PHARMACEUTICAL COMPOSITION AND THERAPEUTIC COMBINATION COMPRISING A CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITOR AND HMG CoA REDUCTASE INHIBITORS

Abstract

The present invention relates to a pharmaceutical composition and a therapeutic combination comprising a novel cholesteryl ester transfer protein (CETP) inhibitor and a HMG CoA Reductase inhibitor, which may be used in the treatment of subjects suffering from or having an increased risk for cardiovascular diseases, in particular hyperlipidemia or mixed dyslipidemia.

Claims

1. A pharmaceutical composition comprising: (a) a compound of the formula: ##STR00005## or a pharmaceutically acceptable salt thereof; (b) at least one HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof; and (c) one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin.

3. The pharmaceutical composition according to claim 1, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, pravastatin sodium, fluvastatin sodium, simvastatin, lovastatin and rosuvastatin calcium.

4. The pharmaceutical composition according to claim 1, wherein the composition comprises about 1 mg to 25 mg of Compound A and about 1 mg to 80 mg of the HMG CoA reductase inhibitor.

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

6. The pharmaceutical composition according to claim 5, wherein the oral fixed dose combination is a solid dosage form.

7. The pharmaceutical composition according to claim 1, wherein the composition is an oral fixed dose combination comprising about 1 mg to 25 mg of Compound A and about 1 mg to 80 mg of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin or pitavastatin.

8. The pharmaceutical composition according to claim 1, wherein the composition comprises polyunsaturated fatty acids.

9. The pharmaceutical composition according to claim 8, wherein the polyunsaturated fatty acids are present in their free acid form.

10-24. (canceled)

25. The pharmaceutical composition according to claim 8, wherein the polyunsaturated fatty acids is omega-3 polyunsaturated fatty acids.

26. The pharmaceutical composition according to claim 25, wherein the omega-3 polyunsaturated fatty acids are selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-Linolenic acid (ALA) or combinations thereof.

27-28. (canceled)

29. A method of treating a subject suffering from or having an increased risk for cardiovascular diseases comprising administering to said subject in need thereof a pharmaceutically effective amount of said pharmaceutical composition according to claim 1.

30. The method of claim 29, wherein said subject is suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia.

31. The method of claim 29, wherein said pharmaceutically effective amount of said pharmaceutical composition is about 1 mg to 25 mg per day of Compound A and about 1 mg to 80 mg per day of HMG CoA reductase inhibitor.

32. The method of claim 31, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin.

33. The method of claim 30, wherein said pharmaceutically effective amount of said pharmaceutical composition is about 1 mg to 25 mg per day of Compound A, or a pharmaceutically acceptable salt thereof, and about 1 mg to 80 mg per day of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, pitavastatin, or a pharmaceutically acceptable salt thereof

34. The method of claim 30, comprising administering to said subject in need thereof a pharmaceutically effective amount of said pharmaceutical composition for at least one week, or at least three weeks.

35. A method of treating a subject suffering from or having an increased risk for cardiovascular diseases comprising administering to said subject in need thereof a pharmaceutically effective amount of said therapeutic combination according to claim 10.

36. The method of claim 35, wherein said subject is suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia.

37. The method of claim 35, wherein said pharmaceutically effective amount of said therapeutic combination is about 1 mg to 25 mg per day of Compound A and about 1 mg to 80 mg per day of HMG CoA reductase inhibitor.

38. The method of claim 35, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin.

39. The method of claim 36, wherein said pharmaceutically effective amount of said therapeutic combination is about 1 mg to 25 mg per day of Compound A, or a pharmaceutically acceptable salt thereof, and about 1 mg to 80 mg per day of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, pitavastatin, or a pharmaceutically acceptable salt thereof

40. The method of claim 35, comprising administering to said subject in need thereof a pharmaceutically effective amount of said therapeutic combination for at least one week, or at least three weeks.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0030] A first aspect of the present invention relates to a pharmaceutical composition comprising: [0031] (a) a compound of the formula:

##STR00002## [0032] (hereinafter: Compound A) or a pharmaceutically acceptable salt thereof; [0033] (b) at least one HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof; and [0034] (c) one or more pharmaceutically acceptable excipients.

