Obicetrapib for the treatment of dementias

Abstract

Methods are also presented for favorably affecting biomarkers involved with neurodegeneration and inflammation in plasma and for lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof. Additionally, methods are presented for slowing progression of neurodegenerative disease in a subject who has or is at risk of developing a neurodegenerative disease. The methods comprise administering a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the subject.

Description

Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-AOBICETRAPIB FOR THE TREATMENT OF DEMENTIAS1. BACKGROUND OF THE INVENTION

[0001] Neurodegenerative diseases, and particularly neurodegenerative diseases that result in cognitive impairment and dementia, are a serious burden on patients, their families, and society. Alzheimer’s Disease (AD) and other dementias have been calculated to have cost 2.55 million disability-adjusted life-years (DALYs) in the United States in 2017. See “Burden of neurological disorders across the US from 1990-2017,” JAMA Neurol. 78(2): 165- 176 (2021). The burden is expected to increase as the median age of the population increases.

[0002] Despite the need for effective treatments, no disease-modifying treatments capable of slowing progression of neurodegenerative diseases, particularly degenerative diseases that result in cognitive impairment and dementia, have been proven to be effective. In addition, patients with cognitive impairment present compliance challenges for treatments that must be administered chronically, and / or administered using a patient-controlled device. Treatments that require parenteral administration impose additional impediments. There is, therefore, a need for disease-modifying treatments capable of slowing progression of neurodegenerative diseases, particularly degenerative diseases that result in cognitive impairment and dementias, and that can be administered orally.2. SUMMARY OF THE INVENTION

[0003] The s4 allele of the apolipoprotein E gene (APOE4) has long been known to be a risk factor for late-onset Alzheimer’s disease (AD). Although the mechanism by which this genotype increases AD risk remains unclear, the strength of this association positions lipoprotein metabolism as central to the pathology of AD.

[0004] Obicetrapib, a potent inhibitor of cholesteryl esterase transfer protein (CETP), has previously been shown to increase HDL levels and ApoE levels in plasma. In a human clinical trial in subjects with Early Alzheimer’s Disease who are hetero / homozygote Apo-E4 allele carriers (NCT05161715), we have now demonstrated that obicetrapib has significant effects on lipoproteins and lipids in the central nervous system. In cerebrospinal fluid (CSF), we observed reduction in levels ApoE4, reduction in ApoE4ZE3 ratio in E4ZE3 heterozygotes, reduction in ApoJ (Clusterin) levels, and reductions of 11% and 12%, respectively, in two oxysterols, 24-hydroxycholesterol and 27-hydroxycholesterol. In the peripheral circulation,-1- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A we observed an increase in levels of total ApoE, increase in the ratio of AP42 / 40, and reduction in levels of the oxysterols 24- hydroxy cholesterol and 27-hydroxy cholesterol. These results provide objective evidence that obicetrapib administration improves the pathophysiology underlying Alzheimer’s Disease in human ApoE4 allelic carriers.

[0005] In addition, we performed a large c / .s-Mendelian randomization analysis to confirm biological consequences of lower CETP activity. After confirming and extending known beneficial effects of lower CETP levels on blood lipids, as well as protective effects on cardiovascular diseases such as CHD, AAA, HF, and small vessel stroke, we explored potential associations with dementia-related traits. The analysis noted protective effects of lower CETP concentrations with Lewy Body Dementia (LBD), which was most pronounced \n APOE- A carriers. The effects of lower CETP concentration were replicated by performing cv.s-MR. weighting CETP variants by their association on Apo-Al and Apo-B concentration. The protective effect on LBD was further supported by a protective effect of lower CETP concentration on dementia in people with Parkinson’s Disease (PD), reflecting underlying shared etiology with Lewy Body Dementia.

[0006] Accordingly, in a first aspect, a method is provided for lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof. The method comprises administering to the subject obicetrapib or pharmaceutically acceptable salt thereof in an amount effective to reduce ApoE4 concentration in the CNS.

[0007] In a second aspect, a method is provided for slowing progression of neurodegenerative disease in a subject who has or is at risk of developing a neurodegenerative disease. The method comprises administering a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof to the subject. In particular embodiments, the subject has, or is at risk for, Lewy Body Dementia or dementia of Parkinson’s disease (PD).

[0008] In another aspect, a method is provided for preventing the onset of neurodegenerative disease in a subject who has not been diagnosed with a neurodegenerative disease.

[0009] In some embodiments, the obicetrapib pharmaceutically acceptable salt thereof is a calcium salt. In some embodiments it is amorphous obicetrapib hemicalcium.

[0010] In some embodiments, obicetrapib or salt thereof is administered orally. In various embodiments, obicetrapib is administered once per day. In certain embodiments, the-2- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A dose is 5-25 mg po QD of obicetrapib or salt thereof, such as 5 mg po QD, 10 mg po QD, 15 mg po QD, 20 mg po QD, or 25 mg po QD.

[0011] In some embodiments, obicetrapib or salt thereof is administered once daily for at least 8 weeks, at least 6 months, at least 12 months, or at least 24 months.

[0012] In some embodiments, the subject has been diagnosed with or is at risk for Alzheimer’s Disease (AD), Lewy Body dementia (LBD), Parkinson’s disease (PD), vascular or multi-infarct dementia, or frontotemporal dementia (FTD), or Multiple Sclerosis (MS). In particular, embodiments, the subject has been diagnosed with or is at risk for developing AD. In specific embodiments, the subject has been diagnosed with AD. In certain embodiments, the subject has at least one ApoE4 allele or two ApoE4 alleles. In specific embodiments, the method comprises the prior step of detecting ApoE4 alleles in the subject.

[0013] In some embodiments, the subject has been diagnosed with mild cognitive impairment (MCI).

[0014] In some embodiments, the subject has been determined, prior to treatment, to have at least one of (i) decreased levels of Ap42 in plasma, (ii) increased levels of Ap40 in plasma, (iii) decreased ratio of AP42 / AP40 in plasma, (iv) increased levels of neurofilament light (NfL) in plasma, and (v) increased levels of neurogranin in plasma, as compared to a healthy control population that does not have and that is not at elevated risk for neurodegenerative disease.

[0015] In some embodiments, the subject has been determined, prior to treatment, to have at least one of (i) decreased levels of Ap42 in CSF, (ii) increased levels of Ap40 in CSF, (iii) decreased ratio of AP42 / AP40 in CSF, (iv) increased levels of neurofilament light (NFL) in CSF, and (v) increased levels of neurogranin in CSF, as compared to a healthy control population that does not have and that is not at elevated risk for neurodegenerative disease.

[0016] In some embodiments, the subject has been determined, prior to treatment, to have elevated levels of phosphorylated tau-181, phosphorylated tau-217 or any other phosphorylated tau fragment and / or abnormal patterns of Tau based on Tau PET imaging.

[0017] In some embodiments, the dose of obicetrapib or salt thereof is sufficient to prevent at least one of (i) further decrease in levels of Ap42 in plasma, (ii) further increase in levels of AP40 in plasma, (iii) further decrease in ratio of AP42 / AP40 in plasma, (iv) further increase in levels of neurofilament light (NFL) in plasma, and (v) further increase in levels of neurogranin in plasma, as compared to levels immediately prior to start of treatment.-3- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A

[0018] In some embodiments, the dose of obicetrapib or salt thereof is sufficient to prevent at least one of (i) further decrease in levels of Ap42 in CSF, (ii) further increase in levels of AP40 in CSF, (iii) further decrease in ratio of AP42 / AP40 in CSF, (iv) further increase in levels of neurofilament light (NFL) in CSF, and (v) further increase in levels of neurogranin in CSF, as compared to levels immediately prior to start of treatment.

[0019] In typical embodiments, obicetrapib is administered as a tablet. In certain embodiments, the tablet comprises obicetrapib as the calcium salt.3. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0021] FIG. 1 is an illustration of alternative immunoaffinity-mass spectrometry approaches employed in determination of ApoE4 / E3 ratios in the clinical trial described in Examples 1 and 2.

[0022] FIGs. 2A-2B are line graphs. FIG. 2A is a line graph showing the effect of 10 mg obicetrapib on plasma ApoE4ZE3 ratios in 5 human subjects in the clinical trial described in Examples 1 and 2. FIG. 2B is a line graph showing the effect of 10 mg obicetrapib on cerebrospinal fluid (CSF) ApoE4ZE3 ratios in subjects in the clinical trial described in Examples 1 and 2.

[0023] FIGs. 3A-3C are plots displaying absolute concentrations of total ApoE in the cerebrospinal fluid (CSF) of healthy control subjects, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6) measured by detecting three different ApoE peptides (Peptide 1-3). FIG. 3A shows the absolute concentration of Peptide 1 in healthy controls, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6). FIG. 3B shows the absolute concentration of Peptide 2 in healthy controls, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6). FIG. 3C shows the absolute concentration of Peptide 3 in healthy controls, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6).

[0024] FIGs. 4A-4C are plots displaying comparisons of absolute concentrations of clusterin (Apo J) in the cerebrospinal fluid (CSF) of healthy control subjects, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects post-treatment with obicetrapib (visit-4- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A6, V6) measured by detecting three different clusterin peptides (Peptide 1-3). FIG. 4A shows the absolute concentration of Peptide 1 in healthy controls, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6). FIG. 4B shows the absolute concentration of Peptide 2 in healthy controls, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6). FIG. 4C shows the absolute concentration of Peptide 3 in healthy controls, clinical trial subjects at baseline (visit 1, VI), and clinical trial subjects’ post-treatment with obicetrapib (visit 6, V6).

[0025] FIG. 5 shows biomarker effects of lower CETP activity estimated through cis- Mendelian randomization (MR) using three weighting strategies. The MR effects were estimated by altematingly selecting instruments based on the genetic association with lower CETP concentration (pg / mL), higher Apolipoprotein- Al (Apo-Al in g / L), and lower Apolipoprotein-B (Apo-B in g / L). Results are presented as effect direction multiplied by the -loglO(p-value), truncated to a maximum of 8. Results with a p-value smaller than 0.05 / 26 are annotated by the point estimates rounded to two decimal places, nominal significance with a p-value between 0.05 and 0.05 / 26 is indicated by a star symbol. For the Apo-Al weighted analyses, the Apo-Al association was removed (reflecting identical data), with similar masking for the Apo-B weighted analysis.

[0026] FIGs. 6A-6C are plots showing cardiovascular effects of lower CETP activity on cardiovascular disease estimated through cis Mendelian randomization (MR) using three distinct weighting strategies. The MR effects were estimated by altematingly selecting instruments based on the genetic association with lower CETP concentration (pg / mL) (FIG. 6A), higher Apolipoprotein- Al (Apo-Al in g / L) (FIG. 6B), and lower Apolipoprotein-B (Apo- B in g / L) (FIG. 6C). The estimated odds ratio (OR) is indicated by a circle if the p-value was smaller than 0.05 / 26, or by a star otherwise, with the horizontal bars representing 95% confidence intervals (95%CI), a neutral effect of 1 is indicated by the dashed vertical line.

[0027] FIGs. 7A-7C are plots showing effect of lower CETP activity on neurological traits estimated through cis Mendelian randomization (MR) using three distinct weighting strategies. The MR effects were estimated by altematingly selecting instruments based on the genetic association with lower CETP concentration (pg / mL) (FIG. 7A), higher Apolipoprotein- Al (Apo-Al in g / L) (FIG. 7B), and lower Apolipoprotein-B (Apo-B in g / L) (FIG. 7C). The estimated odds ratio (OR) is indicated by a circle if the p-value was smaller than 0.05 / 26, or by-5- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A a star otherwise, with the horizontal bars representing 95% confidence intervals (95%CI), a neutral effect of 1 is indicated by the dashed vertical line.

