Combination therapy of obiscetrapib and ezetimibe for use in statin-intolerant patients suffering from hyperlipidemia or mixed dyslipidemia - Patent Application 20100233633

Abstract

The present invention relates to pharmaceutical compositions and therapeutic combinations comprising obiscetrapib and ezetimibe, which may be used in the treatment of subjects suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, wherein said subjects are partially or completely intolerant to statins.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions and therapeutic combinations comprising obiscetrapib and ezetimibe for use in the treatment of subjects suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia who are partially or completely statin intolerant. [Background technology]

[0002] Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death worldwide, resulting in over 17 million deaths each year. For many years, it has been known that abnormal cholesterol levels are associated with an increased risk of cardiovascular disease (CVD), such as cardiomyopathy, atherosclerosis, and myocardial infarction. In particular, it has been observed that individuals who present with high levels of low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol combined with low levels of high-density lipoprotein (HDL) cholesterol are at the highest risk of developing cardiovascular disease.

[0003] It has been found that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors, more commonly known as statins, can lower the level of LDL cholesterol in a patient's blood by lowering cholesterol production and promoting cellular uptake of cholesterol from the bloodstream. The use of statins to combat high levels of cholesterol, also known as hypercholesterolemia, has proven successful, as LDL cholesterol levels have been reduced to the point where a lower risk of developing cardiovascular disease is observed.

[0004] However, there are many safety issues associated with the use of statins. For example, statins can cause increased liver enzymes and myopathy, rhabdomyolysis that can lead to acute renal failure, and unexplained muscle pain and weakness. These symptoms and other adverse events (AEs) can lead to the discontinuation of statin therapy or the use of lower doses of statins that are less frequently associated with side effects. This is commonly referred to as statin intolerance (or statin toxicity) and can occur in a significant proportion of patients, depriving such patients of the full cardioprotective benefits of statins. Furthermore, discontinuation of statin therapy can increase the risk of acute cardiovascular events.

[0005] Another class of compounds with antihyperlipidemic effects are so-called cholesterol absorption inhibitors (CAIs). CAIs can prevent cholesterol uptake from the small intestine by blocking the uptake of micellar cholesterol, which reduces the uptake of cholesterol esters into chylomicrons and chylomicron remnants. CAIs thereby reduce the amount of cholesterol circulating back to the liver, which then increases the activity of LDL receptors in the liver and increases the clearance of LDL cholesterol particles from the bloodstream.

[0006] A known example of a CAI is ezetimibe, formerly known as the Schering-Plough compound "Sch-58235", and sold under the trade names Ezetrol and Zetia, among others (Merck Sharp & Dohme / Merck). The IUPAC name for ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

[0007] Ezetimibe is often administered as monotherapy or in an adjunctive combination therapy approach with one of several statins. Ezetimibe selectively inhibits dietary and biliary cholesterol absorption by binding to a protein encoded by the Niemann-Pick C1-like 1 gene in the brush border membrane of enterocytes. Typically, ezetimibe dosage forms are tablets containing 10 mg of ezetimibe for oral administration. Ezetimibe as monotherapy has been shown to moderately reduce patients' LDL-C levels in patients with hypercholesterolemia, i.e., less than a 20% reduction when compared to placebo.

[0008] Another approach is to inhibit cholesteryl ester transfer protein (CETP). CETP is a plasma protein secreted mainly by the liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (ApoB)-containing particles (mainly LDL and VLDL) in exchange for triglycerides (TG), thereby increasing the cholesterol content in (V)LDL and decreasing the cholesterol content in HDL. Therefore, it is hypothesized that CETP inhibition retains cholesteryl esters in HDL-C and reduces the cholesterol content of the atherogenic ApoB fraction.

[0009] Despite evidence supporting the potential of CETP inhibition in reducing cardiovascular morbidity, clinical development of CETP inhibitors has not been straightforward. The first compound to progress to Phase III clinical trials was torcetrapib, dosed at 60 mg. Torcetrapib was shown to increase HDL-C by 72% and reduce LDL-C by 25%, but development was subsequently halted due to safety concerns, including an unexpected increase in cardiovascular events and deaths.

[0010] Although the mechanisms of these events are not fully understood, there is growing evidence that these events may be due to off-target effects of torcetrapib, such as increased blood pressure, electrolyte changes (increased sodium and bicarbonate and decreased potassium), and increases in aldosterone consistent with mineralocorticoid activity.

[0011] Another CETP inhibitor, dalcetrapib, subsequently entered clinical trials and was shown to be a weak inhibitor that increased HDL-C by 30–40% while having minimal effect on LDL-C concentrations.

[0012] Two additional CETP inhibitors, anacetrapib (MK-0859 from Merck Sharp & Dohme Corp.) and evacetrapib, have also been tested in Phase III clinical trials. Although evacetrapib failed to pass the futility interim analysis, anacetrapib was shown to reduce major adverse cardiovascular events (MACE) through lowering LDL-cholesterol in the 30,000-patient REVEAL trial. However, development of both compounds has been terminated.

[0013] This leaves obiscetrapib (also known as TA-8995) as the only CETP inhibitor currently in full development. In a Phase II study (TULIP; Hoving et al., 2015), it was found that both 10 mg and 5 mg obiscetrapib administered as monotherapy were able to lower LDL cholesterol concentrations. When combined with 20 mg atorvastatin, it was also found that the total reduction in LDL cholesterol was even higher. Furthermore, HDL cholesterol concentrations were significantly increased both as monotherapy and when combined with a statin. Summary of the Invention [Problem to be solved by the invention]

[0014] However, not all patients tolerate statins well. Thus, there remains a need for convenient, safe and effective agents or combinations of agents for use in treating subjects suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia and for reducing the risk of cardiovascular events. [Means for solving the problem]

[0015] A first aspect of the present invention relates to a pharmaceutical composition comprising obiscetrapib and ezetimibe, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier for use in the treatment of a subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, wherein said subject is partially or completely intolerant to statins.

[0016] A second aspect of the invention relates to a therapeutic combination comprising obiscetrapib and ezetimibe, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of a subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, wherein said subject is partially or completely intolerant to statins.

[0017] Surprisingly, it has been found that the compositions and combinations are capable of lowering both LDL-C and ApoB levels. Even more surprisingly, it has been found that the combination of obiscetrapib and ezetimibe can reduce ApoB levels to a greater extent than would be expected based on previous experience with CETP inhibitor and statin combinations in general and with obiscetrapib and statin in particular. This makes the present invention particularly suitable for patients with partial or complete statin intolerance.

[0018] Obicetrapib, also known as "TA-8995," has the following chemical structure:

[0019] [ka]

[0020] Ezetimibe, also known as "Sch-58235," has the following chemical structure:

[0021] [ka]

[0022] Within the present invention, both obiscetrapib and ezetimibe may also be used as different salt forms and solvates. Obicetrapib and ezetimibe may also be formulated as prodrugs.

[0023] definition As used herein, the term "apolipoprotein" has its conventional meaning and refers to proteins that bind lipids to form lipoproteins.

[0024] As used herein, the term "apolipoprotein B" (ApoB) has its conventional meaning and refers to the protein encoded by the ApoB gene.

[0025] As used herein, the term "pharmaceutical composition" has its conventional meaning and refers to a pharma- ceutically acceptable composition.

[0026] The term "pharmacologically acceptable" as used herein has its accustomed meaning and refers to those compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of mammals, particularly humans, without undue toxicity, irritation, allergic response and other problematic complications, commensurate with a reasonable benefit / risk ratio.

[0027] As used herein, the term "carrier" has its conventional meaning and refers to a pharma- ceutically acceptable diluent, adjuvant, excipient, or vehicle with which a pharma- ceutical active ingredient is administered.

[0028] The term "excipient" as used herein has its conventional meaning and refers to a pharma- ceutically acceptable ingredient commonly used in the pharmaceutical arts for preparing granular, solid or liquid oral dosage formulations.

[0029] As used herein, the term "salt" has its conventional meaning and includes acid addition and base salts of pharma- ceutical active compounds.

[0030] The term "solvate" as used herein has its conventional meaning and refers to a compound formed by solvation, for example, as a combination of a solvent molecule with a molecule or ion of the solute. Well-known solvent molecules include water, alcohols, nitriles, and polar organic solvents.

[0031] As used herein, the term "subject" refers to a human suffering from or at risk for a disease or disorder. The terms "subject" and "patient" are used interchangeably herein.

