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 sector 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”). Dry AMD is more prevalent, accounting for approximately 90% of all AMD cases. It is characterized by degeneration of the macula and, with continued progression over multiple years, may ultimately result in atrophy of the central retina associated with central vision loss. By contrast, wet AMD, although less prevalent, is more likely to cause sudden, often substantial, loss of central vision.

[0007] Dry AMD is a significant cause of moderate and severe loss of central vision and is bilateral in most patients. 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 the presence of drusen (yellow crystalline deposits that develop within the macula) located under the RPE. 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 form of late stage dry AMD is associated with thinning and loss of function of the neural retinal located above the affected RPE. 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.

[0008] Although dry AMD is the most common form of the disease, 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.

[0009] Summary of the Invention

[0010] The present invention, generally speaking, provides methods of treating AMD and symptoms / conditions associated therewith using inhibitors of cholesterylester transfer protein (CETP).

[0011] AMD occurs when disruption of the macular surface, the photoreceptor-rich, central part of the retina, is infiltrated by focal or diffuse lipoprotein-rich deposits called drusen. 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. BrM is not a membrane per se, and therefore discoidal apoA-containing lipids (e.g., HDL) easily pass through BrM.

[0012] In the CETP Inhibition by Obicetrapib in Patients with Mild Dyslipidemia (TULIP) trial, which administered obicetrapib 1 , 2.5, 5, or 10 mg obicetrapib or matching placebo, HDL-C was increased by 75.8%, 124.3%, 157.1 %, and 179.0%, respectively. Compared with placebo, total, non-ABCA1 - and ABCA1 -specific cholesterol efflux capacity increased dose dependently by up to 38%, 72%, and 28%, respectively, at the 10 mg dose. Furthermore pre-beta1 HDL, which is the primary acceptor for ABCA1 -driven cholesterol efflux, was increased by 36% and pre-beta-2 HDL by 66%. These particle levels correlated significantly with the total and ABCA1 -driven cholesterol efflux increase. Similarly, the CETP inhibitor, evacetrapib, administered as monotherapy and combined with statins to dyslipidemia patients, was shown to significantly increase total and ABCA1 -specific cholesterol efflux capacity and pre- betal HDL. These results suggest that AMD is treatable with small discoidal HDL particles and, furthermore, because CETP inhibitors robustly increase pre-beta1 HDL, CETP inhibition might constitute a future therapy for the lipid deposition in AMD.

[0013] Thus, the body’s natural cholesterol homeostatic processes of reverse cholesterol transport and cholesterol efflux open a window of opportunity to treat cholesterol accumulation within the RPE and BrM. In fact, smaller, discoidal HDL which cross the RPE and BrM may be size matched for such a purpose. Therefore, therapies which increase pre-beta, small discoidal HDL, or directly deliver apoA to the site of cholesterol accumulation, provide a unique potential target to treat AMD especially because RPEs express SRB-1 receptors providing the natural ligand of apoA1 to initiate cholesterol removal. Research findings have suggested potential for treating retinal neovascularization with apoA1 . An in vitro investigation of primary human retinal vascular endothelial cells transfected with apoA1 -GFP recombinant lentiviral demonstrated that overexpression of apoA1 inhibited angiogenesis and suppressed placental growth factor expression.

[0014] Another potential benefit of raising HDL with CETP inhibition is to increase xanthophyll bioavailability, which may be protective against AMD. As documented by McGwin et al., a large body of preclinical and clinical evidence supports the idea that delivering lipophilic antioxidants to the macula may serve to protect against AMD. The Age-Related Eye Disease Study (AREDS and AREDS2) demonstrated that lutein / zeaxanthin supplementation reduced neovascular AMD. Given that HDL particles are the major carriers of xanthophylls, it is believed that increasing HDL may result in enhanced circulation of xanthophylls.

[0015] Analyses of samples from the OCEAN trial (NCT04770389), Randomized Study of Obicetrapib, optionally combined with Ezetimibe, has now demonstrated (see examples herein below) that 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 a CETP inhibitor increases, in particular, pre-beta1 HDL carried antioxidants (lutein, zeaxanthin and alpha-tocopherol), therefore constitute particularly strong support for the treatment of AMD using a CETP inhibitor.

[0016] 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, preferably Obicetrapib or a pharmaceutically acceptable salt 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 a CETP-inhibitor, preferably Obicetrapib or a pharmaceutically acceptable salt thereof.

