Obicetrapib for the treatment of dementias

Abstract

Methods are also presented for favorably affecting biomarkers involved with neurodegeneration and inflammation in plasma.

Description

OBICETRAPIB FOR THE TREATMENT OF DEMENTIAS1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application Nos. 63 / 725,477, filed on November 26, 2024, 63 / 792,670, filed on April 22, 2025, 63 / 819,510, filed on June 6, 2025, and 63 / 819,526, filed on June 6, 2025, and International Application No. PCT / US24 / 47885, filed on September 21, 2024, which are incorporated herein by reference in their entireties for all purposes.2. BACKGROUND OF THE INVENTION

[0002] 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.

[0003] Despite the need for effective treatments, there remains a dearth of diseasemodifying 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 diseasemodifying treatments capable of slowing progression of neurodegenerative diseases, particularly degenerative diseases that result in cognitive impairment and dementias, and that can be administered orally.3. SUMMARY OF THE INVENTION

[0004] 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.

[0005] We now provide results that demonstrate that obicetrapib has significant effects on lipoproteins and lipids in the central nervous system, with the greatest effects observed in ApoE4 carriers.

[0006] Accordingly, in a first aspect, methods are provided for attenuating increase in plasma phosphorylated Tau 217 (p-Tau217) in a subject in need thereof compared to the increase in plasma p-Tau217 of said subject observed at 12 months of non-obicetrapib therapy, the method comprising: orally administering 10 mg per day of obicetrapib, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject, for at least 3 months.

[0007] In some embodiments, the method is effective to attenuate the increase in plasma p- Tau217 in the subject by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0008] In various embodiments, obicetrapib is administered for at least 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.

[0009] In some embodiments, the subject is determined to have a plasma concentration of p-Tau217 greater than 0.42 pg / mL prior to first administration of obicetrapib.

[0010] In various embodiments, the method is effective to attenuate decrease in plasma AP42 / 40 ratio in the subject compared to the decrease in the plasma AP42 / 40 ratio of said subject observed at 12 months of non-obicetrapib therapy.

[0011] In some embodiments, the method is effective to attenuate decrease in the plasma AP42 / 40 ratio in the subject by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0012] In certain embodiments, the method is effective to stabilize the AP42 / AP40 ratio in the plasma of the subject.

[0013] In some embodiments, the method is effective to attenuate increase in plasma p- tau217 / (Ap42:Ap40) ratio in the subject compared to the increase in plasma p- tau217 / (Ap42:Ap40) ratio of said subject observed at 12 months of non-obicetrapib therapy.|0014| In certain embodiments, the method is effective to attenuate increase in the ratio of plasma p-tau217 / (Ap42:Ap40) in the subject by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0015] In various embodiments, the method is effective to stabilize the p- tau217 / (Ap42:Ap40) ratio in the plasma of the subject.

[0016] In some embodiments, the reference period for attenuation observed prior to treatment with obicetrapib is at least 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0017] In various embodiments, the subject has at least one ApoE2 allele. In some embodiments, the subject has at least one ApoE3 allele. In some embodiments, the subject has at least one ApoE4 allele.

[0018] In various embodiments, the method further comprises the prior step of determining the ApoE isoform status of the subject. In various embodiments, the ApoE isoform status of the subject is determined by ApoE isoform phenotyping. In various embodiments, the ApoE isoform status of the subject is determined by genotyping.

[0019] In certain embodiments, the subject is at least 60 years old. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is at least 70 years old.

[0020] In some embodiments, the subject is determined to be without evidence of cognitive impairment prior to first administration of obicetrapib.

[0021] In some embodiments, the subject is determined to have cognitive impairment prior to first administration of obicetrapib.

[0022] 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).

[0023] In some embodiments, the subject has been diagnosed with or is at risk for developing AD.

[0024] In some embodiments, the subject has been diagnosed with or is at risk for developing late onset AD (LOAD).

[0025] In some embodiments, the subject has been diagnosed with or is at risk for developing Lewy Body dementia.

[0026] In some embodiments, the subject has been diagnosed with or is at risk for developing Parkinson’s disease.

[0027] In some embodiments, the subject has been diagnosed with dementia associated with Parkinson’s disease.

[0028] In some embodiments, the subject has been diagnosed with or is at risk for developing MS.

[0029] In some embodiments, the subject has been diagnosed with or is at risk for developing relapsing remitting MS.

[0030] In some embodiments, the subject has been diagnosed with mild cognitive impairment (MCI).

[0031] In certain embodiments, the subject has been determined, prior to administration of obicetrapib, to test positive for Ap aggregates within the brain.

[0032] In certain 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.

[0033] In certain 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.

[0034] In certain embodiments, the subject has been determined, prior to treatment, to have abnormal patterns of Tau based on Tau PET imaging.

[0035] In certain embodiments, the dose of obicetrapib 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.

[0036] In certain embodiments, the dose of obicetrapib 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.

[0037] In some embodiments, the subject, prior to first administration of obicetrapib, has a fasting serum LDL-C >70 mg / dL, 71 mg / dL, 72 mg / dL, 73 mg / dL, 74 mg / dL, 75 mg / dL, 76 mg / dL, 77 mg / dL, 78 mg / dL, 79 mg / dL, 80 mg / dL, 81 mg / dL, 82 mg / dL, 83 mg / dL, 84 mg / dL, 85 mg / dL, 86 mg / dL, 87 mg / dL, 88 mg / dL, 89 mg / dL, 90 mg / dL, 91 mg / dL, 92 mg / dL, 93 mg / dL, 94 mg / dL, 95 mg / dL, 96 mg / dL, 97 mg / dL, 98 mg / dL, 99 mg / dL, 100 mg / dL, 101 mg / dL, 102 mg / dL, 103 mg / dL, 104 mg / dL, 105 mg / dL, 106 mg / dL, 107 mg / dL, 108 mg / dL, 109 mg / dL, 110 mg / dL, 111 mg / dL, 112 mg / dL, 113 mg / dL, 114 mg / dL, 115 mg / dL, 116 mg / dL, 117 mg / dL, 118 mg / dL, 119 mg / dL, 120 mg / dL, 121 mg / dL, 122 mg / dL, 123 mg / dL, 124 mg / dL, 125 mg / dL, 126 mg / dL, 127 mg / dL, 128 mg / dL, 129 mg / dL, 130 mg / dL, 131 mg / dL, 132 mg / dL, 133 mg / dL, 134 mg / dL, 135 mg / dL, 136 mg / dL, 137 mg / dL, 138 mg / dL, 139 mg / dL, 140 mg / dL, 141 mg / dL, 142 mg / dL, 143 mg / dL, 144 mg / dL, 145 mg / dL, 146 mg / dL, 147 mg / dL, 148 mg / dL, 149 mg / dL, or 150 mg / dL.

[0038] In some embodiments, the subject, has a fasting serum LDL-C >70 mg / dL, 71 mg / dL, 72 mg / dL, 73 mg / dL, 74 mg / dL, 75 mg / dL, 76 mg / dL, 77 mg / dL, 78 mg / dL,79 mg / dL, 80 mg / dL, 81 mg / dL, 82 mg / dL, 83 mg / dL, 84 mg / dL, 85 mg / dL, 86 mg / dL,87 mg / dL, 88 mg / dL, 89 mg / dL, 90 mg / dL, 91 mg / dL, 92 mg / dL, 93 mg / dL, 94 mg / dL,95 mg / dL, 96 mg / dL, 97 mg / dL, 98 mg / dL, 99 mg / dL, or 100 mg / dL.

[0039] In some embodiments, the subject is in need of lipid-modifying therapy.

[0040] In some embodiments, the subject is suffering from HeFH and / or ASCVD.

[0041] In some embodiments, the subject prior to the first administration of obicetrapib, is on lipid-modifying therapy.

[0042] In certain embodiments, the lipid-modifying therapy comprises at least one treatment selected from the group consisting of: a statin, ezetimibe, bempedoic acid, a proprotein convertase subtilisin / kexin type 9 (PCSK9)-targeted therapy, a fibrate other than gemfibrozil, and combinations thereof.

[0043] In various embodiments, the subject prior to the first administration of obicetrapib, is on maximally tolerated lipid-modifying therapy.

[0044] In certain embodiments, the maximally tolerated lipid-modifying therapy comprises at least one treatment selected from the group consisting of: a statin at a maximally tolerated stable dose, ezetimibe, bempedoic acid, a proprotein convertase subtilisin / kexin type 9 (PCSK9)-targeted therapy, a fibrate other than gemfibrozil, and combinations thereof.