[0032] The term "increased risk" has its conventional meaning and refers to the situation in a subject, preferably a human, in which an individual, either male or female, has an LDL cholesterol level above 2.6 mmol / l (100.54 mg / dL), such that the individual is exposed to an increased risk of a cardiovascular event compared to individuals with lower levels.

[0033] The term "treatment" as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment.

[0034] The term "cardiovascular disease" as used herein has its conventional meaning and includes the clinical manifestations of arteriosclerosis, peripheral vascular disease angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and stroke.

[0035] As used herein, the term "cardiovascular event" has its conventional meaning and refers to the occurrence of myocardial infarction, coronary revascularization, stroke, or coronary death (Ference, 2017).

[0036] As used herein, the term "hypercholesterolemia" has its conventional meaning and refers to the condition in which high levels of cholesterol are present in the blood.

[0037] As used herein, the term "hyperlipidemia" has its conventional meaning and refers to the condition in which an excess of lipids is found in the blood.

[0038] As used herein, the term "mixed dyslipidemia" has its conventional meaning and refers to a condition in which there are elevated LDL cholesterol and triglyceride levels, accompanied by low levels of HDL cholesterol in the blood.

[0039] The term "statin intolerance" as used herein has its conventional meaning and refers to the inability of a subject to tolerate two or more statins, one at a low dose, due to adverse safety effects that begin or increase during statin treatment and that resolve or improve when the statins are discontinued, including reference to a similar definition approved by the FDA in the bempedoic acid (Esperion) Phase III trial.

[0040] As used herein, the term "cholesterol absorption inhibitors" (CAIs) has its conventional meaning and refers to compounds used to lower LDL-C by blocking the intestinal and biliary absorption of cholesterol. A known cholesterol absorption inhibitor is ezetimibe.

[0041] As used herein, the term "HMG-CoA reductase inhibitor" has its conventional meaning and is used interchangeably with the term "statin" to refer to compounds used to lower LDL-C by inhibiting the enzyme HMG-CoA reductase. Well-known HMG-CoA reductase inhibitors are atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin.

[0042] As used herein, the term "cholesteryl ester transfer protein inhibitors" (CETP inhibitors) has its conventional meaning and refers to a class of compounds that inhibit the CETP receptor in mammals. A known CETP inhibitor is obiscetrapib.

[0043] The term "unit dosage form" has its conventional meaning and refers to a dosage form capable of being administered to a subject, preferably a human, to be effective, which can be easily handled and packaged and remains as a physically and chemically stable unitary dose containing the therapeutic agents, i.e., obiscetrapib or a combination of therapeutic agents, such as obiscetrapib and ezetimibe.

[0044] As used herein, the term "fixed dose combination" has its conventional meaning and refers to a combination of defined doses of two or more drugs or active ingredients provided in a single dosage unit (e.g., tablet or capsule) and administered as such.

[0045] As used herein, the term "free-dose combination" has its conventional meaning and refers to a combination of two drugs or active ingredients that are administered simultaneously but as two different dosage units. [Brief description of the drawings]

[0046] [Figure 1] [Diagram 2] [Diagram 3] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] A first aspect of the present invention relates to a pharmaceutical composition comprising obiscetrapib and ezetimibe or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier for use in the treatment of a subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, wherein said subject is partially or completely intolerant to statins.

[0048] A second aspect of the invention relates to a therapeutic combination comprising obiscetrapib and ezetimibe or a pharma- ceutically acceptable salt or solvate thereof for use in the treatment of a subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, wherein said subject is partially or completely intolerant to statins.

[0049] Surprisingly, it was found that the reduction in LDL concentration in said patients was much greater than expected based on previous experience with the combination of CETP inhibitors and statins.Indeed, it was surprisingly found that the combination of obiscetrapib and ezetimibe has a strong synergistic effect in patients treated with said combination.This makes the present invention particularly suitable for patients who are partially or completely statin intolerant.

[0050] The inventors found that the use of ezetimibe did not attenuate the LDL-C lowering efficacy of obiscetrapib, which remained the same as obiscetrapib monotherapy, in other words, the relative LDL-C reduction with obiscetrapib when administered in combination with ezetimibe remained similar to the LDL-C reduction with the same dose of obiscetrapib administered as monotherapy.

[0051] This improved LDL-C lowering efficacy is significant given the fact that the causal effect of CETP inhibition on the risk of cardiovascular events may be determined by changes in the concentration of LDL-C levels (Ference et al., 2017).

[0052] A Mendelian randomization analysis (unpublished) revealed that the previously observed interaction between CETP inhibitors and HMGCR inhibitors (i.e., attenuation of the effect of CETP inhibition when combined with HMGCR inhibitors) does not occur when CETP inhibitors are combined with NPC1L1 inhibitors such as ezetimibe. This analysis further reveals that the LDL-C lowering efficacy of CETP inhibitors in general (and obiscetrapib specifically) is not affected (i.e., not attenuated) when used in combination with ezetimibe. The results of this analysis are provided in the Examples below.

[0053] Furthermore, these results show that the LDL-C lowering efficacy of obiscetrapib is not attenuated by the use of a combination of obiscetrapib and ezetimibe in said patients, and that such use results in increased LDL-C lowering. Given the fact that the causal effect of CETP inhibition on the risk of cardiovascular events can be determined by changes in the concentration of LDL-C, the pharmaceutical compositions and therapeutic combinations according to the present invention also show a reduction in the risk of cardiovascular events.

[0054] Thus, the pharmaceutical composition or therapeutic combination according to the present invention is preferably used to reduce the risk of cardiovascular events in patients suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia.

[0055] The pharmaceutical composition or therapeutic combination according to the present invention may also be used for the treatment of mild dyslipidemia.

[0056] Furthermore, a subject in need of a pharmaceutical composition or therapeutic combination according to the present invention is preferably administered said pharmaceutical composition or therapeutic combination of 1-10 mg of obiscetrapib per day and 5-20 mg of ezetimibe per day. More preferably, said subject is administered about 5 mg of obiscetrapib per day and about 10 mg of ezetimibe per day or about 10 mg of obiscetrapib per day and about 10 mg of ezetimibe per day.

[0057] Thus, the pharmaceutical composition or therapeutic combination according to the invention can be used to lower the LDL-C concentration in the blood of said subject. As described in Ference et al., 2017, it is this LDL-C lowering effect that in particular reduces the risk of cardiovascular events.

[0058] The LDL-C concentration in the blood of said subject is preferably about 50% lower when administered the combination of ezetimibe and obicetrapib compared to placebo and about 40% lower when compared to ezetimibe monotherapy.

[0059] In other words, the pharmaceutical composition or therapeutic combination according to the present invention makes it possible to maintain the relative LDL-C reduction achieved by obiscetrapib when administered in combination with ezetimibe similar to the relative LDL-C reduction achieved by the same dose of obiscetrapib administered as monotherapy, i.e. the CETP inhibitory effect of obiscetrapib is not attenuated by the combination of the present invention.

[0060] More specifically, the relative LDL-C reduction with a daily dose of 5 mg obicetrapib when administered in combination with 10 mg ezetimibe remains similar to the relative LDL-C reduction with a daily dose of 5 mg obicetrapib administered as monotherapy. Furthermore, when a combined dose of 10 mg obicetrapib per day and 10 mg ezetimibe per day is administered, a similar effect on relative LDL-C reduction is observed when compared to 10 mg obicetrapib monotherapy.

[0061] The pharmaceutical composition or therapeutic combination according to the present invention is preferably orally administered to the subject who needs the pharmaceutical composition or therapeutic combination according to the present invention.Oral administration may involve swallowing so that the pharma- ceutical active compound enters the digestive tract.As described below, certain pharmaceutical preparations can be developed to facilitate oral administration.

[0062] The pharmaceutical composition according to the present invention is preferably formulated as oral free dose combination or oral fixed dose combination, more preferably as oral fixed dose combination.Different pharmacologic active ingredients can be present in said combination as granules.Preferably, the pharmaceutical composition is oral fixed dose combination, such combination is very convenient for patients and avoids the problem associated with administering the correct amount of these compounds.

[0063] Solid oral dosage forms that may be used within the context of the present invention include, in addition to tablets and capsules, caplets, lozenges, pills, mini-tablets, pellets, beads and granules, among others. Liquid oral dosage forms that may be used in the pharmaceutical preparations of the present invention include, but are not limited to, drinks, solutions, suspensions, syrups, beverages and emulsions.

[0064] The oral fixed dose combination or oral free dose combination is preferably formulated as a solid dosage form such as a tablet or capsule. Administration of these types of formulations is generally considered to be the most convenient for patients.

