METHODS FOR TREATING HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HeFH)

Abstract

The disclosure provides methods of treating heterozygous familial hypercholesterolemia (HeFH), more particularly in subjects who require additional lowering of low-density lipoprotein cholesterol (LDL-C). The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

Description

METHODS FOR TREATING HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HeFH)1. CROSS- REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 583,045, filed on September 15, 2023, and 63 / 675,704, filed on July 25, 2024, which are hereby incorporated in their entireties by reference.2. BACKGROUND

[0002] Elevated low-density lipoprotein cholesterol (LDL-C) is a major modifiable risk factor for the development of cardiovascular disease (CVD). Lowering LDL-C has been shown to reduce the risk of cardiovascular (CV) events, and the risk reduction is linearly proportional to the absolute LDL-C reduction. Lowering LDL-C is the primary therapeutic lipid target in atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH) patients. Intensive LDL-C lowering relative to modest reduction confers a greater benefit in patients at high CV risk.

[0003] Statins are generally the drug of first choice in treating dyslipidemia. Statins are considered first line therapy for reducing LDL-C levels. However, two thirds of patients do not achieve acceptable levels of LDL-C with statins alone, even with high-intensity statin therapy (HIS). Therefore, there is an unmet need in clinical practice for safe and efficacious pharmacological treatment modalities for patients who require additional lowering of LDL-C.3. SUMMARY

[0004] In a general aspect, methods of treating heterozygous familial hypercholesterolemia (HeFH) in a subject are provided. The method comprises administering to the subject a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] 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:

[0006] FIG. l is a schematic of the study design for evaluation of the effect of obicetrapib in patients with heterozygous familial hypercholesterolemia (HeFH).

[0007] FIG. 2A-2B shows mean percent change in low density lipoprotein-C (LDL-C) in patients with HeFH receiving once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) versus placebo at day 84 and day 365. FIG. 2A visually displays this mean percent change versus placebo as a bar graph. FIG. 2B visually displays this mean percent change versus placebo as a line graph.

[0008] FIG. 3 is a bar graph comparing mean percent change in low density lipoprotein-C (LDL-C) in patients with HeFH receiving one daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) versus placebo against mean percent change in LDL-C observed for 10 mg obicetrapib in our prior studies: Japan study (NCT05421078), ROSE study (NCT04753606), and ROSE2 study (NCT05266586) (pO.0001).

[0009] FIG. 4A-4B shows mean percent change in non-high density lipoprotein-C (non- HDL-C) patients with HeFH receiving once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) versus placebo. FIG. 4A is a bar graph displaying mean percent change in non-HDL-C patients with HeFH receiving obicetrapib versus placebo at day 84 (p<0.0001). FIG. 4B is a bar graph comparing mean percent change from baseline in non-HDL-C in patients with HeFH receiving once daily 10 mg obicetrapib versus placebo at day 84 with the mean percent change in non-HDL-C observed for 10 mg obicetrapib in our prior studies: Japan study (NCT05421078), ROSE study (NCT04753606), and ROSE2 study (NCT05266586) (pO.0001).

[0010] FIG. 5 A-5B shows mean percent change in apoprotein B (ApoB) in patients with HeFH receiving once daily 10 mg obicetrapib versus placebo. FIG. 5 A is the mean percent change in ApoB in patients with HeFH receiving once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) versus placebo at day 84. FIG. 5B is a bar graph comparing the mean percent change from baseline in apoprotein B (ApoB) in patients with HeFH receiving once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) at day 84 with the mean percent change in ApoB observed in patients in our prior studies for 10 mg obicetrapib: JAPAN (NCT05421078); ROSE (NCT04753606); and ROSE2 (NCT05266586) (pO.0001).

[0011] FIG. 6 is a bar graph showing mean percent change in lipoprotein (a) (Lp(a)) in patients with HeFH receiving once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) versus placebo.

[0012] FIG. 7A-7B are waterfall plots showing mean percent change from baseline in LDL-C as of day 84 in patients with HeFH following administration of once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) or placebo. FIG. 7A is a waterfall plot showing mean percent change from baseline in LDL-C as of day 84 in patients with HeFH receiving obicetrapib. FIG. 7B is a waterfall plot showing mean percent change from baseline in LDL-C as of day 84 in patients with HeFH receiving placebo.

