Methods for treating and / or preventing major adverse cardiovascular events (MACE) with a combination of a BET bromodomain inhibitor and a dipeptidyl peptidase 4 inhibitor

Abstract

Described herein are methods of treating and / or preventing major adverse cardiovascular events (MACE) by administering to a subject in need thereof, in combination, a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein the variables of formula (I) are as defined herein. TIFF2023509186000009.tif6880

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 958,474, filed January 8, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to methods of treating and / or preventing major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, cardiovascular death, stroke, and hospitalization for cardiovascular disease (CVD) events, by administering to a subject in need thereof a combination of a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. [Background technology]

[0003] Despite the use of current evidence-based therapies, including prompt coronary revascularization, dual antiplatelet therapy, and intensive lipid-lowering therapy, major adverse cardiovascular events (MACE) recur frequently after acute coronary syndrome (ACS). Patients with type 2 diabetes mellitus (T2DM) are at particular high risk, representing approximately one-third of ACS cases (Cannon et al. 2015; Schwartz et al. 2013; Schwartz et al. 2018). Dipeptidyl peptidase 4 (DPP-4) inhibitors are a group of oral antidiabetic medications that inhibit the enzyme DPP-4. These therapies function by inhibiting the degradation of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) and therefore can potentially impact glucose control through multiple effects (Thornberry and Gallwitz 2009). DPP-4 inhibitor treatment has demonstrated noninferior risk of cardiovascular events in patients with established cardiovascular disease, diabetes, chronic kidney disease, and acute coronary syndrome (ACS) (Rosenstock et al. 2019; Green et al. 2015; Scirica et al. 2013; White et al. 2013). However, DPP-4 inhibitors have not been shown to reduce MACE in patients with recent ACS, and substantial residual risk remains for this population. At best, DPP-4 inhibitors have been shown to have a neutral effect on MACE in clinical trials evaluating cardiovascular safety. For example, SAVOR-TIMI-53 and EXAMINE suggested a neutral effect of saxagliptin and alogliptin on the three-point MACE composite outcome of cardiovascular death, myocardial infarction, or ischemic stroke. Similarly, in the TECOS trial evaluating the safety of sitagliptin, the DPP-4 inhibitor was found to be non-inferior to placebo for both the MACE composite outcome of 3 points [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.89-1.10] and 4 points (HR 0.98; 95% CI 0.89-1.08) (Karagiannis et al. 2015).

[0004] Apabetalone (RVX-208 or RVX000222) is a first-in-class bromodomain and exon terminal (BET) inhibitor (BETi) that selectively binds to the second bromodomain of BET proteins (e.g., BRD2, BRD3, BRD4, and BRDT) to prevent BET protein translocation and thereby inhibit the transcription of chronic disease-causing genes. A recently completed Phase 3 clinical trial (BETonMACE, NCT02586155) evaluated the effect of apabetalone (RVX-208) on MACE in patients with type 2 diabetes who had low HDL cholesterol (men <40 mg / dL, women <45 mg / dL) and recent ACS (7-90 days prior). All patients were receiving high-intensity or maximally tolerated statin therapy. The study enrolled 2,425 patients, and the full analysis set (FAS) comprised 2,418 patients who were evaluated for MACE outcomes. A total of 169 patients received both RVX-208 and a DPP-4 inhibitor, a total of 167 patients received a DPP-4 inhibitor but not RVX-208, a total of 1,043 patients received RVX-208 but not a DPP-4 inhibitor, and a total of 1,039 patients received neither RVX-208 nor a DPP-4 inhibitor.

[0005] Surprisingly, as detailed in Example 2, we discovered that patients treated with a combination of RVX-208 and a DPP-4 inhibitor showed a significant reduction in cardiovascular events and cardiovascular disease (CVD) events, measured as a reduction in MACE, compared with treatment with either therapy alone. As mentioned above, DPP-4 inhibitors have not been shown to reduce MACE. The results discussed in Example 2 consistently demonstrate that, like DPP-4 inhibitors, apabetalone itself does not reduce the hazard ratio or the number of patients with MACE events (as a single composite endpoint of non-fatal myocardial infarction, cardiovascular death, stroke, and optional cardiovascular hospitalization) and the specific MACE events of myocardial infarction, cardiovascular death, and cardiovascular hospitalization (see Figures 2, 5, 8, and 11). However, when apabetalone was combined with a DPP-4 inhibitor, the number of patients with MACE events overall or specific individual MACE events was unexpectedly and consistently reduced to an extent that reached statistical significance (e.g., at least about 30% and up to about 80%; see Figures 1, 3, 4, 6, 7, 9, 10, 12, 13, and 15) compared with either apabetalone monotherapy or DPP-4 inhibitor monotherapy. Summary of the Invention

[0006] Therefore, the technical solution provided by the present disclosure includes a method of treating and / or preventing major adverse cardiovascular events (MACE), (including non-fatal myocardial infarction, cardiovascular death, stroke, and hospitalization for CVD events), by administering to a subject in need thereof a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

[0007] Compounds of formula I have been previously described in U.S. Patent No. 8,053,440, which is incorporated herein by reference. Compounds of formula I include: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof; During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen; R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amido, amino, halogen, and hydrogen; R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; R6 is selected from amino, amido, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy; W is selected from C and N, and when W is N, p is 0 or 1, and when W is C, p is 1; W-(R4) p For the formula (I), W is C, p is 1 and R4 is H, or W is N and p is 0.

[0008] Apabetalone (RVX-208 or RVX000222) is a representative example of Formula I.