[0065] In a preferred embodiment, the pharmaceutical composition or therapeutic combination according to the invention is an oral fixed dose combination comprising about 1 to about 10 mg of obiscetrapib and about 5 to about 20 mg of ezetimibe, more preferably said composition or combination comprises about 5 mg of obiscetrapib and about 10 mg of ezetimibe or about 10 mg of obiscetrapib per day and about 10 mg of ezetimibe per day.

[0066] In addition to obistrapib and ezetimibe, their pharmaceutically acceptable salts may also be used in the pharmaceutical compositions or therapeutic combinations according to the present invention. The pharmaceutically acceptable salts of obistrapib and ezetimibe include their acid addition salts and base salts, such as preferably calcium salt, potassium salt or sodium salt. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0067] Pharmaceutically acceptable salts of obiscetrapib or ezetimibe may be readily prepared by mixing together solutions of such compounds and the desired acid or base, as appropriate, The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

[0068] The present invention also relates to the use of a pharma- ceutically acceptable solvate or prodrug of obicetrapib and / or a pharma- ceutically acceptable solvate or prodrug of ezetimibe in the pharmaceutical compositions or therapeutic combinations of the present invention.

[0069] In one embodiment of the invention, the composition or combination according to the invention also comprises a polyunsaturated fatty acid (PUFA), preferably an omega-3 polyunsaturated fatty acid, more preferably a PUFA selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) or a combination thereof. Preferably, the PUFAs are present in the pharmaceutical composition or combination according to the invention in their free acid form.

[0070] PUFA, especially omega-3 PUFA, has specific ability on triglyceride-rich lipoprotein, remnant cholesterol and small dense LDL, whereas CETP inhibitor has no or little effect on triglyceride-rich lipoprotein and remnant cholesterol.Therefore, by combining obi-cetrapib, ezetimibe and PUFA in pharmaceutical composition, such composition is particularly suitable for treating subjects suffering from or at increased risk of cardiovascular disease.

[0071] In this regard, it is also noted that because the amounts of obistrapib and ezetimibe required to obtain a clinically relevant effect are relatively small, oral formulations of compositions according to the present invention may contain relatively large amounts of PUFAs (e.g., per capsule).

[0072] In addition to obiscetrapib and ezetimibe, the pharmaceutical composition or therapeutic combination according to the present invention also includes pharma- ceutically acceptable carriers and excipients. Examples of excipient categories include, but are not limited to, binders, disintegrants, lubricants, glidants, fillers, and diluents. One skilled in the art may select one or more of the above excipients for the particular desired properties of the granular and / or solid oral dosage form by routine experimentation and without undue burden. The amount of each excipient used may vary within the range customary in the art. The following references, all of which are incorporated herein by reference, disclose techniques and excipients used to formulate oral dosage forms. See "The Handbook of Pharmaceutical Excipients", 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and "Remington: The Science and Practice of Pharmacy", 20th edition, Gennaro, Ed. Lippincott Williams & Wilkins (2000).

[0073] A further aspect of the present invention relates to a method for treating a partially or completely statin intolerant subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, comprising administering to said subject in need of treatment an effective dose of a pharmaceutical composition or therapeutic combination according to any of the preceding claims.

[0074] As explained in more detail below, the methods may be used to reduce the risk of a cardiovascular event.

[0075] A further aspect of the invention relates to a pharmaceutical composition or therapeutic combination in the manufacture of a medicament for use in the treatment of a partially or completely statin intolerant subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia.

[0076] The final aspect of the present invention relates to a pharmaceutical composition or therapeutic combination comprising a CETP inhibitor and ezetimibe for use in treating partially or completely statin intolerant subjects suffering from or at increased risk of cardiovascular disease. It is particularly used to reduce the risk of cardiovascular events. Furthermore, the composition or combination can be used to reduce the LDL-C concentration in the blood of the subject. Moreover, the relative LDL-C reduction by obiscetrapib when administered in combination with ezetimibe is, in a further embodiment, similar to the relative LDL-C reduction by obiscetrapib at the same dose administered as monotherapy.

[0077] The present invention is further illustrated by the following non-limiting examples. EXAMPLES

[0078] [Example 1] Using individual-level data from UK Biobank and dbGAP, a Mendelian randomization analysis of 470,471 participants was performed. From these participants, 44,321 had suffered a major cardiovascular event (CHD death, MI, stroke, or coronary revascularization). After analysis, CETP inhibition was found to be causally associated with a reduced risk of major cardiovascular events. It was further found that a substantial attenuation of the effect (i.e., reduced ApoB / LDL-C reduction) occurred when CETP inhibition was added to HMGCR inhibition. However, surprisingly, a similar attenuation of the CETP effect was found not to occur when added to NPC1L1 (i.e., CETP stratified by NPC1L1 inhibition). Thus, other than what would be expected based on HMGCR inhibition by statins, background ezetimibe use does not result in an attenuation of the effect of CETP on lowering ApoB / LDL-C and thereby on cardiovascular events. This makes said combination highly suitable for lowering ApoB / LDL-C levels in statin intolerant patients.

[0079] The results of the analysis are shown below, with tertile 1 representing the lowest degree of inhibition of either HMGCR or NPC1LI, and tertile 3 representing the highest degree of inhibition of said receptors. It is clear from these results that the greater the inhibition of HMGCR, the smaller the effect of CETP inhibition on APO-B / LDL-C. Notably, increased inhibition of NPC1L1 does not result in a smaller effect of CETP inhibition on APO-B / LDL-C:

[0080] [Example 2a] A Placebo-Controlled, Double-Blind, Randomized Phase 2 Study to Evaluate the Efficacy of Obicetrapib in Combination with Ezetimibe in Participants With Mild Dyslipidemia and Potential Statin Intolerance

[0081] (protocol) Research purpose Main purpose The primary objective of this study is to evaluate the effect of obiscetrapib in combination with ezetimibe compared with placebo on low-density lipoprotein cholesterol (LDL-C) at 57 days.

[0082] Secondary Objectives Secondary objectives of this study include:

[0083] To evaluate the effect of obiscetrapib monotherapy compared with placebo on LDL-C at day 57; To evaluate the effect of obiscetrapib in combination with ezetimibe, compared with placebo, on apolipoprotein B (ApoB) at day 57; To evaluate the effect of obiscetrapib monotherapy compared with placebo on ApoB at day 57; To evaluate the effect of obiscetrapib in combination with ezetimibe compared with ezetimibe monotherapy on LDL-C at day 57; To evaluate the effect of obiscetrapib monotherapy compared with ezetimibe monotherapy on LDL-C at day 57; To evaluate the effect of ezetimibe monotherapy compared with placebo on LDL-C at day 57; and To evaluate the effect of obiscetrapib in combination with ezetimibe compared with ezetimibe monotherapy on ApoB at day 57. To evaluate the effect of bempedoic acid (Esperion) in patients who are partially or completely statin intolerant as determined by the FDA definition also used in the Phase III trials.

[0084] exploratory purpose Exploratory objectives of this study include:

[0085] oTo evaluate the effect of ezetimibe monotherapy compared with placebo on ApoB at day 57; To evaluate the effects of obiscetrapib alone, ezetimibe alone, and obiscetrapib in combination with ezetimibe on non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), apolipoprotein E (ApoE), and high-density lipoprotein (HDL)-ApoE (with and without apolipoprotein C3 [ApoC3]) at day 57; To evaluate the effects of obiscetrapib alone, ezetimibe alone, and obiscetrapib in combination with ezetimibe on the proportion of participants who achieved predefined LDL-C targets at day 57; To evaluate mean trough plasma levels of obiscetrapib alone, ezetimibe alone, and obiscetrapib in combination with ezetimibe at steady state on day 57, week 12, and week 16; To evaluate the effects of obiscetrapib alone, ezetimibe alone, and obiscetrapib in combination with ezetimibe on cholesteryl ester transfer protein (CETP) mass at day 57, week 12, and week 16; and To evaluate the safety and tolerability profiles of obiscetrapib alone, ezetimibe alone and obiscetrapib in combination with ezetimibe, as assessed by clinical laboratory values ​​and incidence of adverse events (AEs).

[0086] Study population The population for this study includes men and women aged 18 to 75 years, inclusive, with a body mass index of less than 40 kg / m2 and mild dyslipidemia defined as fasting LDL-C levels greater than 2.5 mmol / L and less than 4.5 mmol / L and TG levels less than 4.5 mmol / L.