[0013] FIG. 8 is a stacked bar graph displaying percentage of patients to reach LDL-C goal of less than 100 mg / dL and what percentage of patients were able to achieve an LDL-C goal of less than 70 mg / dL, following administration of once daily 10 mg obicetrapib on top of maximally tolerated lipid-modifying therapy (standard of care therapy (SoC)) versus placebo, from baseline.5. DETAILED DESCRIPTION5.1. Definitions

[0014] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains.

[0015] The term “subject” refers to a human or non-human mammal, including, but not limited to, bovine, equine, canine, ovine, feline, and rodent, including murine and rattus, subjects. A “patient” is a human subject in need of treatment.

[0016] As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder, and / or signs or symptoms associated therewith, or slowing or halting the progression thereof. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.

[0017] As used herein, “pre-treatment” means prior to the first administration of obicetrapib according the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than obicetrapib.

[0018] As used herein, “post-treatment” means after the administration of obicetrapib according the methods described herein. Post-treatment includes after any administration of obicetrapib at any dosage described herein. Post-treatment also includes after the treatment phase of obicetrapib.

[0019] 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.

[0020] The term “biological sample” refers to any tissue, cell, fluid, or other material derived from an organism (e.g., human subject). In certain embodiments, the biological sample is serum, plasma, or blood.5.2. Methods of Treating Heterozygous Familial Hypercholesterolemia (HeFH)5.2.1 Heterozygous Familial Hypercholesterolemia (HeFH)

[0021] In a first aspect, methods of treating heterozygous familial hypercholesterolemia (HeFH) in a subject are provided. The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0022] In some embodiments, the presence of HeFH is determined by genotyping. In some embodiments, HeFH is determined by clinical assessment.

[0023] In some embodiments, subject is at risk for development of accelerated vascular disease, heart attack and / or stroke. In some embodiments the subject is at risk for coronary artery disease (CAD). 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.

[0024] In some embodiments the subject is at least 30, 35, 40, 45, 50, 55, 60, 65, or 70 years old.5.2.2 Dose Regimen

[0025] In various embodiments, obicetrapib or pharmaceutically acceptable salt thereof is administered orally. Whenever a salt is administered, the dose is expressed as the amount of the obicetrapib anion within the salt.

[0026] In typical embodiments, obicetrapib is administered as a tablet for oral administration. In various embodiments, the dose of obicetrapib or salt thereof is 2.5-25 mg by mouth per day (2.5-25 mg po QD). In some embodiments, the dose of obicetrapib or salt thereof is 5-20 mg by mouth per day (5-20 mg po QD). In some embodiments, the dose of obicetrapib or salt thereof is 10-20 mg by mouth per day (10-20 mg po QD). 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 mg po QD, 5.5 mg po QD, 6 mg po QD, 6.5 mg po QD, 7 mg po QD, 7.5 mg po QD, 8 mg po QD, 8.5 mg po QD, 9 mg po QD, 9.5 mg po QD, 10 mg po QD, 10.5 mg po QD, 11 mg po QD, 11.5 mg po QD, 12 mg po QD, 12.5 mg po QD, 13 mg po QD, 13.5 mg po QD, 14 mg po QD, 14.5 mg po QD, 15 mg po QD, 15.5 mg po QD, 16 mg po QD, 16.5 mg po QD, 17 mg po QD, 17.5 mg po QD, 18 mg po QD, 18.5 mg po QD, 19 mg po QD, 19.5 mg po QD, 20 mg po QD, 25 mg po QD or 30 mg po QD.

[0027] 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 mg po QD, 5.5 mg po QD, 6 mg po QD, 6.5 mg po QD, 7 mg po QD, 7.5 mg po QD, 8 mg po QD, 8.5 mg po QD, 9 mg po QD, 9.5 mg po QD, 10 mg po QD, 10.5 mg po QD, 11 mg po QD, 11.5 mg po QD, 12 mg po QD, 12.5 mg po QD, 13 mg po QD, 13.5 mg po QD, 14 mg po QD, 14.5 mg po QD, 15 mg po QD, 15.5 mg po QD, 16 mg po QD, 16.5 mg po QD, 17 mg po QD, 17.5 mg po QD, 18 mg po QD, 18.5 mg po QD, 19 mg po QD, 19.5 mg po QD, 20 mg po QD, 25 mg po QD or 30 mg po QD.