[0028] FIGs. 8A-8B are plots showing association of lower plasma CETP with select protein values in CSF or brain tissue. Estimates are derived from a cis MR analyses of lower plasma concentration exploring associations with SomaLogic derived proteins expressed in Cerebrospinal fluid (CSF) or brain tissue. Estimates are provided for a pg / mL decrease in CETP plasma concentration as mean difference in standard deviation of protein value is plotted on the x-axis, against the -logio(p-value) on the y-axis. Associations passing a multiplicity corrected p-value of 4.3>< 10'5are depicted in orange, with proteins enriched for neurodegeneration annotated by Ensembl gene name. Neurodegeneration enrichment was based on information from GWAS catalog, automated PubMed queries, and BNF and ChEMBL providing information on known neurological indications or side-effects for drug compounds targeting these proteins. FIG. 8A shows association of lower plasma CETP with select protein values in CSF. FIG. 8B shows association of lower plasma CETP with select protein values in brain tissue.

[0029] FIG. 9 is an x-ray powder diffraction pattern of amorphous obicetrapib hemi calcium.

[0030] FIG. 10 is a solid-state13C-NMR spectrum of amorphous obicetrapib hemicalcium.4. DETAILED DESCRIPTION OF THE INVENTION4.1. Definitions

[0031] 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.

[0032] 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.

[0033] The term “patient” refers to a human subject.

[0034] 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.-6- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A

[0035] 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.

[0036] 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 glylcine 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 salts include anions of the compounds of the present disclosure compounded with a suitable cation.4.2. Other Interpretational Conventions

[0037] 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.

[0038] In this disclosure, “comprises”, “comprising”, “containing”, “having”, “includes”, “including” and linguistic variants thereof have the meaning ascribed to them in U.S. Patent law, permitting the presence of additional components beyond those explicitly recited.

[0039] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.-7- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A

[0040] 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 (z.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.

[0041] 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.

[0042] 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-enanti omers, 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.4.3. Summary Of Experimental Observations

[0043] Obicetrapib, a potent inhibitor of cholesterol esterase transfer protein (CETP), has previously been shown to increase HDL levels and ApoE levels in plasma.

[0044] We have now demonstrated that obicetrapib has significant effects on lipoproteins and lipids in the human central nervous system. In cerebrospinal fluid (CSF), we observed reduction in levels ApoE4, reduction in ApoE4ZE3 ratio, reduction in ApoJ (Clusterin levels), and 11% and 12% reduction of two oxy sterols, 24- hydroxycholesterol and 27- hydroxycholesterol, respectively. In circulation, we observed increase in levels of total ApoE, increase in the ratio of AP42 / 40, and reduction in levels of oxysterols, levels of 24- hydroxycholesterol and 27-hydroxycholesterol.-8- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A4.4. ObicetrapibObicetrapib, formerly known as TA-8995, is a compound of formula (I):(2R,4S){[3,5Bis(trifluoromethyl)benzyl]-[5(3-carboxypropoxy)pyrimidin-2-yl] amino}-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl esterMethods 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] The preparation of obicetrapib is disclosed, for example, in U.S. Patent Number 7,872,126 (“US ‘ 126”). US ‘ 126 Example 177 teaches the formation of obicetrapib, which, as seen in Formula (I), is a free acid. US ‘ 126 Example 178 teaches the formation of a sodium salt of obicetrapib from obicetrapib by exchanging the acidic proton of the free acid moiety of obicetrapib with a sodium atom. In US ‘ 126 Example 179, a calcium salt of obicetrapib is taught. Because calcium is an alkaline earth metal, when it ionizes, it has a +2 charge. Thus, a neutral salt will have two obicetrapib anions (each being obicetrapib minus a proton from its carboxylic acid group) for each calcium cation. The resulting salt of Example 179 is a hemicalcium salt of Formula II, in that there are only half as many calcium atoms as obicetrapib anions in a neutral amorphous obicetrapib calcium salt molecule.-9- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A[Formula II] wherein Et is ethyl.

[0046] The molecular formula of amorphous obicetrapib hemicalcium is (C32H3oN405F9)2Ca. When discussing salts of obicetrapib, such as calcium salts and in particular the hemicalcium salt, it is understood that obicetrapib has lost a proton in order to make such a salt. Thus, the terms obicetrapib hemicalcium and amorphous obicetrapib hemicalcium means that each obicetrapib moiety portion of the salt is not Formula (I) (i.e., obicetrapib) but Formula (I) minus a proton.

[0047] US ‘ 126 Example 179 expressly teaches that the hemicalcium salt of obicetrapib resulting is crystalline; however, the crystalline form has undesirable properties, such as its poor physical stability.4.4.1. Amorphous Obicetrapib Hemicalcium

[0048] The preparation and physico-chemical characteristics of amorphous obicetrapib hemicalcium are disclosed in U.S. Patent Number 12,006,305, (“US ‘305”). Examples 1-16 of US ‘305 teach methods for preparation of amorphous obicetrapib hemicalcium. The disclosure of US ‘305 is incorporated herein by reference in its entirety.4.5. Methods for Favorably Improving Levels of Neuroinflammatory and Neurodegenerative Biomarkers in Plasma / CSF

[0049] In one aspect, methods are presented for improving the levels of neuroinflammatory and neurodegenerative biomarkers in plasma and cerebrospinal fluid of subjects in need thereof. The method comprises administering to the subject obicetrapib, or pharmaceutically acceptable salt, solvate, or co-crystal thereof, in an amount effective to-10- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A favorably improve the biomarker in the plasma and / or CSF compared with the level of the biomarker as determined prior to the first administration of obicetrapib.

[0050] In some embodiments the method is effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject.

[0051] In some embodiments rate of decrease in the AP42 / AP40 ratio in the plasma of the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%,55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, or 90%.

[0052] In some embodiments, the subject has at least one ApoE4 allele.

[0053] In some embodiments, the subject is determined to be without evidence of cognitive impairment prior to first administration of obicetrapib. In some embodiments, cognitive impairment is determined according to the Montreal Cognitive Assessment (MoCA) test. In some embodiments cognitive impairment is determined according to the mini-mental state exam (MMSE), In some embodiments cognitive impairment is determined according to one of the following: Memory Impairment Screen (MIS) / MIS by Telephone (MIS-T), Mental Status Questionnaire (MSQ), 8-item Informant Interview (AD8), Functional Activities Questionnaire (FAQ), 7-Minute Screen (7MS), Abbreviated Mental Test (AMT), St Louis University Mental Status Examination (SLUMS), Telephone Instrument for Cognitive Status (TICS) or Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).

[0054] In some embodiments, the subject is determined to be with cognitive impairment prior to first administration of obicetrapib.

[0055] In various embodiments, the subject undergoes the step of determining the ApoE genotype of the subject prior to the first administration of obicetrapib.

[0056] In some embodiments, the method is effective to stabilize the AP42 / AP40 ratio in the plasma of the subject.-11- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A

[0057] In some embodiments, the method is effective to increase the AP42 / 40 ratio in the plasma of the subject.

[0058] In some embodiments, the method is effective to increase the AP42 / 40 ratio in the plasma of the subject by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%.

[0059] In various embodiments, the method is effective to reduce the rate of increase of levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p- Tau217), or p-Tau / Ap42 ratio in the plasma of the subject determined prior to the first administration of obicetrapib.

[0060] In various embodiments, the method is effective to reduce the rate of increase of levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p- Tau217), or p-Tau / Ap42 ratio in the plasma of the subject determined prior to the first administration of obicetrapib by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%.

[0061] In some embodiments, the method is effective to stabilize levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject.

[0062] In some embodiments, the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,-12- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%..4.6. Methods of Lowering ApoE4 Concentrations in the CNS

[0063] In one aspect, a method is provided for lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof. The method comprises administering to the subject obicetrapib or pharmaceutically acceptable salt, solvate, or cocrystal thereof, in an amount effective to reduce ApoE4 concentration in the CNS. In some embodiments, the ApoE4ZE3 ratio in CNS is lowered.

[0064] In various embodiments, the subject has at least one ApoE2 allele or ApoE4 allele. In some embodiments, the subject has at least one ApoE2 allele. In some embodiments, the subject has at least one ApoE4 allele. In some embodiments, the subject has two ApoE4 alleles.

[0065] In some embodiments, the subject has been diagnosed with or is at risk for Alzheimer’s disease (AD), Lewy Body dementia, Parkinson’s disease (PD), vascular or multi-infarct dementia, frontotemporal dementia (FTD), or Multiple Sclerosis (MS).

[0066] In some embodiments, the amount obicetrapib or pharmaceutically acceptable salt thereof, is effective to increase levels of total ApoE HDL in blood. In some embodiments, the amount is effective to increase levels of ApoE-HDL in particles lacking ApoC3 in blood.

[0067] In some embodiments, the ApoE4 concentration is reduced in brain tissue and / or cerebrospinal fluid (CSF) of said subject. In some embodiments, the ApoE4 concentration is reduced in brain tissue. In some embodiments, the ApoE4 concentration is reduced in brain parenchyma.

[0068] In various embodiments, the ApoE4 concentration in the CNS is calculated by measuring lipidated ApoE in the CNS. In some embodiments, ApoE4 is measured in CSF. In further embodiments, lipidated ApoE4 is measured using microdialysis.

[0069] In some embodiments, the amount of obicetrapib or pharmaceutically acceptable salt, solvate, or co-crystal thereof is effective to reduce the concentration of ApoE4 in CNS, particularly CSF, at least 5% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 in CNS at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%,-13- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.4.7. Methods Of Treating Neurodegenerative Disease

[0070] In another aspect, a method is provided for slowing progression of neurodegenerative disease in a subject who has or is at risk of developing a neurodegenerative disease. The method comprises administering to the subject, a therapeutically effective amount of obicetrapib or a pharmaceutically acceptable salt thereof.

[0071] In various embodiments, the subject has at least one ApoE2 allele or ApoE4 allele. In some embodiments, the subject has at least one ApoE2 allele. In some embodiments, the subject has at least one ApoE4 allele. In some embodiments, the subject has two ApoE4 alleles.

[0072] In some embodiments, the subject has been diagnosed with or is at risk for Alzheimer’s disease (AD), Lewy Body dementia, Parkinson’s disease (PD), vascular or multi-infarct dementia, frontotemporal dementia (FTD), or Multiple Sclerosis (MS).

[0073] In various embodiments, the subject has at least one ApoE2 allele or ApoE4 allele. In some embodiments, the subject has at least one ApoE2 allele. In some embodiments, the subject has at least one ApoE4 allele. In some embodiments, the subject has two ApoE4 alleles. In various embodiments, the subject has undergone the prior step of detecting ApoE4 alleles in said subject.

[0074] In certain embodiments, the subject has been diagnosed with or is at risk for developing AD. In some embodiments, the subject has been diagnosed with or is at risk for developing late onset AD (LOAD) In specific embodiments, the subject has been diagnosed with AD based on the NIA-AA Research Framework criteria, with biomarker classification of A+T+N+or A T N based upon (i) CSF profile consistent with AD (an Ap42 concentration of <1000 pg / mL AND p-tau >19 pg / mL, and / or (ii) a ratio of p-tau / Ap42 of >0.024). In specific embodiments, the biomarkers are measured by Elecsys assay.

[0075] In certain embodiments, the subject has been diagnosed with AD based on documented amyloid positron emission tomography (PET) scan evidence. In certain embodiments, the subject has AD Clinical Stage 3 or 4. In specific embodiments, the subject has AD clinical stage 3 or 4 based on the NIA-AA Research Framework criteria: (i) a mini--14- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A mental state examination (MMSE) score >20 inclusive, and / or Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) global score >0.5 and <1 with memory box score >1.0.