[0045] In various embodiments, the subject, prior to first administration of obicetrapib, is on high-intensity statin therapy (HIS). In some embodiments, the high-intensity statin therapy (HIS) is atorvastatin at 40 mg or 80 mg. In some embodiments, the high-intensity statin therapy (HIS) is rosuvastatin at 20 mg or 40 mg.

[0046] In some embodiments, the subject prior to the first administration of obicetrapib is not in need of lipid lowering therapy.

[0047] In certain embodiments, the subject is not in need of lipid lowering therapy.

[0048] In some embodiments, the subject prior to first administration of obicetrapib has a fasting serum LDL-C <70 mg / dL.

[0049] In some embodiments, the subject has a fasting serum LDL-C<70 mg / dL.

[0050] In certain embodiments, the subject has a fasting triglyceride (TG) blood level of less than 150 mg / dL.

[0051] In various embodiments, a calcium salt of obicetrapib is administered to the subject. In various embodiments, obicetrapib hemicalcium is administered to the subject. In various embodiments, the obicetrapib hemicalcium is amorphous.

[0052] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in a solid dosage form. In various embodiments, the solid dosage form is a tablet. In various embodiments, the tablet further comprises a film coating.

[0053] In various embodiments, the solid dosage form comprises a calcium salt of obicetrapib. In various embodiments, the calcium salt of obicetrapib is amorphous. Invarious embodiments, the solid dosage form comprises obicetrapib hemicalcium. In various embodiments, the obicetrapib hemicalcium is amorphous.

[0054] In various embodiments of the method, the method comprises administering obiceterapib in a fixed dose combination with ezetimibe. In some embodiments, the composition comprises 5 to 20 mg ezetimibe.

[0055] In some embodiments, the fixed dose combination is a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate, solvate or co-crystal thereof; ezetimibe or a pharmaceutically acceptable salt, solvate or co-crystal thereof, and, pharmaceutically acceptable excipients.

[0056] In some embodiments, the composition comprises ezetimibe as anhydrous ezetimibe, ezetimibe monohydrate or a mixture thereof. In certain embodiments, the composition is a dual component composition, and wherein one of the components comprises ezetimibe and another component comprises obicetrapib.

[0057] In some embodiments, the fixed dose pharmaceutical composition further comprises the concurrent treatment with a HMG CoA reductase inhibitor.

[0058] Obicetrapib and ezetimibe combination treatment and fixed dose pharmaceutical compositions are known. See, e.g., International Application Nos. WO 2024 / 042061 and WO 2024 / 165395, the disclosures of which are incorporated herein by reference in their entireties.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] 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:

[0060] FIG. 1 is an illustration of alternative immunoaffinity-mass spectrometry approaches employed in determination of ApoE3 / E4 ratios in the clinical trial described in Examples 1 and 2.

[0061] FIGs. 2A-2B are line graphs. FIG. 2A is a line graph showing the effect of 10 mg obicetrapib on plasma ApoE3ZE4 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) ApoE3 / E4 ratios in subjects in the clinical trial described in Examples 1 and 2.

[0062] 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).

[0063] 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 6, 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).

[0064] 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.

[0065] 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 alternatingly 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.

[0066] 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 alternatingly 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 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.

[0067] 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 analysis 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 * I O-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.

[0068] FIG. 9 is an x-ray powder diffraction pattern of amorphous obicetrapib hemicalcium.

[0069] FIG. 10 is a solid-state13C-NMR spectrum of amorphous obicetrapib hemicalcium.

[0070] FIG. 11 is a bar graph showing the effect of obicetrapib treatment on lutein levels in the cerebrospinal fluid (CSF) of 12 human ApoE4 carrier subjects following 6 months of treatment from baseline (clinical trial described in Examples 1 and 2 at visit 2 (V2) and visit 6 (V6)).

[0071] FIG. 12 is a bar graph showing the effect of obicetrapib treatment on a-tocopherol levels in the CSF of 12 human ApoE4 carrier subjects following 6 months of treatment from baseline (clinical trial described in Examples 1 and 2 at visit 2 (V2) and visit 6 (V6)).

[0072] FIG. 13 is a bar graph of the BROADWAY trial data showing the effect of obicetrapib treatment on plasma levels of p-tau217 versus placebo in median percent change for all patients, ApoE4 carriers, and ApoE4 carriers at or over the age of 60 years, 65 years and 70 years.

[0073] FIG. 14 is a bar graph of the BROADWAY trial data showing the effect of obicetrapib treatment on plasma levels of p-tau217 / (Ap42:Ap40) ratio versus placebo in median percent change for all patients, ApoE4 carriers, and ApoE4 carriers at or over the age of 60 years, 65 years and 70 years.

[0074] FIG. 15 is a bar graph of the BROADWAY trial data showing the effect of obicetrapib treatment on mean percent change in p-tau217 plasma levels versus placebo in all patients and in ApoE subpopulations by age and ApoE4 status (progressively increased risk for Alzheimer’s Disease (AD) pathology).

[0075] FIG. 16A-16B are graphs of the BROADWAY trial data showing the relationship between predicted absolute change in p-tau217 and continuous age by treatment group. FIG. 16A shows the relationship for placebo population and the total obicetrapib treated population. FIG. 16B shows the relationship for the placebo population and obicetrapib treated ApoE4 carrier patients.

[0076] FIG. 17A-17B are graphs of the BROADWAY trial data showing the relationship between predicted absolute change in p-tau217 and continuous p-tau217 by treatment group. FIG. 17A shows the relationship for placebo population and the total obicetrapib-treated population (Pinteraction <0.0001). FIG. 17B shows the relationship for the placebo population and obicetrapib-treated ApoE4 carrier patients (Pinteraction <0.0001).

[0077] FIG. 18 is a bar graph of the BROADWAY trial data showing the mean percent change in various biomarkers relevant for AD following obicetrapib treatment in APOE4 (E3ZE4 and E4ZE4) patients.5. DETAILED DESCRIPTION OF THE INVENTION5.1. Definitions

[0078] 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.

[0079] 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.

[0080] The term “patient” refers to a human subject.

[0081] 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.

[0082] 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.

[0083] The term “pharmaceutically acceptable salt” refers to a salt that is acceptable for administration to a subject.5.2. Other Interpretational Conventions

[0084] 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 wellas 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.

[0085] 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.

[0086] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.

[0087] 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.

[0088] 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.

[0089] 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.5.3. Summary of Experimental Observations

[0090] 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 ApoE4 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 ApoE3ZE4 ratio in E3ZE4 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, we observed an increase in levels of total ApoE, increase in the ratio of AP42 / 40, and reduction in levels of the oxysterols, 24- hydroxycholesterol and 27-hydroxycholesterol. These results provide objective evidence that obicetrapib administration improves the pathophysiology underlying Alzheimer’s Disease in human ApoE4 allelic carriers.

[0091] 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.

[0092] We have also shown that levels of antioxidants (e.g., lutein, a-tocopherol, zeaxanthin) were increased in the CSF of Alzheimer’s disease patients after treatment with 10 mg obicetrapib therapy.

[0093] Finally, in a multicenter, placebo-controlled, double-blind, randomized, Phase 3 study in approximately 2500 participants with underlying heterozygous familial hypercholesterolemia (HeFH) and / or a history of atherosclerotic cardiovascular disease (ASCVD) not adequately controlled by maximum tolerated doses of lipid-modifying agents (NCT05142722), we have now demonstrated that obicetrapib significantly slows Alzheimer’s disease (AD) biomarker progression over 12 months, with the greatest effects in ApoE4 carriers.5.4. 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.

[0094] The preparation of obicetrapib is disclosed, for example, in U.S. Patent Number 7,872,126 (“US ‘ 126”). US ‘ 126 Example 177 teaches the formation of obicetrapib, which, as seen in Formula (I), is a free acid. US ‘ 126 Example 178 teaches the formation of a sodium salt of obicetrapib from obicetrapib by exchanging the acidic proton of the free acid moiety of obicetrapib with a sodium atom. In US ‘ 126 Example 179, a calcium salt of obicetrapib is taught. Because calcium is an alkaline earth metal, when it ionizes, it has a +2 charge. Thus, a neutral salt will have two obicetrapib anions (each being obicetrapib minus a proton from its carboxylic acid group) for each calcium cation. The resulting salt of Example 179 is a hemicalcium salt of Formula II, in that there are only half as many calcium atoms as obicetrapib anions in a neutral amorphous obicetrapib calcium salt molecule.[Formula II] wherein Et is ethyl.

[0095] 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.

