. Deionized water (245 kg, 7.00 wt.) was added, the reaction mixture was stirred at 23°C for 35 minutes, then the stirring was stopped, the phases were separated, and the lower aqueous phase was removed. The process of adding deionized water (245 kg, 7 wt.), stirring, and removing the lower aqueous phase was repeated further 3 times. The organic phase was then concentrated under reduced pressure to approximately 71 L (approximately 2 vol.) maintaining an internal temperature of 55°C or less. Ethanol (115 kg, 3.29 wt.) was then added, and the reaction mixture was concentrated under reduced pressure to approximately 78 L (approximately 2 vol.) maintaining an internal temperature of 55°C or less. The process of adding ethanol (115 kg, 3.29 wt.) and concentrating was repeated twice more. The reaction mixture was then cooled to

[0644] 105

[0645] SUBSTITUTE SHEET (RULE 26) 25°C and subjected to a charcoal treatment via a cartridge. The cartridge was then rinsed with ethanol (100 kg, 2.86 wt.) and concentrated to 147 L (approximately 3.8 vol.) at 55°C or less in vacuo followed by addition of 35 L of EtOH (1 .0 vol.) to provide the free base form of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (compound 1) in ethanol. The 14% wt. NaOH solution (15.8 kg, 1.13 eq.) was then added to the reaction vessel containing compound 1 in ethanol maintaining a reaction temperature of 20°C. The reaction mixture was stirred at 20°C for 5 hours to achieve full conversion.

[0646] 34 % wt. Calcium chloride (aq.) (10.8 kg) was added to an inert reactor. Deionized water (336 L, 9.61 wt. relative to compound 1) and ethyl acetate (15 kg, 0.43 wt. relative to compound 1) was then added and the mixture was stirred for 30 minutes to provide “Solution B.”

[0647] Solution B was then cooled to 9°C with agitation. Solution A (see above) was then added via a filter to Solution B over 90 minutes, maintaining a temperature of 10°C. The Solution A vessel was then rinsed forward to solution B with additional ethanol (50 kg, 1 .43 wt. relative to compound 1). The resulting slurry was stirred for 1 hour at 9°C. The solids were then collected by filtration and rinsed with deionized water (2 x 175 kg, 5 wt. relative to compound 1). The solids were then dried in vacuo at 50°C for 21 hours to obtain 27.6 kg of amorphous obicetrapib hemicalcium (compound 3) with <1 weight percent water (77% yield, based the number of moles of compound 2). The compound 3 was reworked as described below in Example 3.12.

[0648] Example 3.12 - Rework of Compound 3

[0649] Compound 3 (27.6 kg) was dissolved in ethanol (55.2 kg 2 wt. relative to compound 3) at 45 - 48°C and subsequently cooled to 11 °C. The solution was filtered into a pre-cooled (approximately 10°C) mixture of an aqueous CaC solution (8.2 kg of 33-35 weight percent, 0.3 wt.), water (262 kg, 9.5 wt.) and ethyl acetate (12.6 kg, 0.46 wt.). The resulting suspension was filtered off and washed with water (2 x 5 wt., 138 kg per washing step) and the solid was dried in vacuo maintaining an internal temperature of 45°C or less for 23 hours to obtain 24.8 kg (91 % yield) of the amorphous hemicalcium salt of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3- carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1 -carboxylic acid ethyl ester (compound 3) with <1 weight percent water and a purity of 97.5 % wt. and >99.9 area%.

[0650] Example 3.13 - Additional Preparation of Compound 3

[0651] Compound 2 was neutralized and dissolved with aqueous NaOH in EtOH. The solution was filtered through activated carbon. Vacuum distillation was performed to concentrate the solution. Aqueous NaOH solution was dosed to obtain the sodium salt of Compound 1 in solution and for saponification of esters, which were formed in this and previous steps.