[0009] In some embodiments, the present invention provides methods of preventing cardiovascular death by administering to a subject in need thereof a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

[0010] In some embodiments, the present invention provides methods of treating and / or preventing hospitalization due to a CVD event by administering to a subject in need thereof a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

[0011] In some embodiments, the present invention provides methods of treating and / or preventing non-fatal myocardial infarction by administering to a subject in need thereof a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

[0012] In some embodiments, the compound of Formula I is administered simultaneously with the DPP-4 inhibitor. In some embodiments, the compound of Formula I is administered sequentially with the DPP-4 inhibitor. In some embodiments, the compound of Formula I is administered together with the DPP-4 inhibitor in a single pharmaceutical composition. In some embodiments, the compound of Formula I and the DPP-4 inhibitor are administered in separate compositions.

[0013] In some embodiments, the compound of formula Ia is [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof; During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen; R2 is selected from alkoxy, alkyl, and hydrogen; R5 and R7 are each independently selected from alkyl, alkoxy, and hydrogen; R6 is selected from alkyl, hydroxyl, and alkoxy; W is selected from C and N, and when W is N, p is 0 or 1, and when W is C, p is 1; W-(R4) p For the formula (I), W is C, p is 1 and R4 is H, or W is N and p is 0.

[0014] In some embodiments, the compound of Formula I is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the DPP-4 inhibitor is sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin, anagliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, gemigliptin, teneligliptin, or dutogliptin.

[0016] In some embodiments, the MACE endpoint is narrowly defined as a single composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction, or stroke.

[0017] In some embodiments, the MACE endpoint is broadly defined as a single composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction, hospitalization due to CVD events, or stroke. In one embodiment, the CVD is congestive heart failure. In one embodiment, the hospitalization due to cardiovascular disease events is hospitalization due to congestive heart failure. [Brief explanation of the drawings]

[0018] [Figure 1] Figure 1 shows a comparison of the cumulative incidence of MACE in the narrow sense in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving a placebo with a DPP-4 inhibitor.

[0019] [Figure 2] Figure 2 shows a comparison of the cumulative incidence of MACE in the narrow sense between patients receiving RVX-208 without a DPP-4 inhibitor and patients receiving placebo without a DPP-4 inhibitor.

[0020] [Figure 3] Figure 3 shows a comparison of the cumulative incidence of MACE in the narrow sense in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving RVX-208 without a DPP-4 inhibitor.

[0021] [Figure 4] Figure 4 shows a comparison of the cumulative incidence of broadly defined MACE in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving a placebo with a DPP-4 inhibitor.

[0022] [Figure 5] Figure 5 shows a comparison of the cumulative incidence of broadly defined MACE in patients receiving RVX-208 without a DPP-4 inhibitor and in patients receiving placebo without a DPP-4 inhibitor.

[0023] [Figure 6] Figure 6 shows a comparison of the cumulative incidence of broadly defined MACE in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving RVX-208 without a DPP-4 inhibitor.

[0024] [Figure 7] FIG. 7 shows a comparison of the cumulative incidence of non-fatal myocardial infarction in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving a placebo with a DPP-4 inhibitor.

[0025] [Figure 8] FIG. 8 shows a comparison of the cumulative incidence of non-fatal myocardial infarction in patients receiving RVX-208 without a DPP-4 inhibitor and in patients receiving placebo without a DPP-4 inhibitor.

[0026] [Figure 9] FIG. 9 shows a comparison of the cumulative incidence of non-fatal myocardial infarction in patients receiving RVX-208 with a DPP-4 inhibitor versus patients receiving RVX-208 without a DPP-4 inhibitor.

[0027] [Figure 10] FIG. 10 shows a comparison of the cumulative incidence of CV death in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving a placebo with a DPP-4 inhibitor.

[0028] [Figure 11] FIG. 11 shows a comparison of the cumulative incidence of CV death in patients receiving RVX-208 without a DPP-4 inhibitor and in patients receiving placebo without a DPP-4 inhibitor.

[0029] [Figure 12] FIG. 12 shows a comparison of the cumulative incidence of CV death in patients receiving RVX-208 with a DPP-4 inhibitor versus patients receiving RVX-208 without a DPP-4 inhibitor.

[0030] [Figure 13] FIG. 13 shows a comparison of the cumulative incidence of hospitalization due to congestive heart failure in patients receiving RVX-208 with a DPP-4 inhibitor and in patients receiving a placebo with a DPP-4 inhibitor.

[0031] [Figure 14] FIG. 14 shows a comparison of the cumulative incidence of hospitalization due to congestive heart failure events in patients receiving RVX-208 without a DPP-4 inhibitor and patients receiving placebo without a DPP-4 inhibitor.

[0032] [Figure 15] FIG. 15 shows a comparison of the cumulative incidence of hospitalization due to congestive heart failure events in patients receiving RVX-208 with a DPP-4 inhibitor versus patients receiving RVX-208 without a DPP-4 inhibitor.

[0033] definition "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl," as defined below. Those of skill in the art will understand that with respect to any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or inherently unstable.

[0034] As used herein, the term "hydrate" refers to a crystalline form in which either stoichiometric or non-stoichiometric amounts of water are incorporated into the crystal structure.

[0035] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight-chain or branched group of 2 to 8 carbon atoms, referred to herein as (C2-C8) alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0036] As used herein, the term "alkoxy" refers to an alkyl group attached to oxygen (O-alkyl). An "alkoxy" group also includes an alkenyl group attached to oxygen ("alkenyloxy") or an alkynyl group attached to oxygen ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, groups having alkyl, alkenyl, or alkynyl groups of 1 to 8 carbon atoms, referred to herein as (C1-C8)alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy.