[0076] In certain embodiments, the subject is at risk for developing AD. In particular embodiments, the subject has at least one ApoE4 allele. In particular embodiments, the subject has one ApoE4 allele and one ApoE3 allele. In some embodiments, the subject having at least one ApoE4 allele displays reduced expression of endogenous MMP-9 compared to healthy subjects. In some particular embodiments of the method, subjects are healthy subjects having at least one ApoE4 allele. In particular embodiments, the subject has two ApoE4 alleles. In some embodiments, the method further comprises the prior step of detecting the presence of ApoE4 alleles in the subject. In some embodiments, the subject having at least one ApoE4 allele is at least 40, 50, 55, 60, 65, or 70 years old. In some particular embodiments of the method, the subject is healthy and has no ApoE4 allele.

[0077] In some embodiments, the subject is at increased risk for developing Parkinson’s disease (PD) within the next 1-10 years. In some embodiments, the increased risk of development is within 1-9 years. In some embodiments, the increased risk of development is within 1-8 years. In some embodiments, the increased risk of development is within 1-7 years. In some embodiments, the increased risk of development is within 1-6 years. In some embodiments, the increased risk of development is within 1-5 years. In some embodiments, the increased risk of development is within 1-4 years. In some embodiments, the increased risk of development is within 4-10 years. In some embodiments, the increased risk of development is within 4-9 years. In some embodiments, the increased risk of development is within 4-8 years. In some embodiments, the increased risk of development is within 5-7 years. In some embodiments, the increased risk of development is within 4-6 years. In some embodiments, the subject has impairment in episodic memory. In some embodiments, the subject is at least 40, 50, 55, 60, 65, or 70 years old. In some embodiments, the subject has elevated total Tau (t-Tau). In some embodiments, the subject has elevated phosphorylated Tau (p-Tau).

[0078] In some embodiments the subject diagnosed with PD is at least 40, 50, 55, 60, 65, or 70 years old.

[0079] In some embodiments, the subject has been diagnosed with mild cognitive impairment (MCI). In certain embodiments, the diagnosis of MCI is made using the Short Test of Mental Status, the Montreal Cognitive Assessment (MoCA) or the Mini -Mental State Examination (MMSE). In some embodiments the subject is at least 40, 50, 55, 60, 65, or 70-15- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A years old. In some embodiments, the subject with mild cognitive impairment has high p-tau levels in the central nervous system (CNS) compared with healthy subjects. In particular embodiments, the high p-tau levels are present in the brain of the subject. In some particular embodiments, the high p-tau levels are present in the cerebrospinal fluid (CSF) of the subject. In some embodiments, the subject with mild cognitive impairment does not have high p-tau levels compared with healthy subjects.

[0080] In some embodiments, the subject is at increased risk of developing mild cognitive impairment within the next 1-10 years. In some embodiments, the increased risk of development is within 1-9 years. In some embodiments, the increased risk of development is within 1-8 years. In some embodiments, the increased risk of development is within 1-7 years. In some embodiments, the increased risk of development is within 1-6 years. In some embodiments, the increased risk of development is within 1-5 years. In some embodiments, the increased risk of development is within 1-4 years. In some embodiments, the increased risk of development is within 4-10 years. In some embodiments, the increased risk of development is within 4-9 years. In some embodiments, the increased risk of development is within 4-8 years. In some embodiments, the increased risk of development is within 5-7 years. In some embodiments, the increased risk of development is within 4-6 years. In some embodiments, the subject has impairment in episodic memory. In some embodiments, the subject is at least 40, 50, 55, 60, 65, or 70 years old.

[0081] In some embodiments the subject diagnosed with mild cognitive impairment (MCI) is at least 40, 50, 55, 60, 65, or 70 years old.

[0082] In various embodiments, the subject has amyloid-beta (AP) aggregates within the brain. In some embodiments, the subject has been determined, prior to administration of obicetrapib, to test positive for Ap aggregates within the brain.

[0083] In various embodiments, the subject has been determined prior to treatment to have at least one of (i) decreased levels of Ap42 in plasma, (ii) increased levels of Ap40 in plasma, (iii) decreased ratio of AP42 / AP40 in plasma, (iv) increased levels of neurofilament light (NFL) in plasma, and (v) increased levels of neurogranin in plasma, as compared to a healthy control population that does not have neurodegenerative disease.

[0084] In various embodiments, the subject has been determined prior to treatment to have at least one of (i) decreased levels of Ap42 in CSF, (ii) increased levels of Ap40 in CSF, (iii) decreased ratio of AP42 / AP40 in CSF, (iv) increased levels of neurofilament light (NFL)-16- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A in CSF, and (v) increased levels of neurogranin in CSF, as compared to a healthy control population that does not have and that is not at elevated risk for neurodegenerative disease.

[0085] In various embodiments, the subject has been determined prior to treatment to have abnormal patterns of Tau based on Tau PET imaging.4.7.1. Dose regimen

[0086] In some embodiments, a calcium salt of obicetrapib is administered to the subject. In some embodiments, amorphous calcium salt of obicetrapib is administered to the subject. In some embodiments, obicetrapib hemicalcium is administered to the subject. In some embodiments, amorphous obicetrapib hemicalcium is administered to the subject. Whenever a salt is administered, the dose is expressed as the amount of the obicetrapib anion within the salt.

[0087] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered orally. In some embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in a solid dosage form. In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet further comprises a film coating. In typical embodiments, obicetrapib is administered as a tablet for oral administration. In various embodiments, the dose of obicetrapib or salt thereof is 2.5-40 mg by mouth per day (2.5-40 mg po QD). In some embodiments, the dose of obicetrapib or salt thereof is 5-40 mg by mouth per day (5-40 mg po QD). In some embodiments, the dose of obicetrapib or salt thereof is 10-40 mg by mouth per day (10-40 mg po QD).

[0088] In some specific embodiments, the dose of obicetrapib or salt thereof 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, 5.0 mg po QD, 5.5 mg po QD, 6.0 mg po QD, 6.5 mg po QD, 7.0 mg po QD, 7.5 mg po QD, 8.0 mg po QD, 8.5 mg po QD, 9.0 mg po QD, 9.5 mg po QD, 10.0 mg po QD, 10.5 mg po QD, 11.0 mg po QD, 11.5 mg po QD, 12.0 mg po QD, 12.5 mg po QD, 13.0 mg po QD, 13.5 mg po QD, 14.0 mg po QD, 14.5 mg po QD, 15.0 mg po QD, 15.5 mg po QD, 16.0 mg po QD, 16.5 mg po QD, 17.0 mg po QD, 17.5 mg po QD, 18.0 mg po QD, 18.5 mg po QD, 19.0 mg po QD, 19.5 mg po QD, 20.0 mg po QD, 20.5 mg po QD, 21.0 mg po QD, 21.5 mg po QD, 22.0 mg po QD, 22.5 mg po QD, 23.0 mg po QD, 23.5 mg po QD, 24.0 mg po QD, 24.5 mg po QD, 25.0 mg po QD, 25.5 mg po QD, 26.0 mg po QD, 26.5 mg po QD, 27.0 mg po QD, 27.5 mg po QD, 28.0 mg po QD, 28.5 mg po QD, 29.0 mg po QD, 29.5 mg po QD, 30.0 mg po QD, 30.5 mg po QD, 31.0 mg po QD, 31.5 mg po QD, 32.0 mg po QD, 32.5 mg po QD, 33.0 mg po QD, 33.5-17- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A mg po QD, 34.0 mg po QD, 34.5 mg po QD, 35.0 mg po QD, 35.5 mg po QD, 36.0 mg po QD, 36.5 mg po QD, 37.0 mg po QD, 37.5 mg po QD, 38.0 mg po QD, 38.5 mg po QD, 39.0 mg po QD, 39.5 mg po QD, or 40.0 mg po QD..

[0089] In some specific embodiments, the dose of obicetrapib or salt thereof is about 2.5 mg po QD, 3.0 mg po QD, 3.5 mg po QD, 4.0 mg po QD, 4.5 mg po QD, 5.0 mg po QD, 5.5 mg po QD, 6.0 mg po QD, 6.5 mg po QD, 7.0 mg po QD, 7.5 mg po QD, 8.0 mg po QD, 8.5 mg po QD, 9.0 mg po QD, 9.5 mg po QD, 10.0 mg po QD, 10.5 mg po QD, 11.0 mg po QD,11.5 mg po QD, 12.0 mg po QD, 12.5 mg po QD, 13.0 mg po QD, 13.5 mg po QD, 14.0 mg po QD, 14.5 mg po QD, 15.0 mg po QD, 15.5 mg po QD, 16.0 mg po QD, 16.5 mg po QD, 17.0 mg po QD, 17.5 mg po QD, 18.0 mg po QD, 18.5 mg po QD, 19.0 mg po QD, 19.5 mg po QD, 20.0 mg po QD, 20.5 mg po QD, 21.0 mg po QD, 21.5 mg po QD, 22.0 mg po QD,22.5 mg po QD, 23.0 mg po QD, 23.5 mg po QD, 24.0 mg po QD, 24.5 mg po QD, 25.0 mg po QD, 25.5 mg po QD, 26.0 mg po QD, 26.5 mg po QD, 27.0 mg po QD, 27.5 mg po QD, 28.0 mg po QD, 28.5 mg po QD, 29.0 mg po QD, 29.5 mg po QD, 30.0 mg po QD, 30.5 mg po QD, 31.0 mg po QD, 31.5 mg po QD, 32.0 mg po QD, 32.5 mg po QD, 33.0 mg po QD,33.5 mg po QD, 34.0 mg po QD, 34.5 mg po QD, 35.0 mg po QD, 35.5 mg po QD, 36.0 mg po QD, 36.5 mg po QD, 37.0 mg po QD, 37.5 mg po QD, 38.0 mg po QD, 38.5 mg po QD, 39.0 mg po QD, 39.5 mg po QD, or 40.0 mg po QD.

[0090] In some specific embodiments, the dose of obicetrapib or 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, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3,13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9,15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5,16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1,18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7,19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3,21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9,23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4, 24.5,24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1,26.2, 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7,27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3,29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9,31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5,-18- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1,34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7,35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3,37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9,39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg po QD.

[0091] In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and the 2.5-40 mg total daily dose, or 5-20 mg total daily dose, or 10-20 mg total daily dose, is administered as a plurality of divided doses.

[0092] In some specific embodiments, the daily dose of obicetrapib or 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, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2,13.3, 13.4, 13.5, 13.6 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8,14.9, 15.0, 15,1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4,16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0,18.1, 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6,19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2,21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8,22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9. 24.0, 24.1, 24.2, 24.3, 24.4,24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0,26.1, 26.2, 26.3, 26.4, 26.5. 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6,27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2,29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8,30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4,32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0,34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6,35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2,37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8,38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg per day. In some embodiments, the dose is provided in a plurality of doses.

[0093] In some embodiments, the tablet comprises 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 some embodiments, the tablet contains obicetrapib as the calcium salt. In particular embodiments, the table contains 5 mg obicetrapib as a calcium salt.-19- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A

[0094] 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.

[0095] In various embodiments, the solid dosage form contains obicetrapib hemicalcium of Formula I(Formula I) wherein Et is ethyl.

[0096] In various embodiments, the solid dosage form contains stable amorphous obicetrapib hemicalcium. In some embodiments, the solid dosage form contains substantially pure amorphous obicetrapib hemicalcium. In some embodiments, the amorphous obicetrapib calcium salt is substantially free of any crystalline salt of obicetrapib calcium.

[0097] In some embodiments, the amorphous obicetrapib calcium salt has an x-ray powder diffraction pattern substantially the same as that of FIG. 1. In some embodiments, the amorphous obicetrapib calcium salt has an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°29, about 7.0°29, and about 9.2°29. In some embodiments, the amorphous obicetrapib calcium salt does not birefringe. In some embodiments, the amorphous obicetrapib calcium has a glass transition temperature between about 107°C and about 112°C. In some embodiments, the glass transition temperature is measured with modulated differential scanning calorimetry. In some embodiments, the-20- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A measurement with modulated differential scanning calorimetry uses a sample pan which is open. In some embodiments, the opening is a pinhole.