[0652] Subsequently, a mixture of aqueous CaC solution and EtOAc was prepared in a second vessel. The Na-salt of Compound 1 from the first vessel was then dosed into this mixture, whereby Compound 3 precipitated. Optionally, the suspension may be heated to NMT 25°C and subsequent cooled to 8°C. The solid Compound 3 was filtered off at 8 °C, washed with water and dried in vacuo.

[0653] Example 3.14 - Milling of Reworked Compound 3

[0654] Compound 3 was jet-milled using an 8-inch spiral mill. Feed rate, venturi pressure, and mill pressure were adjusted within the ranges listed below to allow the production of micronized compound 3 in compliance with particle size acceptance criteria (D90 = 6-15 pm). Feed rate: 17 - 20 kg / h Mill pressure: 20 PSI 1 1.4 bar Venturi pressure: 100 PSI 16.9 bar Process gas: Nitrogen Analytics: Mastersizer 3000.

[0655] Example 3.15 - Milling of Another Compound 3 Preparation

[0656] Particle size distribution was adjusted via micronization on a Spiral Jetmill, 8 inch Jet Mill, 8005 and KT4 LIW feeder to target parameters d90: 6 - 15 microns. Three samples were jet milled with the following results: d90: 8 microns, 8 microns, and 9 microns d50: 4 microns, 3 microns, and 4 microns d10: 2 microns, 1 micron, 1 micron Example 3.16 - Crystalline Obicetrapib Hemicalcium

[0657] 2g of amorphous obicetrapib hemicalcium was added to Acetonitrile (ACN) / Methyl tert butyl ketone (MIBK), 6:1 ratio at 200 mg / ml and the sample was heated to 50°C for 5 minutes, until all the solids dissolved. The sample was then placed in a water bath and cooled from 50°C to 5°C over 48 hours at 0.9°C / min. The samples were kept at 5°C for 3 days and then transferred to -20°C for 30 mins prior to isolation of solids. The solids were air dried for 2 hours prior to further characterization. The process resulted in the formation of crystalline obicetrapib hemicalcium.

[0658] Example 3.17- Polarized Light Microscopy (PLM)

[0659] Polarized light microscopic pictures were captured using a Nikon DS-Fi2 upright microscope at room temperature. Samples (2 mg) were mounted on a glass slide and covered with a drop of silicone oil with a cover slip on top of the sample for analysis. Samples were not protected from light.

[0660] Example 3.18 - X-ray Powder Diffraction (XRPD)

[0661] XRPD was performed with Panalytical X’Pert3Powder diffractometer using an incident beam of Cu radiation produced using an Empyran tube, fine focused source, on a silicon zero-background holder. Prior to the analysis, a silicon standard (NIST SRM 640d) was analyzed to verify that the Si 111 peak position is consistent with the NIST-certified position. Approximately 5 to10 mg of sample was placed on a silicon zero-background holder and flattened manually using an aluminum spatula to minimize difference in the overall sample height. The holder was then loaded on the instrument for analysis. The XRPD parameters used are listed in the following table.

[0662] Parameters for XRPD test

[0663] Parameters Reflection Mode

[0664] Cu, ka

[0665] Ka1 (A): 1.540598,

[0666] X-Ray wavelength

[0667] Ka2 (A): 1.544426,

[0668] Ka2 / Ka1 intensity ratio: 0.50

[0669] X-Ray tube setting 45 kV, 40 mA

[0670] Divergence slit Fixed 1 / 8°

[0671] Scan mode Continuous

[0672] Scan range

[0673] 3-40

[0674] (° 2TH)

[0675] Scan step time [s] 18.87

[0676] Step size

[0677] 0.0131

[0678] (° 2TH)

[0679] Test Time 4 min 15 s

[0680] Example 3.19 - X-ray Powder Diffraction Pattern

[0681] A PANalytical x-ray powder diffractometer was used with the following measurement conditions, with data acquisition by DataViewer and data evaluation by X’Pert High Score Plus: Example 3.20 - X-ray Powder Diffraction Pattern

[0682] The diffraction pattern for Figure 27 was measured using an Empyrean powder diffractometer in transmission mode from Malvern PANalytical. The sample was prepared as a thin layer between two Kapton foils and measured in continuous mode. The detector measures from approx. 2°20 to 4O°20. Peaks can be seen at signals at about 3.4°20, about 7.O°20 and about 9.2°20. The peak at about 5.6°20 is assigned to Kapton foil.