[0037] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon, e.g., a straight-chain or branched group of 1 to 8 carbon atoms, referred to herein as (C1-C8) alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0038] As used herein, the term "amide" refers to NR a C(O)(R b ) or C(O)NR b R c Refers to the form of R a , R b and R c are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Amides are formed by combining carbon, nitrogen, R b , or R c The amide may also be cyclic, e.g., R b and R c may be linked to form a 3- to 8-membered ring, such as a 5- or 6-membered ring. The term "amide" includes groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof. The term "amide" also includes an amide group attached to a carboxy group, e.g., a salt such as amide-COOH or amide-COONA, and an amino group attached to a carboxy group (e.g., a salt such as amino-COOH or amino-COONA).

[0039] As used herein, the term "amine" or "amino" refers to NR d R e or N(R d )R e Refers to the form of R d and R e are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen. The amino can be attached to the parent molecular group through the nitrogen. The amino can also be cyclic, e.g., any two R d and R e may be bonded together or with N to form a 3- to 12-membered ring (e.g., morpholino or piperidinyl). The term amino also includes quaternary ammonium salts of any corresponding amino group. Exemplary amino groups include alkylamino groups, R d and R e At least one of R is an alkyl group. d and R e Each may be optionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.

[0040] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or other polycyclic carbocyclic, aromatic ring system. The aryl group may optionally be fused to one or more rings selected from aryl, cycloalkyl, and heterocyclyl. The aryl groups of the present disclosure may be substituted with a group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems in which the ring contains 6 carbon atoms, referred to herein as "(C6)aryl."

[0041] As used herein, the term "arylalkyl" refers to an alkyl group having at least one aryl substituent (e.g., aryl-alkyl). Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system, where the ring contains 6 carbon atoms, referred to herein as "(C6)arylalkyl."

[0042] As used herein, the term "carbamate" refers to a group consisting of R g OC(O)N(R h ), R g OC(O)N(R h )R i , or OC(O)NR h R i Refers to the form of R g , R h and R iare each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, aryl carbamates or heteroaryl carbamates (e.g., R g , R h and R i at least one of which is independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine.

[0043] As used herein, the term "carbocycle" refers to an aryl or cycloalkyl group.

[0044] As used herein, the term "carboxy" refers to COOH or its corresponding carboxylate salt (e.g., COONa). The term carboxy also includes "carboxycarbonyl," e.g., where the carboxy group is bonded to a carbonyl group, e.g., C(O)-COOH, or to a salt, e.g., C(O)-COONa.

[0045] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group attached to an oxygen.

[0046] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic, or bridged hydrocarbon group of 3 to 12 carbons or 3 to 8 carbons, referred to herein as "(C3-C8)cycloalkyl," derived from cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups may be fused to other saturated or unsaturated cycloalkyl groups, aryl groups, or heterocyclyl groups.

[0047] As used herein, the term "dicarboxylic acid" refers to a group containing at least two carboxylic acid groups, such as saturated and unsaturated hydrocarbon dicarboxylic acids and their salts. Exemplary dicarboxylic acids include alkyl dicarboxylic acids. Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+) / (-)-malic acid, (+) / (-)-tartaric acid, isophthalic acid, and terephthalic acid. Dicarboxylic acids further include carboxylic acid derivatives such as anhydrides, imides, hydrazides (eg, succinic anhydride and succinimide).

[0048] The term "ester" refers to an ester having the structure C(O)O-, C(O)OR j , R k C(O)OR j , or R k C(O)O-, where O is not bonded to a hydrogen atom, and R j and R k R may be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. k can be hydrogen, but R j cannot be hydrogen. Esters may be cyclic, e.g., having a carbon atom and R j , oxygen atom and R k , or R j and R k may be linked to form a 3- to 12-membered ring. Exemplary esters include, but are not limited to, R j and R k is alkyl, such as O-C(O)-alkyl, C(O)-O-alkyl, and alkylC(O)-O-alkyl. Exemplary esters also include aryl or heteroaryl esters, where R j and R k At least one of the groups is a heteroaryl group, such as, for example, pyridine, pyridazine, pyrimidine, and pyrazine, such as, for example, a nicotine ester. Exemplary esters are those having the structure R k Also included are reverse esters with C(O)O-, where the oxygen is attached to the parent molecule. Exemplary reverse esters include succinate, D-arginine, L-arginine, L-lysinate, and D-lysinate. Esters also include carboxylic acid anhydrides and acid halides.

[0049] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0050] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. "Haloalkyl" also includes alkenyl or alkynyl groups substituted with one or more halogen atoms.

[0051] As used herein, the term "heteroaryl" refers to a mono-, bi-, or polycyclic aromatic ring system containing one or more heteroatoms, such as, for example, nitrogen, oxygen, and 1 to 3 heteroatoms such as sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls can also be fused to non-aromatic rings. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, the ring containing 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "(C2-C5)heteroaryl."

[0052] As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to a saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocycle can be aromatic (heteroaryl) or non-aromatic. The heterocycle can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heterocycle also includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the above heterocycles is fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycle.Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, and the like. quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

[0053] As used herein, the terms "hydroxy" and "hydroxyl" refer to --OH.

[0054] As used herein, the term "hydroxyalkyl" refers to a hydroxy attached to an alkyl group.

[0055] As used herein, the term "hydroxyaryl" refers to a hydroxy attached to an aryl group.