[0087] Sample size determination A sample size of at least 100 evaluable participants (i.e., 25 participants per treatment group) would provide greater than 90% power to detect a 30% difference (SD 15%) in LDL-C reduction at day 57 for the combination therapy group compared with the placebo group at a two-sided significance level of 0.05.

[0088] The sample size for this study was determined to provide sufficient power (>80%) for the analysis of the primary and secondary efficacy endpoints listed above, and also to contribute sufficient participant exposure and safety data.

[0089] Participants will be stratified according to LDL-C levels (<3.5 mmol / L or ≥3.5 mmol / L) at the screening visit (Visit 1).

[0090] Inclusion criteria Participants who meet all of the following criteria are eligible to participate in the study:

[0091] 1. Understanding of study procedures, willingness to comply with the study schedule and diet, and consent to participate in the study by giving written informed consent prior to the screening procedures; 2. Male or female aged between 18 and 75 years, inclusive; o Women may be enrolled if all three of the following criteria are met: · Not pregnant; · Not breastfeeding; and · Not planning to become pregnant during the study; o Women of childbearing potential must have a negative urine pregnancy test at the screening visit. Note: Women will not be considered of childbearing potential if they meet one of the following criteria documented by the investigator: Have had a hysterectomy or tubal ligation for at least one menstrual cycle prior to signing the ICF; or · Being postmenopausal, defined as being more than 1 year since last menstrual period for women aged 55 years or older, or more than 1 year since last menstrual period for women under 55 years old, and having a follicle-stimulating hormone (FSH) level within the menopausal range; o Women of childbearing potential must agree to use an effective method to avoid pregnancy from the screening visit until 90 days after their last visit. Men whose partners are of childbearing potential must agree to use an effective method to avoid pregnancy from the screening visit until 90 days after their last visit. An effective method to avoid pregnancy is a contraceptive method with a Pearl Index of less than 1 used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragms containing spermicide, male or female condoms containing spermicide, or cervical caps), or a non-fertile sexual partner; 3. Fasting LDL-C levels >2.5mmol / L and <4.5mmol / L and TG levels <4.5mmol / L (Visit 1); and 4. Willingness to maintain stable dietary and physical activity levels throughout the study.

[0092] Exclusion criteria Participants who meet any of the following criteria will be excluded from participating in the study:

[0093] 1. Body mass index ≥40kg / m2; 2. Participation in another clinical trial involving an investigational or marketed drug within 30 days prior to the screening visit; 3.Currently receiving any lipid-altering therapy; 4. Any clinical signs of atherosclerotic CVD or any evidence of ischemic coronary artery disease on 12-lead ECG at the time of the screening visit; 5. Diagnosis of type 1 or type 2 diabetes; or, if no prior diagnosis of diabetes, glycosylated hemoglobin (HbA1c) ≥ 6.5% at the screening visit; 6. Uncontrolled hypertension, i.e., sitting systolic blood pressure >160 mmHg and / or sitting diastolic blood pressure >90 mmHg. One retest is permitted, at which point the participant may be randomized if the retest result is no longer exclusionary. 7. Active myopathy or persistent creatine kinase concentrations greater than 3 times the upper limit of normal (ULN). One retest at 1 week will be allowed to verify the results, at which point participants may be randomized if the retest results are no longer exclusionary. 8. History of polymorphic ventricular tachycardia; 9. Estimated glomerular filtration rate of less than 60 mL / min calculated using the Chronic Kidney Disease Epidemiology Collaboration formula; 10. Liver dysfunction as evidenced by any of the following laboratory abnormalities: gamma-glutamyltransferase, alanine aminotransferase, or aspartate aminotransferase >2×ULN, or total bilirubin >1.5×ULN; 11. Anemia defined as hemoglobin concentration <11 g / dL in men and hemoglobin concentration <9 g / dL in women. 12. History of malignancy within the past 5 years, excluding non-melanoma skin cancer; 13. Evidence of any other clinically significant non-cardiac disease or condition that, in the opinion of the investigator, would preclude participation in the study; or 14. Known allergy or intolerance to ezetimibe or CETP inhibitors.

[0094] Withdrawal Criteria Participation in this clinical trial may be discontinued for any of the following reasons:

[0095] Participant withdraws consent or requests to discontinue the study for any reason. the occurrence of any medical condition or situation which places the Participant at substantial risk and / or prevents the Participant from complying with the requirements of the Protocol; Any serious adverse event (SAE), clinically significant AE, serious laboratory abnormality, intercurrent illness, or other medical condition that indicates to the investigator that continued participation is not in the participant's best interest; ·pregnancy; · the need for prohibited concomitant medications; A participant fails to comply with protocol requirements or study-related procedures; or Cancellation of a trial by the sponsor or regulatory authority.

[0096] If a participant withdraws early from the study due to the above criteria or for any other reason, study staff should make every effort to complete all scheduled assessments at the Early Termination Visit. The reason for the participant's withdrawal must be recorded on the electronic Case Report Form (eCRF).

[0097] If a participant is lost to follow-up, at least three attempts to contact the participant must be made and documented in the participant's medical record.

[0098] Participants who drop out will not be replaced.

[0099] Dosage form and route of administration The test drugs used in this study are as follows:

[0100] · 5mg obiscetrapib tablets; · 10mg ezetimibe tablet overencapsulated in a capsule; - obistrapib placebo tablets; and Ezetimibe placebo capsules.

[0101] All products are manufactured in accordance with current European Union Good Manufacturing Practices.

[0102] Obicetrapib tablets are unlabelled, round, white film-coated tablets containing 5 mg of obistrapib calcium drug substance. Excipients present in the tablet core are microcrystalline cellulose, mannitol, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. A commercially available film coating formula (Opadry II White, sold by Colorcon) is applied to the core.

[0103] The obiscetrapib placebo tablets are counterbalanced round white film-coated tablets without identifying markings. Excipients present in the tablet core are microcrystalline cellulose, mannitol, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. A commercially available film coating formula (Opadry II White, sold by Colorcon) is applied to the core.

[0104] The ezetimibe capsules are 10 mg ezetimibe tablets filled into a capsule shell, one tablet per capsule. Each capsule also contains excipients common to tablets as a filler to prevent the tablet from rattling within the capsule shell. The placebo capsules corresponding to the ezetimibe capsules are identical capsule shells (without tablets) filled with excipient fill material only.

[0105] Obicetrapib and placebo tablets and ezetimibe and placebo capsules will be packaged in foil blisters and assembled on blister cards to provide two study medications for each treatment group. The blister cards will be clearly labeled to indicate which blister to use on each day. The blister cards will be assembled into kits, with each kit providing a sufficient supply for one month of dosing. Shelf life will be assigned based on the stability of the individual products and will not exceed the expiration date of the input ezetimibe tablets. Kits should be stored below 25°C.

[0106] Participants will be randomized to receive two of the study medications listed above for the duration of the study. Both assigned study medications will be administered orally by participants once daily on days 1-57.

[0107] Rationale for Medication In previous multiple-dose clinical trials of obiscetrapib in healthy subjects and patients, near-maximal efficacy was observed at a 5 mg obiscetrapib dose. At this dose level, CETP activity and concentration were effectively reduced, and HDL-C levels increased, while LDL-C levels decreased. According to the product description, the recommended daily dose of ezetimibe is 10 mg. Therefore, this study utilizes a dose of 5 mg obiscetrapib administered with or without 10 mg ezetimibe in participants with mild dyslipidemia after a TLC meal.

[0108] Management system Study medication will be administered by participants orally, once daily on days 1-57. Study medication should be administered at approximately the same time each morning with food. On days when a clinic visit is scheduled, study medication should be administered with food after all fasting blood samples. If a participant forgets to take study medication on a given day, they should take the next dose as usual and should not take a double dose to make up for the missed dose.

[0109] Study design This is a placebo-controlled, double-blind, randomized Phase 2 study to evaluate the efficacy, safety, and tolerability of combination therapy with obiscetrapib and ezetimibe in participants with mild dyslipidemia.

[0110] Participants, investigators, contract research organizations, and sponsors will be blinded to all lipid results from Day 1 (Visit 2) for the first participant to the PK visit (Visit 6) for the last participant to protect blinding to treatment assignment.

[0111] Screening Period At the screening visit (Visit 1), participants will be required to sign an informed consent form (ICF) before any study-related procedures are performed. After signing the ICF, participants will be assessed for study eligibility. Participants will also receive counseling regarding the Therapeutic Lifestyle Modification (TLC) diet and instructions on how to adhere to this diet. The TLC diet is adapted from the National Institutes of Health Therapeutic Lifestyle Modification [TLC] diet and is exemplified below in Table 1. Participants will be required to begin the diet beginning at the screening visit.