[0683] Example 3.21 - X-ray Powder Diffraction Methodology for Crystalline Obicetrapib HCI / Compound 1D

[0684] Diffraction patterns were measured using a Thermo Fisher Scientific ARL Equinox 1000 powder diffractometer. The diffractometer is equipped with a copper source and a germanium (111 ) monochromator providing monochromatic Cu Ka1 radiation, and a position sensitive gas-ionization detector.

[0685] Samples were measured in reflection mode using an Al sample holder without any further preparation (i.e., grinding). The detector measures over the entire angle range from approx. 2°20 to 120° 20 simultaneously; in the case of HCI obicetrapib, discernible signals useful for phase identification are seen up to approx. 45°20. The temperature in the diffractometer is typically around 30 °C during measurements.

[0686] Example 3.22 - X-ray Powder Diffraction Methodology for Crystalline Obicetrapib HCI

[0687] A Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Data collection parameters are shown in the following table.

[0688] X-Ray Powder Diffraction Parameters

[0689] Example 3.23 - FT-IR Spectroscopy

[0690] The FTIR spectrum a sample of amorphous obicetrapib hemicalcium is set forth in Figure 28. The FTIR spectrum was acquired using a Bruker Tensor 27 spectrometer with a Platinum ATR-QL-Diamond unit. The milled sample was placed onto the ATR unit without any pretreatment.

[0691] Example 3.24 -1H-NMR Spectroscopy

[0692] The NMR spectra of a solution made from a sample of amorphous obicetrapib hemicalcium is set forth in Figure 29. The NMR spectrum was obtained using a 600 MHz AVANCE NEO Bruker and in deuterated MeOH as solvent using tetramethylsilane (TMS) as the internal reference for chemical shift at 0.0 ppm. The spectral shifts are consistent with the chemical structure.

[0693] Example 3.25 - Modulated Differential Scanning Calorimetry (mDSC)

[0694] Samples with mDSC thermograms are set forth at Figure 36 and Figure 37 were prepared with Tzero aluminum pan with a pinhole. The ramp rate was from 25°C to 225°C at 2°C / min with modulation of ±0.5°C every 60 seconds. The Instrument used was a TA Q2500 DSC from TA Instruments. Example 3.26 - Modulated Differential Scanning Calorimetry (mDSC)

[0695] Using a TA Instruments DSC2500, the starting temperature was 25 °C and the sample was heated with 2 °C per minute, modulating by ± 0.5 °C every 60 seconds up to 225 °C. Tzero aluminium pans and Tzero hermetic lids with factory pinholes, which were additionally pierced through and enlarged, were employed for this testing. An integrated thermogram (displaying reversing heat flow) from the sample is included in Figure 37. The sample exhibited a glass transition with a Tg of approx. 111 °C.

[0696] Example 3.27 - Methods to Assess Stability

[0697] Stability study was conducted on crystalline and amorphous forms of obicetrapib at 70°C / 75% relative humidity (RH). The solids were placed into a 4.0 ml glass vial without caps (open condition) and stored at 70°C / 75% RH. Samples were pulled out of the stability chamber at day 1 (24 hours) and at 7-day time point. The solids were analyzed by XRPD for physical stability and by HPLC for chemical purity. The sample collected at each time point was dissolved in methanol before HPLC analysis. In order to minimize the effect of potential analyte adsorption on the filter, the initial 0.5 mL of supernatant passing through the filter was discarded prior to collecting sample for HPLC analysis. Purity for each sample was determined based on peak area percent and compared to the sample at T=0.