[0056] As used herein, the term "ketone" refers to a C(O)-R n (e.g., C(O)CH3 as acetyl) or R n -C(O)-R o Ketones are those with the R n or R o R can be attached to another group via n and R o may be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl, or R n and R o can be linked to form a 3- to 12-membered ring.

[0057] As used herein, the term "phenyl" refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. The phenyl may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.

[0058] As used herein, the term "thioalkyl" refers to an alkyl group attached to a sulfur (S-alkyl).

[0059] The "alkyl," "alkenyl," "alkynyl," "alkoxy," "amino," and "amido" groups may optionally be substituted, interrupted, or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N. The substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.

[0060] As used herein, appropriate substitutions on an optionally substituted group refer to groups that do not abrogate the synthetic or pharmaceutical utility of the disclosed compounds or intermediates useful in their preparation. Examples of suitable substitutions include, but are not limited to, C1-C8 alkyl, C2-C8 alkenyl or alkynyl; C6 aryl, 5- or 6-membered heteroaryl; C3-C7 cycloalkyl; C1-C8 alkoxy; C6 aryloxy; CN; OH; oxo; halo, carboxy; amino, such as NH(C1-C8 alkyl), N(C1-C8 alkyl)2, NH((C6)aryl), or NH((C6)aryl)2; formyl; ketones, such as CO(C1-C8 alkyl), —CO((C6 aryl), esters, such as CO2(C1-C8 alkyl) and CO2(C6 aryl). One of ordinary skill in the art can readily select appropriate substitutions based on the stability and pharmacological and synthetic activity of the disclosed compounds.

[0061] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0062] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and formulations for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions. As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated with one or more pharmaceutically acceptable carriers.

[0063] As used herein, the term "pharmaceutically acceptable prodrug" refers to a prodrug of a compound of the present invention that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and effective for the intended use, and, where possible, is a zwitterionic form of the compound of Formula I. A discussion is provided in Higuchi et al., "Prodrugs as Novel Delivery Systems," Symposium Series, Vol. 14, and Roche, EB, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0064] The term "pharmaceutically acceptable salt" refers to the salt of an acidic or basic group that may be present in the compound used in the present composition.The compound contained in the present composition that is basic in nature can form a wide variety of salts with various inorganic and organic acids.The acid that can be used to prepare the pharmaceutically acceptable acid addition salt of such a basic compound is an acid that forms a non-toxic acid addition salt, that is, a salt containing a pharmacologically acceptable anion, including but not limited to, sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinic acid, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate. Salts include benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that contain an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0065] Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts.

[0066] Compounds of Formula I or Ia may contain one or more chiral centers and / or double bonds and therefore exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated with the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated by the term "(±)," although those skilled in the art will recognize that the structure may implicitly indicate chiral centers.

[0067] Individual stereoisomers of the compounds used in the methods of the present invention may be synthetically prepared from commercially available starting materials containing asymmetric or stereogenic centers, or racemic mixtures may be prepared using resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) binding the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary; (2) forming salts using an optically active resolving agent; or (3) directly separating the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0068] Geometric isomers can also exist in compounds of Formula I or Ia. The present invention encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring. Substituents around a carbon-carbon double bond are designated in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both E and Z isomers.

[0069] Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are located on both the same and opposite sides of the plane of the ring is designated "cis / trans."

[0070] The compounds of Formula I disclosed herein may exist as tautomers, and both tautomeric forms are intended to be encompassed within the scope of the invention, even though only one tautomeric structure is depicted.

[0071] As used herein, the term "dipeptidyl peptidase 4 inhibitor" or "DPP-4 inhibitor" refers to a substance, such as a small molecule organic chemical compound (≦1 kDa), or a large biological molecule, such as a peptide (e.g., a soluble peptide), a protein (e.g., an antibody), a nucleic acid (e.g., siRNA), or a complex combining two or more of the foregoing, that has the activity of inhibiting the dipeptidyl peptidase 4 (DPP-4) enzyme. Non-limiting examples of DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin, anagliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, gemigliptin, teneligliptin, or dutogliptin, or a pharmaceutically acceptable salt of any of the foregoing.

[0072] As used herein, "treatment" or "treating" refers to the improvement of a disease or disorder, or at least one discernible symptom thereof. In another embodiment, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to reducing the progression of a disease or disorder, either physically, e.g., stabilizing a discernible symptom, physiologically, e.g., stabilizing a physical parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset or progression of a disease or disorder. For example, treating a cholesterol disorder can include reducing blood cholesterol levels.

[0073] As used herein, "prevention" or "preventing" refers to a reduction in the risk of acquiring a given disease or disorder, or a symptom of a given disease or disorder.

[0074] The term "MACE in the strict sense" is defined as a single composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction, or stroke.

[0075] The term "broad MACE" is defined as a single composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction, hospitalization for a CVD event, or stroke.

[0076] As used herein, a "cardiovascular disease event" or "CVD event" refers to a physical manifestation of a cardiovascular disorder, including events such as stroke, non-fatal myocardial infarction, cardiovascular death, and hospitalization for a CVD event and congestive heart failure. As used herein, a "hospitalization for a CVD event" is defined as a hospitalization for unstable angina, symptoms of progressive obstructive coronary artery disease, urgent revascularization at any time, or urgent revascularization 30 days or more after the index event prior to randomization. In some embodiments, a "hospitalization for a CVD event" includes a hospitalization for a physical manifestation of a cardiovascular disorder, including congestive heart failure. In one embodiment, the hospitalization for a CVD event is a hospitalization for congestive heart failure.