[0096] 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.5.4.1. Amorphous Obicetrapib Hemicalcium

[0097] 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.5.5. Methods for Favorably Improving Levels of Neuroinflammatory and Neurodegenerative Biomarkers in Plasma / CSF

[0098] 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 favorably improve thebiomarker in the plasma and / or CSF compared with the level of the biomarker as determined prior to the first administration of obicetrapib.

[0099] In some embodiments, the method is effective to reduce the rate of increase in p-tau217 levels in the plasma of the subject. In some embodiments, the method is effective to reduce the rate of increase in p-tau217 levels in the plasma of the subject that has at least one ApoE4 allele.

[0100] In some embodiments, the method is effective to stabilize p-tau217 levels in the plasma of the subject who has at least one ApoE4 allele. In some embodiments, the method is effective to arrest the increase in p-tau217 levels in the plasma of the subject that has at least one ApoE4 allele.

[0101] In some embodiments, the method is effective to reduce the rate of increase in the p- tau217 / (Ap42:Ap40) ratio in the plasma of the subject. In some embodiments, the method is effective to reduce the rate of increase in the p-tau217 / (Ap42: Ap40) ratio in the plasma of the subject that has at least one ApoE4 allele.

[0102] In some embodiments, the method is effective to reduce the rate of decrease in the AP42 / AP40 ratio in the plasma of the subject.

[0103] In some embodiments, the 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%.

[0104] In some embodiments, the method is effective to increase the level of lutein in the CSF of the subject. In some embodiments, the level of lutein in the CSF of the subject is increased by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% compared to a subject not treated with obicetrapib. Insome cases, the level of lutein in the CSF of the subject is increased after 6 months of obicetrapib treatment. In some cases, the subject has a ApoE3 allele. In some cases, the subject has at least one ApoE4 allele. In some cases, the subject has a ApoE3 allele and a ApoE4 allele. In some cases, the subject has two ApoE4 alleles. In some embodiments, the method is effective to increase the level of a-tocopherol in the CSF of the subject. In some embodiments, the level of a-tocopherol in the CSF of the subject is increased by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%,35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100% compared to a subject not treated with obicetrapib. In some cases, the level of a-tocopherol in the CSF of the subject is increased after 6 months of obicetrapib treatment. In some cases, the subject has a ApoE3 allele. In some cases, the subject has at least one ApoE4 allele. In some cases, the subject has a ApoE3 allele and a ApoE4 allele. In some cases, the subject has two ApoE4 alleles.

[0105] In some embodiments, the method is effective to increase the level of zeaxanthin in the CSF of the subject. In some embodiments, the level of zeaxanthin in the CSF of the subject is increased by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%,45%, 46%, 47%, 48%, 49%, 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%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% compared to a subject not treated with obicetrapib. In some cases, the level of zeaxanthin in the CSF of the subject is increased after 6 months of obicetrapib treatment. In some cases, the subject has a ApoE3 allele. In some cases, the subject has a ApoE4 allele. In some cases, the subject has a ApoE3 allele and a ApoE4 allele.

[0106] In some embodiments, the subject has at least one ApoE4 allele.

[0107] In some embodiments, the subject is determined to be without evidence of cognitive impairment prior to first administration of obicetrapib. In some embodiments, cognitiveimpairment 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).

[0108] In some embodiments, the subject is determined to be with cognitive impairment prior to first administration of obicetrapib.

[0109] In various embodiments, the subject undergoes the step of determining the ApoE genotype of the subject prior to the first administration of obicetrapib. In various embodiments, ApoE status is determined using ApoE isoform phenotyping.

[0110] In some embodiments, the method is effective to stabilize the AP42 / AP40 ratio in the plasma of the subject.[OHl] In some embodiments, the method is effective to increase the AP42 / 40 ratio in the plasma of the subject.

[0112] 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%.

[0113] 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.

[0114] 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), p-tau217 / (Ap42 / 40), 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%.

[0115] In some embodiments, the method is effective to stabilize levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), p- tau217 / (Ap42 / 40), or p-Tau / Ap42 ratio in the plasma of the subject.

[0116] In some embodiments, the method is effective to reduce levels of Total Tau, phosphorylated Tau at Thrl81 (p-Taul81), phosphorylated Tau 217 (p-Tau217), p- tau217 / (Ap42 / 40), 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%, 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%.

[0117] In some embodiments, the method is effective to reduce levels of glial fibrillary acidic protein (GFAP) by at least 5%, 10%, 15% or 20%.

[0118] In some embodiments the subject is at least 40, 45, 50, 55, 65 or 70 years old.5.6. Methods of Lowering ApoE4 Concentrations in the CNS

[0119] 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 co-crystal thereof, in an amount effective to reduce ApoE4 concentration in the CNS. In some embodiments, the ApoE3ZE4 ratio in CNS is lowered.

[0120] 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.

[0121] 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).

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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%,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%, or 60% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.5.7. Methods of Treating Neurodegenerative Disease

[0126] 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.

[0127] 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, thesubject has at least one ApoE4 allele. In some embodiments, the subject has two ApoE4 alleles.

[0128] 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).

[0129] In various embodiments, the subject has at least one ApoE2 allele, ApoE3 allele, or ApoE4 allele. In some embodiments, the subject has at least one ApoE2 allele. In some embodiments, the subject has at least one ApoE3 allele. In some embodiments, the subject has at least one ApoE4 allele. In some embodiments, the subject has two ApoE3 alleles. In some embodiments, the subject has two ApoE4 alleles. In some embodiments, the subject has one ApoE3 allele and one ApoE4 allele. In various embodiments, the subject has undergone the prior step of detecting ApoE alleles in said subject. In some embodiments, the subject having at least one ApoE2, ApoE3, or ApoE4 allele is at least 40, 50, 55, 60, 65, or 70 years old.

[0130] 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.

[0131] 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 minimental 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.

[0132] 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 subjectshaving 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.

[0133] 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).

[0134] In some embodiments the subject diagnosed with PD is at least 40, 50, 55, 60, 65, or 70 years old.

[0135] 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 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.

[0136] 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.

[0137] In some embodiments the subject diagnosed with mild cognitive impairment (MCI) is at least 40, 50, 55, 60, 65, or 70 years old.

[0138] 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.

[0139] 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.

[0140] 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) 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.

[0141] In various embodiments, the subject has been determined prior to treatment to have abnormal patterns of Tau based on Tau PET imaging.

[0142] In certain embodiments, risk enhancers include: family history of premature ASCVD, chronic kidney disease, metabolic syndrome, conditions specific to women (e.g.,preeclampsia, premature menopause), inflammatory diseases, ethnicity (e.g., South Asian ancestry), persistently elevated triglycerides >175 mg / dL, hs-CRP >2.0 mg / L, Lp(a) levels >50mg / dL, and ankle-brachial index <0.9.5.7.1. Dose regimen

[0143] 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.

[0144] 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).

[0145] 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 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 poQD, 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..

[0146] 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.

[0147] 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, 32.5,32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1,34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7,35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3,37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9,39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0 mg po QD.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] In various embodiments, the solid dosage form contains obicetrapib hemicalcium of Formula I(Formula I) wherein Et is ethyl.

[0153] 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.

[0154] 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 ismeasured with modulated differential scanning calorimetry. In some embodiments, the measurement with modulated differential scanning calorimetry uses a sample pan which is open. In some embodiments, the opening is a pinhole.

[0155] 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.

[0156] 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%.

[0157] 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.

[0158] In some embodiments, the amorphous obicetrapib hemicalcium is made in accordance with the process of Scheme 1.

[0159] 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.

[0160] 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.

[0161] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to increase levels of ApoAI in CSF.

[0162] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease levels of ApoE4 in CSF. In some embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease ratio of ApoE3 / E4 levels in CSF.

[0163] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease levels of Apo J (clusterin) in CSF.

[0164] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to increase levels of lutein in CSF of the subject.

[0165] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to increase levels of a-tocopherol in CSF of the subject.

[0166] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered in an amount effective to increase levels of zeaxanthin in CSF of the subject.

[0167] 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 ApoC3.5.7.2. Clinical Endpoints

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.5.7.3. ApoE4 Carriers

[0172] 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.

[0173] 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..

[0174] 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.

[0175] 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.

[0176] In some embodiments, the dose of obicetrapib is effective to reduce the rate of increase in Total Tau, phosphorylated Tau at Thrl81 (p-Tau!81), 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.

[0177] 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.5.8. Further Embodiments

[0178] In one aspect, methods are provided for 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.