[0698] Example 3.28 - Method Used to Assess Kinetic Solubility in Biorelevant Media

[0699] Kinetic solubility study was conducted on crystalline and amorphous forms of obicetrapib in biorelevant media including Fed state simulated intestinal fluid (FeSSIF) at pH 5.0 and Fasted state simulated intestinal fluid (FaSSIF) at pH 6.5 at 37°C. The solids were magnetically stirred at 600 RPM in a shaker bath and samples were drawn with a 1.0 ml syringe at T= 15 mins, 30 mins, 60 mins, 90 mins and 120 mins. The solubility was measured using HPLC method provided by the client. The compound was added to 4.0 ml glass vials at approximately 20.0 mg / ml. Samples were agitated with a vortex mixer for about 5 minutes to ensure the presence of undissolved excess powder. The sample collected at each time point was centrifuged at 1200 RPM, filtered with 0.45pm Polytetrafluoroethylene (PTFE) filters and diluted with methanol before HPLC analysis. In order to minimize the effect of potential analyte adsorption on the filter, the initial 0.5 mL of supernatant passing through the filter was discarded prior to collecting sample for HPLC analysis. Example 4: phase 2 clinical trial (NOT 05421078)

[0700] NCT05421078 (A Dose-Finding Study in Japanese Patients to Evaluate the Effect of Obicetrapib as an Adjunct to Stable Statin Therapy) was designed as a placebo-controlled, double-blind, randomized phase 2 dose-finding study in Japanese patients to evaluate the efficacy, safety and tolerability of obicetrapib as an adjunct to stable statin therapy. A total of 108 patients were randomized to receive placebo, 2.5 mg obicetrapib, 5 mg obicetrapib or 10 mg obicetrapib for an 8-week treatment period.

[0701] The primary efficacy endpoint was the percent change from start to end of the treatment period in LDL-C for the treatment groups compared to the placebo group.

[0702] Like for the OCEAN study (see example 1 ), effects of treatment on lipophilic antioxidants (lutein, zeaxanthin and alpha-tocopherol) were assessed by determining the plasma levels of these lipophilic antioxidants before and after treatment. Results of these analyses are presented as figures 46-48. As can be derived from the results presented therein, treatment with 2.5, 5 or 10 mg obicetrapib increased the plasma levels of Lutein, zeaxanthin and alpha-tocopherol. These results indicate that treatment with 2.5 mg obicetrapib is already sufficient to induce a therapeutic effect.

[0703] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0704] Example 5: A Randomized, Parallel Trial to Assess the Effects of Obicetrapib on Macular Pigment Optical Density in Healthy Adults

[0705] Objective

[0706] The objective of this trial is to assess the effects of 16-weeks of obicetrapib administration, compared to a placebo product, on macular pigment optical density (MPOD) in healthy adults receiving background supplementation with 10 mg lutein and 2 mg zeaxanthin based on the Age Related Eye Disease Study-2 (AREDS2) supplement (AREDS2 Research Group, 2013; Davey, 2020). Participants

[0707] Participants will include men and women 18 to 75 years of age, inclusive, with body mass index (BMI) 25.0 to 39.9 kg / m2, inclusive. Participants will have no history of macular degeneration.

[0708] Study Drug

[0709] Individuals are randomly assigned to obicetrapib 10 mg or placebo every day for 16 weeks plus background supplementation with 10 mg lutein and 2 mg zeaxanthin based on the AREDS2 supplement.

[0710] Study Design

[0711] The trial is a randomized, parallel trial with five clinic visits: Screening (visit 1 , week -1 ), baseline (visit 2, week 0), two visits during treatment (visits 3 and 4; weeks 8 and 16), and one follow-up safety visit (visit 5; week 20).

[0712] At the screening visit, participants complete a practice MPOD assessment, which is measured by macular densitometer that uses heterochromatic flicker photometry (e.g., QuantifEye or Macular Metrics Corporation).

[0713] At visit 2 (week 0), participants are randomly assigned to receive obicetrapib 10 mg or placebo.