[0077] As used herein, "cardiovascular disorder" includes cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for a CVD event including unstable angina, symptoms of advanced obstructive coronary artery disease, urgent revascularization procedure at any time or more than 30 days after the index event, and congestive heart failure.

[0078] As used herein, "recent acute coronary syndrome" or "recent ACS" refers to a condition or range of conditions associated with a sudden reduction in blood flow to the heart occurring in a subject 7 to 90 days before the subject is treated with at least one agent selected from a statin (high-intensity statin therapy or maximally tolerated statin therapy), apabetalone, and a DPP-4 inhibitor as defined herein. One such condition, when cell death leads to damage or destruction of heart tissue, is a heart attack or myocardial infarction. Another such condition, when a sudden reduction in blood flow to the heart does not cause cell death but changes how the heart functions, is a sign of a high risk of a heart attack. Signs and symptoms of ACS, which usually begin suddenly, include, but are not limited to, chest pain (angina) or discomfort often described as aching, pressure, tightness, or burning; pain that radiates from the chest to the shoulders, arms, upper abdomen, back, neck, or jaw; nausea or vomiting; indigestion; shortness of breath (dyspnea); sudden, heavy sweating (sweating); lightheadedness, dizziness, or fainting; unusual or unexplained fatigue; and feeling restless or anxious. DETAILED DESCRIPTION OF THE INVENTION

[0079] In one embodiment, the present invention provides a method of treating and / or preventing major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, CV death, stroke, and hospitalization for a CVD event, by administering to a subject in need thereof a combination of a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof; [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen; R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amido, amino, halogen, and hydrogen; R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; R6 is selected from amino, amido, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy; W is selected from C and N, and when W is N, p is 0 or 1, and when W is C, p is 1; W-(R4) p For the formula (I), W is C, p is 1 and R4 is H, or W is N and p is 0.

[0080] In one embodiment, the compound of formula I is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the DPP-4 inhibitor is selected from sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin, anagliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, gemigliptin, teneligliptin, or dutogliptin.

[0082] In one embodiment, the MACE endpoint is narrowly defined as a single composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction, or stroke.

[0083] In one embodiment, the MACE endpoint is broadly defined as a single composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction, hospitalization for a CVD event, or stroke.

[0084] In one embodiment, a method for treating and / or preventing any individual component of MACE, including cardiovascular (CV) death, non-fatal myocardial infarction, hospitalization for a CVD event, or stroke, by administering to a subject in need thereof a dipeptidyl peptidase 4 (DPP-4) inhibitor and a compound of Formula Ia, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, comprising: [ka] During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen; R2 is selected from alkoxy, alkyl, and hydrogen; R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; R6 is selected from alkyl, hydroxyl, and alkoxy; W is selected from C and N, and when W is N, p is 0 or 1, and when W is C, p is 1; W-(R4) p For the formula (I), W is C, p is 1 and R4 is H, or W is N and p is 0.

[0085] In one embodiment, the compound of Formula I is administered simultaneously with a DPP-4 inhibitor.

[0086] In one embodiment, the compound of Formula I is administered sequentially with the DPP-4 inhibitor.

[0087] In one embodiment, the compound of Formula I is administered with a DPP-4 inhibitor in a single pharmaceutical composition.

[0088] In one embodiment, the compound of Formula I and the DPP-4 inhibitor are administered as separate compositions.

[0089] In one embodiment, a subject in need thereof is administered 200 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0090] In one embodiment, a subject in need thereof is administered 100 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily.

[0091] In one embodiment, the subject is a human.

[0092] In one embodiment, the subject is a human with type 2 diabetes and low HDL cholesterol (less than 40 mg / dL for men and less than 45 mg / dL for women) and a recent acute coronary syndrome (ACS).

[0093] In one embodiment, the subject is a human with type 2 diabetes.

[0094] In one embodiment, the subject is a human with low HDL cholesterol (ie, less than 40 mg / dL for men and less than 45 mg / dL for women).

[0095] In one embodiment, the subject is a human with a recent ACS.

[0096] In one embodiment, the subject is a human receiving statin therapy. In one embodiment, the subject is a human receiving high-intensity or maximally tolerated statin therapy. In one embodiment, high-intensity statin treatment or therapy refers to a daily dose of at least 20 mg, or at least 40 mg, or 20-80 mg, or 20-40 mg, or 40-80 mg. In one embodiment, maximally tolerated statin treatment or therapy refers to a daily loss of at least 40 mg, or 40 mg-80 mg, or 80 mg. In one embodiment, the subject is receiving rosuvastatin therapy. In one embodiment, the subject is receiving atorvastatin therapy. (References) Cannon, CP, Blazing, MA, Giugliano, RP, et al. (2015) Ezetimibe added to statin therapy after coronary acute syndromes. N Engl J Med, 372(25), 2387-97. Schwartz, GG, Olsson, AG & Barter, PJ (2013) Dalcetrapib in patients with an acute coronary syndrome. N Engl J Med, 368(9), 869-70. Schwartz,GG,Steg,PG,Szarek,M.,et al.(2018)Alirocumab and cardiovascular outcomes after acute coronary syndrome.N Engl J Med,379(22),2097-107. Thornberry, NA, and Gallwitz, B. (2009) Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab, 23(4), 479-86. Rosenstock, J., Perkovic, V., Johansen, O. E., et al. (2019) Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk. JAMA, 321(1), 69 - 79. Green, J. B., Bethel, M. A., Armstrong, P. W., et al. (2015) Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 373, 232 - 42. Scirica, B. M., Bhatt, D. L., Braunwald, E., et al. (2013) Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med, 369, 1317 - 26. White, W. B., Cannon, C. P., Heller, S. R., et al. (2013) Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med, 369, 1327 - 35. Karagiannis, T., Bekiari, E., Boura, P., et al. (2015) Cardiovascular Risk with DPP - 4 Inhibitors: Latest Evidence and Clinical Implications. Ther Adv Drug Saf, 7(2), 36 - 38.