[0028] 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, or 30.0 mg.

[0029] 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, or 30.0 mg po QD.

[0030] In various embodiments, the dose is administered once per day. In some embodiments, the dose is divided and the 2.5-25 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.

[0031] In various embodiments, obicetrapib is administered as a tablet. In some embodiments, the tablet comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of obicetrapib or pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains obicetrapib as the calcium salt. In particular embodiments, the table contains 5 mg obicetrapib as a calcium salt.

[0032] 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, tabletsare 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.

[0033] 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.

[0034] In some embodiments obicetrapib is amorphous obicetrapib hemicalcium.

[0035] In some embodiments, the subject, prior to first administration of obicetrapib, is on maximally tolerated lipid-modifying therapy. In some of these embodiments, the maximally tolerated lipid-modifying therapy is 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, and combinations thereof. In certain 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.

[0036] In some embodiments, the subject, prior to first administration of obicetrapib, has a fasting serum LDL-C equal to or greater than 70 mg / dL (1.8 mmol / L). In some embodiments, the subject, prior to first administration of obicetrapib, has a fasting serum TG less than 400 mg / dL (4.5 mmol / L). In some embodiments, the subject, prior to first administration of obicetrapib, has an estimated glomerular filtration rate (eGFR) equal to or greater than 30 mL / min / 1.73 m2, calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

[0037] In some embodiments, administering the pharmaceutical composition reduces the serum level of LDL-C as compared to pre-treatment levels. In some embodiments, administering the pharmaceutical composition reduces the serum level of ApoB as compared to pre-treatment levels. In some embodiments, administering the pharmaceutical composition reduces the serum level of non-HDL-C as compared to pre-treatment levels. In some embodiments, administering the pharmaceutical composition reduces the serum level of total cholesterol (TC) as compared to pre-treatment levels. In some embodiments, administering the pharmaceutical composition reduces the serum level of Lp(a) as compared to pre-treatment levels. In some embodiments, administering the pharmaceutical composition reduces the serum level of triglycerides (TG) as compared to pre-treatment levels.

[0038] In some embodiments, administering the pharmaceutical composition increases the serum level of HDL-C as compared to pre-treatment levels. In some embodiments, administering the pharmaceutical composition increases the serum level of ApoAl as compared to pre-treatment levels.

[0039] In some embodiments, administering the pharmaceutical composition reduces the fasting serum level of LDL-C as compared to pre-treatment levels. In some embodiments the percentage reduction in fasting serum level of LDL-C as compared to pre-treatment levels is60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%,44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%,28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0040] In some embodiments, administering the pharmaceutical composition reduces the fasting serum level of ApoB as compared to pre-treatment levels. In some embodiments the percentage reduction in fasting serum level of ApoB as compared to pre-treatment levels is 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%,44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%,28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0041] In some embodiments, administering the pharmaceutical composition reduces the fasting serum level of non-HDL-C as compared to pre-treatment levels. In some embodiments the percentage reduction in fasting serum level of non-HDL-C as compared to pre-treatment levels is 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0042] In some embodiments, administering the pharmaceutical composition reduces the fasting serum level of total cholesterol (TC) as compared to pre-treatment levels. In some embodiments the percentage reduction in fasting serum level of total cholesterol (TC) as compared to pre-treatment levels is 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%,34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%,18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0043] In some embodiments, administering the pharmaceutical composition reduces the fasting serum level of Lp(a) as compared to pre-treatment levels. In some embodiments the percentage reduction in fasting serum level of Lp(a) as compared to pre-treatment levels is 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0044] In some embodiments, administering the pharmaceutical composition reduces the fasting serum level of triglycerides (TG) as compared to pre-treatment levels. In some embodiments the percentage reduction in fasting serum level of triglycerides (TG) as compared to pre-treatment levels is 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0045] In some embodiments, administering the pharmaceutical composition increases the fasting serum level of HDL-C as compared to pre-treatment levels. In some embodiments, the percentage increase in fasting serum levels of ApoAl as compared to pre-treatment levels is 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%, or 60%.