[0714] All participants take the lutein and zeaxanthin supplement. Individuals administer obicetrapib or placebo and the lutein / zeaxanthin supplement for a 16-week period during which they return to the clinic every 8 weeks.

[0715] At visits 2, 3, and 4, MPOD is measured, and samples are collected to measure serum levels of lutein and zeaxanthin, obicetrapib pharmacokinetic (PK) trough levels, and safety.

[0716] Participants return to the clinic for a safety follow-up visit (week 20) approximately 4 weeks after the end of the treatment period (week 16) for additional safety assessments.

[0717] Participants turn in 3-d day diet records at visits 2, 3, and 4 for assessment of dietary intake of lutein / zeaxanthin.

[0718] Primary Endpoint

[0719] • Change from baseline to end of treatment in MPOD Secondary Endpoints

[0720] • Change from baseline to end of treatment in serum lutein and zeaxanthin

[0721] • Fasting lipoprotein lipids o Total cholesterol (TC) o Low-density lipoprotein cholesterol (LDL-C) o High-density lipoprotein cholesterol (HDL-C) o Non-HDL-C (total-C minus HDL-C) o Triglycerides (TG)

[0722] Pharmacokinetic Endpoint

[0723] Blood samples for obicetrapib trough PK assessment will be collected at baseline (week 0), week 8, week 16, and week 20.

[0724] Safety and Tolerability Measurements

[0725] The safety and tolerability profile of obicetrapib 10 mg will be assessed by clinical laboratory assessments (chemistry and hematology), vital signs, physical examinations, urine pregnancy tests, and the incidence of adverse events (AEs). Collection of AEs will start following the signing of the ICF. Sample Size / Power Calculations Based on previous research, approximately 47 participants per group (94 total) will be evaluable for efficacy, assuming an approximate 10% drop out rate (Stringham, 2017). This sample size of at least 43 evaluable participants per group will provide more than 90% power to detect a 0.085 increase in MPOD (standard deviation 0.120) levels in the obicetrapib group compared to the placebo group at a 1 -sided significance level of 0.025.

[0726] Key Inclusion Criteria

[0727] 1 . Male or female 18 to 75 years of age, inclusive. i. A female participant may be enrolled if all 3 of the following criteria are met:

[0728] 1 . She is not pregnant;

[0729] 2. She is not breastfeeding; and

[0730] 3. She is do not plan to become pregnant during the study. ii. Females of childbearing potential (FOCBP) must have a negative serum [3- human chorionic gonadotropin ([3-hCG) pregnancy test. 1 . Note: Females are considered to be of childbearing potential if they meet 1 of the following criteria as documented by the principle investigator: a. Had a hysterectomy, oophorectomy, or tubal ligation at a minimum of 30 days prior to screening; or b. Are postmenopausal defined as > 1 year since their last menstrual period, and 1 ) are > 55 years of age, or 2) are < 55 years of age and have a follicle-stimulating hormone (FSH) level in the postmenopausal range. iii. FOCBP must agree to use an effective method of avoiding pregnancy and refrain from egg donation from screening to 90 days after the end of treatment visit (visit 4, week 16). Men whose partners are FOCBP must agree to use an effective method of avoiding pregnancy and refrain from sperm donation from screening to 90 days after the end of treatment visit (visit 4, week 16). Effective methods of avoiding pregnancy are contraceptive methods with a Pearl index of < 1 used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap) or a sterile sexual partner;

[0731] 2. Individual has BMI 25.0 to 39.9 kg / m2, inclusive.

[0732] 3. Individual is judged by the Investigator to be in generally good health on the basis of medical history and screening measurements.

[0733] 4. Individual has LDL-C level of > 70 mg / dL and < 190 mg / dL.

[0734] 5. Individual has TG levels < 400 mg / dL.

[0735] 6. If on statin therapy, dosing should be stable for 8 weeks prior to screening.

[0736] 7. Individual has a visual acuity > 20 / 60 in the study eye. The study eye will be the right eye unless there is a reason it cannot be used.