[0017] In a further aspect, the invention provides a compound selected from the group consisting of CETP inhibitors, preferably Obicetrapib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, 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 a CETP-inhibitor. A further aspect of the invention provides a compound selected from the group consisting of CETP inhibitors, preferably Obicetrapib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, 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 a CETP-inhibitor.

[0018] Yet, a further aspect of the invention concerns the use of a CETP inhibitor, preferably Obicetrapib or a pharmaceutically acceptable salt 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, preferably Obicetrapib or a pharmaceutically acceptable salt 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.

[0019] Other aspects of the invention concern pharmaceutical compositions, preferably in unit dosage form, comprising a CETP inhibitor, preferably Obicetrapib or a pharmaceutically acceptable salt 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 self-administer said unit dosage forms in order to treat and / or prevent age-related macular degeneration, especially dry age- related macular degeneration.

[0020] 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.

[0021] Definitions

[0022] 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.

[0023] 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.

[0024] The term “patient” refers to a human subject.

[0025] 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. 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.

[0026] 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.

[0027] Other interpretational conventions

[0028] 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.

[0029] 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. Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] Detailed description of the Invention

[0034] CETP Inhibitors

[0035] The present invention, broadly stated, concerns the use of 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. In specific embodiments, the CETP inhibitor is anacetrapib, evacetrapib, MK-8262, or dalcetrapib, or a pharmaceutically acceptable salt thereof, especially obicetrapib or a pharmaceutically acceptable salt thereof. “Evacetrapib”, also known as LY2484595 and CASH 86486-62-3, refers to trans-4-({(5S)-5-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(2-methyl-2H-tetrazol-5- yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1 H-benzazepin-1 -yl}methyl) cyclohexanecarboxylic acid, which is the compound of formula (I). Evacetrapib, as well as methods of making and using the compound, are described in WO2011002696, the disclosure of which is incorporated herein by reference in its entirety.

[0036] [Formula I]

[0037] “Anacetrapib”, also known as MK 0859 and CAS 875446-37-0, refers to ((4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-5'-(propan-2-yl)-4- (triluoromethyl)[1 , 1 '-biphenyl]-2-yl]methyl}-4-methyl-1 ,3-oxazolidin-2-one), which is the compound of formula (II). Anacetrapib, as well as methods of making and using the compound, are described in W02006 / 014413, W02006 / 014357, W02007005572, the disclosures of which are incorporated herein by reference in their entireties. “Dalcetrapib” refers to thioisobutyric acid S-(2-{[1 -(2-ethyl-butyl)- cyclohexanecarbonyl]-amino}-phenyl) ester, also known as S-[2-([[1-(2-ethylbutyl)- cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate, or dalcetrapib, which is a compound of formula (III). S-[2-([[1 -(2-ethylbutyl)cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate, as well as methods of making and using the compound, are described in WO 2007 / 051714, WO 2008 / 074677 or WO2011 / 000793, the disclosures of which are incorporated herein by reference in their entireties.

[0038] [Formula III]

[0039] “MK-8262” refers to 4-(5-(2-((1 R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-3- oxohexahydropyrrolo[1 ,2-c]oxazol-5-yl)-4-(trifluoromethyl)phenyl)-6-methoxypyridin- 3-yl)-3-methylbenzoic acid, or MK-8262, which is a compound of formula (IV).

[0040] [Formula IV]

[0041] “Obicetrapib”, formerly known as TA-8995, refers to (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, the compound according to formula (V). 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.

[0042] Methods of treatment

[0043] In one aspect, the present invention relates to methods of treating a subject with AMD, especially dry AMD, comprising administering to the subject a 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.

[0044] 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 a 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.

[0045] 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 a 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.

[0046] 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 a 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.

[0047] 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 a 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.

[0048] In one aspect, the present invention relates to methods of reversing the formation of drusen in a subject, comprising administering to the subject a 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.

[0049] In one aspect, the present invention relates to methods of reducing the amount of drusen in a subject, comprising administering to the subject a 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.

[0050] In one aspect, the present invention relates to methods of reducing the formation of drusen in a subject, comprising administering to the subject a 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.

[0051] 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.

[0052] 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 a 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.

[0053] In one aspect, the present invention relates to methods of treating a subject with GA secondary to AMD, comprising administering to the subject a 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.

[0054] 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 a 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. 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 a 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.

[0055] 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 a 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.

[0056] 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 a 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.

[0057] 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 a 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.

[0058] 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 a 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.

[0059] 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 a 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.

[0060] 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 a 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.

[0061] 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 a 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.

[0062] 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 a 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.

[0063] 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 a 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.

[0064] 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 a 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.