[0046] In some embodiments, administering the pharmaceutical composition increases the fasting serum level of ApoAl as compared to pre-treatment levels. In some embodiments, the percentage increase in fasting serum levels of ApoAl as compared to pre-treatment levels is 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%, or 60%.

[0047] In some embodiments, obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally at a dose of 10 mg once daily. In some embodiments,obicetrapib, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally at a dose of 5 mg once daily.5.3. Pharmaceutical Compositions

[0048] Pharmaceutical compositions disclosed herein comprise, as the active pharmaceutical ingredient (API), obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof. Obicetrapib is the INN of the compound having the IUPAC name (2R,4S)-4-{[3,5- bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid ethyl ester and the following structural formula:

[0049] The term “pharmaceutically acceptable” as used herein has its conventional meaning and refers to compounds, material, compositions and / or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications, commensurate with a reasonable benefit / risk ratio.

[0050] As used herein, “a pharmaceutically acceptable salt” includes any salt that retains the activity of the active agent(s) and is acceptable for pharmaceutical use. Pharmaceutically acceptable salts of the compound (I) may include, for example, alkali metal salts such as lithium, sodium or potassium salt; alkali earth metal salts such as calcium or magnesium salt; salts with zinc or aluminum; salts with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucosamine, triethanolamine or dehydroabiethylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid; or salts derived from acidic amino acids such as aspartic acid or glutamic acid. Additionally, the pharmaceutically acceptable salts of the compound (I) may include, for example, quaternary salts formed between a compound of the formula (I) and an alkyl halide or phenylalkyl halide. In certain embodiments, the pharmaceutically acceptable salt is the calcium salt of obicetrapib.

[0051] The pharmaceutically acceptable salt of the disclosed compounds may be prepared by methods well known to those skilled in the art. Synthetic routes are described in EP 1730152 and US 7,872,126, incorporated herein by reference in their entireties; in EP2007728 and US 8,084,611, incorporated herein by reference in their entireties; and in EP3180314 and US 10,112,904, incorporated herein by reference in their entireties.

[0052] Amorphous obicetrapib hemicalcium and methods for synthesizing are known. See, e.g., U.S. Patent No. 12,006,305, the disclosure of which is incorporated herein by reference in its entirety.

[0053] Furthermore, the compositions can comprise obicetrapib in the form of a solvate, comprising a pharmaceutically acceptable solvent, such as water (‘hydrate’), ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0054] As used herein, the term “pharmaceutical composition” refers to a composition comprising obicetrapib or a salt or solvate thereof and, as the case may be, one or more additional non-toxic ingredients, which composition is in a form suitable for administration to a (human) subject, through any route of administration, and which composition is physiologically tolerated upon such administration.

[0055] In a preferred embodiment, the composition comprises one or more carriers and / or excipients. As is known by those of average skill in the art, the appropriate choice of excipients is dependent on multiple factors, including the physicochemical properties of the API, the preferred pharmaceutical form, the preferred route of administration, the desired rate of release, etc. The compositions can be formulated for a variety of routes of administration, oral administration being particularly preferred. It is within the purview of those of average skill in the art to conceive and develop suitable formulations, relying on the common general knowledge as reflected in text books such as Remington: The Science and Practice of Pharmacy (23rdedition, 2020; ISBN: 9780128200070), the entire disclosure of which is herein incorporated by reference, and routine development efforts.6. EXAMPLES

[0056] The following examples are provided by way of exemplification and illustration, not limitation.6.1. Example 1: Obicetrapib on Top of Maximum Tolerated Lipid- Modifying Therapies (BROOKLYN, NCT05425745): A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to Evaluate the Effect of 10 mg Obicetrapib in Participants With a History of HeFH and LDL-C >70 mg / dL Who are Not Adequately Controlled by Their Lipid- Modifying Therapies

[0057] A Phase 3 clinical study is 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) who require additional lowering of low-density lipoprotein cholesterol (LDL-C).Obicetrapib

[0058] Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Obicetrapib is administered at 10 mg orally, once daily to patients in the treatment group.Objectives of the Study

[0059] The primary objective of this study is to evaluate the effect of obicetrapib on LDL-C levels in patients with underlying HeFH and elevated LDL-C who are not adequately controlled by their lipid-modifying therapies.