[0035] Compound A as such has already been described in the European patent application EP1730152, wherein it has been identified as a CETP-inhibitor among many other CETP-inhibitors. Surprisingly, clinical studies have now shown that compared to other known CETP-inhibitors only a relatively low dose of Compound A is needed to significantly increase the HDL-C concentration and significantly lower the LDL-C concentration. This makes Compound A particularly suitable to be used in combination with other pharmaceutically active compounds.

[0036] It has now surprisingly been shown in clinical studies that combining Compound A with HMG CoA reductase inhibitors gives a synergistic effect with respect to the lowering of the LDL-C concentration in blood. In other words, when Compound A is used in combination with a HMG CoA reductase inhibitor, such as atorvastatin or rosuvastatin, the LDL-C concentration decreases more than when these compounds are used separately. Moreover, no serious side effects have been observed by using a combination of these compounds.

[0037] The pharmaceutical composition according to the present invention is therefore preferably used in the treatment of subjects suffering from or having an increased risk for cardiovascular diseases. Said pharmaceutical composition is more preferably used in the treatment of subjects suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia.

[0038] Furthermore, with the present invention it is possible to use a lower dose of HMG CoA reductase inhibitor than conventionally used, thereby overcoming possible intolerance to these types of inhibitors. In addition, it has also been found that Compound A alone and in combination with statins enhanced the ability of serum to promote cholesterol efflux. As has been described in Niesor E J, et al., Cardiovasc Drugs Ther. 2015 Feb;29(1):7-14, statins generally have a tendency to decrease cholesterol efflux. It has now remarkably been found that this can be avoided when said statins are used in combination with Compound A.

[0039] Compound A is preferably used together with a HMG CoA reductase inhibitor which is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin.

[0040] More preferably, the HMG CoA reductase used is atorvastatin calcium, pravastatin sodium, fluvastatin sodium, simvastatin, lovastatin and rosuvastatin calcium. These inhibitors have been used in many patients for many years and have shown to be able to significantly reduce the LDL-C concentration in patients.

[0041] The pharmaceutical composition according to the present invention preferably comprises 1 to 25 mg of Compound A and 1 to 80 mg of the HMG CoA reductase inhibitor. Alternatively, the pharmaceutical composition according to the present invention comprises 1 to 25 mg of Compound A and 1 to 50 mg, optionally 1 to 30 mg or 1 to 20 mg of the HMG CoA reductase inhibitor In a further embodiment of the pharmaceutical composition according to the present invention the composition comprises 5 to 10 mg of Compound A and 1 to 20 mg of HMG CoA reductase inhibitor.

[0042] Due to the synergistic effect between Compound A and HMG CoA reductase inhibitors it is now surprisingly also possible to lower the amount of HMG CoA reductase inhibitors used, thereby avoiding side effects commonly observed in these kinds of pharmaceutical compounds. In this regard it is also noted that such lower doses could also overcome intolerance to HMG CoA reductase inhibitors,which is also referred to as statin intollerance.

[0043] The pharmaceutical composition according to the present invention is preferably administered orally to subjects in need thereof. Oral administration may involve swallowing, so that the pharmaceutically active compounds enter the gastrointestinal tract. Specific pharmaceutical preparations, as described below, may be developed which facilitate the oral administration.

[0044] The pharmaceutical composition according to the present invention is preferably formulated as an oral free dose combination or as an oral fixed dose combination. The different pharmaceutically active ingredients may be present in said combinations as granulates. Preferably, the pharmaceutical composition is an oral fixed dose combination, such a combination is very convenient for patients and avoids problems with administering the correct amounts of these compounds.

[0045] Solid oral dosage forms which may be used within the context of the present invention include besides tablets and capsules amongst others caplets, lozenges, pills, mini-tablets, pellets, beads and granules. Liquid oral dosage forms which may be used for the pharmaceutical preparation of the present invention include, but are not limited to drinks, solutions, suspensions, syrups, beverages and emulsions.

[0046] The oral fixed dose combination or oral free dose combination is preferably formulated as a solid dosage form, such as a tablet or capsule. Generally, the administration of these kinds of formulations is considered to be the most convenient for patients.