[0098] In some embodiments, the glass transition temperature is between about 110°C and about 112°C. In some embodiments, the amorphous obicetrapib calcium has a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan. In some embodiments, the amorphous obicetrapib calcium has a glass transition temperature between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan.

[0099] In some embodiments, the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0100] In some embodiments, the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum substantially the same as that of FIG. 17. In some embodiments, the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum where no peak is present at about 22.1 ppm. In some embodiments, the solid dosage form contains amorphous obicetrapib calcium having a solid- state13C-NMR spectrum where no peak is present at about 29.5 ppm.

[0101] In some embodiments, the amorphous obicetrapib hemicalcium is made in accordance with the process of Scheme 1.

[0102] In various embodiments, obicetrapib or salt thereof 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.

[0103] 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.

[0104] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to increase levels of ApoAI in CSF.

[0105] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease levels of ApoE4 in CSF. In some-21- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease ratio of ApoE4ZE3 levels in CSF.

[0106] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease levels of ApoJ (clusterin) in CSF.

[0107] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to increase levels of total ApoE-HDL in blood as compared to the level prior to commencement of treatment. In typical embodiments, blood levels of ApoE-HDL are measured in plasma. In preferred embodiments, obicetrapib or salt thereof is administered in an amount effective to increase plasma levels of ApoE-HDL in particles lacking ApoC3 and / or percentage of plasma HDL-ApoE in HDL particles lacking ApoC3.4.7.2. Clinical Endpoints

[0108] In various embodiments, the dose of obicetrapib or salt thereof is effective to prevent at least one of (i) further decrease in levels of Ap42 in plasma, (ii) further increase in levels of AP40 in plasma, (iii) further decrease in ratio of AP42 / AP40 in plasma, (iv) further increase in levels of neurofilament light (NFL) in plasma, and (v) further increase in levels of neurogranin in plasma, as compared to levels immediately prior to start of treatment.

[0109] In some embodiments, the dose of obicetrapib or salt thereof is effective to prevent at least one of (i) further decrease in levels of AP42 in CSF, (ii) further increase in levels of AP40 in CSF, (iii) further decrease in ratio of AP42 / AP40 in CSF, (iv) further increase in levels of neurofilament light (NFL) in CSF, and (v) further increase in levels of neurogranin in CSF, as compared to levels immediately prior to start of treatment.

[0110] In some embodiments, the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the CNS. In some embodiments, the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the brain. In some embodiments, the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the CSF. In some embodiments, the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the CNS. In some embodiments, the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the brain. In some embodiments, the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the CSF.-22- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A[OHl] In some embodiments, the dose of obicetrapib or salt thereof is effective to lower oxysterol levels in CSF. In some embodiments, the oxysterol is 24-hydroxy cholesterol. In some embodiments, the oxysterol is 27-hydroxycholesterol.4.7.3. ApoE4 Carriers

[0112] In some embodiments, the dose of obicetrapib is effective to increase the AP42 / AP40 ratio in the plasma and / or CSF of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.

[0113] In some embodiments, the dose of obicetrapib is effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma and / or CSF of subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo..

[0114] In some embodiments, the dose of obicetrapib is effective to stabilize the AP42 / AP40 ratio in the plasma and / or CSF of subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.

[0115] In some embodiments, the dose of obicetrapib is effective to reduce Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), p-Tau / Ap42 ratio in the plasma and / or CSF of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.

[0116] In some embodiments, the dose of obicetrapib is effective to reduce the rate of increase in Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), p-Tau / Ap42 ratio in the plasma and / or CSF of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.

[0117] In some embodiments, the dose of obicetrapib is effective to reduce stabilize the Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), p-Tau / Ap42 ratio in the plasma and / or CSF of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.-23- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5. EXAMPLES

[0118] 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.5.1. Example 1: Study protocol for a Phase 2a, open-label, multicenter study to evaluate the efficacy and safety of obicetrapib in participants with early Alzheimer’s Disease (Hetero / Homozygote E4 Carriers)5.1.1. Study Design and Duration

[0119] This study (NCT05161715) is a multi-center, proof of concept, Phase 2a study in participants with early AD to evaluate the efficacy, safety, and tolerability of obicetrapib therapy. Study duration for individual participants is approximately 24 weeks (excluding Screening and Follow-up).5.1.2. Objectives

[0120] One objective of this study is to evaluate the effect of obicetrapib in participants with early Alzheimer’s Disease (AD) on levels of ApoA-1, ApoE, and cholesterol efflux capacity in cerebrospinal fluid (CSF). Another objective is to confirm the safety and tolerability of obicetrapib in participants with early AD. A further objective is to assess the following:• the effect of obicetrapib in participants with early AD on lipoprotein profiles (pharmacodynamics [PD]).• the effect of obicetrapib in participants with early AD on biomarkers involved with neurodegeneration and inflammation.• the effect of obicetrapib in participants with early AD on other PD exploratory biomarkers.• the efficacy of obicetrapib in participants with early AD in delaying disease progression compared to standard of care.• the efficacy of obicetrapib in participants with early AD on cognition.-24- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.1.3. Inclusion Criteria

[0121] Participants who meet all of the following criteria are eligible to participate in the study:1. Age range: 50-75 years of age at the Screening Visit2. Males, or females who are post-menopausal or otherwise not of child-bearing potential3. Diagnosis of AD based on the NIA-AA Research Framework criteria: a. Biomarker classification A+T+N+ or A+T+N- based upon: i. CSF profile consistent with AD (an Ap42 concentration of <1000 pg / mL AND p- tau >19 pg / mL, or a ratio of p-tau / Ap42 of >0.024 (Elecsys assay)) taken during the Screening period prior to the day of the first dose of study medication or, ii. Documented evidence of a CSF profile consistent with AD obtained within the previous 12 months, or iii. Documented amyloid positron emission tomography (PET) scan evidence acquired within the previous 12 months4. AD Clinical Stage 3 or 4 based on the NIA-AA Research Framework criteria a. Have a mini-mental state examination (MMSE) score at screening and baseline >20 inclusive b. Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) global score >0.5 and <1 with memory box score >1.05. Able to speak, read and write the local language fluently6. Have an APOE genotype of E4ZE4 or E3ZE47. Patients should either be: a. Not treated with any approved treatments for AD with a reasonable expectation that, based on the course of illness, need for treatment is not imminent and the patient should not be initiated on treatment for the length of the study, or b. Stabilized on an approved medication(s) for the treatment of AD for at least 3 months prior to baseline. The dose of the AD treatment should remain the same after entering the study.-25- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A8. Patient and care partner are willing to consent to all study procedures5.1.4. Exclusion Criteria

[0122] Participants who meet any of the following criteria are excluded from participation in the study:1. Other than AD, neurologic or medical disorder which may impair cognition including: head trauma, seizure disorder, neurodegenerative disease, hydrocephalus, cerebral / spinal hematoma, inflammatory disease, central nervous system infection (e.g., encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes), or endocrine disorder, or any significant medical conditions that, in the opinion of the investigator, prohibits their participation in the study.2. Any contra-indication to undergo magnetic resonance imaging (MRI), as judged by local Principal Investigator (PI) or radiologist.3. MRI of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, deep white matter lesions corresponding to a Fazekas score of 3, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (eg, abscess or brain tumor such as meningioma). Small incidental meningiomas may be allowed if discussed and approved by the Medical Monitor.4. History of any of the following neurological, psychiatric or medical conditions: a. History of large vessel stroke b. History of myocardial infarction or unstable angina within the previous 12 months c. Or other clinical manifestations of atherosclerotic vascular disease d. Type 1 diabetes and uncontrolled type 2 diabetes (hemoglobin Ale [HbAlc] >8%) e. Systemic blood pressure >150 / 90 mmHg on 3 separate determinations f. History of hyperaldosteronism g. Significant renal or hepatic dysfunction h. Current or previous hepatitis B infection (defined as positive test for hepatitis B surface antigen (HbSAg) and / or hepatitis B core antibody (anti-HBc). Subjects with immunity to hepatitis B (if due to natural infection defined as negative HBsAg, positive hepatitis B antibody [anti-HBs] and positive anti-HBc; if due to vaccination-26- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A defined as negative HBsAg, negative anti-HVc and positive anti-HBs) are eligible to participate in the study i. History or positive test at Screening for hepatitis C virus antibody (anti-HCV) j . History or positive test at Screening for human immunodeficiency virus (HIV) k. Diagnosed with cancer with metastatic potential within the last 5 years other than carcinoma in situ of the breast or cervix, or basal cell carcinoma of the skin that has been completely excised l. Major depressive episode requiring initiation of medication or hospitalization within the previous 90 days m. Presence of hallucinations or delusions n. Surgery within 12 weeks of screening o. For female subjects, pregnancy or ongoing lactation. Any of the following laboratory abnormalities at Screening a. Clinically significant (as determined by a cardiologist or local PI) 12-lead ECG abnormalities b. Any serum chemistry value (e.g. aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, creatine kinase [CK], total bilirubin etc) >2x the upper limit of normal (ULN) on 2 successive determinations less than 2 weeks apart c. Serum creatinine above the ULN or estimated glomerular filtration rate (eGFR) <60 mL / min d. Platelet count, international normalized ratio (INR), prothrombin time (PT) or partial thromboplastin time (PTT) not within the normal range or other risk for increased or uncontrolled bleeding e. Not carrying an APOE 4 allele (e.g. E3ZE3; E3ZE2; E2ZE2). Presence of contraindication to lumbar puncture as judged by local PI. Any other significant medical conditions that, in the opinion of the investigator, would prohibit participation in the study, including inability to tolerate the MRI scan or lumbar puncture procedures.-27- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A8. Taking any of the following medications a. Antipsychotic agents, including pimavanserin b. Stimulant medications c. Antidepressant medications whose dose has not been stable for at least 90 days d. Immunosuppressant medications, including chronic corticosteroids e. Injected or infused antibody therapies, including but not limited antibodies directed against tumor necrosis factor (TNF), anti-interleukin(IL)-6, natalizumab, rituximab and similar agents f. Insulin g. Anticoagulant or anti-platelet medications including warfarin, heparinoids and direct coagulation factor inhibitors (e.g. apixaban, dagibatran, rivaroxaban) either aspirin at a dose of <100 mg / day or clopidogrel at a dose of 75 mg / day, but not both in combination is permitted9. Participation in any other interventional clinical trial, or treatment with any investigational drug or investigational use of an approved therapy within 30 days (or 5 half-lives of such agent) prior to the first Screening visit.10. Regular use of cannabis or cannabis products, including non-prescription products containing cannabidiol (CBD)11. History of drug (including cannabis) or alcohol abuse within the last 5 years5.1.5. Retesting

[0123] If laboratory abnormalities during Screening are considered by the Investigator to be transient, then the laboratory tests may be repeated once during Screening. The Investigator’s rationale for retesting should be documented. If the retest result is no longer exclusionary, the participant may be enrolled.5.1.6. Rescreening

[0124] Participants who have screen-failed are permitted to rescreen once, following consultation with the Medical Monitor. Rescreening may be scheduled after at least 5 days have elapsed from the previous study visit.-28- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.1.7. Withdrawal Criteria

[0125] Participation in this clinical study may be discontinued for any of the following reasons:1. The participant withdraws consent or requests discontinuation from the study for any reason;2. Occurrence of any medical condition or circumstance that exposes the participant to substantial risk and / or does not allow the participant to adhere to the requirements of the protocol;3. Any SAE, clinically significant adverse event (AE), severe laboratory abnormality, intercurrent illness, or other medical condition which indicates to the Investigator that continued participation is not in the best interest of the participant;4. Pregnancy;5. Requirement of prohibited concomitant medication;6. Participant failure to comply with protocol requirements or study-related procedures; or7. Termination of the study by the Sponsor or the regulatory authority.