[0060] The secondary objectives of this study include evaluating the effect of obicetrapib on apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), high- density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG), and lipoprotein (a) (Lp[a]) levels. The secondary objectives also include evaluating the safety and tolerability profile of obicetrapib in a representative population of adult males and females with HeFH, assessed by adverse events (AEs), events of special interest (ESIs), vital signs (including blood pressure), electrocardiogram (ECG) measurements, and clinical laboratory values.

[0061] The exploratory objectives of this study include evaluating the effect of obicetrapib on the number of participants reaching prespecified LDL-C, non-HDL-C, and ApoB levels, and the effect of obicetrapib on apolipoprotein Al (ApoAl).Efficacy Endpoints

[0062] The primary efficacy endpoint was the percent change from Baseline to Day 84 inLDL-C in the obicetrapib group compared to the placebo group.

[0063] The secondary efficacy endpoints included the following:• Percent change from Baseline to Days 180 and 365 in LDL-C in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Days 84, 180, and 365 in ApoB in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Days 84, 180, and 365 in non-HDL-C in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Days 84, 180, and 365 in HDL-C in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Days 84 and 365 in Lp(a) in the obicetrapib group compared to the placebo group;• Percent change from Baseline to Days 84, 180, and 365 in TC in the obicetrapib group compared to the placebo group; and• Percent change from Baseline to Days 84, 180, and 365 in TG in the obicetrapib group compared to the placebo group.

[0064] The exploratory efficacy endpoints included the following:• Individual responsiveness defined as the number of participants reaching on treatment LDL-C levels of <40 mg / dL (<1.04 mmol / L), <55 mg / dL (<1.4 mmol / L), <70 mg / dL (<1.8 mmol / L), and <100 mg / dL (<2.6 mmol / L) at Days 84 and 365;• Individual responsiveness defined as the number of participants reaching on treatment non-HDL-C levels of <85 mg / dL (<2.2 mmol / L), <100 mg / dL (<2.6 mmol / L), and <130 mg / dL (<3.4 mmol / L) at Days 84 and 365;• Individual responsiveness defined as the number of participants reaching on treatment ApoB levels of <65 mg / dL (<0.65 g / L), <80 mg / dL (<0.80 g / L), and <130 mg / dL (<1.30 g / L) at Days 84 and 365;• Percent change from Baseline to Days 84 and 365 in ApoAl in the obicetrapib group compared to the placebo group; and• Trough levels of obicetrapib from Baseline to Day 365 in the obicetrapib group.Study Design

[0065] This was a multicenter, placebo-controlled, double-blind, randomized, Phase 3 study in approximately 300 participants with a history of HeFH who were not adequately controlled by their lipid-modifying therapies. The participants were randomized in a 2: 1 ratio toObicetrapib 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. See FIG. 1. Unless otherwise stated, Baseline values were the last non-missing measurements taken prior to the participant receiving study drug.

[0066] Key inclusion criteria included a history of HeFH, defined by at least 1 of the following: genotyping by a central laboratory, clinical assessment using the WHO Criteria / Dutch Lipid Clinical Network Criteria with a score of >8 points, and / or meet the Simon Broome Register Diagnostic Criteria for definite or possible Familial Hypercholesterolemia (FH). The patients were on maximally tolerated lipid-modifying therapy, as an adjunct to diet, defined as the following: a statin at a maximally tolerated stable dose, ezetimibe for at least 8 weeks with or without maximally tolerated statin, bempedoic acid for at least 8 weeks in combination with maximally tolerated statin, and / or a proprotein convertase subtilisin / kexin type 9 (PCSK9)-targeted therapy alone or in combination with other lipid-modifying therapy for at least 4 stable doses. At least 70% of the participants enrolled into this study took high-intensity statin therapy (HIS), which include: Atorvastatin 40 mg and 80 mg; and Rosuvastatin 20 mg and 40 mg. The patients had a fasting serum LDL-C >70 mg / dL (>1.8 mmol / L), a fasting TG <400 mg / dL (<4.5 mmol / L), and an estimated glomerular filtration rate (eGFR) >30 mL / min / 1.73 m2calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