[0047] In a particularly preferred embodiment the pharmaceutical composition according to the present invention is an oral fixed dose combination comprising 1 to 25 mg of Compound

[0048] A and 1 to 80 mg of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin or pitavastatin, preferably atorvastatin or rosuvastatin. In an even further embodiment thereof, said pharmaceutical composition comprises 1 to 25 mg of Compound A and 1 to 20 mg of said HMG CoA reductase inhibitors. Besides Compound A and the HMG CoA reductase inhibitors as such, pharmaceutically acceptable salts thereof may also be used in the pharmaceutical composition according to the present invention. Pharmaceutically acceptable salts of Compound A and the HMG CoA reductase inhibitors include the acid addition and base salts thereof, such as preferably the calcium, potassium or sodium salts. For a review on suitable salts, reference is made “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0049] A pharmaceutically acceptable salt of Compound A or of HMG CoA reductase inhibitors 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.

[0050] The present invention also relates to the use of pharmaceutically acceptable solvates or pro-drugs of Compound A and/or pharmaceutically acceptable solvates or pro-drugs of the HMG CoA reductase inhibitors in the pharmaceutical composition of the present invention.

[0051] In a further embodiment of the present invention, the composition according the present invention comprises polyunsaturated fatty acids (PUFAs), preferably omega-3 polyunsaturated fatty acids, more preferably PUFAs chosen from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), acid a-Linolenic acid (ALA) or combinations thereof.

[0052] PUFA's, in particular omega-3 PUFAs, have a specific capacity against triglyceride rich lipoproteins, remnant cholesterol and small dense LDL, whereas HMG CoA reductase inhibitors have no effect on remnant cholesterol , little efficacy towards triglyceride rich lipoproteins and CETP-inhibitors have no or little effect against triglyceride rich lipoprotein and remnant cholesterol. Hence, combining HMG CoA reductase inhibitors, CETP inhibitors and PUFAs in a pharmaceutical composition makes such a composition particularly suitable for the treatment of subjects suffering from or having an increased risk for cardiovascular diseases.

[0053] The PUFAs are preferably present in their free acid form, i.e. not in the form of ethyl esters in which the PUFA species are present in substantially esterified form. When the

[0054] PUFAs are used in this form, the HMG CoA reductase inhibitors are better soluble in said PUFAs. In this regard reference is made to WO2013/169797, which document is herewith incorporated by reference.

[0055] The pharmaceutical composition according to the present invention comprises besides Compound A and the at least one HMG CoA reductase inhibitor also a pharmaceutically acceptable excipient, i.e. a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing granulate, solid or liquid oral dosage formulations.

[0056] Examples of categories of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, fillers and diluents. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby incorporated 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).

[0057] A second aspect of the present relates to a therapeutic combination comprising [0058] (a) a compound of the formula:

##STR00003## [0059] (hereinafter: Compound A) or a pharmaceutically acceptable salt thereof; [0060] (b) at least one HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof.

[0061] Preferably, the HMG CoA reductase inhibitor of said therapeutic combination is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin.

[0062] More preferably, the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin calcium, pravastatin sodium, fluvastatin sodium, simvastatin, lovastatin and rosuvastatin calcium.

[0063] In a preferred embodiment the combination comprises about 1 to 25 mg of Compound A and about 1 to 80 mg of the HMG CoA reductase inhibitor. Alternatively, the pharmaceutical composition according to the present invention comprises 1 to 25 mg of Compound A and 1 to 50 mg, optionally 1 to 30 mg or 1 to 20 mg of the HMG CoA reductase inhibitor. In a further embodiment of the therapeutic combination according to the present invention the combination comprises 5 to 10 mg of Compound A and 1 to 20 mg of HMG CoA reductase inhibitor.

[0064] Due to the synergistic effect between Compound A and HMG CoA reductase inhibitors it is now also possible to lower the amount of HMG CoA reductase inhibitors used, thereby avoiding side effects commonly observed in these kinds of pharmaceutical compounds. In this regard it is also noted that such lower doses could also overcome intolerance to HMG CoA reductase inhibitors,which is also referred to as statin intollerance.

[0065] The therapeutic combination according to the present invention is preferably formulated as a fixed dose combination or a free dose combination, preferably a fixed dose combination.