[0126] If a participant withdraws prematurely from the study due to the above criteria or any other reason, study staff should make every effort to complete the full panel of assessments scheduled for the Early Termination Visit. The reason for participant withdrawal must be documented in the electronic case report form (eCRF).

[0127] In the case of participants lost to follow-up, at least 3 attempts to contact the participant must be made and documented in the participant’s medical records. Withdrawn participants will not be replaced.5.1.8. Study Treatments

[0128] Participants are treated with obicetrapib 10 mg per day.5.1.8.1 Rationale for Dosing

[0129] In previous multiple-dose clinical studies of obicetrapib in healthy subjects and patients, near maximal effects were observed with the 5 mg obicetrapib dose. At this dose level, CETP activity and concentrations were effectively reduced, and HDL-C levels were increased while LDL-C levels decreased.-29- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.1.8.2 Randomization and Blinding

[0130] Participants who meet all eligibility criteria are enrolled into the study. All participants are treated with Obicetrapib 10 mg. Breaking the blind is not applicable, as this an open-label study.5.1.8.3 Drug Supplies5.1.8.3.1 Formulation and Packaging

[0131] The study drugs consist of 5 mg obicetrapib tablets. All products are manufactured in accordance with current European Union Good Manufacturing Practice.

[0132] Obicetrapib tablets are round, white film-coated tablets, with no identifying markings, containing 5 mg of obicetrapib calcium drug substance. The excipients present in the tablet cores are microcrystalline cellulose, mannitol, sodium starch glycollate, colloidal silicon dioxide, and magnesium stearate. A commercially available film-coating formula (Opadry II white, ex Colorcon) is applied to the cores.

[0133] Obicetrapib tablets are packaged into foil blisters and assembled into blister cards. The blister cards are clearly labelled to indicate which blisters to use on each day. Blister cards are assembled into kits, and each kit provides a sufficient supply for the necessary dosing. The shelf-life is assigned based on the stability of the individual products. The kits should be stored below 25°C.

[0134] The physical, chemical, and pharmaceutical formulation properties and characteristics of the obicetrapib tablets are described in the Investigator’s Brochure.

[0135] All study drugs are labelled in accordance with all applicable local regulatory requirements.5.1.8.3.2 Study Drug Preparation and Dispensing

[0136] The study drugs used in this study are 5 mg obicetrapib tablets.

[0137] At each appropriate visit, participants receive a kit containing blister cards with the study drug appropriate for the participant’s treatment group. Participants are instructed to take 2 tablets from the blister cards in the kit each day. The blister cards are clearly labelled to indicate which blisters to use on each day. Each kit provides a sufficient supply for 1 month of dosing. Participants are instructed to return all unused study drugs at the next visit.-30- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.1.8.3.3 Study Drug Administration

[0138] Study drugs are administered by the participant orally and once daily on Days 1 through 126. Study drugs should be administered at approximately the same time each morning, with food. On days with visits scheduled, study drugs should be administered with food following all fasted blood samples. If a participant forgets to take study drug on a given day, they should take the next dose as normal and should not take a double dose to make up for the forgotten dose.5.1.8.3.4 Treatment Compliance

[0139] Compliance to the study drug regimen is evaluated by counting unused tablets and capsules. During the Treatment Period, if compliance is not between 80% and 120%, inclusive, the participant is counselled about the importance of compliance to the regimen. If the limits are exceeded at 2 consecutive visits, a decision is made by the Investigator and Sponsor as to whether the participant should be withdrawn from the study.5.1.8.3.5 Storage and Accountability

[0140] All study drugs are stored below 25°C in a secure area with access limited to the Investigator and authorized site personnel.

[0141] In accordance with regulatory requirements, the Investigator or designated site personnel must document the amount of study drug dispensed and / or administered to participants, the amount returned by participants, and the amount received from and returned to the Sponsor (or representative) when applicable. Study drug accountability records must be maintained throughout the course of the study. Discrepancies are to be reconciled or resolved. Procedures for final disposition of unused study drug are provided in the appropriate study manual.5.1.9. Prior and Concomitant Medications and / or Procedures5.1.9.1 Excluded Medications and / or Procedures

[0142] Any lipid-altering therapy other than the investigational study drug is prohibited during the study.5.1.9.2 Documentation of Prior and Concomitant Medication Use

[0143] Medications used within 28 days prior to the Screening Visit are recorded. Any medications administered in addition to the study drugs, whether allowed per the protocol or not, must be documented on the concomitant medication eCRF.-31- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.1.10. Study Procedures

[0144] Study procedures follows the Schedule of Procedures:-32- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-AAPOE E4 = apolipoprotein E-E4; CDR-SB = Clinical Dementia Rating scale-Sum of Boxes;CFC = Cognitive-Functional Composite; ECG = electrocardiogram; EOT = End of Treatment; ET = Early Termination; MMSE = mini-mental state examination; MoCA = Montreal Cognitive Assessment; MRI = magnetic resonance imaging.-33- 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.1.10.1.1 Clinical Laboratory Evaluations

[0145] Blood for chemistry and hematology are obtained as indicated in the Schedule of Procedures and sent to a central laboratory for analysis. In particular, the following lipid profile data are collected:Apolipoprotein BApolipoprotein E (ApoE)High-density lipoprotein- ApoE [1]High-density lipoprotein cholesterolLow-density lipoprotein cholesterol [2]Non-high-density lipoprotein cholesterolTriglyceridesVery low-density lipoprotein cholesterolApolipoprotein AlApolipoprotein AllWith and without apolipoprotein C3.

[0146] As indicated in the Schedule of Procedures, the following are among the AD biomarker profile data collected in the CSF and / or plasma:Tau and pTau epitopesAPi-42, APi-40, AP1-42 / AP1-40 ratioNeurograninNeurofilament lightGFAP (glial fibrillary acidic protein)YKL40PDGFRb.

[0147] Blood samples for chemistry and hematology must be obtained under fasting conditions (i.e., after the participant has fasted for >10 hours). For the purposes of this study, fasting is defined as nothing by mouth except water and any essential medications. If a participant is not fasting, the Investigator is to reschedule the visit as soon as possible.34 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-AEstimated glomerular filtration rate is calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. At the Screening Visit only, the hematology panel includes Elb Ale, INR, PT and PTT.

[0148] Urine is obtained as indicated in the Schedule of Procedures and is sent to a central laboratory for complete urinalysis.

[0149] A urine pregnancy test is performed only prior to participation in the study at the screening visit.5.1.10.1.2 Electrocardiograms

[0150] A single, standard 12-lead ECG is performed by the Investigator or trained site personnel at the Screening Visit and centrally read.5.1.10.1.3 Physical Examinations

[0151] A physical examination is performed as indicated in above Schedule of Procedures.5.1.11. Efficacy Assessments

[0152] The primary efficacy endpoint is the change from baseline in levels of ApoA-I, ApoE, and cholesterol efflux capacity in CSF, measured at week 24.

[0153] Among secondary efficacy endpoints specific to lipid profile measurement in CSF and plasma, are:• percent change of HDL-C at Screening (Visit 1) or Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of HDL subfractions at Screening (Visit 1) or Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of HDL-ApoE in HDL particles lacking ApoC3 at Screening (Visit 1) or Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of ApoA-II at Screening (Visit 1) or Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of 24S-hydroxycholesterol and 27-hydroxycholesterol at Baseline (Visit 2), at Day 84 (Visit 4) and the End of Treatment (Visit 6).

[0154] Additional secondary efficacy endpoints specific to AD biomarkers in CSF:35 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A• percent change of Tau and pTau epitopes at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of A01-42, A0i-4o, AP1-42 / AP1-40 ratio at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of neurogranin at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of neurofilament light at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of GFAP at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of YKL40 at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of PDGFRb at Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).

[0155] Additional secondary efficacy endpoints specific to AD biomarkers in plasma are:• percent change of Tau and pTau epitopes at Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of A01-42, A0i-4o, AP1-42 / AP1-40 ratio at Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of neurogranin at Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).• percent change of neurofilament light at Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6).

[0156] Additional secondary efficacy endpoints to track disease progression are:• administer the Cognitive-Functional Composite test at Baseline (Visit 2) and End of Treatment (Day 168, Visit 6).36 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A• administer the CDR-SB test at Screening (Visit 1) and End of Treatment (Day 168, Visit 6).• administer the Mini-Mental State Examination at Screening (Visit 1), Baseline (Visit 2), Day 84 (Visit 4) and End of Treatment (Day 168, Visit 6).5.2. Example 2: Results - Quantitative Analysis of Apolipoproteins and Other Biomarkers in Alzheimer’s Disease Patients Treated with Obicetrapib Following Phase 2A Study

[0157] We assessed the effects of obicetrapib on the levels of apolipoproteins and other biomarkers in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients, comparing baseline, post-treatment, and age-matched healthy control samples. A total of 13 patients were given 10 mg obicetrapib per day and observed for 24 weeks. There were 15 healthy controls.

[0158] The primary pharmacodynamic endpoint was the change from baseline in CSF and blood levels of total ApoE and the following AD biomarkers: Ap42, Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), p-Tau / Ap42 ratio, and Total Tau / p-Tau ratio. The subjects’ cerebrospinal fluid and blood were drawn on the first day and total ApoE and biomarker levels were analyzed to establish a baseline. The subjects were then treated for 168 successive days with 10 mg of obicetrapib per day, at the end of which the subjects’ fluids were once again drawn and analyzed.

[0159] Additionally, using an immunoaffinity-mass spectrometer approach, we assessed the impact of obicetrapib on apolipoprotein E isoform ratios of E4ZE3 in plasma and CSF.5.2.1. Methods

[0160] Sample Preparation: CSF samples (15 pL) were processed using Waters ProteinWorks eXpress Direct Digest Kit including reduction, alkylation, and overnight digestion steps. Stable isotope-labelled recombinant protein and peptide-level internal standards were added to samples prior to digestion. A calibration curve of recombinant protein standards was prepared in bovine serum albumin (BSA) and analyzed alongside clinical samples in duplicate. Recombinant proteins were spiked into BSA and control CSF at 3 different concentrations, and analyzed as Quality Control (QC) samples alongside clinical samples.

[0161] LC-MS / MS Assay: Tryptic peptides were quantified using an ACQUITY UPLC H-Class coupled to a TQ-XS triple quadrupole mass spectrometer fitted with a CORTECS37 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-APremier T3 Column (1.6 m, 2.1 mm x 100 mm) at a flow rate of 600 pL / min and a total run time of 7 min per sample. Unique peptides and corresponding stable isotope-labelled internal standards were monitored for each target protein using a scheduled MRM method and at least 2 MRM transitions per peptide. Chromatograms were analyzed using Skyline software - the most intense transition for each peptide was used for absolute quantification.

[0162] Analytical Validation: Technical validation was performed on 3 independent days using dilution series of freshly prepared recombinant proteins. 5 technical replicates (individual injections into LC-MS / MS) were obtained on each day. BSA and CSF-based QC samples were analyzed alongside the calibration curves in 5 technical replicates on each day. Validation criteria for calibration points were <20% CV and 80-120% accuracy. Lower limit of quantification (LLOQ) was determined as the lowest calibration curve point passing both criteria.