[0067] 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, a 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, glycosylated hemoglobin 10.0% (0.100 hemoglobin fraction) or fasting glucose >270 mg / dL (>15.0 mmol / L), thyroid-stimulating hormone >1.5 x ULN, and creatine kinase (CK) >3 x ULN.6.2. Analysis of Clinical Trial Data

[0068] The patients were on maximally tolerated lipid-modifying therapy, as an adjunct to diet, defined as the following: a statin at a maximally tolerated stable dose, ezetimibe for atleast 8 weeks with or without maximally tolerated statin, bempedoic acid for at least 8 weeks in combination with maximally tolerated statin, and / or a proprotein convertase subtilisin / kexin type 9 (PCSK9)-targeted therapy alone or in combination with other lipid- modifying therapy for at least 4 stable doses. In addition to these standard of care (SoC) therapies, patients either received once a day 10 mg obicetrapib or placebo.6.2.1 Patients showed reduction in LDL-C

[0069] Patients who received once daily 10 mg obicetrapib showed significant reduction in low density lipoprotein-C (LDL-C) versus patients receiving placebo. Patients displayed a mean percent change versus placebo of -36.3 and -41.5% in LDL-C at day 84 and day 365. See FIG. 2A-2B, and Table 1.Table 1: LDL-C% least square mean change day 84 and 365ObicetrapibTime Placebo 10 mgN = 118 N = 232Baseline Mean LDL-C (mg / dL) 119.9 123.4% Change from Baseline -0.06 -36.37LS Mean % Change from 0.25 -36.05BL0.9191 <0.0001Day 84 P-value -36 31Comparison to Placebo %<QQQ-^LS mean p-value (2-sided)% Change from Baseline 4.00 -33.23LS Mean % Change from 10.30 -31.14BL0.0149 <0.0001Day 365 P-value -41 45Comparison to Placebo %LS mean p-value (2-sided)

[0070] The results also showed efficacy in line with applicable data from prior trials:JAPAN, Japanese patients were administered 10 mg obicetrapib (NCT05421078); ROSE,-15- 37726 / 57372 / FW / 20226111.1patients were administered 10 mg obicetrapib as an adjunct to high intensity statin therapy (NCT04753606); and ROSE2, patients were administered 10 mg obicetrapib monotherapy as an adjunct to high intensity statin therapy (NCT05266586) (p<0.0001). Measuring from baseline, the mean percent change in LDL-C for JAPAN was -37%, ROSE showed a -40 % change in LDL-C, and ROSE2 showed a -37 percent change in LDL-C (p<0.0001). See FIG. 3. The percent mean change was calculated using least square regression analysis.6.2.2 Patients showed reduction in non-HDL-C

[0071] Patients receiving obicetrapib also showed a non-high density lipoprotein-C (non- HDL-C) percent change versus placebo of -34.5% as of day 84. See FIG. 4A and Table 2.Table 2: Non-HDL-C% least square mean change day 84Non-HDL-C % LS mean change Day 84ObicetrapibTime Placebo 10 mgD.. N = 118 N = 234BaselineMean (mg / dL) 146.7 148.4Day 84N = 115 N = 230Mean (mg / dL)148 4 98 0% Change from „„ ,. 2.53 -31.69BaselineN = 118 N = 234% Change from „ „„ „„ 2.83 -31.62BL LS meanP-value 0.0951 <0.0001Comparison to Placebo % LS -34.45 mean p-value (2-sided) <.0001

[0072] Measuring from baseline, patients showed a mean percent change in non-HDL-C measured of -31.6% at day 84. These results are in line with data from prior trials: JAPAN, Japanese patients were administered 10 mg obicetrapib (NCT05421078); ROSE, patients were administered 10 mg obicetrapib as an adjunct to high intensity statin therapy-16- 37726 / 57372 / FW / 20226111.1(NCT04753606); and R0SE2, patients were administered 10 mg obicetrapib monotherapy as an adjunct to high intensity statin therapy (NCT05266586) (p<0.0001). JAPAN showed a -30.3% change in non-HDL-C, ROSE showed a -39.9% change in non-HDL-C, and ROSE2 showed a -33.8% change in non-HDL-C (p<0.0001). See FIG. 4B.6.2.3 Patients showed reduction in ApoB