[0066] In an alternative embodiment of the present invention the combination comprises a first unit dosage form comprising about 1 to 25 mg of Compound A or a pharmaceutically acceptable salt thereof and a second unit dosage form comprising about 1 to 80 mg of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, pitavastatin or a pharmaceutically acceptable salt thereof. The first and second unit dosage forms are in such a case preferably provided as a kit of parts. Preferably said combination comprises in such a case a package comprising said unit dosage forms.

[0067] The combination according the present invention may comprise polyunsaturated fatty acids (PUFAs), preferably omega-3 polyunsaturated fatty acids, more preferably PUFAs chosen from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), acid a-Linolenic acid (ALA) or combinations thereof.

[0068] PUFA's, in particular omega-3 PUFAs, have a specific capacity against triglyceride rich lipoproteins, remnant cholesterol and small dense LDL, whereas HMG CoA reductase inhibitors have no effect on remnant cholesterol, little efficacy towards triglyceride rich lipoproteins and CETP-inhibitors have no or little effect against triglyceride rich lipoprotein and remnant cholesterol. Hence, combining HMG CoA reductase inhibitors, CETP inhibitors and PUFAs in a therapeutic combination makes such a combination particularly suitable for the treatment of subjects suffering from or having an increased risk for cardiovascular diseases.

[0069] The PUFAs are preferably present in their free acid form, i.e. not in the form of ethyl esters in which the PUFA species are present in substantially esterified form. When the PUFAs are used in this free acid form, the HMG CoA reductase inhibitors are better soluble in said PUFAs. In this regard reference is made to WO2013/169797, which document is herewith incorporated by reference.

[0070] A third aspect of the present invention relates to the use of the pharmaceutical composition or the therapeutic combination as described above in the treatment of subjects suffering from or having an increased risk for cardiovascular diseases.

[0071] The pharmaceutical composition or the therapeutic combination is preferably for use in the treatment of subjects suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia.

[0072] Preferably, a subject in need of the pharmaceutical composition or the therapeutic combination according to the present invention is administered by means of said composition or combination 1 to 25 mg per day of Compound A and 1 to 80 mg per day HMG CoA reductase inhibitor. Alternatively, a subject in need of said composition or combination is administered 1 to 25 mg of Compound A and 1 to 50 mg, optionally 1 to 30 mg or 1 to 20 mg of the HMG CoA reductase inhibitor. More preferably, the pharmaceutical composition or therapeutic combination is administered in such amounts that a subject in need thereof receives 1 to 25 mg per day of Compound A and 1 to 20 mg per day of the CoA reductase inhibitor.

[0073] In a further embodiment, the pharmaceutical composition or the therapeutic combination as described above are administered to subjects suffering from or having an increased risk for hyperlipidemia or mixed dyslipidemia in such amount that such a subject receives 1 to 25 mg per day of Compound A or a pharmaceutically acceptable salt thereof and 1 to 80 mg of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, pitavastatin or a pharmaceutically acceptable salt thereof.

[0074] The pharmaceutical composition or therapeutic combination according to the present invention is generally administered to subjects in need thereof for at least one week, preferably at least three weeks.

[0075] The present invention will be illustrated further by means of the following non-limiting example.

EXAMPLE

Double Blind Randomized Study of Subjects Receiving Compound A and Receiving Compound A in Combination with Statins

[0076] In a double-blind, placebo controlled clinical study the effects of 12 weeks of administration of Compound A alone and in combination with statins in patients with mild dyslipidemia was examined.

Patients

[0077] This randomised, double-blind, placebo-controlled, parallel-group phase 2 trial was conducted in male and female patients (18-75 years) with fasting LDL-C levels >2.Math.5 mmol/L and <4.Math.5 mmol/L, HDL-C levels <1˜8 mmol/L and >0.Math.8 mmol/L and TG levels <4.Math.5mmol/L after run-in, or washout of existing therapies. Key exclusion criteria included patients with clinical manifestation of atherosclerotic vascular disease, type 1 diabetes, uncontrolled type 2 diabetes (haemoglobin Alc≧8%), uncontrolled hypertension, history of hyperaldosteronism, active muscle disease or persistent creatine kinase >3× the upper limit of normal (ULN), clinically significant renal or hepatic dysfunction, or evidence of any other clinically significant non-cardiac disease. Patients were recruited at 20 sites in the Netherlands and Denmark. The trial was approved by Independent Ethics Committees, and each patient provided written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines and the protocol was registered on ClinicalTrials.gov (NCT01970215).