[0163] Statistical Analysis: A Wilcoxon rank sum test was performed for all pairwise comparisons between Healthy Controls, visit 1 (pre-treatment) and visit 6 (post-treatment). Specifically, an unpaired test was performed for all comparisons with Healthy Controls and a paired test was carried out for the comparison of visit 1 and visit 6. Significance was assessed using a p-value of 0.05.5.2.2. Results I: ApoE, Clusterin (ApoJ)

[0164] In CSF, healthy controls displayed significantly lower total ApoE concentration compared to baseline AD samples. See Peptide 3, FIG. 3C (p = 0.004).

[0165] In CSF, ApoE4ZE3 ratios fell between visits 2 and 6 in two out of three subjects. See FIG. 2B. In one subject, CSF ApoE4ZE3 ratio fell between visits 2 and 4, and then rose somewhat between visits 4 and 6.

[0166] Plasma apolipoprotein (Apo) isoforms E4ZE3 ratios rose in 4 out of 5 subjects from visit 1 to visit 6. FIG. 2A. The subject whose CSF E4ZE3 ratio had increased between visits 4 and 6 (subject 1-005), showed a rise in plasma ApoE4ZE3 ratio between visit 2 and visit 4, subsequent to which the ratio fell. See FIG. 2A.

[0167] Clusterin (ApoJ) showed significantly lower concentration in healthy controls compared to baseline AD samples for 1 out of 3 peptides (p = 0.006). See peptide 3, FIG. 4C. Clusterin (Peptide 2) in Obicetrapib-treated patients was significantly lower compared to both healthy controls and baseline AD groups (p = 0.038 and 0.001, respectively) (FIG. 4B).38 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.2.3. Results II: Biomarkers

[0168] CSF reductions in oxysterols were observed, specifically, reductions of 11% and 12% in the levels of 24-hydroxycholesterol and 27-hydroxycholestrol, respectively. See Table 2. Reductions in 24- and 27-hydroxycholestrol were also observed in plasma. See Table 3. In addition, an increase of 8% in the AP42 / 40 ratio in patient’s plasma was observed and pTaul81 levels were observed to be stable. See Table 4 and Table 5 respectively.Additional biomarker data from the 24-week study is provided in Tables 6-13.39 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-ATable 2: CSF Oxysterol Levels Following Treatment with 10 mg Obicetrapib40 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A41 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A42 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A43 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A44 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A45 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A46 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A47 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A48 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A49 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A50 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A51 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A52 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.3. Example 3: Mendelian Randomization analysis of the effect of lower CETP concentration on plasma lipids, cardiovascular disease outcomes, and neurodegenerative disease5.3.1. Methods

[0169] Cis-MR (Mendelian randomization) was used to identify associations between plasma CETP concentration and protein values in cerebrospinal fluid (CSF) and brain tissue, identifying associations with proteins previously implicated with neurodegeneration. Genetic instruments associating with CETP concentration (pg / mL) were identified from a GWAS conducted by Blauw et al. Circulation: Genomic and Precision Medicine 11.5 (2018). To limit the potential for bias-inducing pre-translational horizontal pleiotropy we applied a cis window of ±25 kilobase pair (kbp) around CETP (ENSG00000087237, build 37). CETP concentration participants were 4,248, Apo-Al concentration participants were 355,729, and Apo-B concentration participants were 355,729. Variants were selected to have an F-statistic of 24 or larger, and a minor allele frequency (MAF) of 0.01 or larger. The F-statistic was selected to limit the potential influence of weak-instrument bias. The MAF threshold was chosen to ensure we could robustly model genetic linkage disequilibrium (LD) based on a random sample of 5,000 UK biobank participants as a reference. Using these references data, the genetic variants were clumped to an R-squared of 0.30, using the same reference data to model the residual LD. We used GWAS on plasma concentration of Apo-Al and Apo-B from which we extracted genetic variants, applying the same variant selection criteria centered on the cis-CETP region. We differentiate between the three analyses by referring to MR analyses weighted by “CETP”, “Apo-Al”, or “Apo-B”.5.3.2. Statistical Analysis

[0170] Mendelian randomization (MR) estimates were calculated using generalized least squares (GLS) implementations of the inverse-variance weighted (IVW) estimator and the MR-Egger estimator, the latter being unbiased in the presence of horizontal pleiotropy at the cost of lower precision. We used GLS to directly model the LD reference structure, after clumping to an R-squared of 0.30, optimizing power while preventing potential multicollinearity-based numerical instability. To minimize the potential influence of horizontal pleiotropy, variants beyond 3 times the mean leverage or with an outlier (Chi- square) statistic larger than 10.83, were pruned. Finally, a model selection framework was applied to select the most appropriate estimator, IVW or MR-Egger. This model selection framework utilizes the difference in heterogeneity between the IVW Q-statistic and the Egger53 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-AQ-statistic to decide which method provides the best model to describe the available data and hence optimizes the bias-variance trade-off.

[0171] Effect estimates are presented in the CETP lowering direction, for the CETP and Apo-B weighted MR analyses this implies the results are presented towards decreasing direction, while the Apo-Al weighted analyses are presented in the increasing direction. Results are provided with 95% confidence intervals (CI) and p-values. Statistical significance was determined by comparing the p-values against a multiplicity corrected threshold of 0.05 / 26 ~ 1.8* 10'3for the main analysis focusing on associations with biomarkers and disease, with a p-value threshold of 4.3 * 10'5employed for the more exploratory analysis of the association between plasma CETP concentration and the levels of 1155 proteins measured in brain and / or CSF. Furthermore, results of the main analysis were replicated by identifying significant and directionally concordant results using the cv.s-MR. analysis of CETP activity weighted by Apo-Al concentration and Apo-B concentration.5.3.3. Results and DiscussionEffects of Lower CETP Concentration on Biomarker Traits

[0172] Lower CETP concentration was associated with a decrease in plasma concentration of LDL-C (-0.08 standard deviation (SD), 95%CI -0.09; -0.08), intermediate density lipoprotein cholesterol (IDL-C: -0.04 SD, 95%CI -0.05; -0.03), very low-density lipoprotein cholesterol (VLDL-C: -0.24 SD, 95%CI -0.27; -0.21), remnant-cholesterol (-0.16 mmol / L, 95%CI -0.17; -0.15, representing the sum of IDL-C and VLDL-C), non-HDL-C (- 0.11 SD, 95%CI -0.12; -0.11, representing HDL-C subtracted from total cholesterol), total triglycerides (-0.09 SD, 95%CI -0.09; -0.08), Apo-B (-0.14 SD, 95%CI -0.15; -0.14), and Lp[a] (-1.62 nmol / L, 95%CI -1.91; -1.32). Tracking the canonical CETPi effects, genetically instrumented lower CETP increased the concentration of HDL-C (0.59 SD, 95%CI 0.57; 0.60), and Apo-Al (0.48 SD, 95%CI 0.45; 0.52), respectively.

[0173] CETP additionally affected non-lipid traits, where lower CETP concentration decreased diastolic blood pressure (DBP) -0.07 mmHg (95%CI -0.11; -0.03), and increased total brain volume 0.04 SD (95%CI 0.02; 0.06), respectively. The presented results were replicated in MR analyses selecting and weighting CETP genetic instruments by Apo-Al and / or Apo-B concentration as a proxy for reduced CETP activity (FIG. 5).54 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-AEffects of Lower CETP Concentration on Cardiovascular Outcomes

[0174] We confirmed that lower plasma CETP concentration decreased the risk of CHD (OR 0.92, 95%CI 0.89; 0.96, p-value 2.47 / 10), any stroke (OR 0.90, 95%CI 0.85; 0.95), any ischemic stroke (OR 0.96, 95%CI 0.94; 0.98), as well as small vessel stroke (OR 0.90, 95%CI 0.85; 0.96); FIG. 6A. We additionally observed that lower plasma concentration of CETP decreased the risk of AAA (OR 0.76, 95%CI 0.73; 0.80) and HF (OR 0.97, 95%CI 0.93; 1.00, p-value 4.39 / 102), although the latter only reached nominal significance. Aside from the stroke and ischemic stroke signals, which were partially replicated by Apo-Al weighted MRs, the associations with congestive heart disease (CHD), small vessel stroke, heart failure (HF) and abdominal aortic aneurysm (AAA) were fully replicated by cz -MR analyses selecting and weighting CETP variants by their associations on Apo-Al or Apo-B concentration; FIG. 6B-6C.Effects of Lower CETP Concentrations on Neurodegenerative Outcomes

[0175] Noting that lower plasma concentration of CETP associated with higher brain volume, we next explored associations with neurodegenerative traits. We found that lower CETP concentration was associated with a decrease in Lewy Body Dementia (LBD) (OR 0.81, 95%CI 0.74; 0.89, p-value 2.95 / 10), where APOE4- s4 status modified this association: LBD \n AP()E-?A carriers (OR 0.61, 95%CI 0.51; 0.73, p-value 4.91 x 10), and non APOE-&4 carriers (OR 0.89, 95%CI 0.79; 1.01, p-value 8.06 / 102); interaction p-value 5.81 / 10'4. We further observed that lower CETP concentration protected against dementia in Parkinson’s disease (PD) (OR 0.26, 95%CI 0.14; 0.48, p-value 1.29 / 10), which partially overlaps with known LBD pathophysiology. FIG. 7A. Additionally, we observed a nominal risk decreasing effect of lower CETP on ALS (OR 0.85, 95%CI 0.75; 0.97, p-value 1.64 / 10-2). The apolipoprotein (both Apo-Al and Apo-B) weighted analyses replicated the LBD in APOE-A carriers, with the Apo-Al weighted analysis also replicating the associations for dementia in PD, as well as the ALS association. FIG. 7B - 7C.Association of plasma CETP concentration with protein values in brain and CSF

[0176] We identified associations between lower plasma CETP concentrations and the levels of 26 proteins previously implicated with neurodegenerative traits. FIG. 8A-8B. This set included the LRP1B encoding gene, whose variants showed an APOE- s4 dependent association with dementia in PD37. We additionally found that lower CETP was associated with lower CSF values of EPHA2 and CSF-1, which are targeted by inhibiting compounds in55 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A clinical testing for AD. FIG. 8A. Similarly, we observed that lower CETP increased the values of brain HSP 6038 and CSF FAM3B39, which are anticipated to prevent P-amyloid aggregation and generation. FIG. 8A-8B. FAM3B was also affected by CETP in plasma. Not shown.Summary

[0177] In the current analysis we employed cv.s-MR to determine biological consequences of lower CETP activity. We recapitulated and extended known beneficial effects of lower CETP levels on blood lipids, as well as protective effects on cardiovascular diseases such as CHD, AAA, HF, and small vessel stroke. Subsequently we explored potential associations with dementia related traits, noting protective effects of lower CETP concentrations with LBD which was most pronounced in A POE-sA carriers - compatible with the previously observed protective effect of loss-of-function CETP variants in APOE-eA carriers. The effects of lower CETP concentration were replicated by performing cv.s-MR weighting CETP variants by their association on Apo-Al and Apo-B concentration. The protective effect on LBD was further supported by a protective effect of lower CETP concentration on dementia in people with PD, reflecting underlying shared etiology due to Lewy body disorders. We additionally, observed that lower plasma concentrations of CETP were associated with protein pathways in CSF and the brain, some of which are already in clinical phase testing for AD treatment, linked to neurodegeneration through APOE- A dependent lipid metabolism and / ? -amyloid aggregation and degradation.