[0073] The change in ApoB was also measured in patients receiving obicetrapib versus placebo. The results showed that patients who received once a day 10 mg obicetrapib on top of standard of care therapies displayed a mean change of -24.4% in concentration of ApoB versus placebo at day 84. See FIG. 5 A and Table 3.Table 3: ApoB % least square mean change day 84ApoB % LS mean change Day 84ObicetrapibTime Placebo 10 mgD.. N = 118 N = 234BaselineMean (mg / dL) 105.3 107.2Day 84N = 115 N = 230Mean (mg / dL) 107.I 81.4% Change from „„ ,. 2.89 -21.61BaselineN = 118 N = 234% Change from2 g3 21 45BL LS meanP-value 0.0951 <0.0001Comparison to Placebo % LS -24.39 mean p-value (2-sided) <.0001

[0074] Patients who were administered once daily 10 mg obicetrapib also showed a mean percent change in ApoB concentration of -21.6% at day 84 when measured from baseline. These results also showed consistency with past clinical trials: JAPAN showed a -26.7 mean37726 / 57372 / FW / 20226111.1percent change from baseline, ROSE showed a -27.2 mean percent change from baseline, and ROSE2 showed a -21.7 mean percent change from baseline. See FIG. 5B.6.2.4 Patients showed reduction in Lp(a)

[0075] Mean percent change from baseline for obicetrapib versus placebo was measured for lipoprotein (a) (Lp(a)) at day 84 (p<0.0001). Patients displayed -45.9% change. See FIG. 6 and Table 4.Table 4: Lp(a) % least square mean change day 84Lp(a) % LS mean change Day 84ObicetrapibTime Placebo 10 mgD.. N = 118 N = 234BaselineMean (mg / dL) 34.85 45.80Day 84N = 115 N = 230Median (mg / dL)39 9018.80% Change from „ „„„ ,. 8.23 -34.56BaselineN = 118 N = 234% Change from1Q 52_35 42BL LS meanP-value 0.2647 <0.0001Comparison to Placebo % LS -45.94 mean p-value (2-sided) <.0001

[0076] Overall, in patients with heterozygous familial hypercholesterolemia, obicetrapib at10 mg orally once daily on top of maximally tolerated standard of care therapies significantly reduced LDL-C level in HeFH patients compared with placebo. The results showed that 40% of patients receiving 10 mg once a day obicetrapib achieved over 50% reduction in LDL-C at day 84. See FIG. 7 A. Obicetrapib enabled over three quarter of patients to reach an LDL-C goal of less than 100 mg / dL. Furthermore, 51% of patients were able to achieve less than 70 mg / dL LDL-C levels. See FIG. 8 (BL = baseline). Obicetrapib at 10 mg also significantly-18- 37726 / 57372 / FW / 20226111.1reduced ApoB, non-HDL-C, and Lp(a) levels compared to placebo. In addition, obicetrapib at 10 mg significantly increases HDL-C and ApoAl levels compared to placebo. Obicetrapib was well tolerated in patients. They did not display observed evidence of increase in blood pressure, liver enzymes or high sensitivity C- reactive protein (hs-CRP), nor a decrease in renal function.Table 5: Baseline characteristics for all randomized participantsObicetrapib 10 Placebo mg TotalN=118 N=236 N-354LDL-C at BL mg / dL 119.9 123.4< 70 mg / dL 4(3.4) 17(7.2) 21(5.9)70 to < 100 mg / dL 45(38.1) 63(26.7) 108(30.5)> = 100 mg / dL 69(58.5) 152(64.4) 221(62.4)Non-HDL-C at BL mg / dL 146.7 148.4<100 mg / dL 19(16.1) 38(16.1) 57(16.1)100 to < 130 mg / dL 41(34.7) 68(28.8) 109(30.8)> = 130 mg / dL 58(49.2) 128(54.2) 186(52.5)Lipoprotein(a) at BL nmol / L 115.25 107.04< 75 nmol / L 66(55.9) 141(59.7) 207(58.5)75 to < 125 nmol / L 8(6.8) 21(8.9) 29(8.2)> = 125 nmol / L 44(37.3) 72(30.5) 116(32.8)Obicetrapib 10 Placebo mg TotalN=118 N=236 N-354ApoB at Baseline 105.3 107.2< 60 mg / dL 2 ( 1.7) 4 ( 1.7) 6 ( 1.7)60 to <90 mg / dL 45(35.6) 73(30.9) 115(32.5)> = 90 mg / dL 74(62.7) 157(66.5) 231(65.3)HDL-C at Baseline<40 mg / dL 33(28.0) 42(17.8) 75(21.2)40 to <60 mg / dL 55(46.6) 119(50.4) 174(49.2)> = 60 mg / dL 30(25.4) 73(30.9) 103(29.1)TG at Baseline<150 mg / dL 67(56.8) 162(68.6) 229(64.7)> = 150 mg / dL 51(43.2) 72(30.5) 123(34.7) hs-CRP at Baseline< 2 mg / dL 74 ( 62.7) 142 ( 60.2) 345 ( 97.5)> = 2 mg / dL 44(37.3) 94(39.8) 3(0.8)37726 / 57372 / FW / 20226111.17. INCORPORATION BY REFERENCE