[0737] 8. Individual is willing and able to undergo the scheduled study procedures.

[0738] 9. Individual understands the study procedures and signs forms documenting informed consent to participate in the study and authorization for release of relevant protected health information to the study Investigator. Key Exclusion Criteria

[0739] 1. Individual is unable to provide a valid MPOD measurement during the practice session at the screening visit.

[0740] 2. Individual has an MPOD > 0.45 during the practice session at the screening visit. i. Note: The literature indicates that the average MPOD values in the United States is 0.34 ± 0.11 (range 0.21-0.57) (lannaccone, 2007). We selected 0.45 as the cut-off because this is 1 standard deviation above the mean, thus only 16% of the population would be above this level. MPOD values are nominal between 0.00 and 1.00.

[0741] 3. Individual has taken a supplement containing lutein, zeaxanthin, or meso- zeaxanthin within 3 months of the screening visit.

[0742] 4. Individual has taken a supplement or pharmaceutical product that may affect visual function within 3 months of the screening visit.

[0743] 5. Individual has a laboratory test result of clinical significance based on the judgment of the Principal Investigator or qualified designee.

[0744] 6. Individual has any visual pathology (e.g., macular degeneration, glaucoma, cataract, cataract surgery).

[0745] 7. Individual has a clinically significant medical condition (hepatic, renal, endocrine, cardiovascular, gastrointestinal, etc.) that, in the opinion of the Investigator, could interfere with the interpretation of the study results.

[0746] 8. Individual has used tobacco / nicotine products (e.g., cigarette smoking, vaping, chewing tobacco) within 12 months of visit 1 .

[0747] 9. Individual has uncontrolled hypertension (systolic blood pressure >180 mm Hg and / or diastolic blood pressure >100 mm Hg) at screening.

[0748] 10. Individual has a history of cancer in the prior 5 years, except non-melanoma skin cancer or carcinoma in situ of the cervix.

[0749] 11 . Individual has had a weight change of ± 4.5 kg (10 lbs.) in the previous 3 months.

[0750] 12. Individual has extreme sleeping (e.g., shift workers) or dietary habits (e.g., Atkins, vegan, very low carbohydrate diet).

[0751] 13. Individual has a history of bariatric surgery, is currently taking a weight loss drug, or is actively attempting to lose or gain body weight.

[0752] 14. Individual has taken a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor agent within 6 months prior to screening. 15. Individual has taken the following lipid-altering medications within 4 weeks prior to screening (bile acid sequestrants, fibrates, niacin (drug form), ezetimibe, bempedoic acid, or omega-3-ethyl ester drugs). Stable use of statins is permitted.

[0753] 16. Individual has taken any hypoglycemic medications within 4 weeks prior to screening including: insulin, sodium-glucose cotransporter-2 (SGLT2)-inhibitors, alpha glucosidase inhibitors, biguanides, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sulfonylureas, glucagon-like peptide-1 (GLP-1 ) receptor agonists, GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) modulators.

[0754] 17. Individual has unstable use (defined as initiation or change in dose) of anti hypertensive medications within 4 weeks prior to screening.

[0755] 18. Individual has used systemic corticosteroids within 4 weeks prior to screening.

[0756] 19. Individual has taken high-dose omega-3 fatty acid supplements [>900 mg / day of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or the combination] within 3 months prior to screening.

[0757] 20. Individual has signs or symptoms of an active infection of clinical significance or has taken antibiotics within 5 days prior to any visit (washout is permitted for re scheduling of the clinic visit).

[0758] 21. Individual has an allergy, sensitivity or intolerance to any components of obicetrapib, placebo, or the lutein / zeaxanthin supplement.

[0759] 22. Individual has been exposed to any other investigational products or devices within 30 days or 5 half-lives prior to screening, whichever is longer.