[0178] In conclusion, our cv.s-MR recapitulated the beneficial on-target effects of lower CETP activity on blood lipids and CVD outcomes, mimicking the effect of pharmacologic CETP-inhibition. Consistent with known pathophysiology we expanded these analyses to show that lower CETP activity may elicit an APOE4 dependent protective effect on Lewy body dementia and dementia associated with Parkinson’s disease. In conjunction with human data of loss-of-function alleles of CETP that protect against dementia in A POE- A positive carriers and preclinical data in a humanized rodent model of dementia that show rescue of cognition loss by a CETP-inhibition, these results suggest that CETP-inhibition might be repurposed for treatment of dementia in A POE- positive carriers.56 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A5.4. Example 4: Obicetrapib on Top of Maximum Tolerated Lipid- Modifying Therapies (BROADWAY): assessment of biomarkers involved with neurodegeneration and inflammation

[0179] This study (NCT05142722) is a Phase 3 clinical study conducted to evaluate the effect of 10 mg of obicetrapib as an adjunct to diet and maximally tolerated lipid-lowering therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) and / or a history of atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C).5.4.1. Obicetrapib

[0180] Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Obicetrapib is administered at 10 mg orally, once daily to patients in the treatment group.5.4.2. Study Design

[0181] This is a multicenter, placebo-controlled, double-blind, randomized, Phase 3 study in approximately 2400 participants with underlying HeFH and / or a history of ASCVD who are not adequately controlled by their lipid-modifying therapy. The participants are randomized in a 2: 1 ratio to Obicetrapib group (one 10 mg obicetrapib tablet once daily) or Placebo group (one placebo tablet once daily). Starting on Day 1, each participant selfadministers their assigned study drug once daily until Day 365. Unless otherwise stated, Baseline values are the last non-missing measurements taken prior to the participant receiving study drug.

[0182] Key inclusion criteria include diagnosis of HeFH and / or history of ASCVD. Diagnosis of HeFH is made by either genotyping (analyzed by a central laboratory) or by clinical assessment using the WHO Criteria / Dutch Lipid Clinical Network Criteria with a score that is >8 points or the Simon Broome Register Diagnostic Criteria with an assessment of “definite or possible HeFH.” History of ASCVD is defined by at least 1 of the following conditions: coronary artery disease, cerebrovascular disease, and peripheral arterial disease. The patients are on maximally tolerated lipid-modifying therapy, defined as following: a statin at a maximally tolerated stable dose, ezetimibe for at least 4 weeks, bempedoic acid for at least 4 weeks, a proprotein convertase subtilisin / kexin type 9 (PCSK9)-targeted therapy for at least 3 stable doses, and / or a fibrate at a stable dose for at least 6 weeks (with the exception of gemfibrozil, which is not allowed). A majority of the participants enrolled into this study take high-intensity statin therapy (HIS), which include: Atorvastatin 40 and 80 mg; and57 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-ARosuvastatin 20 and 40 mg. The patients have either a fasting serum LDL-C >100 mg / dL (>2.59 mmol / L) or a fasting serum LDL-C >70 mg / dL (>1.81 mmol / L) to <100 mg / dL (<2.59 mmol / L) with at least one risk enhancer. The patients also have a fasting TG <400 mg / dL (<4.52 mmol / L) and an estimated glomerular filtration rate (eGFR) >30 mL / min / 1.73 m2calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

[0183] Key exclusion criteria include current or previous history of New York Heart Association class III or IV HF or left ventricular ejection fraction <30%, hospitalization for HF within 5 years prior to Screening, an clinical event including non-fatal MI, non-fatal stroke, non-elective coronary revascularization, and / or hospitalization for unstable angina and / or chest pain within 3 months prior to Screening, uncontrolled severe hypertension, defined as either systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg, formal diagnosis of homozygous familial hypercholesterolemia (FH), active liver disease, HbAlc >10%, thyroid-stimulating hormone >1.5 * ULN, and creatine kinase (CK) >3 x ULN.5.4.3. Objectives of the Study

[0184] The primary objective of this study is to evaluate the effect of obicetrapib on LDL-C levels in patients with underlying HeFH and / or ASCVD who are not adequately controlled by their lipid-modifying therapies.

[0185] The secondary objectives of this study include evaluating the effect of obicetrapib on apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), high- density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) levels. The secondary objectives also include evaluating the effect of obicetrapib on CV death, non- fatal MI, non-fatal stroke, or non-elective coronary revascularization. The secondary objectives further include evaluating the safety and tolerability profile of obicetrapib in a broadly representative population of adult males and females of all ages, including elderly and very elderly participants, assessed by AEs, events of special interest (ESIs), vital signs (including blood pressure), ECG measurements, and clinical laboratory values.

[0186] An additional objective of this study is to evaluate the effect of obicetrapib on biomarkers involved with neurodegeneration and inflammation, including: AP42 / AP40, Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), p-Tau / Ap42 ratio, phosphorylated Tau 217 (p-Tau217), and Total Tau / p-Tau ratio.58 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A

[0187] The exploratory objectives of this study include evaluating the effect of obicetrapib on the proportion of participants achieving prespecified LDL-C targets. The exploratory objectives also include evaluating the effect of obicetrapib on biomarkers, including Lp(a), ApoAl, glycosylated hemoglobin (HbAlc), homeostatic model assessment of insulin resistance (HOMA-IR), and blood glucose. The exploratory objectives further include evaluating the effect of obicetrapib on hospitalization for unstable angina and / or chest pain, hospitalization for heart failure (HF), and transient ischemic attack (TIA).5.4.4. Inclusion Criteria

[0188] Ages eligible for study is 18 years and older. All sexes are eligible for study. Specifically, females may be enrolled if all 3 of the following criteria are met:• They are not pregnant;• They are not breastfeeding; and• They do not plan on becoming pregnant during the study.Additional inclusion criteria include:• Have underlying heterozygous familial hypercholesterolemia (HeFH) and / or a history of established ASCVD with additional risk factors• Are on maximally tolerated lipid-modifying therapy, including a maximally tolerated statin, at a stable dose for at least 4 weeks prior to Screening• Atorvastatin 40 or 80 mg; or• Rosuvastatin 20 or 40 mg;• Fasting serum LDL-C >70 and < 100 mg / dL (>1.8 and <2.6 mmol / L) at Screening;• Fasting triglyceride (TG) < 400 mg / dL (<4.52 mmol / L) at Screening; and• Have an estimated glomerular filtration rate (eGFR) >30 mL / min at Screening.5.4.5. Exclusion Criteria• New York Heart Association class IV heart failure or last known left ventricular ejection fraction < 25%;• Major adverse cardiac event (MACE) within 3 months prior to Randomization;• Uncontrolled severe hypertension, defined as either systolic blood pressure > 160 mmHg or diastolic blood pressure >100 mmHg prior to Randomization;• Formal diagnosis of homozygous familial hypercholesterolemia (HoFH);• Active liver disease;• HbAlc >10% at Screening;59 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A• Thyroid-stimulating hormone >1.5 X upper limit of normal (ULN) at Screening;• Creatine kinase 3 X upper limit of normal (ULN) at Screening;• History of malignancy that required surgery (excluding local and wide local excision), radiation therapy, and / or systemic therapy during the 3 years prior to Randomization;• Known history of alcohol and / or drug abuse within 5 years prior to Screening;• Received treatment with other investigational products or devices within 30 days of Screening or 5 half-lives of the previous investigational product, whichever is longer;• Planned use of other investigational products or devices during the course of the study;• Participated in any clinical trial evaluating obicetrapib; or• Known allergy or hypersensitivity to obicetrapib, placebo, or any of the excipients in obicetrapib or placebo; and• Any condition that, according to the Investigator, could interfere with the conduct of the study.5.4.6. Efficacy Endpoints

[0189] The primary efficacy endpoint is the percent change from Baseline to Day 84 in LDL-C in the obicetrapib group compared to the placebo group.

[0190] The secondary efficacy endpoints include the following:• Percent change from Baseline to Day 84 in ApoB in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 84 in non-HDL-C in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 84 in HDL-C in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 180 in LDL-C in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 365 in LDL-C in the obicetrapib group compared to the placebo group;• The time from Randomization until the first confirmed occurrence of a composite of CV death, non-fatal MI, non-fatal stroke, or non-elective coronary revascularization;• The time from Randomization until the first confirmed occurrence of a composite of CV death, non-fatal MI, or non-fatal stroke;60 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A• Percent change from Baseline to Day 84 in TC in the obicetrapib group compared to the placebo group; and• Percent change from Baseline to Day 84 in TG in the obicetrapib group compared to the placebo group.

[0191] The exploratory efficacy endpoints include the following:• Proportion of participants at Day 84 who achieve LDL-C <70 mg / dL in the obicetrapib group compared to the placebo group;• Proportion of participants at Day 84 who achieve LDL-C <55 mg / dL in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 84 in Lp(a) and ApoAl in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 365 in HbAlc in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 365 in HOMA-IR in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Day 365 in blood glucose in the obicetrapib group compared to the placebo group;• Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group; and• The time from Randomization until the first confirmed occurrence of hospitalization for unstable angina and / or chest pain, hospitalization for HF, and TIA.5.4.7. Neurodegeneration biomarker results

[0192] Obicetrapib favorably affects biomarkers involved with neurodegeneration and inflammation.

[0193] Obicetrapib at 10 mg orally once daily reduces the rate of decrease in the AP42 / AP40 ratio in plasma of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo. Obicetrapib at 10 mg orally once daily stabilizes the AP42 / 40 ratio in plasma of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo. Obicetrapib at 10 mg orally once daily increases the AP42 / AP40 ratio in plasma of trial subjects who have at least61 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.

[0194] Obicetrapib at 10 mg orally once daily reduces Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), p-Tau / Ap42 ratio in plasma of trial subjects who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0195] 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.

[0196] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.62 37726 / 60599 / FW / 18416668.4

Claims

1. Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-AWHAT IS CLAIMED IS:

1. A method of reducing the rate of decrease in the AP42 / AP40 ratio in the plasma of a subject in need thereof, the method comprising: administering to the subject obicetrapib, or pharmaceutically acceptable salt, solvate, or co-crystal thereof, in an amount effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject determined prior to the first administration of obicetrapib.

2. The method of claim 1, wherein the subject has at least one ApoE4 allele.

3. The method of claim 2, wherein the subject is determined to be without evidence of cognitive impairment prior to first administration of obicetrapib.

4. The method of claim 2, wherein the subject is determined to be with cognitive impairment prior to first administration of obicetrapib.

5. The method of any one of claims 2-4, further comprising the prior step of determining the ApoE genotype of the subject.

6. The method of any one of claims 1-5, wherein the method is effective to stabilize the AP42 / AP40 ratio in the plasma of the subject.

7. The method of claim 6, wherein the method is effective to increase the AP42 / 40 ratio in the plasma of the subject.

8. The method of any one of claims 1-7, wherein the method is effective to reduce the rate of increase of levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p-Tau / Ap42 ratio in the plasma of the subject determined prior to the first administration of obicetrapib.

9. The method of claim 8, wherein the method is effective to stabilize levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject.

10. The method of claim, wherein the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject.

11. The method of any of claims 1-10, wherein the method is effective to reduce the rate of decrease in the AP42 / AP40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 20%.63 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A12. The method of claim 11, wherein the method is effective to reduce the rate of decrease in the AP42 / AP40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 30%.

13. The method of claim 12, wherein the method is effective to reduce the rate of decrease in the AP42 / AP40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 40%.

14. The method of claim 13, wherein the method is effective to reduce the rate of decrease in the AP42 / AP40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 50%.

15. The method of claim 7, wherein the method is effective to increase the AP42 / 40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 20%.

16. The method of claim 15, wherein the method is effective to increase the AP42 / 40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 30%.

17. The method of claim 16, wherein the method is effective to increase the AP42 / 40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 40%.

18. The method of claim 17, wherein the method is effective to increase the AP42 / 40 ratio in plasma of the subject compared to the AP42 / AP40 ratio in plasma of the subject prior to the first administration of obicetrapib by at least 50%.

19. The method of any of claims 8-18, wherein the method is effective to reduce the rate of increase of the levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p-Tau / Ap42 ratio in plasma of the subject compared to respective levels in plasma of the subject prior to the first administration of obicetrapib by at least 20%.