[0179] In some embodiments of the method, the subject has at least one ApoE4 allele.

[0180] In some embodiments of the method, the subject is determined to be without evidence of cognitive impairment prior to first administration of obicetrapib.

[0181] In various embodiments of the method, the subject is determined to be with cognitive impairment prior to first administration of obicetrapib.

[0182] In some embodiments of the method, the method further comprises the prior step of determining the ApoE genotype of the subject. In various embodiments, ApoE status is determined using ApoE isoform phenotyping.

[0183] In various embodiments of the method, the method is effective to stabilize the AP42 / AP40 ratio in the plasma of the subject.

[0184] In certain embodiments of the method, method is effective to increase the AP42 / 40 ratio in the plasma of the subject.

[0185] In various embodiments of the method, 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.

[0186] In various embodiments of the method, 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.

[0187] In various embodiments of the method, 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.

[0188] In certain embodiments of the method, 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%, 30%, 40%, or 50%.

[0189] In various embodiments of the method, 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%, 30%, 40%, or 50%.

[0190] In various embodiments of the method, 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%, 30%, 40%, or 50%.

[0191] In some embodiments of the method, 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%, 30%, 40%, or 50%.

[0192] In a different aspect, methods are provided for 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.

[0193] In various embodiments of the method, the subject is human.

[0194] In various embodiments of the methos, the ApoE4 concentration is reduced in brain tissue and / or cerebrospinal fluid (CSF) of said subject.

[0195] In certain methods of the method, the ApoE4 concentration is reduced in brain tissue. In some embodiments of the method, the ApoE4 concentration is reduced in brainparenchyma. In some embodiments of the method, ApoE4 concentration is reduced in the CSF.

[0196] In some embodiments of the method, the ApoE4 concentration in the CNS is calculated by measuring lipidated ApoE4 in the CNS. In some embodiments of the method, lipidated ApoE4 is measured using microdialysis.

[0197] In some embodiments of the method, 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.

[0198] In various embodiments of the method, 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.

[0199] In various embodiments of the method, 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. In some embodiments, the amount of obicetrapib or pharmaceutically acceptable salt thereof is effective to reduce the concentration of ApoE4 at least 40%, 50%, or 60% as compared to the concentration prior to first administration of obicetrapib or pharmaceutically acceptable salt thereof.

[0200] In certain embodiments of the method, a calcium salt of obicetrapib is administered to the subject. In some embodiments of the method, an amorphous calcium salt of obicetrapib is administered to the subject. In some embodiments of the method, obicetrapib hemicalcium is administered to the subject.

[0201] In some embodiments of the method, the subject has at least one ApoE4 allele. In some embodiments of the method, the subject has two ApoE4 alleles.

[0202] In some embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered orally.

[0203] In certain embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered once per day.

[0204] In various embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered in a dose of 10-40 mg po QD.

[0205] In various embodiments of the method, the dose is 10 mg po QD. In certain embodiments of the method, the dose is 15, 20, 25, 30, 35, or 40 mg po QD.

[0206] In certain embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 8 weeks.

[0207] In some embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 6 months. In some embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 12 months. In some embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered once daily for at least 24 months.

[0208] In some embodiments of the method, amorphous obicetrapib hemicalcium is administered to the subject.

[0209] In various embodiments of the method, obicetrapib or pharmaceutically acceptable salt thereof is administered in a solid dosage form.

[0210] In various embodiments of the method, the solid dosage form is a tablet. In some embodiments, the tablet further comprises a film coating.

[0211] In certain embodiments of the method, a calcium salt of obicetrapib is administered to the subject. In some embodiments, an amorphous calcium salt of obicetrapib is administered to the subject. In some embodiments of the method, obicetrapib hemicalcium is administered to the subject. In some embodiments of the method, amorphous obicetrapib hemicalcium is administered to the subject.

[0212] In certain embodiments of the method, the solid dosage form contains obicetrapib hemi calcium of Formula I(Formula I) wherein Et is ethyl.

[0213] In some embodiments of the method, the solid dosage form contains stable amorphous obicetrapib hemicalcium.

[0214] In various embodiments of the method, the solid dosage form contains substantially pure amorphous obicetrapib hemicalcium.

[0215] In certain embodiments of the method, the amorphous obicetrapib calcium salt is substantially free of any crystalline salt of obicetrapib calcium.

[0216] In some embodiments of the method, the amorphous obicetrapib calcium salt has an x-ray powder diffraction pattern substantially the same as that of FIG. 9.

[0217] In some embodiments of the method, 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.

[0218] In some embodiments of the method, the amorphous obicetrapib calcium salt does not birefringe.

[0219] In various embodiments of the method, the amorphous obicetrapib calcium has a glass transition temperature between about 107°C and about 112°C.

[0220] In certain embodiments of the method, the glass transition temperature is measured with modulated differential scanning calorimetry.

[0221] In some embodiments of the method, the measurement with modulated differential scanning calorimetry uses a sample pan which is open.

[0222] In some embodiments of the method, the opening is a pinhole.

[0223] In some embodiments of the method, the glass transition temperature is between about 110°C and about 112°C.

[0224] In various embodiments of the method, 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.

[0225] In certain embodiments of the method, 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.

[0226] In some embodiments of the method, the solid dosage form contains amorphous obicetrapib calcium having a chemical purity of at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0227] In certain embodiments of the method, the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum substantially the same as that of FIG. 10.

[0228] In some embodiments of the method, the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum where no peak is present at about 22.1 ppm.

[0229] In some embodiments of the method, the solid dosage form contains amorphous obicetrapib calcium having a solid-state13C-NMR spectrum where no peak is present at about 29.5 ppm.

[0230] In some embodiments of the method, the amorphous obicetrapib hemicalcium is made in accordance with the process of Scheme 1.

[0231] In various embodiments of the method, 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).

[0232] In various embodiments of the method, the subject has been diagnosed with or is at risk for developing AD.

[0233] In certain embodiments of the method, the subject has at least one ApoE2 allele or ApoE4 allele.

[0234] In certain embodiments, the subject has at least one ApoE4 allele. In some embodiments, the subject has two ApoE4 alleles.

[0235] In various embodiments of the method, the method further comprises the prior step of detecting the ApoE genotype of the subject. In various embodiments, ApoE status is determined using ApoE isoform phenotyping.

[0236] In some embodiments of the method, the subject has been diagnosed with or is at risk for developing a condition selected from: late onset AD (LOAD), Lewy Body dementia, Parkinson’s disease, multiple sclerosis (MS), relapsing remitting MS, and mild cognitive impairment (MCI).

[0237] In certain embodiments of the method, 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.

[0238] In various embodiments of the method, 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.

[0239] In some embodiments of the method, 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.

[0240] In some embodiments of the method, the subject has been determined, prior to treatment, to have abnormal patterns of Tau based on Tau PET imaging.

[0241] In certain embodiments of the method, 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.

[0242] In various embodiments of the method, 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.

[0243] In some embodiments of the method, the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the CNS.

[0244] In various embodiments of the method, the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the brain.

[0245] In certain embodiments of the method, the dose of obicetrapib or salt thereof is effective to lower low density lipoproteins (LDL) concentrations in the CSF.

[0246] In certain embodiments of the method, the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the CNS.

[0247] In some embodiments of the method, the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the brain.

[0248] In some embodiments of the method, the dose of obicetrapib or salt thereof is effective to lower Ap aggregate concentrations within the CSF.

[0249] In another aspect, methods are provided 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.

[0250] In certain embodiments of the method, 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).

[0251] In some embodiments of the method, 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.

[0252] In certain embodiments of the method, amorphous obicetrapib hemicalcium is administered.

[0253] In various embodiments of the method, the subject is administered amorphous obicetrapib hemicalcium at a dose equivalent to 10 mg obicetrapib per day.6. EXAMPLES

[0254] 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.6.1. 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)6.1.1. Study Design and Duration

[0255] 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). Results are provided in Section 6.2.6.1.2. Objectives

[0256] 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.6.1.3. Inclusion Criteria

[0257] 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 status of E4ZE4 or E3 / E47. 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.8. Patient and care partner are willing to consent to all study procedures6.1.4. Exclusion Criteria

[0258] 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 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. 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 / mind. 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. 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 permitted 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. Regular use of cannabis or cannabis products, including non-prescription products containing cannabidiol (CBD) History of drug (including cannabis) or alcohol abuse within the last 5 years6.1.5. Retesting

[0259] 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.6.1.6. Rescreening

[0260] 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.6.1.7. Withdrawal Criteria

[0261] 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.