Example

[0097] Example 1: Clinical Development Apabetalone (RVX-208) was evaluated in a recently completed phase 3 clinical trial (BETonMACE, NCT02586155) for its effect on MACE in patients with type 2 diabetes and low HDL cholesterol (<40 mg / dL in men and <45 mg / dL in women) and recent acute coronary syndrome (ACS). All patients were receiving high-intensity statin therapy: rosuvastatin at 20-40 mg / day or a maximum daily dose of 40 mg; or atorvastatin at 40-80 mg / day or a maximum daily dose of 80 mg.

[0098] Patients (n=2425) with type 2 diabetes and low HDL cholesterol (≤40 mg / dL for men and ≤45 mg / dL for women) and a history of ACS within the past 7 to 90 days, receiving intensive or maximally tolerated atorvastatin or rosuvastatin therapy, were assigned in a double-blind fashion to receive oral apabetalon 100 mg twice daily or matching placebo. Baseline characteristics included female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization as index ACS event (76%), treatment with dual antiplatelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg / dL, and median HbA1c 7.3%. The primary efficacy measure was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke. Assumptions included a 7% annual primary event rate in the placebo group and a median follow-up of 1.5 years. Patients were followed until at least 250 primary endpoint events occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalon.

[0099] Example 2: Post-hoc analysis In the BETonMACE clinical trial, a total of N = 336 patients (N = 169 in the apabetalon group and N = 167 in the placebo group) received a DPP-4 inhibitor (selected from alogliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin) in addition to RVX-208 and other guideline-defined treatments with specific statin therapy (atorvastatin and rosuvastatin). Patients who were randomized and received at least one dose of DPP-4 inhibitor treatment before the first event date were censored as a MACE event on the date of the confirmed event. Patients who received at least one dose of DPP-4 inhibitor treatment after the first event date were censored as a non-MACE event, with the date of last contact used as the censoring date. For all patients who did not receive treatment with a DPP-4 inhibitor during the study, the time to first event was calculated using the date of randomization and the date of the confirmed event, or the date of last contact for censored subjects.

[0100] The distribution of endpoints within the apabetalone and placebo groups was compared using a two-sided log-rank test (LRT) with a significance level of alpha = 0.05. Cumulative incidence rates are presented as 1-KM (Kaplan-Meier) estimates of event rates.

[0101] MACE in the narrow sense Figures 1 to 3 compare the cumulative incidence of narrowly defined MACE (i.e., as a single composite endpoint of multiple primary endpoints defined as cardiovascular death, nonfatal myocardial infarction, or stroke) between the two groups of patients in the test and control groups, respectively, and are described as follows: i. Patients undergoing DPP-4 inhibitor treatment, receiving apabetalone (test) or placebo (control) (Figure 1). ii. Patients who were not receiving DPP-4 inhibitor treatment, received apabetalone (test) or placebo (control) (Figure 2), and iii. Patients receiving apabetalone treatment, either with a DPP-4 inhibitor (test) or without a DPP-4 inhibitor (control) (Figure 3).

[0102] In Figure 1, when patients were treated with a DPP-4 inhibitor and received either apabetalone or a placebo, there were a total of 36 primary endpoints: 10 (5.9%) in the apabetalone group and 26 (15.6%) in the placebo group, representing a Kaplan-Meier estimated event rate of 4.8% in the apabetalone group and 11.8% in the placebo group at 18 months. This means that at 18 months, patients treated with a DPP-4 inhibitor alone had an estimated MACE event rate of 11.8%, but when patients were treated with the combination of apabetalone and a DPP-4 inhibitor, the estimated MACE event rate was reduced by nearly 60%, to 4.8%. As illustrated in Figure 1, the combination of apabetalone and a DPP-4 inhibitor significantly reduced the composite endpoint of narrowly defined MACE compared with treatment with a DPP-4 inhibitor alone, specifically by reducing the number of patients with narrowly defined MACE events at any given time point by 62% (hazard ratio [HR], 0.38; 95% CI, 0.20 to 0.74; P = 0.004).

[0103] Figure 2 shows that when patients were not treated with a DPP-4 inhibitor and received either apabetalon or a placebo, there were a total of 228 primary endpoints, 114 (10.9%) in the apabetalon group and 114 (11.0%) in the placebo group, which resulted in a Kaplan-Meier estimated event rate of 8.0% in the apabetalon group and 8.3% in the placebo group at 18 months. This means that at 18 months, patients treated with apabetalone alone had an estimated narrowly defined MACE event rate of 10.9%, while patients not treated with apabetalone or a DPP-4 inhibitor had an estimated narrowly defined MACE event rate of 11.0%. As shown in Figure 2, apabetalone monotherapy did not reduce the composite endpoint of narrowly defined MACE compared with no treatment (hazard ratio [HR], 0.99; 95% CI, 0.77 to 1.29; P = 0.96).

[0104] As illustrated in Figure 3, patients treated with the combination of apabetalone and a DPP-4 inhibitor showed a significant hazard ratio of 0.59 (95% CI, 0.36 to 0.97; P = 0.04) for the composite endpoint of narrowly defined MACE compared with patients treated with apabetalone alone. This means that the combination of apabetalone and a DPP-4 inhibitor reduced the number of patients with narrowly defined MACE events at any given time point by 41% compared with treatment with apabetalone alone.