[0112] [Table 1]

[0113] If participants are screened on a day other than Day -1, they will return to the site on Day -1 for pharmacokinetic (PK) and CETP mass assessments.

[0114] Duration of treatment Up to 2 weeks after the screening visit, participants will return to the site on Day 1 (Visit 2) to be randomized and begin treatment. Approximately 100 eligible participants (25 participants per treatment group) will be randomly assigned in a 1:1:1:1 ratio to one of the following treatment groups:

[0115] Combination therapy: 5mg obiscetrapib + 10mg ezetimibe; · Obicetrapib monotherapy: 5 mg obicatetrapib + placebo ezetimibe; Ezetimibe monotherapy: placebo obiscetrapib + 10 mg ezetimibe; or Placebo: placebo obicetrapib + placebo ezetimibe.

[0116] During the 12-week treatment period, the assigned study drug will be administered by participants orally, once daily on days 1-57. Participants will return to the site every 4 weeks for efficacy, safety, pharmacokinetic (PK) and CETP mass assessments. Participants, investigators, contract research organizations and sponsors will be blinded to all lipid results from Day 1 (Visit 2) for the first participant to the PK visit (Visit 6) for the last participant to protect blinding to treatment assignment.

[0117] Follow-up period Participants will return to the site for a safety follow-up visit approximately 4 weeks after the end of the treatment period for safety, PK and CETP mass assessments (Visit 6).

[0118] Pharmacokinetic Period Participants will return to the site for a PK visit approximately 8 weeks after the end of the treatment period for PK and CETP mass assessment (Visit 7).

[0119] Evaluation items Efficacy variables The primary efficacy endpoint was the percent change in LDL-C from Day 1 to Day 57 in the combination therapy group compared with the placebo group.

[0120] Secondary efficacy endpoints included, in hierarchical order: · Percent change in LDL-C from Day 1 to Day 57 in the obiscetrapib monotherapy group compared with the placebo group; · Percent change in ApoB from Day 1 to Day 57 in the combination therapy group compared with the placebo group; · Percent change in ApoB from Day 1 to Day 57 in the obiscetrapib monotherapy group compared with the placebo group; · Percent change in LDL-C from Day 1 to Day 57 in the combination therapy group compared with the ezetimibe monotherapy group; · Percent change in LDL-C from Day 1 to Day 57 in the obiscetrapib monotherapy group compared with the ezetimibe monotherapy group; - the percent change in LDL-C from Day 1 to Day 57 in the ezetimibe monotherapy group compared with the placebo group; and · Percent change in ApoB from Day 1 to Day 57 in the combination therapy group compared with the ezetimibe monotherapy group; Exploratory efficacy endpoints included the following: · Percent change in ApoB from Day 1 to Day 57 in the ezetimibe monotherapy group compared with the placebo group; · Pairwise comparisons between the various treatment groups for percent change from day 1 to day 57 in non-HDL-C, VLDL-C, HDL-C, TG, ApoE, and HDL-ApoE (with and without ApoC3); Pairwise comparisons between the various treatment groups for the proportion of participants at day 57 achieving LDL-C<2.6mmol / L (<100mg / dL), LDL-C<1.8mmol / L (<70mg / dL), and LDL-C<1.3mmol / L (<50mg / dL); Pairwise comparisons of the changes in mean trough plasma levels of obiscetrapib from Day 1 to Day 57, Day 1 to Week 12, and Day 1 to Week 16 between the various treatment groups; and Pairwise comparisons between the various treatment groups for change in CETP mass from Day 1 to Day 57, Day 1 to Week 12, and Day 1 to Week 16; and Safety Variables The safety and tolerability profiles of obiscetrapib alone, ezetimibe alone and obiscetrapib in combination with ezetimibe will be assessed by laboratory values ​​and the occurrence of (S)AEs.

[0121] statistical analysis Analysis population The intention to treat (ITT) population included all participants randomized into the study. Treatment classification was based on randomized treatment.

[0122] The modified ITT (mITT) population includes all participants in the ITT population who received at least one dose of any study drug and have baseline values ​​for LDL-C assessment. Any efficacy measurements obtained after participants received restrictive lipid-modifying treatment, which are outside the scope of this study design, are excluded from the mITT analysis. Treatment classification is based on randomized treatment. The mITT population is used for the primary analysis of all efficacy endpoints.

[0123] The per-protocol (PP) population includes all participants in the mITT population who had a baseline value for LDL-C assessment, had a day 85 value for LDL-C assessment, and did not experience major protocol deviations that could affect the primary efficacy endpoint. The PP population will be terminated prior to unblinding of the study, along with the reason for exclusion.

[0124] The PK population includes all participants in the mITT population from whom sufficient blood samples were collected for valid estimation of PK parameters.

[0125] The Safety Analysis Population includes all participants who receive at least one dose of any study drug. Treatment classification is based on the actual treatment received. The Safety Analysis Population is the primary population used for safety analyses.

[0126] statistical methods All data collected in the study will be summarized by treatment group using descriptive statistics, graphs and / or raw data listings. Descriptive statistics for continuous variables will include number of participants (n), mean, standard deviation (SD), median, minimum and maximum. Analysis of categorical variables will include frequencies and percentages.

[0127] Efficacy Analysis The mITT population is the primary population for efficacy analysis. Efficacy will also be analyzed using the ITT and PP populations as a confirmatory analysis.

[0128] Primary efficacy analysis The analysis is performed using a mixed model for repeated measures (MMRM) approach. The analysis includes fixed effects for treatment, visit, and treatment-visit interactions, along with covariates for baseline values. A restricted maximum likelihood estimation approach is used with an unstructured covariance matrix. Least squares means, standard errors, and two-sided 95% confidence intervals for each treatment group are provided for pairwise comparisons of combination therapy, obiscetrapib monotherapy, and ezetimibe monotherapy with placebo, and for pairwise comparisons of combination therapy versus obiscetrapib monotherapy. Treatment comparisons are performed using two-sided tests with a significance level of α=0.05.

[0129] Missing data will be imputed using multiple imputation methods. Results will be pooled using the method of Rubin. Full details of the model and imputation will be provided in the Statistical Analysis Plan (SAP).

[0130] Secondary and exploratory efficacy analyses Similar MMRM models will be used for the analysis of secondary and exploratory efficacy endpoints corresponding to percent change from baseline. For binary efficacy endpoints, logistic regression analyses will be performed with treatment group and baseline LDL-C modeled covariates.

[0131] Secondary efficacy endpoints will be tested sequentially at the 0.05 significance level according to a pre-specified hierarchical order to maintain an overall type I error rate. No adjustment for multiplicity will be made when testing exploratory efficacy endpoints. Nominal p-values ​​will be given where applicable. Narrative and graphical summaries by treatment group are also provided. Additional sensitivity and / or supplementary analyses will be defined in the SAP.

[0132] Safety analysis The Safety Analysis Set is the primary population for the safety analysis. All safety endpoints will be summarized narratively. No statistical inferences will be applied to the safety endpoints.

[0133] AEs will be classified by primary system organ class and preferred term coded using Medical Dictionary for Regulatory Activities (MedDRA) category names. A summary of AEs will be provided, including the number and percentage of participants experiencing an AE.

[0134] Laboratory values ​​will be summarized descriptively, including change from baseline, by treatment group and overall. In addition, shift tables will be presented to describe changes in laboratory parameter values ​​at post-baseline visits using normal range categories (low, normal, high).

[0135] Pharmacokinetic analysis Plasma obistrapib concentrations will be summarized using descriptive statistics based on the PK population and, where appropriate, exploration of any relationships with obistrapib exposure will be performed.

[0136] [Example 2b] A placebo-controlled, double-blind, randomized phase 2 study to evaluate the effects of obiscetrapib in combination with ezetimibe in participants with mild dyslipidemia and potential statin intolerance (analysis, results and conclusions)

[0137] Participants, treatment and analyses Duration of treatment: 8 weeks. Note: 44 participants completed the study under Clinical Trial Protocol Version 3.0 and received 12 weeks of treatment.