[0065] 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 a 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.

[0066] 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 a 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.

[0067] 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 a 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] As will be apparent to those skilled in the art, based on the present teachings, the methods of the invention further comprises 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.

[0073] Administration and Dosage

[0074] In various embodiments, the CETP inhibitor is administered orally.

[0075] In typical embodiments, the CETP inhibitor is administered as a tablet for oral administration.

[0076] In typical embodiments, the CETP inhibitor is obicetrapib or a pharmaceutically acceptable salt thereof. 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, 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. 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).

[0077] In some embodiments, the dose of the CETP inhibitor is equipotent to 10-20 mg of obicetrapib by mouth per day (10-20 mg po QD). In some specific embodiments, the dose of the CETP inhibitor 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.

[0078] 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,

[0079] 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,

[0080] 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,

[0081] 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,

[0082] 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.

[0083] 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,

[0084] 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,

[0085] 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,

[0086] 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,

[0087] 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,

[0088] 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,

[0089] 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,

[0090] 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. In some specific embodiments, the dose of the CETP inhibitor is equipotent to 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,

[0091] 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9,

[0092] 13.0, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1 , 14.2, 14.3, 14.4,

[0093] 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1 , 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9,

[0094] 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,

[0095] 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1 , 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9,

[0096] 19.0, 19.1 , 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1 , 20.2, 20.3, 20.4,

[0097] 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1 , 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1 , 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1 , 23.2, 23.3, 23.4,

[0098] 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1 , 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9,

[0099] 25.0, 25.1 , 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1 , 26.2, 26.3, 26.4,

[0100] 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1 , 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9,

[0101] 28.0, 28.1 , 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1 , 29.2, 29.3, 29.4,

[0102] 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg po QD of obicetrapib.

[0103] 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,

[0104] 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 ,

[0105] 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

[0106] 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 ,

[0107] 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,

[0108] 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 ,

[0109] 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,

[0110] 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 ,

[0111] 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,

[0112] 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 ,

[0113] 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,

[0114] 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 ,

[0115] 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,

[0116] 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.

[0117] In some specific embodiments, the daily dose of the CETP inhibitor is equipotent to 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,

[0118] 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,

[0119] 12.8, 12.9, 13.0, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1 , 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15,1 , 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,

[0120] 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,

[0121] 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1 , 18.2, 18.3, 18.4. 18.5, 18.6, 18.7,

[0122] 18.8, 18.9, 19.0, 19.1 , 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1 , 20.2,

[0123] 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,

[0124] 21.8, 21.9, 22.0, 22.1 , 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1 , 23.2,

[0125] 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1 , 24.2, 24.3, 24.4, 24.5, 24.6, 24.7,

[0126] 24.8, 24.9, 25.0, 25.1 , 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1 , 26.2,

[0127] 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1 , 27.2, 27.3, 27.4, 27.5, 27.6, 27.7,

[0128] 27.8, 27.9, 28.0, 28.1 , 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1 , 29.2,

[0129] 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, or 30.0 mg of obicetrapib po.

[0130] 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.

[0131] 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.

[0132] In specific embodiments, tablets are round, 6 mm in diameter, white film-coated tablets, containing 5 mg of obicetrapib as the calcium salt. In 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.

[0133] In typical embodiments, anacetrapib, or pharmaceutically acceptable salt thereof is administered as a tablet for oral administration. In various embodiments, the dose of anacetrapib or pharmaceutically acceptable salt thereof is 10-250 mg by mouth per day (10-250 mg po QD). In some embodiments, the dose of the CETP inhibitor is 10-40 mg by mouth per day (10-40 mg po QD). In some embodiments, the dose of the CETP inhibitor is 40-200 mg by mouth per day (40-250 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 10 mg po QD, 20 mg po QD, 30 mg po QD, 40 mg po QD, 45 mg po QD, 50 mg po QD, 55 mg po QD, 60 mg po QD, 65 mg po QD, 70 mg po QD, 75 mg po QD, 80 mg po QD, 85 mg po QD, 90 mg po QD, 95 mg po QD, 100 mg po QD, 105 mg po QD, 110 mg po QD, 115 mg po QD, 120 mg po QD, 125 mg po QD, 130 mg po QD, 135 mg po QD, 140 mg po QD, 145 mg po QD, 150 mg po QD, 155 mg po QD, 160 mg po QD, 165 mg po QD, 170 mg po QD, 175 mg po QD, 180 mg po QD, 185 mg po QD, 190 mg po QD, 195 mg po QD, 200 mg po QD, 210 mg po QD, 220mg po QD, 230 mg po QD, 240 mg po QD or 250 mg po QD. In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and the 10-250 mg total daily dose, or I Q- 40 mg total daily dose, or 40-250 mg total daily dose, is administered as a plurality of divided doses. In various embodiments, anacetrapib is administered as a tablet. In some embodiments, the tablet comprises 5mg, 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250mg of anacetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains anacetrapib as the calcium salt. In particular embodiments, the tablet contains 40 mg anacetrapib as a calcium salt.