[0105] In conclusion, apabetalone monotherapy did not reduce the number of patients with MACE events at any given time point compared to non-treatment (see Figure 2). Furthermore, as established in the background of the present disclosure, DPP-4 inhibitors have not been shown to have any effect on reducing MACE. Therefore, it was unexpected that the combination therapy of apabetalone and a DPP-4 inhibitor, each of which is ineffective as a monotherapy, would result in any reduction in patients with MACE events at any given time point, much less a significant reduction of 62% compared to DPP-4 inhibitor monotherapy or 59% compared to apabetalone monotherapy.

[0106] MACE in the broad sense Figures 4-6 compare the cumulative incidence of MACE, broadly defined (i.e., as a single composite endpoint of multiple primary endpoints defined as cardiovascular death, nonfatal myocardial infarction, stroke, or hospitalization for cardiovascular disease (CVD)), between the same two patient groups described above in Figures 1-3, respectively.

[0107] In Figure 4, when patients were treated with a DPP-4 inhibitor and received either apabetalon or placebo, the combination of apabetalone and a DPP-4 inhibitor was seen to reduce the composite endpoint of broad-defined MACE compared with treatment with a DPP-4 inhibitor alone (with trending statistical significance), specifically by reducing the number of patients with broad-defined MACE events at any given time point by 56% (hazard ratio [HR], 0.44; 95% CI, 0.23 to 0.82; P = 0.01).

[0108] Figure 5 shows that when patients were not treated with a DPP-4 inhibitor but received either apabetalon or placebo, apabetalone monotherapy did not reduce the broad-based composite endpoint of MACE compared with no treatment (hazard ratio [HR], 1.00; 95% CI, 0.79 to 1.28; P = 0.99).

[0109] As shown in Figure 6, patients treated with the combination of apabetalone and a DPP-4 inhibitor had a significant hazard ratio of 0.61 (95% CI, 0.38 to 0.97; P = 0.04) for the composite endpoint of broad-defined MACE compared with patients treated with apabetalone alone. This means that the combination of apabetalone and a DPP-4 inhibitor reduced the number of patients with broad-defined MACE events at any given time point by 39% compared with treatment with apabetalone alone.

[0110] In conclusion, apabetalone monotherapy did not reduce the number of patients with broad-defined MACE events at any given time point compared to non-treatment (see Figure 5). Furthermore, as established in the background of the present disclosure, DPP-4 inhibitors have not been shown to have any effect on reducing MACE. Therefore, it was unexpected that combination therapy of apabetalone and a DPP-4 inhibitor, each of which is ineffective as a monotherapy, would result in any reduction in patients with broad-defined MACE events at any time point, much less a significant reduction of 56% compared to DPP-4 inhibitor monotherapy or 39% compared to apabetalone monotherapy.

[0111] Nonfatal myocardial infarction Figures 7-9 compare the cumulative incidence of non-fatal myocardial infarction between the same two patient groups as described above in Figures 1-3, respectively.

[0112] In Figure 7, it can be seen that when patients were treated with a DPP-4 inhibitor and received either apabetalon or placebo, the combination of apabetalon and a DPP-4 inhibitor significantly reduced the nonfatal myocardial infarction endpoint compared with treatment with a DPP-4 inhibitor alone, particularly by reducing the number of patients with a nonfatal myocardial infarction event at any given time point by 58% (hazard ratio [HR], 0.42; 95% CI, 0.20-0.89; P = 0.02).

[0113] In Figure 8, it can be seen that when patients were not treated with a DPP-4 inhibitor but received either apabetalon or placebo, apabetalon monotherapy did not reduce the endpoint of nonfatal myocardial infarction compared with no treatment (hazard ratio [HR], 0.99; 95% CI, 0.71 to 1.39; P = 0.96).

[0114] As shown in Figure 9, patients treated with the combination of apabetalone and a DPP-4 inhibitor had a hazard ratio of 0.72 (95% CI, 0.38-1.06, P = 0.31) for the endpoint of nonfatal myocardial infarction compared with patients treated with apabetalone alone. This means that the combination of apabetalone and a DPP-4 inhibitor reduced the number of patients with nonfatal myocardial infarction events at any given time point by 28% compared with treatment with apabetalone alone.

[0115] In conclusion, apabetalone monotherapy did not reduce the number of patients with non-fatal myocardial infarction events at any given time point compared to no treatment (see Figure 8). Furthermore, as established in the background of the present disclosure, DPP-4 inhibitors have not been shown to have any effect on reducing MACE. Therefore, it was unexpected that combination therapy of apabetalone and a DPP-4 inhibitor, each of which is ineffective as a monotherapy, would result in any reduction in the number of patients with non-fatal myocardial infarction events at any given time point, much less a significant 58% reduction compared to DPP-4 inhibitor monotherapy or a 28% reduction compared to apabetalone monotherapy.

[0116] cardiovascular death Figures 10-12 compare the cumulative incidence of cardiovascular death between the same two patient groups as described above in Figures 1-3, respectively.

[0117] In Figure 10, it can be seen that when patients were treated with a DPP-4 inhibitor and received either apabetalon or placebo, the combination of apabetalone and a DPP-4 inhibitor significantly reduced the cardiovascular death endpoint compared with treatment with a DPP-4 inhibitor alone, specifically by reducing the number of patients with a cardiovascular death event at any given time point by 77% (hazard ratio [HR], 0.23; P 95% CI, 0.05 to 1.02, P = 0.05).