[0138] Number of participants: Scheduled: 100 people Screened: 234 Randomized: 112 participants (1 participant misrandomized) Treatment completed: 103 participants Study discontinued: 14 participants Treatment discontinued: 8 participants

[0139] Diagnosis and main inclusion criteria: Men or women aged 18-70 years, including age 18 and 70 years, with BMI < 40 kg / m2, fasting LDL-C levels > 2.5 mmol / L (> 100 mg / dL) and < 4.5 mmol / L (< 175 mg / dL), and TG levels < 4.5 mmol / L (< 400 mg / dL) were eligible to participate in the study. Participants were excluded from the study if they were currently receiving any lipid-modifying therapy, had clinical signs of atherosclerotic cardiovascular disease or evidence of ischemic coronary artery disease on a 12-lead electrocardiogram (ECG) at the screening visit, had a diagnosis of type 1 or type 2 diabetes at the screening visit or glycosylated hemoglobin ≥ 6.5% if not previously diagnosed with diabetes, or had uncontrolled hypertension, i.e., a sitting systolic blood pressure > 160 mmHg and / or a sitting diastolic blood pressure > 90 mmHg as the mean of triplicate measurements.

[0140] Investigational Product and Comparator Information: Study medication consisted of 5 mg obistrapib tablets or matched dose placebo tablets, and overencapsulated 10 mg ezetimibe tablets or matched dose placebo capsules. All products were manufactured in accordance with the International Conference on Harmonization (ICH) current good manufacturing practice.

[0141] Statistical methods: Analysis population: The intention to treat (ITT) population included all participants randomized into the study. Treatment classification was based on randomized treatment.

[0142] The modified intention-to-treat (mITT) population included all participants in the ITT population who received at least one dose of any study drug and had baseline values ​​for LDL-C assessment. All efficacy measurements obtained after participants received restrictive lipid-modifying treatment, which were outside the scope of the study design, were excluded from the mITT analysis (the study prohibited any lipid-modifying therapy other than the investigational drug). Treatment classification was based on randomized treatment. The mITT population was used for the primary analysis of all efficacy endpoints.

[0143] The per-protocol (PP) population included all participants in the mITT population who had baseline values ​​for LDL-C assessment, had day 57 values ​​for LDL-C assessment, and did not experience major clinical trial protocol deviations that could affect the primary efficacy endpoint. Major clinical trial protocol deviations were defined in a protocol deviation plan within the trial documentation, consistent with ICH guidelines. The decision to be a member of the PP population was made prior to unblinding of the study. The PP population was a secondary population for the analysis of the primary efficacy endpoint.

[0144] The safety analysis population included all participants who received at least one dose of any study drug. Treatment classification was based on the actual treatment received. The safety analysis population was the primary population used for safety analysis.

[0145] The PK population included all participants in the mITT population from whom sufficient blood samples were collected for valid estimation of PK parameters.

[0146] The numbers and percentages of participants in each analysis population will be summarized by treatment and in total, based on all randomized participants. Reasons for exclusion from the PP population will also be summarized.

[0147] Efficacy Analysis The mITT population was the primary population for efficacy analyses. Efficacy was also analyzed using the ITT and PP populations as confirmatory analyses for selected endpoints.

[0148] LDL-C levels were collected using two approaches: 1. At each scheduled visit, LDL-C levels were calculated using the Friedewald formula; and 2. In addition, LDL-C was measured in all participants by preparative ultracentrifugation (PUC) at baseline (day 1) and at the end of the 8-week treatment period (day 57).

[0149] Primary efficacy endpoint; primary analysis The primary analysis of efficacy of percent change in LDL-C from day 1 to day 57 was performed using a mixed model for repeated measures (MMRM) approach. Analyses included fixed effects for treatment, visit, and treatment-visit interactions, with baseline value covariates as continuous covariates. To ensure a similar distribution of LDL-C across all treatment groups, randomization was stratified only by LDL-C value category (<3.5 mmol / L [<135 mg / dL] or ≥3.5 mmol / L [≥135 mg / dL]), but the MMRM model included the original scale of LDL-C values ​​as a continuous covariate. A restricted maximum likelihood estimation approach was used with an unstructured covariance matrix. Least squares (LS) means, standard errors, and two-sided 95% confidence intervals (CIs) for each treatment group are provided for pairwise comparisons of combination therapy, obiscetrapib monotherapy, and ezetimibe monotherapy with placebo, and for pairwise comparisons of combination therapy and obiscetrapib monotherapy versus ezetimibe monotherapy. Treatment comparisons were performed using two-sided tests with a significance level of α=0.05.

[0150] The MMRM approach included all available assessments of percent change in LDL-C from baseline to days 29, 57, and 85. The model assumed that data were missing at random. When data were missing, the model used all information from other time points to estimate the mean treatment difference at a given time point. Missing data were not imputed for the analysis of the primary efficacy endpoint.

[0151] Primary efficacy endpoint; sensitivity analysis Sensitivity analyses were performed for the primary efficacy endpoint. In the first analysis, missing data were imputed using a control-based pattern imputation model, assuming that data were missing not at random. Missing data on days 29, 57, and 85 were imputed using a multiple imputation method in two stages, which were performed such that only observations from the placebo group were used to derive imputation models for missing LDL-C values. First, 25 data sets were imputed for non-monotonic missing values ​​in the original data set. In the second stage, the remaining monotonic missing values ​​were imputed. If, at the completion of the study, the percentage of cases with incomplete data was greater than initially expected, the number of imputations was increased for the final analysis.

[0152] The variables in the imputation model consisted of LDL-C values ​​from baseline and days 29, 57 and 85. For each imputed data set, the percent change from baseline to day 57 was analyzed using the MMRM model. The results from these 25 analyses were combined to construct treatment estimates using parameter estimates and associated standard errors. Similarly, the adjusted treatment mean difference (combination therapy minus placebo) is shown with associated standard errors and 95% CI. A randomly selected number of seeds was selected and retained for analysis.

[0153] In a second sensitivity analysis, the percent change in LDL-C from day 1 to day 57 was analyzed by the Friedewald formula for the combination therapy group compared with the placebo group using an analysis of covariance (ANCOVA) model with the fixed effect of treatment group and baseline LDL-C value as a continuous covariate. LS means, standard errors, and two-sided 95% CIs for each treatment group are provided for pairwise comparisons of combination therapy, obiscetrapib monotherapy, and ezetimibe monotherapy with placebo. Treatment comparisons were performed using two-sided tests with a significance level of α = 0.05. Missing data were not imputed for this sensitivity analysis.

[0154] In a third sensitivity analysis, we used PUC, also known as beta quantification, to measure LDL-C levels to evaluate the percent change in LDL-C from day 1 to day 57. We analyzed the percent change in LDL-C from day 1 to day 57 by PUC for the combination therapy group compared to the placebo group using an ANCOVA similar to the model described in the second sensitivity analysis. Missing data were not imputed for this sensitivity analysis.

[0155] A fourth sensitivity analysis utilized a similar ANCOVA model as above for evaluation of percent change in LDL-C from baseline to day 57 as measured by PUC. In this analysis, missing data at day 57 were imputed using a last observed last-observed (LOCB) approach, where the next available LDL-C measurement measured by PUC after day 57 was used in the analysis. The previous TULIP trial (NCT01970215) observed similar values ​​of percent change in LDL-C at weeks 8 and 12, providing justification for the LOCB approach in this study.

[0156] Secondary efficacy endpoints Similar MMRM models were developed to examine percent change from day 1 to day 57 in LDL-C (using the Friedewald formula for other pairwise treatment group comparisons outside of the analyses specified for the primary efficacy endpoint) or ApoB. Secondary efficacy endpoints were tested sequentially at a significance level of 0.05 according to a prespecified hierarchical order to maintain an overall type I error rate. This was applied to the following analyses: · Percent change in LDL-C from Day 1 to Day 57 in the obiscetrapib monotherapy group compared with the placebo group; · Percent change in ApoB from Day 1 to Day 57 in the combination therapy group compared with the placebo group; · Percent change in ApoB from Day 1 to Day 57 in the obiscetrapib monotherapy group compared with the placebo group; · Percent change in LDL-C from Day 1 to Day 57 in the combination therapy group compared with the ezetimibe monotherapy group; · Percent change in LDL-C from Day 1 to Day 57 in the obiscetrapib monotherapy group compared with the ezetimibe monotherapy group; - the percent change in LDL-C from Day 1 to Day 57 in the ezetimibe monotherapy group compared with the placebo group; and · Percent change in ApoB from Day 1 to Day 57 in the combination therapy group compared with the ezetimibe monotherapy group; Exploratory efficacy endpoints Similar MMRM models were used for exploratory efficacy endpoints: proportion of participants at day 57 who achieved LDL-C < 2.6 mmol / L (< 100 mg / dL), LDL-C < 1.8 mmol / L (< 70 mg / dL), and LDL-C < 1.3 mmol / L (< 50 mg / dL) through logistic regression models for binary variables with covariates for treatment group and baseline variables.