[0262] 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).

[0263] 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.6.1.8. Study Treatments

[0264] Participants are treated with obicetrapib 10 mg per day.6.1.8.1 Rationale for Dosing

[0265] 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.6.1.8.2 Randomization and Blinding

[0266] 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.6.1.8.3 Drug Supplies6.1.8.3.1 Formulation and Packaging

[0267] The study drugs consist of 5 mg obicetrapib tablets. All products are manufactured in accordance with current European Union Good Manufacturing Practice.

[0268] 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.

[0269] 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.

[0270] The physical, chemical, and pharmaceutical formulation properties and characteristics of the obicetrapib tablets are described in the Investigator’s Brochure.

[0271] All study drugs are labelled in accordance with all applicable local regulatory requirements.6.1.8.3.2 Study Drug Preparation and Dispensing

[0272] The study drugs used in this study are 5 mg obicetrapib tablets.

[0273] 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.6.1.8.3.3 Study Drug Administration

[0274] 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.6.1.8.3.4 Treatment Compliance

[0275] 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.6.1.8.3.5 Storage and Accountability

[0276] All study drugs are stored below 25°C in a secure area with access limited to the Investigator and authorized site personnel.

[0277] 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.6.1.9. Prior and Concomitant Medications and / or Procedures6.1.9.1 Excluded Medications and / or Procedures

[0278] Any lipid-altering therapy other than the investigational study drug is prohibited during the study.6.1.9.2 Documentation of Prior and Concomitant Medication Use

[0279] 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.6.1.10. Study Procedures

[0280] Study procedures follow the Schedule of Procedures:APOE 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.6.1.10.1.1 Clinical Laboratory Evaluations

[0281] 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.

[0282] 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, A 1-4O, AP1-42 / AP1-40 ratioNeurograninNeurofilament lightGFAP (glial fibrillary acidic protein)YKL40PDGFRb.

[0283] 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.Estimated glomerular filtration rate is calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. At the Screening Visit only, the hematology panel includes HbAlc, INR, PT and PTT.

[0284] Urine is obtained as indicated in the Schedule of Procedures and is sent to a central laboratory for complete urinalysis.

[0285] A urine pregnancy test is performed only prior to participation in the study at the screening visit.6.1.10.1.2 Electrocardiograms

[0286] A single, standard 12-lead ECG is performed by the Investigator or trained site personnel at the Screening Visit and centrally read.6.1.10.1.3 Physical Examinations

[0287] A physical examination is performed as indicated in above Schedule of Procedures.6.1.11. Efficacy Assessments

[0288] 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.

[0289] 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), atDay 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 (Visit1) 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).

[0290] Additional secondary efficacy endpoints specific to AD biomarkers in CSF:• 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,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).

[0291] 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 AP1-42, 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).

[0292] 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).• 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).6.2. Example 2: Quantitative Analysis of Apolipoproteins and Other Biomarkers in Alzheimer’s Disease Patients Treated with Obicetrapib Following Phase 2 A Study

[0293] 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.

[0294] 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.

[0295] Additionally, using an immunoaffinity-mass spectrometer approach, we assessed the impact of obicetrapib on apolipoprotein E isoform ratios of E3ZE4 in plasma and CSF.6.2.1. Methods

[0296] Sample Preparation: CSF samples (15 pL) were processed using WatersProteinWorks eXpress Direct Digest Kit including reduction, alkylation, and overnightdigestion 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.

[0297] LC-MS / MS Assay: Tryptic peptides were quantified using an ACQUIT Y UPLC IT- Class coupled to a TQ-XS triple quadrupole mass spectrometer fitted with a CORTECS Premier T3 Column (1.6 pm, 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.

[0298] 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.

[0299] 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 0.05.6.2.2. Results I: ApoE, Clusterin (ApoJ)

[0300] In CSF, healthy controls displayed significantly lower total ApoE concentration compared to baseline AD samples. See Peptide 3, FIG. 3C (p = 0.004).

[0301] In CSF, ApoE3 / E4 ratios fell between visits 2 and 6 in two out of three subjects.See FIG. 2B. In one subject, CSF ApoE3ZE4 ratio fell between visits 2 and 4, and then rose somewhat between visits 4 and 6.

[0302] Plasma apolipoprotein (Apo) isoforms E3 / E4 ratios rose in 4 out of 5 subjects from visit 1 to visit 6. FIG. 2A. The subject whose CSF E3 / E4 ratio had increased between visits 4 and 6 (subject 1-005), showed a rise in plasma ApoE3ZE4 ratio between visit 2 and visit 4, subsequent to which the ratio fell. See FIG. 2A.

[0303] 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).6.2.3. Results II: Biomarkers

[0304] 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.Table 2: CSF Oxysterol Levels Following Treatment with 10 mg ObicetrapibTable 2: CSF Oxysterol Levels Following Treatment with 10 mg Obicetrapib

[0305] In addition, an increase of 8% in the AP42 / 40 ratio in patient 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.

[0306] Additionally, increases in levels of antioxidants were observed after 6 months of obicetrapib therapy in subjects with ApoE3 / ApoE4 alleles or ApoE4 / ApoE4 alleles. Levels of lutein (FIG. 11) and a-tocopherol (FIG. 12) were increased after 6 months of obicetrapib therapy compared to the levels measured at baseline. Further, patients with ApoE3 / ApoE4 alleles also had an increase in the level of zeaxanthin in the CSF after 6 months of obicetrapib therapy compared to levels measured at baseline (data not shown).Table 8: CSF Amyloid-P protein concentrations in pg / mL6.3. Example 3: Mendelian Randomization analysis of the effect of lower CETP concentration on plasma lipids, cardiovascular disease outcomes, and neurodegenerative disease6.3.1. Methods

[0307] 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”.6.3.2. Statistical Analysis

[0308] 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 EggerQ-statistic to decide which method provides the best model to describe the available data and hence optimizes the bias-variance trade-off.

[0309] 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.6.3.3. Results and DiscussionEffects of Lower CETP Concentration on Biomarker Traits

[0310] 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.

[0311] 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).Effects of Lower CETP Concentration on Cardiovascular Outcomes

[0312] We confirmed that lower plasma CETP concentration decreased the risk of CHD (OR 0.92, 95%CI 0.89; 0.96, p-value 2.47x 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 cv.s-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

[0313] 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 2.95x 10), where APOE4- s4 status modified this association: LBD \n APOE-?A carriers (OR 0.61, 95%CI 0.51; 0.73, p-value 4.91 x 10), and non APOE-& 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 / 102). The apolipoprotein (both Apo-Al and Apo-B) weighted analyses replicated the LBD m 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

[0314] 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 inclinical 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

[0315] 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 APOE-e.4 carriers - compatible with the previously observed protective effect of loss-of-function CETP variants in APOE-e.4 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-e.4 dependent lipid metabolism and / ? -amyloid aggregation and degradation.

[0316] 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 APOE- 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 APOE-e.4 positive carriers.6.4. Example 4: Obicetrapib on Top of Maximum Tolerated Lipid- Modifying Therapies (BROADWAY): assessment of biomarkers involved with neurodegeneration and inflammation

[0317] This study (NCT05142722) was 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).6.4.1. Obicetrapib

[0318] Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Obicetrapib was administered at 10 mg orally, once daily, to patients in the treatment group.6.4.2. Study Design

[0319] This was a multicenter, placebo-controlled, double-blind, randomized, Phase 3 study in approximately 2500 participants with underlying HeFH and / or a history of ASCVD not adequately controlled by maximum tolerated doses of 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 self-administered their assigned study drug once daily until Day 365. Unless otherwise stated, Baseline values were the last non-missing measurements taken prior to the participant receiving study drug.

[0320] Key inclusion criteria included 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 was defined by at least 1 of the following conditions: coronary artery disease, cerebrovascular disease, and peripheral arterial disease. The patients were 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 took high-intensity statin therapy (HIS), which included: Atorvastatin 40 and 80 mg; and Rosuvastatin 20 and 40 mg. The patients had 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 had 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.

[0321] Key exclusion criteria included 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 x ULN, and creatine kinase (CK) >3 x ULN.6.4.3. Objectives of the Study

[0322] The primary objective of this study was 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.

[0323] The secondary objectives of this study included 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 included evaluating the effect of obicetrapib on CV death, non- fatal MI, non-fatal stroke, or non-elective coronary revascularization. The secondary objectives further included 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.

[0324] An additional objective of this study was 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, including in ApoE4 carriers. ApoE status was determined using ApoE isoform phenotyping, with participants classified into standard allelecombination subtypes: ApoE2ZE2, ApoE2ZE3, ApoE2ZE4, ApoE3ZE3, ApoE3ZE4, or ApoE4ZE4.