[0118] Figure 11 shows that when patients were not treated with a DPP-4 inhibitor but received either apabetalon or placebo, apabetalone monotherapy did not reduce the cardiovascular death endpoint compared with no treatment (hazard ratio [HR], 0.97; 95% CI, 0.64 to 1.47; P = 0.89).

[0119] As illustrated in Figure 12, patients treated with the combination of apabetalone and a DPP-4 inhibitor had a significant hazard ratio of 0.37 (95% CI, 0.16 to 0.85; P = 0.02) for the cardiovascular death endpoint compared with patients treated with apabetalone alone. This means that the combination of apabetalone and a DPP-4 inhibitor reduced the number of patients with a cardiovascular death event at any given time point by 63% compared with treatment with apabetalone alone.

[0120] In conclusion, apabetalone monotherapy does not reduce the number of patients with cardiovascular death events at any time point compared to non-treatment (see Figure 11). Furthermore, as established in the background of the present disclosure, DPP-4 inhibitors have not been shown to have any effect on reducing MACE. Therefore, it was unexpected that combination therapy of apabetalone and a DPP-4 inhibitor, each of which is ineffective as a monotherapy, would result in any reduction in patients with cardiovascular death events at any time point, much less a significant reduction of 77% compared to DPP-4 inhibitor monotherapy and 63% compared to apabetalone monotherapy.

[0121] Hospitalization for congestive heart failure Figures 13-15 compare the cumulative incidence of hospitalization for congestive heart failure between the same two patient groups as described above in Figures 1-3, respectively.

[0122] In Figure 13, patients treated with a DPP-4 inhibitor received either apabetalon or placebo, and it can be seen that the combination of apabetalone and a DPP-4 inhibitor significantly reduced the endpoint of congestive heart failure hospitalization compared with treatment with a DPP-4 inhibitor alone, particularly by reducing the number of patients hospitalized for a congestive heart failure event at any given time point by 80% (hazard ratio [HR], 0.20; 95% CI, 0.05-0.75; P=0.02).

[0123] In Figure 14, it can be seen that when patients were not treated with a DPP-4 inhibitor but received either apabetalon or placebo, apabetalone monotherapy reduced the endpoint of congestive heart failure hospitalization compared with no treatment, particularly by reducing the number of patients hospitalized for a congestive heart failure event at any given time point by 27% (hazard ratio [HR], 0.73; 95% CI, 0.46 to 1.19, P=0.20).

[0124] As shown in Figure 15, patients treated with the combination of apabetalone and a DPP-4 inhibitor had a hazard ratio of 0.41 (95% CI, 0.14 to 1.19; P = 0.10) for the endpoint of hospitalization for congestive heart failure compared with patients treated with apabetalone alone. This means that the combination of apabetalone and a DPP-4 inhibitor reduced the number of patients hospitalized for congestive heart failure events at any time by 59% compared with treatment with apabetalone alone.

[0125] In conclusion, apabetalone monotherapy was able to reduce the number of patients hospitalized for congestive heart failure events at any given time point by 27% compared to patients receiving placebo alone (see Figure 14). Furthermore, as established in the background of this disclosure, DPP-4 inhibitors have not been shown to have any effect on reducing MACE. Therefore, it was unexpected that combination therapy of apabetalone and a DPP-4 inhibitor, when the DPP-4 inhibitor is ineffective as monotherapy, would result in a significant 80% reduction in the number of patients hospitalized for congestive heart failure at any given time point compared to DPP-4 inhibitor monotherapy, or a 59% reduction compared to apabetalone monotherapy.

Claims

1. 1. A medicament for the treatment and / or prevention of major adverse cardiovascular events (MACE) in a subject in need thereof, comprising a dipeptidyl peptidase 4 (DPP-4) inhibitor and 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222), or a pharmaceutically acceptable salt or hydrate thereof, the 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt or hydrate thereof is administered simultaneously or sequentially with a DPP-4 inhibitor; the DPP-4 inhibitor is selected from alogliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin; the subject is a human with type 2 diabetes, low HDL cholesterol (less than 40 mg / dL for men and less than 45 mg / dL for women) and recent acute coronary syndrome (ACS); the subject is receiving statin therapy; The medicine.

2. 1. A medicament for the treatment and / or prevention of any independent component of a major adverse cardiovascular event (MACE) in a subject in need thereof, comprising a dipeptidyl peptidase 4 (DPP-4) inhibitor and 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222), or a pharmaceutically acceptable salt or hydrate thereof, the 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt or hydrate thereof is administered simultaneously or sequentially with a DPP-4 inhibitor; the DPP-4 inhibitor is selected from alogliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin; the subject is a human with type 2 diabetes, low HDL cholesterol (less than 40 mg / dL for men and less than 45 mg / dL for women) and recent acute coronary syndrome (ACS); the subject is receiving statin therapy; The medicine.

3. The pharmaceutical composition according to claim 1 or 2, which comprises administering 200 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof per day to a subject in need of treatment.

4. 4. The method of claim 3, wherein a subject in need of treatment is administered 100 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof twice a day.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the MACE is selected from non-fatal myocardial infarction, cardiovascular death, stroke, and hospitalization due to a cardiovascular disease event.

6. The method of claim 5, wherein the hospitalization due to a cardiovascular disease event is hospitalization due to congestive heart failure.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the MACE is selected from non-fatal myocardial infarction, cardiovascular death, and stroke.

8. The medicament of any one of claims 1 to 7, wherein 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) is administered together with the DPP-4 inhibitor as separate compositions.

9. The medicament of any one of claims 1 to 7, wherein 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) is administered together with the DPP-4 inhibitor as a single composition.

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