[0157] No adjustments were made for multiplicity when testing exploratory efficacy endpoints. Nominal p values ​​are given where applicable.

[0158] Safety analysis: The safety analysis population was the primary population for safety analysis. All safety endpoints were summarized narratively. No statistical inferences were applied to the safety endpoints.

[0159] AEs will be classified by primary system organ class (SOC) and preferred term (PT) coded using the Medical Dictionary for Regulatory Activities (Version 23.0) category nomenclature. A summary of AEs will be provided, including the number and percentage of participants who experienced an AE.

[0160] A summary of treatment-emergent adverse events (TEAEs) including numbers and percentages of participants (and number of events) will be provided.

[0161] TEAEs, treatment-emergent serious adverse events (TESAEs), and TEAEs leading to discontinuation of study drug will be specifically tabulated.

[0162] For clinical tests, laboratory values ​​will be summarized descriptively, including change from baseline, by treatment, and overall. In addition, shift tables will be provided to describe changes in laboratory parameter values ​​at post-baseline visits using normal range categories (low, normal, high).

[0163] For vital signs, values ​​and changes from baseline will be summarized by treatment and for each visit, along with descriptive statistics.

[0164] Summary statistics for the 12-lead ECG data are provided for continuous results (PR, QRS, heart rate, RR, QT, QTc and QTcF) as well as per-treatment and overall global interpretations.

[0165] Efficacy Results This was a placebo-controlled, double-blind, randomized, phase 2 study to evaluate the efficacy, safety, and tolerability of combination therapy with obiscetrapib and ezetimibe in participants with mild dyslipidemia.The primary efficacy outcome measure was the percent change in LDL-C from Day 1 to Day 57 in the obiscetrapib 5 mg + ezetimibe 10 mg group compared with the placebo group.

[0166] At day 57, mean LDL-C by Friedewald formula was 71.3 mg / dL in the obicetrapib 5 mg + ezetimibe 10 mg group, 87.0 mg / dL in the obicetrapib 5 mg group, 109.1 mg / dL in the ezetimibe 10 mg group, and 136.2 mg / dL in the placebo group. The mean percent change in LDL-C by Friedewald formula from baseline to day 57 was -45.63% in the obicetrapib 5 mg + ezetimibe 10 mg group, -31.88% in the obicetrapib 5 mg group, -12.69% in the ezetimibe 10 mg group, and -0.17% in the placebo group. In this regard, reference is made to Table 2 and Figure 3.

[0167] PUC and Martin / Hopkins calculated LDL-C values ​​were similar to Friedewald values ​​on day 57.

[0168] At day 57, both the obiscetrapib 5 mg group and the obiscetrapib 5 mg + ezetimibe 10 mg group showed significant reductions in percent change from baseline for ApoB and non-HDL-C compared to placebo. In this regard, reference is made to Table 3.

[0169] At day 57, both the obiscetrapib 5 mg group and the obiscetrapib 5 mg + ezetimibe 10 mg group demonstrated significantly increased percent change from baseline compared to placebo for HDL-C and ApoE.

[0170] The number of participants who achieved LDL-C < 70 mg / dL by Friedewald formula on day 57 was 13 (48.1%) participants in the obicetrapib 5 mg + ezetimibe 10 mg group, 7 (25.0%) participants in the obicetrapib 5 mg group, 1 (3.6%) participants in the ezetimibe 10 mg group, and 0 (0.0%) participants in the placebo group. The number of participants who achieved LDL-C < 100 mg / dL by Friedewald formula on day 57 was 21 (77.8%) participants in the obicetrapib 5 mg + ezetimibe 10 mg group, 16 (57.1%) participants in the obicetrapib 5 mg group, 8 (28.6%) participants in the ezetimibe 10 mg group, and 2 (7.1%) participants in the placebo group.

[0171] In conclusion, the study met its primary efficacy objectives: the combination of obiscetrapib 5 mg plus ezetimibe 10 mg significantly reduced LDL-C, non-HDL-C, and ApoB, increased HDL-C and ApoE, and increased the proportion of participants who achieved LDL-C below the clinically meaningful thresholds of 100 mg / dL and 70 mg / dL compared with both placebo and ezetimibe 10 mg monotherapy.

[0172] Safety Results The majority of participants in the placebo, ezetimibe 10 mg, and obicetrapib 5 mg treatment groups were exposed to the study medication for less than 8 to 12 weeks.

[0173] Overall, 27 (24.3%) participants experienced at least one TEAE: 9 (33.3%) participants in the obiscetrapib 5 mg + ezetimibe 10 mg group, 4 (14.3%) participants in the obiscetrapib 5 mg group, 8 (28.6%) participants in the ezetimibe 10 mg group, and 6 (21.4%) participants in the placebo group.

[0174] The majority of TEAEs were mild or moderate in severity. In total, 9 (8.1%) participants experienced a TEAE with a maximum severity of moderate: 2 (7.4%) participants in the obiscetrapib 5 mg + ezetimibe 10 mg group, 1 (3.6%) participant in the obiscetrapib 5 mg group, 4 (14.3%) participants in the ezetimibe 10 mg group, and 2 (7.1%) participants in the placebo group. One (0.9%) participant in the ezetimibe 10 mg group (Participant 106-010) experienced a severe TEAE of multiple fractures.

[0175] The most common SOCs for TEAEs were gastrointestinal disorders (9 [8.1%] participants), infections and infestations (6 [5.4%] participants), and nervous system disorders (6 [5.4%] participants). The most common PTs experienced among all participants were diarrhea and headache (4 [3.6%] participants each).

[0176] Overall, 11 (9.9%) participants experienced at least one study drug-related TEAE: 3 (11.1%) participants in the obiscetrapib 5 mg + ezetimibe 10 mg group, 1 (3.6%) participant in the obiscetrapib 5 mg group, 3 (10.7%) participant in the ezetimibe 10 mg group, and 4 (14.3%) participants in the placebo group. The most common SOC for study drug-related TEAEs was gastrointestinal disorders (7 [6.3%] participants).

[0177] In total, there were 4 (3.6%) participants who experienced at least one TEAE leading to discontinuation of study drug: 2 (7.4%) participants in the obiscetrapib 5 mg + ezetimibe 10 mg group, and 1 (3.6%) participant each in the ezetimibe 10 mg group and placebo group. A total of 2 (1.8%) participants, both in the ezetimibe 10 mg group, experienced a TESAE.

[0178] There were no deaths in this study.

[0179] Two participants in the ezetimibe 10 mg group experienced serious adverse events (SAEs): Participants 004-003 experienced an SAE of hyperventilation rated as moderate and not related to study drug. Participants 106-010 experienced an SAE of multiple fractures rated as severe and not related to study drug. Both participants recovered from their SAEs.

[0180] There were no clinically significant chemistry, hematology or urinalysis parameters.

[0181] In general, no clinically meaningful changes were observed in vital signs, physical examinations, or ECGs. Differences in mean blood pressure values ​​showed no significant increases or trends between treatment groups.

[0182] Consistent with previous studies, treatment with obiscetrapib 5 mg, both as monotherapy and in combination with ezetimibe 10 mg, was generally safe and well tolerated.

[0183] conclusion This was a placebo-controlled, double-blind, randomized phase 2 study to evaluate the effects of obiscetrapib in combination with ezetimibe in participants with mild dyslipidemia.

[0184] The key findings are as follows:

[0185] -Obicetrapib 5mg + ezetimibe 10mg combination therapy significantly reduced LDL-C, non-HDL-C and ApoB, and increased HDL-C and ApoE; · The combination of obiscetrapib 5 mg + ezetimibe 10 mg significantly increased the proportion of participants who achieved LDL-C below clinically meaningful thresholds of 100 mg / dL and 70 mg / dL compared with both placebo and ezetimibe 10 mg monotherapy; -Obicetrapib 5mg + ezetimibe 10mg combination therapy significantly reduced LDL-C, non-HDL-C and ApoB compared with bicetrapib 5mg monotherapy; ·PUC and Martin / Hopkins calculations of LDL-C levels were similar to Friedewald formula values ​​at day 57 in this population; · The PK profile of obiscetrapib was consistent with previous findings, showing near complete elimination of obiscetrapib by 8 weeks after chronic daily dosing; The study drug was well tolerated and there was no evidence of safety signals associated with obiscetrapib therapy.