[0325] P-tau217 outcomes were assessed in the overall analysis population and separately for all ApoE4 carriers (E2ZE4, E3ZE4, E4ZE4), ApoE carriers excluding ApoE2ZE4, ApoE3ZE4, and ApoE4ZE4. Other biomarkers were assessed overall and separately for ApoE4 carriers (excluding ApoE2ZE4), ApoE3ZE4, and ApoE4 / E4. Additional analyses examined correlations between changes in AD biomarkers and concurrent changes in lipid parameters, as well as associations with achieved obicetrapib plasma concentrations.

[0326] The exploratory objectives of this study included 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 (14b Ale), homeostatic model assessment of insulin resistance (HOMA-IR), and blood glucose. The exploratory objectives further included evaluating the effect of obicetrapib on hospitalization for unstable angina and / or chest pain, hospitalization for heart failure (HF), and transient ischemic attack (TIA).6.4.4. Inclusion Criteria

[0327] Ages eligible for study were 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.6.4.5. 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;• 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.6.4.6. Efficacy Endpoints

[0328] The primary efficacy endpoint was the percent change from Baseline to Day 84 in LDL-C in the obicetrapib group compared to the placebo group.

[0329] The secondary efficacy endpoints included 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;• 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.

[0330] The exploratory efficacy endpoints included 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.6.4.7. Interim Neurodegeneration biomarker results

[0331] Obicetrapib favorably affected biomarkers involved with neurodegeneration and inflammation in subjects showing no evidence of cognitive impairment prior to firstadministration of obicetrapib, compared with placebo, particularly in subjects who have at least one apoE4 allele. Results are provided in Table 14.

[0332] Results showed that obicetrapib at 10 mg orally once daily for a course of 12 months significantly lowered LDL-C by 33%, and increased HDL-C by 125% relative to placebo.Additionally, treatment with obicetrapib substantially attenuated increase in plasma p-tau217 versus placebo. Results showed a 1.1% median change in subjects receiving obicetrapib versus 4.8% median change in subjects receiving the placebo (p=0.01 ). Additionally,treatment with obicetrapib at 10 mg was effective to greatly attenuate increase in p- tau217 / Ap42:Ap40 ratio over the course of 12-month treatment (2.7% obicetrapib vs. 6.5% placebo; p=0.006).

[0333] Notably, ApoE4 carriers had greater baseline p-tau217 levels when compared with non-carriers (0.47 pg / ml vs 0.39 pg / ml; p<0.0001). ApoE4 carriers also showed greater response to obicetrapib versus non-carriers. 10 mg obicetrapib was effective to stabilize p- tau217 levels in ApoE4 carriers (0% increase vs. 5.7% with placebo; p=0.03). Additionally, 10 mg obicetrapib reduced increases in the p-tau217 / Ap42:Ap40 ratio (2.1% vs. 10.2% placebo; p=0.005). Results also showed that in ApoE4 carriers placebo arm, p-tau217 and p- tau217 / Ap42:Ap40 ratio greatly increased as a function of increased age over 60. Notably, obicetrapib produced a greater reduction in median percent change for p-tau217 and p- tau217 / Ap42:Ap40 ratio as a function of said increased age. FIGs. 13 and 14.

[0334] Results of this study showed that obicetrapib is effective to slow progression of AD biomarkers over the course of 12 months, particularly p-tau217 and p-tau217 / Ap42:Ap40 ratio in plasma in trial subjects, particularly those who have at least one apoE4 allele and no evidence of cognitive impairment prior to first administration of obicetrapib, compared with placebo.6.4.8. 12-Month End of Study Data Collection and Analysis

[0335] Biomarker measurements were performed as follows: Plasma p-tau217 concentrations were measured using the ALZpath SIMOA pTau-217 v2 assay (ALZpath Inc.) performed on the Quanterix HD-X analyzer instrument. Plasma p-taul81 was quantified using the Simoa pTau-181 Advantage V2.1 kit on the HD-l / HD-X platform (Quanterix Corporation). Both assays utilized EDTA-plasma samples and were conducted in clinical laboratory improvement amendments (CLIA)-certified laboratories following established protocols for single molecule array (SIMOA) digital immunoassay technology. Other AD biomarkers were analyzed using similar high-sensitivity immunoassay platforms appropriate for each analyte as is the state of the art.

[0336] Blood samples for AD biomarker assessment were collected at baseline (Visit 2) and at 12 months (Visit 7) as part of the stored sample collection protocol. Sample handling required immediate placement on wet ice prior to centrifugation at 4°C. When cooled centrifuges were unavailable, centrifuge racks were pre-cooled for 30 minutes at -20°Cbefore centrifugation. These standardized conditions were critical for preserving sample integrity, especially for amyloid-beta peptides which degrade readily at ambient temperature.

[0337] Baseline characteristics were summarized by median (QI, Q3) for continuous data and n (%) for categorical data; comparisons between ApoE status (pooled across treatment groups) were by Kruskal-Wallis or chi-square tests. Treatment group differences in absolute and percent changes in AD biomarkers from baseline to end of study were analyzed by robust regression with M-estimation due to the presence of outliers. Treatment group means and 95% confidence intervals (Cis) were estimated unadjusted for baseline characteristics as well as adjusted for mean-centered baseline biomarker values and age. Unadjusted treatment group means and Cis were also estimated for selected subgroups.

[0338] Loess curves of predicted changes in p-tau217 were estimated from a robust regression model with terms for mean-centered baseline p-tau217, treatment group, meancentered age, and the interaction between treatment and age, and plotted as a function of age. Predicted changes were also plotted as a function of baseline p-tau217. The likelihood of having end-of-study p-tau217 >0.42 pg / mL among the subset below this threshold at baseline was compared between treatment groups with logistic regression including baseline p-tau217 and age as covariates. Relationships between end-of study obicetrapib concentration, time- averaged achieved lipid and lipoprotein concentrations, and absolute change in p-tau217 were estimated by Spearman correlations.

[0339] Two-tailed p-values less than 0.05 were considered statistically significant, with no adjustment for multiplicity. Analyses were performed in SAS, version 9.4 (SAS Institute) by an independent academic statistician who had access to the raw data.6.4.9. 12-Month End-of-Study Results

[0340] Significant baseline differences in p-tau217 levels were observed according to APOE status. E2 carriers demonstrated the lowest p-tau217 concentrations (median 0.36-0.39 pg / mL), while E3ZE3 patients showed intermediate levels (0.39-0.40 pg / mL). APOE4 carriers exhibited progressively elevated p-tau217 levels, with E3ZE4 heterozygotes showing higher concentrations (0.43-0.50 pg / mL) and E4ZE4 patients displaying the highest baseline levels (0.56-0.57 pg / mL), representing approximately a 45% increase compared to E3ZE3 carriers. Similar patterns were observed for AP42 / 40 and p-tau217 / (Ap42 / 40), with E4 carriers having concentrations indicating greater pathology relative to the other APOE status groups.

[0341] APOE4 carriers showed higher baseline p-tau217 levels than non-carriers and notably demonstrated more pronounced treatment responses. In APOE4 carriers overall, obicetrapib reduced p-tau217 increases (1.45% vs 7.19% with placebo; P = 0.022) and p- tau217 / Ap42:40 ratio increases (2.95% vs 11.61%; P = 0.020). APOE4 homozygotes experienced a 7.81% decrease in p-tau217 with obicetrapib versus a 12.67% increase with placebo (P = 0.010), representing a 20.5% treatment difference.

[0342] P-tau217and GFAP levels followed similar APOE4-dependent patterns, with E4ZE4 patients showing the highest values (ratios nearly double those of E3ZE3 carriers), while baseline Ap42:40 ratio, neurofilament light chain, and p-taul81 levels were generally similar across APOE status.

[0343] Tables 15 and 17 summarize the baseline characteristics of the various ApoE status group populations.Note: values in table are n (%) or median (QI, Q3)*P-values for comparisons between ApoE status (pooled across treatment groups) by Kruskal- Wallis or chi-square tests6.4.9.1 Obicetrapib Therapy on AD Biomarkers

[0344] Over the course of the 12-month treatment period, obicetrapib demonstrated significant effects on multiple AD biomarkers. ApoE4 carriers displayed the most pronounced beneficial response to obicetrapib therapy. Results are summarized in Table 16.Note: values in table are mean (95% CI)*Results reflect adjustment for mean-centered baseline p-tau217 and mean-centered age.P-tau217

[0345] In the overall treated population, obicetrapib significantly attenuated p-tau217 progression compared to placebo. The adjusted percent change was 1.99% (95% CI, 0.54 to 3.34) vs 4.98% (95% CI, 2.95 to 7.01), representing a 3% reduction from placebo (p=0.019). However, the most pronounced treatment group differences were observed in ApoE4 carriers (E2 / E4, E3 / 34, E4 / E4).