[0134] In typical embodiments, evacetrapib, or pharmaceutically acceptable salt thereof is administered as a tablet for oral administration. In various embodiments, the dose of evacetrapib or pharmaceutically acceptable salt thereof is 100-300 mg by mouth per day (100-300 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 100 mg po QD, 105 mg po QD, 110 mg po QD, 115 mg po QD, 120 mg po QD, 125 mg po QD, 130 mg po QD, 135 mg po QD, 140 mg po QD, 145 mg po QD, 150 mg po QD, 155 mg po QD, 160 mg po QD, 165 mg po QD, 170 mg po QD, 175 mg po QD, 180 mg po QD, 185 mg po QD, 190 mg po QD, 195 mg po QD, 200 mg po QD, 205 mg po QD, 210 mg po QD, 215 mg po QD, 220 mg po QD, 225 mg po QD, 230 mg po QD, 235 mg po QD, 240 mg po QD, 245 mg po QD, 250 mg po QD, 255 mg po QD, 260 mg po QD, 270 mg po QD, 280 mg po QD, 290 mg po QD, or 300 mg po QD. In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and the 100-300 mg total daily dose is administered as a plurality of divided doses. In various embodiments, evacetrapib is administered as a tablet. In some embodiments, the tablet comprises 5mg, 10 mg, 20 mg, 40 mg, 50 mg, 60mg, 70mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130mg, 140 mg, 150mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg of evacetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains evacetrapib as the calcium salt. In particular embodiments, the tablet contains 130 mg evacetrapib as a calcium salt.

[0135] In typical embodiments, MK-8262, or pharmaceutically acceptable salt thereof is administered as a tablet for oral administration.

[0136] In typical embodiments, torcetrapib, or pharmaceutically acceptable salt thereof is administered as a tablet for oral administration.

[0137] In typical embodiments, dalcetrapib, or pharmaceutically acceptable salt thereof is administered as a tablet for oral administration. In various embodiments, the dose of dalcetrapib or pharmaceutically acceptable salt thereof is 600-1500 mg by mouth per day (600-1500 mg po QD). In some specific embodiments, the dose of the CETP inhibitor is 610 mg po QD, 620 mg po QD, 630 mg po QD, 640 mg po QD, 650 mg po QD, 660 mg po QD, 670 mg po QD, 680 mg po QD, 690 mg po QD, 700 mg po QD, 710 mg po QD, 720 mg po QD, 730 mg po QD, 740 mg po QD, 750 mg po QD,

[0138] 760 mg po QD, 770 mg po QD, 780 mg po QD, 790 mg po QD, 800 mg po QD, 810 mg po QD, 820 mg po QD, 830 mg po QD, 840 mg po QD, 850 mg po QD, 860 mg po QD, 870 mg po QD, 880 mg po QD, 890 mg po QD, 900 mg po QD, 910 mg po QD,

[0139] 920 mg po QD, 930 mg po QD, 940 mg po QD, 950 mg po QD, 960 mg po QD, 970 mg po QD, 980 mg po QD, 990 mg po QD, 1000 mg po QD, 1010 mg po QD, 1020 mg po QD, 1030 mg po QD, 1040 mg po QD, 1050 mg po QD, 1060 mg po QD, 1070 mg po QD, 1080 mg po QD, 1090 mg po QD, 1100 mg po QD, 1110 mg po QD, 1120 mg po QD, 1130 mg po QD, 1140 mg po QD, 1150 mg po QD, 1160 mg po QD, 1170 mg po QD, 1180 mg po QD, 1190 mg po QD, 1200 mg po QD, 1210 mg po QD, 1220 mg po QD, 1230 mg po QD, 1240 mg po QD, 1250 mg po QD, 1260 mg po QD, 1270 mg po QD, 1280 mg po QD, 1290 mg po QD, 1300 mg po QD, 1310 mg po QD, 1320 mg po QD, 1330 mg po QD, 1340 mg po QD, 1350 mg po QD, 1360 mg po QD, 1370 mg po QD, 1380 mg po QD, 1390 mg po QD, 1400 mg po QD 1410 mg po QD, 1420 mg po QD, 1430 mg po QD, 1440 mg po QD, 1450 mg po QD, 1460 mg po QD, 1470 mg po QD, 1480 mg po QD, 1490 mg po QD, or 1500 mg po QD. In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and the 600-1500 mg total daily dose is administered as a plurality of divided doses. In various embodiments, dalcetrapib is administered as a tablet. In some embodiments, the tablet comprises 5mg, 10 mg, 20 mg, 40 mg, 50 mg, 60mg, 70mg, 80 mg, 90 mg, 100 mg, 1 10 mg, 120 mg, 130mg, 140 mg, 150mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg,