[0186] In conclusion, treatment with obiscetrapib 5 mg alone or in combination with ezetimibe 10 mg was well tolerated and led to a significant improvement of the lipid profile in participants with mild dyslipidemia, shifting towards a lower atherogenic lipid profile.

[0187] [Table 2]

[0188] [Table 3]

[0189] Scheme 1 Chemical name and formula of obiscetrapib

[0190] [ka]

[0191] {4-[(2-{[3,5-bis(trifluoromethyl)benzyl][(2R,4S)-1-(ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}pyrimidin-5-yl)oxy]butanoic acid}

[0192] Scheme 2 Chemical name and formula of ezetimibe

[0193] [ka]

[0194] (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

Claims

1. 1. A pharmaceutical composition for use in treating a subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, comprising obiscetrapib and ezetimibe, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier, wherein the subject is partially or completely intolerant to statins.

2. 10. The pharmaceutical composition of claim 1 for use in reducing the risk of cardiovascular events.

3. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the subject suffers from mild dyslipidemia.

4. 2. The pharmaceutical composition for use according to claim 1, wherein the subject in need of said treatment is administered 1-10 mg of obiscetrapib per day and 5-20 mg of ezetimibe per day.

5. A pharmaceutical composition for use as described in claim 1, wherein a subject in need of said treatment is administered 5 mg of obiscetrapib per day and 10 mg of ezetimibe per day, or 10 mg of obiscetrapib per day and 10 mg of ezetimibe per day.

6. 2. The pharmaceutical composition for use according to claim 1, wherein said composition reduces apolipoprotein B (ApoB) levels in the blood of said subject.

7. 2. The pharmaceutical composition for use according to claim 1, wherein said composition reduces LDL-C levels in the blood of said subject.

8. 2. The pharmaceutical composition for use according to claim 1, wherein said composition does not attenuate the LDL-C lowering effect of obiscetrapib when compared to obiscetrapib monotherapy.

9. 2. The pharmaceutical composition for use according to claim 1, wherein the relative LDL-C reduction with obiscetrapib when administered in combination with ezetimibe is similar to the relative LDL-C reduction with the same dose of obiscetrapib administered as monotherapy.

10. 2. The pharmaceutical composition for use according to claim 1, wherein the relative LDL-C reduction with a daily dose of 5 mg obiscetrapib when administered in combination with 10 mg ezetimibe is similar to the relative LDL-C reduction with a daily dose of 5 mg obiscetrapib administered as monotherapy.

11. 2. The pharmaceutical composition for use according to claim 1, wherein the relative LDL-C reduction with a 10 mg daily dose of obiscetrapib when administered in combination with 10 mg of ezetimibe is similar to the relative LDL-C reduction with a 10 mg daily dose of obiscetrapib administered as monotherapy.

12. 2. The pharmaceutical composition for use according to claim 1, wherein the composition is formulated as an oral free dose combination or an oral fixed dose combination.

13. The pharmaceutical composition for use according to claim 1, wherein the composition is formulated as an oral fixed dose combination.

14. 2. The pharmaceutical composition for use according to claim 1, wherein the oral fixed dose combination is in a solid dosage form such as a capsule or tablet.

15. 2. The pharmaceutical composition for use according to claim 1, wherein said composition is an oral fixed dose combination comprising 1-10 mg of obiscetrapib and 5-20 mg of ezetimibe.

16. The pharmaceutical composition for use according to claim 1, wherein the composition is an oral fixed dose combination comprising 5 mg of obistrapib and 10 mg of ezetimibe, or an oral fixed dose combination comprising 10 mg of obistrapib and 10 mg of ezetimibe.

17. 1. A pharmaceutical composition for use in a method for treating hyperlipidemia or mixed dyslipidemia in a subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia, wherein the subject is partially or completely intolerant to statins, The method further comprises administering to the subject a therapeutically effective amount of (i) obiscetrapib or a pharma- ceutically acceptable salt or solvate thereof, and (ii) ezetimibe or a pharma- ceutically acceptable salt or solvate thereof. and The pharmaceutical composition comprises a therapeutically effective amount of (i) obiscetrapib or a pharma- ceutically acceptable salt or solvate thereof, and / or (ii) ezetimibe or a pharma- ceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising:

18. 18. The pharmaceutical composition of claim 17 for use in reducing the risk of cardiovascular events.

19. 19. The pharmaceutical composition for use according to claim 18, wherein the subject suffers from mild dyslipidemia.

20. 18. The pharmaceutical composition for use according to claim 17, wherein the subject in need of said treatment is administered 1-10 mg of obiscetrapib per day and 5-20 mg of ezetimibe per day.

21. A pharmaceutical composition for use as described in claim 17, wherein a subject in need of said treatment is administered 5 mg of obiscetrapib per day and 10 mg of ezetimibe per day, or 10 mg of obiscetrapib per day and 10 mg of ezetimibe per day.

22. 18. The pharmaceutical composition for use according to claim 17, wherein said composition reduces apolipoprotein B (ApoB) levels in the blood of said subject.

23. 18. The pharmaceutical composition for use according to claim 17, wherein said composition does not attenuate the LDL-C lowering effect of obiscetrapib when compared to obiscetrapib monotherapy.

24. 18. The pharmaceutical composition for use according to claim 17, wherein the relative LDL-C reduction with obiscetrapib when administered in combination with ezetimibe is similar to the relative LDL-C reduction with the same dose of obiscetrapib administered as monotherapy.

25. 18. The pharmaceutical composition for use according to claim 17, wherein the relative LDL-C reduction with a daily dose of 5 mg obiscetrapib when administered in combination with 10 mg ezetimibe is similar to the relative LDL-C reduction with a daily dose of 5 mg obiscetrapib administered as monotherapy.

26. 18. The pharmaceutical composition for use according to claim 17, wherein the relative LDL-C reduction with a 10 mg daily dose of obiscetrapib when administered in combination with 10 mg of ezetimibe is similar to the relative LDL-C reduction with a 10 mg daily dose of obiscetrapib administered as monotherapy.

27. 18. The pharmaceutical composition for use according to claim 17, wherein said composition is formulated as an oral free dose combination or an oral fixed dose combination.

28. 18. The pharmaceutical composition for use according to claim 17, wherein said composition comprises a first unit dosage form comprising 1-10 mg of obiscetrapib and a second unit dosage form comprising 5-20 mg of ezetimibe.

29. A pharmaceutical composition for use as described in claim 17, wherein the composition comprises a first unit dosage form comprising 5 mg of obiscetrapib and a second unit dosage form comprising 10 mg of ezetimibe, or a first unit dosage form comprising 10 mg of obiscetrapib and a second unit dosage form comprising 10 mg of ezetimibe.

30. 30. The pharmaceutical composition of claim 28, wherein the composition comprises a package containing the unit dosage form.

31. The pharmaceutical composition of claim 30, comprising a package containing a unit dosage form of the composition, tablet or capsule.

32. 20. Use of a pharmaceutical composition according to claim 1 or 17 in the manufacture of a medicament for use in the treatment of a partially or completely statin intolerant subject suffering from or at increased risk of hyperlipidemia or mixed dyslipidemia.

33. 33. The use according to claim 32, wherein said use reduces the risk of a cardiovascular event.

34. 1. A pharmaceutical composition for use in a method for treating cardiovascular disease in a partially or completely statin intolerant subject suffering from or at increased risk of cardiovascular disease, comprising: The method further comprises administering to the subject a therapeutically effective amount of (i) a CETP inhibitor, and (ii) ezetimibe or a pharma- ceutically acceptable salt or solvate thereof. and The pharmaceutical composition comprises a therapeutically effective amount of (i) a CETP inhibitor, and / or (ii) ezetimibe or a pharma- ceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising:

35. The pharmaceutical composition described in claim 34, wherein the CETP inhibitor is obiscetrapib.

36. 35. A pharmaceutical composition for use according to claim 34 for reducing the risk of cardiovascular events.

37. 35. The pharmaceutical composition for use according to claim 34, for reducing apolipoprotein B (ApoB) concentration in the blood of said subject.

38. 36. The pharmaceutical composition for use according to claim 35, wherein the relative LDL-C reduction with obiscetrapib when administered in combination with ezetimibe is similar to the relative LDL-C reduction with the same dose of obiscetrapib administered as monotherapy.

39. 36. The pharmaceutical composition for use according to claim 35, wherein said composition does not attenuate the LDL-C lowering effect of obiscetrapib when compared to obiscetrapib monotherapy.

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