[0346] When the population was limited to ApoE4 carriers (E2ZE4, E3ZE4, E4 / E4) and analyzed together, obicetrapib treatment yielded a significantly smaller increase of 1.92% (95% CI, -0.95 to 4.79) compared to an increase of 6.91% in placebo (95% CI, 2.98 to 10.85), or a 4.99% difference in means (p=0.041).

[0347] When ApoE4 carriers were restricted to ApoE3ZE4 and ApoE4ZE4, the results showed a substantially better response with obicetrapib (1.45% increase; 95% CI, -1.47 to 4.38) compared to placebo (7.19% increase; 95% CI, 3.18 to 11.2; p=0.022). Obicetrapib provided a 5.74% benefit versus placebo.

[0348] The treatment effect was most evident in APOE4ZE4 patients. In these patients, obicetrapib reduced p-tau217 levels by 7.81% (95%CI, -18.21 to 2.60) while placebo showed a 12.67% (95% CI, 0.85 to 24.49) increase (p=0.010), yielding a 20.5% improvement over placebo.

[0349] Additionally, the effect of placebo treatment and obicetrapib was analyzed in ApoE4 carriers in subgroups of increasing age and therefore at progressively greater risk for Alzheimer’s disease (AD) pathology. The data show that the deterioration in the placebo group and the protective effects of obicetrapib in the obicetrapib-treated ApoE4 population tended to increase with age and pathological risk. See FIG. 15. In ApoE4 carriers aged >60 years (n=283), obicetrapib resulted in a 2.23% adjusted mean increase versus 7.63% with placebo, yielding a 5.40% difference (p=0.06). Among those aged >65 years (n=223), the adjusted mean increases were 1.81% for obicetrapib versus 7.83% for placebo, representing a 6.02% difference (p=0.06). Finally, among those aged >70 years (n=139), obicetrapib yieldeda 6.39% adjusted mean increase compared to 14.78% with placebo, translating to 8.39% difference (p=0.039). See FIG. 15.

[0350] Applicants studied the relationship between age, p-tau217 at baseline, and p-tau217 change from treatment. FIG. 16A illustrates the relationship between continuous age and absolute change in p-tau217 by treatment group for the overall analysis population. FIG. 16B illustrates the relationship between continuous age and absolute change in p-tau217 by treatment group for ApoE4 carriers.

[0351] In the placebo group, absolute increases tended to be greater among older participants in the overall analysis population (P=0.029), but not in the subset of ApoE4 carriers (P=0.62). FIG. 16A-16B. The interaction p-value between age and treatment was 0.61 for the overall analysis population and 0.58 in the subset of ApoE4 carriers, indicating that the reduction in absolute change by obicetrapib relative to placebo did not depend on age.

[0352] The relationship between absolute change in p-tau217 and continuous p-tau217 by treatment group is shown in FIGs. 17A-17B. Significant interactions between baseline p- tau217 and treatment groups were observed in the overall analysis population (FIG. 17A) and the subset of APOE4 carriers (FIG. 17B). The interaction p-value between baseline p-tau217 and treatment was <0.0001 for both the overall analysis population and the subset of ApoE4 carriers, indicating higher baseline concentrations were associated with greater decreases in p-tau217 with obicetrapib treatment relative to placebo. Furthermore, among those with baseline p-tau217 concentrations below 0.42 pg / mL, fewer participants in the obicetrapib group exceeded this threshold at study end compared to placebo [15.9% vs 20.9%; OR (95% CI) = 0.54 (0.36, 0.82), p=0.0041]. We note that while there were greater increases in p- tau217 with higher baseline concentrations in the placebo group, there were greater corresponding decreases in the obicetrapib group.AB42 / 40

[0353] No significant differences in AP42 / 40 were observed in the overall population. However, it is noted that obicetrapib limited decreases in the AP42 / 40 ratio in ApoE4 / E4 patients: 0.36% (95% CI, -3.90 to 3.18) decrease with obicetrapib versus a 8.32% (95%CI, - 13.43 to -3.21) decrease with placebo (p=0.013). FIG. 18.P-tau217 / (AB42 / 40)

[0354] Obicetrapib significantly limited increases in this ratio across all participants (2.51%, 95% CI, 0.90 to 4.12; vs 6.55%, 95% CI, 4.30 to 8.80 with placebo; p=0.004), representing a 4.04% improvement. The effect was particularly pronounced in APOE4 carriers. The combined E3ZE4 and E4 / E4 groups showed a 2.95% (95% CI, -0.32 to 6.23) increase with obicetrapib versus 11.61% (95% CI, 7.13 to 16.10) with placebo (p=0.020), and yielded a 8.66% benefit. E4ZE4 patients showed a 1.67% (95% CI, -14.97 to 11.62) decrease with obicetrapib while experiencing a 21.0% (95% CI, 5.26 to 36.69) increase with placebo, representing a 22.7% improvement over placebo (p=0.032). FIG. 18.Glial Fibrillary Acidic Protein (GFAP)

[0355] Changes in GFAP showed a trend toward benefit in the overall population. The GFAP changes did not reach statistical significance 1.48% for obicetrapib (95% CI, 0.28 to 2.68) vs 3.40% for placebo (95% CI, 1.72 to 5.07) (p=0.07), representing a -2.0% difference between the groups. However, E4 / E4 patients notably demonstrated a 6.39% (95% CI, -12.78 to -0.01) decrease with obicetrapib compared to an 8.85% (95% CI, -0.58 to 17.12) increase with placebo, representing a 15.2% benefit over placebo (p=0.006). FIG. 18.Neurofilament Light (NFL)

[0356] Treatment effects on NFL were generally modest across most groups. However, ApoE4 / E4 patients showed a significant difference, with obicetrapib associated with a 10.49% (95% CI, -20.84 to -0.14) decrease versus a 6.82% (95% CI, -6.12 to 19.76) increase with placebo, representing a 17.3% improvement over placebo (p=0.020). FIG. 18.P-taul81

[0357] Overall changes in p-taul81 were not significantly different between treatment groups (1.27%, 95% CI, -0.211 to 2.76; vs 1.68%, 95% CI, -0.41 to 3.76, with placebo; p=0.76), representing a 0.41% difference. However, ApoE4 / E4 patients showed a notable 10.51% (95% CI, -18.82 to -2.19) decrease with obicetrapib compared to a 3.16% (95% CI, - 7.64 to 13.97) increase with placebo, representing a 13.7% improvement over placebo (p=0.06). FIG. 18.Lipid and Obicetrapib Concentration and P-tau217 Change are Correlated

[0358] The presented data shows a correlation between lipids and obicetrapib concentration and p-tau217 change in ApoE4 carriers. APOE4 carriers showed that higher achieved HDL-C and lower achieved LDL-C scores, as well as lipoprotein(a) and ApoB, were associated withdecreases in p-tau217. Most importantly, the pharmacokinetic levels of obicetrapib had the strongest relationship with efficacy toward p-tau217. Specifically, obicetrapib plasma concentration had strong and statistically significant negative correlations with p-tau217 change (r=-0.64 and -0.61 for absolute and percent change, respectively), indicating higher end-of-study levels were associated with greater decreases in p-tau217. Table 23.

[0359] In summary, the data show that obicetrapib treatment is capable of significantly modifying the progression of blood biomarkers of AD pathology, notably p-tau 217, over a 12-month period. The greatest magnitude of neuroprotective benefit was observed in ApoE4 carriers. It is specifically noted that significant effects were observed between baseline p-tau 217 and treatment groups (Pinteraction<0.0001) with greater increases in p-tau217 with higher baseline concentrations in the placebo group, and greater corresponding decreases in the obicetrapib group. In addition, all participants in the obicetrapib arm, had a significant decrease in the conversion to elevated p-tau217 defined by the threshold of 0.42pg / ml (p=.004), suggesting that these results suggest that obicetrapib may also have benefits for prevention of AD beyond those with APOE4 genotype.