[0760] 23. Individual has a current or recent history (within 5 years prior to screening) or strong potential for illicit drug or excessive alcohol intake defined as >14 drinks per week (1 drink = 12 oz beer, 5 oz wine, or 1.5 oz hard liquor).

[0761] 24. Individual has received a blood transfusion or immunization within 3 months of the screening visit or has plans to receive them during the study period.

[0762] 25. Individual has a condition the Investigator believes would interfere with his or her ability to provide informed consent, comply with the study protocol, which might confound the interpretation of the study results or put the person at undue risk. Flow Chart (N = 94)

[0763] 1lf laboratory abnormalities during screening are considered by the Investigator to be transient, then the laboratory tests may be repeated once during screening. Retesting will be performed by the central laboratory, not the local laboratory. The Investigator’s rationale for retesting should be documented. If the retest result is no longer exclusionary, the participant may be enrolled.

[0764] 2A participant who is screened and does not meet the study eligibility criteria may be considered for rescreening upon Sponsor and / or Medical Monitor consultation and approval. Rescreened participants will be assigned a new study number. Rescreening should occur no less than 5 days after the last Screening Visit.

[0765] 3Signed informed consent must be obtained before any study-related procedures are performed.

[0766] 4Confirm the participant continues to meet the inclusion and exclusion criteria and assess any updates since the Screening Visit.5Weight and height (visit 1 only) will be measured at the Screening Visit and will be used to calculate body mass index. Measurement of weight at all visits should be performed with the participant dressed in indoor clothing, with shoes removed, and bladder empty.

[0767] 6Visual acuity will be measured using the ETDRS chart-based acuity test. Participants will stand at a standardized distance from the chart and read sequences of letters within a specified row using the study eye (typically right) only. Visual acuity > 20 / 60 is inclusionary.

[0768] 7Vital signs will consist of heart rate and triplicate blood pressure (systolic and diastolic) measurements. 8Serum FSH test for women who are < 55 years of age and are > 1 year since their last menstrual period. To be considered postmenopausal, serum FSH must be in the postmenopausal range.

[0769] 9ln the case of a positive or borderline serum p-hCG pregnancy test at Screening (Visit 1), the participant must not be enrolled in the study. In the case of a positive or borderline urine pregnancy test during the study, a serum p-hCG pregnancy test will be checked to confirm the pregnancy.

[0770] 10Urine dipstick will test for bilirubin, blood, glucose, ketone, leukocytes, nitrite, pH, protein, specific gravity, and urobilinogen. Urine sample collected for urine albumin-to-creatine ratio (UACR) and urine protein-to-creatine ratio (UPCR).

[0771] 11Inability to provide a valid MPOD measurement during the practice test at the screening visit is exclusionary. MPOD will be measured in the study eye, which will usually be the right eye.

[0772] 12A PK sample will be collected prior to study drug administration for trough measurements of obicetrapib in plasma at Visits 2, 3, and 4. At Visits 2 (Week 0) and Visit 3 (Week 8), participants will take study drug after a trough PK sample has been collected. PK samples will not be collected at the Visit 4 / ET visit for participants who discontinue study drug early or for participants who withdraw prematurely from the study.

[0773] 13A 3-d diet record will be used to assess background diets prior to study commencement and during weeks 8 and 16 of the treatment period. The diet records will include 2 weekdays and 1 weekend day or holiday.

[0774] ^Participants will have a 16-week treatment period starting at Visit 2 (Week 0) and continuing through completion of Visit 4 (end of Week 16). Participants will administer one 10 mg tablet of obicetrapib or placebo orally with water, with or without a meal, once daily (QD). On days with visits scheduled, obicetrapib will be administered with water following collection of all fasting blood samples. Participants will be asked to bring remaining tablets to Visit 3 (Week 8) for a reconciliation check, and then the remaining tablets will be returned to the participant. All bottles will be returned to the clinic at Visit 4 (Week 16).