[0077] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.8. EQUIVALENTS

[0078] While various specific embodiments have been illustrated and described, the above specification is not restrictive. It will be appreciated that various changes can be made.-20- 37726 / 57372 / FW / 20226111.1

Claims

WHAT IS CLAIMED IS:

1. A method of treating heterozygous familial hypercholesterolemia (HeFH) in a subject, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

2. The method of claim 1, wherein the presence of HeFH is determined by genotyping.

3. The method of claim 1, wherein HeFH is determined by clinical assessment.

4. The method of any one of claims 1 to 3, wherein the subject, prior to first administration of obicetrapib, is on maximally tolerated lipid-modifying therapy.

5. The method of claim 4, wherein the maximally tolerated lipid-modifying therapy is 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, and combinations thereof.

6. The method of claim 5, wherein the subject , prior to first administration of obicetrapib, is on high-intensity statin therapy (HIS).

7. The method of claim 6, wherein the high-intensity statin therapy (HIS) is atorvastatin at 40 mg or 80 mg.

8. The method of claim 6, wherein the high-intensity statin therapy (HIS) is rosuvastatin at 20 mg or 40 mg.

9. The method of any one of claims 1 to 8, wherein the subject, prior to first administration of obicetrapib, has a fasting serum LDL-C equal to or greater than 70 mg / dL (1.8 mmol / L).

10. The method of any one of claims 1 to 9, wherein the subject, prior to first administration of obicetrapib, has a fasting serum TG less than 400 mg / dL (4.5 mmol / L).

11. The method of any one of claims 1 to 10, wherein the subject, prior to first administration of obicetrapib, has an estimated glomerular filtration rate (eGFR) equal to or greater than 30 mL / min / 1.73 m2calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.-21- 37726 / 57372 / FW / 20226111.

112. The method of any one of claims 1 to 11, wherein administering the pharmaceutical composition reduces the serum level of LDL-C as compared to pre-treatment levels.

13. The method of any one of claims 1 to 12, wherein administering the pharmaceutical composition reduces the serum level of ApoB as compared to pre-treatment levels.

14. The method of any one of claims 1 to 13, wherein administering the pharmaceutical composition reduces the serum level of non-HDL-C as compared to pre-treatment levels.

15. The method of any one of claims 1 to 14, wherein administering the pharmaceutical composition reduces the serum level of total cholesterol (TC) as compared to pre-treatment levels.

16. The method of any one of claims 1 to 15, wherein administering the pharmaceutical composition reduces the serum level of Lp(a) as compared to pre-treatment levels.

17. The method of any one of claims 1 to 16, wherein administering the pharmaceutical composition reduces the serum level of total triglycerides (TG) as compared to pre-treatment levels.

18. The method of any one of claims 1 to 17, wherein administering the pharmaceutical composition increases the serum level of HDL-C as compared to pre-treatment levels.

19. The method of any one of claims 1 to 18, wherein administering the pharmaceutical composition increases the serum level of ApoAl as compared to pre-treatment levels.

20. The method of any one of claims 1 to 19, wherein obicetrapib or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally at a dose of 10 mg once daily.-22- 37726 / 57372 / FW / 20226111.1

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