[0360] These findings have important implications for AD prevention, particularly for APOE4 patients who currently have no effective prevention options. The ability to reduce pathological biomarker progression suggests potential for altering disease trajectory in this population. Future research should include dedicated prevention trials in asymptomatic APOE4 carriers and mechanistic studies to optimize (combined) treatment approaches.Note: values in table are mean (95% CI)♦Results reflect adjustment for mean-centered baseline AB42 / 40 and mean-centered age.Note: values in table are mean (95% CI)*Results reflect adjustment for mean-centered baseline p-tau217 / (AB42 / 40) and mean-centered ageNote: values in table are mean (95% CI)♦Results reflect adjustment for mean-centered baseline GFAP and mean-centered age.Note: values in table are mean (95% CI)*Results reflect adjustment for mean-centered baseline NFL and mean-centered age.Note: values in table are mean (95% CI)’Results reflect adjustment for mean-centered baseline o-taul81 and mean-centered ageNote: time-averaged achieved lipids and lipoproteins were calculated with all available values from baseline to end of study using the linear trapezoidal rule and observed assessment times relative to baseline.7. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0361] 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.

[0362] 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.

Claims

WHAT IS CLAIMED IS:

1. A method of attenuating plasma phosphorylated Tau 217 (p-Tau217) in a subject in need thereof, the method comprising: orally administering 10 mg per day of obicetrapib, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject, for at least 12 months.

2. The method of claim 1, wherein the method is effective to attenuate increase in p- Tau217 in plasma of the subject by 10% of the increase in p-Tau217 observed in the subject for 12 months to prior to the first administration of obicetrapib.

3. The method of claim 1, wherein the method is effective to attenuate increase in p- Tau217 in plasma of the subject by 30% of the increase in p-Tau217 observed in the subject for 12 months to prior to the first administration of obicetrapib.

4. The method of claim 1, wherein the method is effective to attenuate increase in p- Tau217 in plasma of the subject by 40% of the increase in p-Tau217 observed in the subject for 12 months to prior to the first administration of obicetrapib.

5. The method of any one of claims 1-4, wherein the subject is determined to have a plasma concentration of p-Tau217 greater than 0.42 pg / mL prior to first administration of obicetrapib.

6. The method of any one of claims claim 1-5, wherein the method is effective to attenuate decrease in the AP42 / 40 ratio in the plasma of the subject.

7. The method of claim 6, wherein the method is effective to attenuate decrease in the AP42 / 40 ratio in plasma of the subject by 20% of the decrease in AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

8. The method of claim 6, wherein the method is effective to attenuate decrease in the AP42 / 40 ratio in plasma of the subject by 30% of the decrease in AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

9. The method of claim 6, wherein the method is effective to attenuate decrease in the AP42 / 40 ratio in plasma of the subject by 40% of the decrease in AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

10. The method of claim 6, wherein the method is effective to attenuate decrease in the AP42 / 40 ratio in plasma of the subject by 50% of the decrease in AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

11. The method of claim 10, wherein the method is effective to stabilize the AP42 / AP40 ratio in the plasma of the subject.

12. The method of any one of claims 1-11, wherein the method is effective to attenuate increase in the ratio of p-Tau217 to the AP42 / 40 ratio in the plasma of the subject.

13. The method of any one of claims 1-12, wherein the method is effective to attenuate increase in the ratio of p-Tau217 to the AP42 / 40 ratio in plasma of the subject by 10% of the increase in the ratio of p-Tau217 to the AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

14. The method of any one of claims 1-12, wherein the method is effective to attenuate increase in the ratio of p-Tau217 to the AP42 / 40 ratio in plasma of the subject by 20% of the increase in the ratio of p-Tau217 to the AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

15. The method of any one of claims 1-12, wherein the method is effective to attenuate increase in the ratio of p-Tau217 to the AP42 / 40 ratio in plasma of the subject by 30% of the increase in the ratio of p-Tau217 to the AP42 / 40 ratio observed in the subject for 12 months to prior to the first administration of obicetrapib.

16. The method of any one of claims 1-15, wherein the method is effective to stabilize the ratio of p-Tau217 to the AP42 / 40 ratio in the plasma of the subject.

17. The method of any one of claims 1-16, wherein the subject has at least one ApoE4 allele18. The method of claim 17, further comprising the prior step of determining the ApoE isoform status of the subject.

19. The method of claim 18, wherein the ApoE isoform status of the subject is determined by ApoE isoform phenotyping.

20. The method of claim 18, wherein the ApoE isoform status of the subject is determined by genotyping.

21. The method of any one of claims 1-20, wherein the subject is at least 60 years old.

22. The method of any one of claims 1-21, wherein the subject is at least 65 years old.

23. The method of any one of claims 1-22, wherein the subject is at least 70 years old.9424. The method of any one of claims 1-23, wherein the subject is determined to be without evidence of cognitive impairment prior to first administration of obicetrapib.

25. The method of any one of claims 1-23, wherein the subject is determined to have cognitive impairment prior to first administration of obicetrapib.

26. The method of any one of claims 1-25, 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).

27. The method of claim 26, wherein the subject has been diagnosed with or is at risk for developing AD.

28. The method of claim 27, wherein the subject has been diagnosed with or is at risk for developing late onset AD (LOAD).

29. The method of claim 26, wherein the subject has been diagnosed with or is at risk for developing Lewy Body dementia.

30. The method of claim 26, wherein the subject has been diagnosed with or is at risk for developing Parkinson’s disease.

31. The method of clam 26, wherein the subject has been diagnosed with dementia associated with Parkinson’s disease.

32. The method of claim 26, wherein the subject has been diagnosed with or is at risk for developing MS.

33. The method of claim 26, wherein the subject has been diagnosed with or is at risk for developing relapsing remitting MS.

34. The method of any one of claims 1-33, wherein the subject has been diagnosed with mild cognitive impairment (MCI).

35. The method of claim 34, wherein the subject has been determined, prior to administration of obicetrapib, to test positive for Ap aggregates within the brain.

36. The method of any one of claims 1-35, 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, as95compared to a healthy control population that does not have and that is not at elevated risk for neurodegenerative disease.

37. The method of any one of claims 1-36, 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.

38. The method of any one of claims 1-37, wherein the subject has been determined, prior to treatment, to have abnormal patterns of Tau based on Tau PET imaging.

39. The method of any one of claims 1-38, wherein the dose of obicetrapib 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.

40. The method of any one of claims 1-39, wherein the dose of obicetrapib 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.

41. The method of any one of claims 1-40, wherein the subject, prior to first administration of obicetrapib, has a fasting serum LDL-C >100 mg / dL.

42. The method of any one of claims 1-41, wherein the subject is suffering from HeFH and / or ASCVD.

43. The method of any one of claims 1-42, wherein the subject prior to the first administration of obicetrapib, in on maximally tolerated lipid-modifying therapy.

43. The method of claim 42, wherein the maximally tolerated lipid-modifying therapy comprises at least one treatment selected from the group consisting of: a statin at a maximally tolerated stable dose, ezetimibe, bempedoic acid, a proprotein convertase subtilisin / kexin type 9 (PCSK9)-targeted therapy, a fibrate other than gemfibrozil, and combinations thereof.9644. The method of claim 43, wherein the subject, prior to first administration of obicetrapib, is on high-intensity statin therapy (HIS).

45. The method of claim 44, wherein the high-intensity statin therapy (HIS) is atorvastatin at 40 mg or 80 mg.

46. The method of claim 44, wherein the high-intensity statin therapy (HIS) is rosuvastatin at 20 mg or 40 mg.

47. The method of any one of claims 1-41, wherein the subject is not in need of lipid lowering therapy.

48. The method of any one of claims 1-41, wherein the subject prior to first administration of obicetrapib has a fasting serum LDL-C <100 mg / dL.

49. The method of any one of claims 1-48, wherein a calcium salt of obicetrapib is administered to the subject.

50. The method of claim 49, wherein obicetrapib hemicalcium is administered to the subject.

51. The method of claim 50, wherein the obicetrapib hemicalcium is amorphous.

52. The method of any one of claims 1-51, wherein obicetrapib or pharmaceutically acceptable salt thereof is administered in a solid dosage form.

53. The method of claim 52, wherein the solid dosage form is a tablet.

54. The method of claim 53, wherein the tablet further comprises a film coating.

55. The method of any one of claims 52-54, wherein the solid dosage form comprises a calcium salt of obicetrapib.

56. The method of any one of claims 52-54, wherein the calcium salt of obicetrapib is amorphous.

57. The method of any one of claims 52-54, wherein the solid dosage form comprises obicetrapib hemicalcium.

58. The method of any one of claims 52-54, or 57, wherein the obicetrapib hemicalcium is amorphous.97

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