[0775] Results

[0776] A positive effect on MPOD (increase from baseline) in the obicetrapib group, relative to the placebo group, provides further confirmation of the efficacy of obicetrapib in treating and / or preventing AMD, or symptoms thereof, especially in subjects that also receive background supplementation with 10 mg lutein and 2 mg zeaxanthin (in accordance with recommendations / guidelines based on AREDS2).

Claims

Claims1. A CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, for use in a method of treating, preventing or slowing down the progression of age-related macular degeneration (AMD) in a subject, the method comprising administering to the subject a therapeutically effective amount of the CETP inhibitor.

2. A CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from age-related macular degeneration, said method comprising the administration to said subject a therapeutically effective amount of the CETP inhibitor.

3. The compound for use according to claim 1 or 2, wherein the CETP inhibitor is amorphous obicetrapib hemicalcium.

4. The compound for use according to any one of the preceding claims, wherein the age-related macular degeneration is dry age-related macular degeneration.

5. The compound for use according to any one of the preceding claims, wherein the CETP inhibitor is administered orally.

6. The compound for use according to any one of the preceding claims wherein, the method increases the plasma level of pre-beta1 HDL.

7. The compound for use according to any one of the preceding claims wherein, the method increases the plasma level of lutein.

8. The compound for use according to any one of the preceding claims wherein, the method increases the level of lutein carried by HDL and / or pre-beta1 HDL.

9. The compound for use according to any one of the preceding claims wherein, the method increases the plasma level of zeaxanthin.

10. The compound for use according to any one of the preceding claims wherein, the method increases the level of zeaxanthin carried by HDL and / or pre-beta1 HDL.11 . The compound for use according to any one of the preceding claims wherein, the method increases the level of alpha-tocopherol carried by HDL and / or pre- betal HDL.

12. The compound for use according to any one of the preceding claims, wherein the method further comprises identifying the subject to be treated, such as by determining whether the subject has dry AMD, has GA secondary to dry AMD, or has GA secondary to AMD.

13. The compound for use according to any one of the preceding claims, wherein the dose of obicetrapib or pharmaceutically acceptable salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD)14. A method of treating, preventing or slowing down the progression of age-related macular degeneration (AMD) in a subject, the method comprising administering to the subject a therapeutically effective amount of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof.

15. A method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from age-related macular degeneration, said method comprising the administration to said subject a therapeutically effective amount of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof.

16. The method according to claim 1 or 2, wherein the CETP inhibitor is amorphous obicetrapib hemicaclium.

17. The method according to any one of the preceding claims, wherein the age- related macular degeneration is dry age-related macular degeneration.

18. The method according to any one of the preceding claims, wherein the CETP inhibitor is administered orally.

19. The method according to any one of the preceding claims wherein, the method increases the plasma level of pre-beta1 HDL.

20. The method according to any one of the preceding claims wherein, the method increases the plasma level of lutein.21 . The method according to any one of the preceding claims wherein, the method increases the level of lutein carried by HDL and / or pre-beta1 HDL.

22. The method according to any one of the preceding claims wherein, the method increases the plasma level of zeaxanthin.

23. The method according to any one of the preceding claims wherein, the method increases the level of zeaxanthin carried by HDL and / or pre-beta1 HDL.

24. The method according to any one of the preceding claims wherein, the method increases the level of alpha-tocopherol carried by HDL and / or pre-beta1 HDL.

25. The method according to any one of the preceding claims, wherein the method further comprises identifying the subject to be treated, such as by determining whether the subject has dry AMD, has GA secondary to dry AMD, or has GA secondary to AMD.

26. The method according to any one of the preceding claims, wherein the dose of obicetrapib or pharmaceutically acceptable salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD).

27. Use of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from age- related macular degeneration, said method comprising the administration to said subject of a therapeutically effective amount of the CETP inhibitor.

28. Use of a CETP inhibitor selected from the group consisting of obicetrapib and pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical composition for use in a method for treating, preventing or slowing down the progression of age-related macular degeneration in a subject, said method comprising the administration to said subject of a therapeutically effective amount of the CETP inhibitor.

Images