20. The method of claim 19, wherein the method is effective to reduce the rate of increase of the levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p-Tau / Ap42 ratio in plasma of the subject compared to respective levels in plasma of the subject prior to the first administration of obicetrapib by at least 30%.64 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A21. The method of claim 20, wherein the method is effective to reduce the rate of increase of the levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p-Tau / Ap42 ratio in plasma of the subject compared to respective levels in plasma of the subject prior to the first administration of obicetrapib by at least 40%.

22. The method of claim 21, wherein the method is effective to reduce the rate of increase of the levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p-Tau / Ap42 ratio in plasma of the subject compared to respective levels in plasma of the subject prior to the first administration of obicetrapib by at least 50%.

23. The method of claim 10, wherein the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject by at least 20%.

24. The method of claim 23, wherein the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject by at least 30%.

25. The method of claim 24, wherein the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject by at least 40%.

26. The method of claim 10, wherein the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), or p- Tau / Ap42 ratio in the plasma of the subject by at least 50%.

27. A method of lowering ApoE4 concentration in the central nervous system (CNS) of a subject in need thereof, the method comprising: administering to the subject obicetrapib, or pharmaceutically acceptable salt, solvate, or co-crystal thereof, in an amount effective to reduce ApoE4 concentration in the CNS.

28. The method of claim 27, wherein the subject is human.

29. The method of claim 28, wherein the ApoE4 concentration is reduced in brain tissue and / or cerebrospinal fluid (CSF) of said subject.

30. The method of claim 29, wherein the ApoE4 concentration is reduced in brain tissue.

31. The method of claim 30, wherein the ApoE4 concentration is reduced in brain parenchyma32. The method of claim 29, wherein ApoE4 concentration is reduced in the CSF.65 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A33. The method of any one of claims 27-33, wherein the ApoE4 concentration in the CNS is calculated by measuring lipidated ApoE4 in the CNS.

34. The method of claim 33, wherein lipidated ApoE4 is measured using microdialysis.

35. The method of any one of claims 27-34, wherein the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 at least 10% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 at least 20% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 at least 30% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 at least 40% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

39. The method of claim 38, wherein the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE at least 50% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 at least 60% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

41. The method of any one of claims 1-40, wherein a calcium salt of obicetrapib is administered to the subject.

42. The method of any one of claims 1-41, wherein an amorphous calcium salt of obicetrapib is administered to the subject.66 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A43. The method of any one of claims 1-42, wherein obicetrapib hemicalcium is administered to the subject.

44. The method of any one of claims 27-43, wherein the subject has at least one ApoE4 allele.

45. The method of claim 44, wherein the subject has two ApoE4 alleles.

46. The method of any one of claims 1-45, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered orally.

47. The method of claim 46, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered once per day.

48. The method of claim 46 or 47, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered in a dose of 10-40 mg po QD.

49. The method of claim 48, wherein the dose is 10 mg po QD.

50. The method of claim 48, wherein the dose is 15 mg po QD.

51. The method of claim 48, wherein the dose is 20 mg po QD.

52. The method of claim 48, wherein the dose is 25 mg po QD.

53. The method of claim 48, wherein the dose is 30 mg po QD.

54. The method of claim 48, wherein the dose is 35 mg po QD.

55. The method of claim 48, wherein the dose is 40 mg po QD.

56. The method of any one of claims 1-55, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 8 weeks.

57. The method of claim 56, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 6 months.

58. The method of claim 57, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 12 months.

59. The method of claim 58, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 24 months.

60. The method of any one of claims 41-59, wherein amorphous obicetrapib hemicalcium is administered to the subject.67 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A61. The method of any one of claims 1-61, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered in a solid dosage form.

62. The method of claim 61, wherein the solid dosage form is a tablet.

63. The method of claim 62, wherein the tablet further comprises a film coating.

64. The method of any one of claims 61-63, wherein a calcium salt of obicetrapib is administered to the subject.

65. The method of any one of claims 62-64, wherein an amorphous calcium salt of obicetrapib is administered to the subject.

66. The method of any one of claims 62-64, wherein obicetrapib hemicalcium is administered to the subject67. The method of any one of claims 62-64, or 66 wherein amorphous obicetrapib hemicalcium is administered to the subject.

68. The method of claim 67, wherein the solid dosage form contains obicetrapib hemi calcium of Formula I(Formula I) wherein Et is ethyl.

69. The method of claim 68, wherein the solid dosage form contains stable amorphous obicetrapib hemicalcium.

70. The method of claim 68 or claim 69, wherein the solid dosage form contains substantially pure amorphous obicetrapib hemicalcium.68 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A71. The method of any one of claims 67-70, wherein the amorphous obicetrapib calcium salt is substantially free of any crystalline salt of obicetrapib calcium.

72. The method of any one of claims 67-71, wherein the amorphous obicetrapib calcium salt has an x-ray powder diffraction pattern substantially the same as that of FIG. 9.

73. The method of claim 72, wherein the amorphous obicetrapib calcium salt has an x-ray powder diffraction pattern comprising one or more x-ray powder diffraction peaks at about 3.4°29, about 7.0°29, and about 9.2°29.

74. The method of any one of claims 67-73, wherein the amorphous obicetrapib calcium salt does not birefringe.

77. The method of any one of claims 67-74, wherein the amorphous obicetrapib calcium has a glass transition temperature between about 107°C and about 112°C.

76. The method of claim 77, wherein the glass transition temperature is measured with modulated differential scanning calorimetry.

77. The method of claim 76, wherein the measurement with modulated differential scanning calorimetry uses a sample pan which is open.

78. The method of claim 77, wherein the opening is a pinhole.

79. The method of any one of claims 67-74, wherein the glass transition temperature is between about 110°C and about 112°C.

80. The method of any one of claims 67-74, wherein the amorphous obicetrapib calcium has a glass transition temperature of less than about 100°C when measured by differential scanning calorimetry using a closed sample pan.

81. The method of claim 80, wherein the amorphous obicetrapib calcium has a glass transition temperature between about 70°C and about 92°C when measured by differential scanning calorimetry using a closed sample pan.

82. The method of any one of claims 67-81, wherein the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.0%.

83. The method of claim 82, wherein the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.5%.

84. The method of claim 83, wherein the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.6%.69 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A85. The method of claim 84, wherein the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.7%.

86. The method of claim 85, wherein the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.8%.

87. The method of claim 86, wherein the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.9%.

88. The method of any one of claims 67-87, wherein the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum substantially the same as that of FIG. 10.

89. The method of any one of claims 67-88, wherein the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum where no peak is present at about 22.1 ppm.

90. The method of any one of claims 67-89, wherein the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum where no peak is present at about 29.5 ppm.

91. The method of any of claims 67-89, wherein the amorphous obicetrapib hemicalcium is made in accordance with the process of Scheme 1.

92. The method of any one of claims 1-91, wherein the subject has been diagnosed with or is at risk for Alzheimer’s disease (AD), Lewy Body dementia, Parkinson’s disease (PD), vascular or multi-infarct dementia, frontotemporal dementia (FTD), or Multiple Sclerosis (MS).

93. The method of claim 92, wherein the subject has been diagnosed with or is at risk for developing AD.

94. The method of claim 93, wherein the subject has at least one ApoE2 allele or ApoE4 allele.

95. The method of claim 94, wherein the subject has at least one ApoE4 allele.

96. The method of claim 95, wherein the subject has two ApoE4 alleles.

97. The method of any one of claims 94-96, further comprising the prior step of detecting the ApoE genotype of the subject.70 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A98. The method of claim 93, wherein the subject has been diagnosed with or is at risk for developing late onset AD (LOAD).

99. The method of claim 92, wherein the subject has been diagnosed with or is at risk for developing Lewy Body dementia.

100. The method of claim 92, wherein the subject has been diagnosed with or is at risk for developing Parkinson’s disease.

101. The method of clam 92, wherein the subject has been diagnosed with dementia associated with Parkinson’s disease.

102. The method of claim 92, wherein the subject has been diagnosed with or is at risk for developing MS.

103. The method of claim 92, wherein the subject has been diagnosed with or is at risk for developing relapsing remitting MS.

104. The method of any one of claims 1-103, wherein the subject has been diagnosed with mild cognitive impairment (MCI).

105. The method of any one of claims 1-90, wherein the subject has amyloid-beta (AP) aggregates within the brain.

106. The method of claim 105, wherein the subject has been determined, prior to administration of obicetrapib, to test positive for Ap aggregates within the brain.

107. The method of any one of claims 1-106, wherein the subject has been determined, prior to treatment, to have at least one of (i) decreased levels of Ap42 in plasma, (ii) increased levels of Ap40 in plasma, (iii) decreased ratio of AP42 / AP40 in plasma, (iv) increased levels of neurofilament light (NFL) in plasma, and (v) increased levels of neurogranin in plasma, as compared to a healthy control population that does not have and that is not at elevated risk for neurodegenerative disease.

108. The method of any one of claims 1-107, wherein the subject has been determined, prior to treatment, to have at least one of (i) decreased levels of Ap42 in CSF, (ii) increased levels of Ap40 in CSF, (iii) decreased ratio of AP42 / AP40 in CSF, (iv) increased levels of neurofilament light (NFL) in CSF, and (v) increased levels of neurogranin in CSF, as compared to a healthy control population that does not have and that is not at elevated risk for neurodegenerative disease.71 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A109. The method of any one of claims 1-108, wherein the subject has been determined, prior to treatment, to have abnormal patterns of Tau based on Tau PET imaging.

110. The method of any one of claims 1-109, wherein the dose of obicetrapib or salt thereof is effective to prevent at least one of (i) further decrease in levels of Ap42 in plasma, (ii) further increase in levels of Ap40 in plasma, (iii) further decrease in ratio of AP42 / AP40 in plasma, (iv) further increase in levels of neurofilament light (NFL) in plasma, and (v) further increase in levels of neurogranin in plasma, as compared to levels immediately prior to start of treatment.

111. The method of any one of claims 1-110, wherein the dose of obicetrapib or salt thereof is effective to prevent at least one of (i) further decrease in levels of Ap42 in CSF, (ii) further increase in levels of Ap40 in CSF, (iii) further decrease in ratio of AP42 / AP40 in CSF, (iv) further increase in levels of neurofilament light (NFL) in CSF, and (v) further increase in levels of neurogranin in CSF, as compared to levels immediately prior to start of treatment.

112. The method of any one of claims 1-111, wherein the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the CNS.

113. The method of claim 112, wherein the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the brain.

114. The method of claim 113, wherein the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the CSF.

115. The method of any one of claims 1-114, wherein the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the CNS.

116. The method of claim 115, wherein the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the brain.

117. The method of claim 115, wherein the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the CSF.

118. A method for slowing progression of neurodegenerative disease in a subject who has or is at risk of developing a neurodegenerative disease, comprising: administering to the subject, a therapeutically effective amount of obicetrapib, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.72 37726 / 60599 / FW / 18416668.4Atty. Docket No. 37726-60599 / WOClient Ref: 041WO-A119. The method of claim 118, wherein the neurodegenerative disease is Alzheimer’s disease (AD), Lewy Body dementia, Parkinson’s disease (PD), vascular or multi-infarct dementia, frontotemporal dementia (FTD), or Multiple Sclerosis (MS).

120. The method of claim 119, wherein the neurodegenerative disease is Parkinson’s disease and administration of obicetrapib, or pharmaceutically acceptable salt, solvate, or cocrystal thereof, is effective to reduce progression of dementia.

121. The method of claim 120, wherein amorphous obicetrapib hemicalcium is administered.

122. The method of claim 121, wherein the subject is administered amorphous obicetrapib hemicalcium at a dose equivalent to 10 mg obicetrapib per day.73 37726 / 60599 / FW / 18416668.4

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