[0140] 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg,

[0141] 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg,

[0142] 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg,

[0143] 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 1350 mg, 1360 mg, 1370 mg, 1380 mg, 1390 mg, 1400mg, 1410 mg, 1420 mg, 1430 mg, 1440 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, or 1500mg of dalcetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains dalcetrapib as the calcium salt. In particular embodiments, the tablet contains 600 mg dalcetrapib as a calcium salt.

[0144] 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.

[0145] 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.

[0146] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof 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-beta1 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. 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.

[0147] As will be apparent to those skilled in the art, based on the present teachings, the methods of the invention further comprises 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.

[0148] Biomarkers

[0149] 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.

[0150] 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 levellevel 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.

[0151] 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. 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] Pharmaceutical Kits

[0156] 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 a 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.

[0157] 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 a 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 a CETP inhibitor and ezetimibe.

[0158] 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. Other Aspects of the Present Invention

[0159] 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.

[0160] 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.

[0161] 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.

[0162] Description of the Figures

[0163] 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 .

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] Figure 7: HDL vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0170] Figure 8: triglycerides vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0171] Figure 9: Plasma tocopherol vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0172] Figure 10: Tocopherol in HDL vs. Pre-beta1 HDL at baseline in all participants (OCEAN study).

[0173] Figure 11 : Plasma Zeaxanthin vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0174] Figure 12: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0175] Figure 13: Tocopherol in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib and obicetrapib+ezetimibe treatment groups (OCEAN study).

[0176] Figure 14: Plasma Zeaxanthin vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0177] Figure 15: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0178] Figure 16: Plasma tocopherol vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0179] Figure 17: Tocopherol in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0180] Figure 18: Tocopherol in non-HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0181] Figure 19: Zeaxanthin in HDL vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (OCEAN study).

[0182] Figure 20: Pre-beta1 HDL plasma levels at baseline (V2) and after treatment (V4) in placebo group (ROSE2 study).

[0183] Figure 21 : Pre-beta1 HDL plasma levels at baseline (V2) and after treatment (V4) in obicetrapib treatment group (ROSE2 study).

[0184] Figure 22: Plasma tocopherol vs. Pre-beta1 HDL at baseline in all participants (ROSE2 study). Figure 23: Plasma tocopherol vs. Pre-beta1 HDL at baseline in the obicetrapib treatment group (ROSE2 study).

[0185] Figure 24: Plasma tocopherol vs. Pre-beta1 HDL after treatment in the obicetrapib treatment group (ROSE2 study).

[0186] Examples

[0187] Example 1: phase 2 clinical trial (OCEAN; NCT04770389)

[0188] 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.

[0189] 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.

[0190] 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 )). Table 1. Lipophilic antioxidants measured at baseline and after treatment

[0191] Table 2 below shows the results of the Pre-beta1 HDL analyses. Further results of antioxidant analyses are presented as figures 1 -19.

[0192] Table 2: Pre-beta1 HDL (Ocean trial samples)

[0193] 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.

[0194] Example 2: phase 2b clinical trial (R0SE2; NCT05266586)

[0195] 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. 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.

Claims

Claims1 . A compound selected from the group consisting of CETP inhibitors, 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 compound selected from the group consisting of CETP inhibitors, 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 obicetrapib or a pharmaceutically acceptable salt thereof.

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 compound selected from the group consisting of CETP inhibitors.

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 compound selected from the group consisting of CETP inhibitors.

16. The method according to claim 1 or 2, wherein the CETP inhibitor is obicetrapib or a pharmaceutically acceptable salt thereof.

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 compound selected from the group consisting of CETP inhibitors 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 comprisingthe administration to said subject of a therapeutically effective amount of the CETP inhibitor.

28. Use of a compound selected from the group consisting of CETP inhibitors 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.

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