Trial Design

[0078] The trial consisted of a screening visit, followed by a run-in phase of 4 weeks (or 6 weeks for patients that required a washout of existing lipid-lowering therapy). After the run-in phase, patients were randomly assigned to receive one of the following nine treatments: 1 mg, 2,5 mg, 5 mg or 10 mg of Compound A or matching placebo; 10 mg of Compound A plus atorvastatin (20 mg), 10 mg of Compound A plus rosuvastatin (10 mg), atorvastatin (20 mg) or rosuvastatin (10 mg). All treatments were to be taken once daily with food for 12 weeks. During the double-blind treatment phase visits were conducted at baseline (Week 0) and at Weeks 4, 8 and 12. Follow-up visits were conducted 2 and 8 weeks after the end of treatment. Safety was assessed throughout the trial by monitoring adverse events and concomitant medication use, 12-lead electrocardiograms (ECGs), vital signs, laboratory safety assessments and physical examinations. Additional assessments included salivary cortisol, plasma aldosterone, high-sensitivity C-reactive protein (hsCRP) and endothelin 1.

[0079] Efficacy assessments included fasted lipid profiles including total cholesterol (TC), HDL-C, LDL-C, triglycerides, apolipoproteins AI, B and E (ApoAI, Apo B and ApoE), lipoprotein a (Lp[a]) and derived parameters. Exploratory endpoints included assessments of PCSK9, HDL-driven endothelial production of nitric oxide (NO), HDL particle numbers (using nuclear magnetic resonance [NMR] spectroscopy and ion mobility analysis), HDL particle subfractions (using 2D gel electrophoresis), CETP levels and activity, and insulin resistance (based on fasting plasma glucose and insulin levels using homeostasis model assessment insulin resistance [HOMA-IR] method). Blood samples were collected for pharmacokinetic analysis of Compound A.

Analytical Methods

[0080] Total cholesterol and triglycerides were measured by homogenous enzymatic assay using a Modular analyser (cholesterol oxidase peroxidase-peroxidase aminophenazone phenol [CHOP-PAP]) method and a glycerol phosphate oxidase [GPO-PAP] method, respectively. Apolipoproteins A1, A2, B and E were measured by immunoturbidimetry using reagents from Rolf Greiner Biochemica (Germany) and N apoprotein standard serum from Siemens (Germany). Lp(a) was measured by immunoturbidimetry using reagents and standards from Wako Chemicals (Germany). LDL particle size was determined by gradient gel electrophoresis. HDL fraction was separated by a combined ultracentrifugation-precipitation method ((β-quantification). HDL-2 and HDL-3 fractions were then separated by further ultracentrifugation. Total-cholesterol in HDL, HDL 2 and HLD-3 fractions, free cholesterol in HDL fraction, triglycerides in HDL fraction and phospholipids in plasma and HDL-fraction were measured using enzymatic methods and reagents from Diasys Diagnostics (Germany). The measurements were performed on an Olympus AU600 automatic analyzer and were calibrated using secondary standards from Roche Diagnostics (total-cholesterol, triglycerides) and Diasys Diagnostics (free cholesterol, phospholipids), respectively. Esterified cholesterol was calculated as the difference between total-cholesterol and free cholesterol.

Statistical Analysis

[0081] The co-primary efficacy endpoints were the percentage changes in both HDL-C and LDL-C levels at Week 12 compared to baseline. Secondary and exploratory efficacy endpoints included the percentage changes in other efficacy parameters at Week 12 compared to baseline. The primary and secondary efficacy analyses were performed using an analysis of covariance (ANCOVA) model with treatment and use of statin therapy at randomisation as factors and the baseline value for the respective efficacy variable as a covariate. Least-squares means, standard errors and 2-tailed 95% confidence intervals for each treatment group and for pairwise comparisons between Compound A doses and placebo, between Compound A plus atorvastatin and atorvastatin alone, and between Compound A plus rosuvastatin and rosuvastatin alone were provided. As there were two co-primary efficacy variables, a closed testing procedure was used in order to control the family-wise error. No interim analyses were planned or conducted.

[0082] The sample size of 37 completed patients per treatment group was intended to provide 88% power to detect a 22.Math.5% (standard deviation [SD] 30%) increase in HDL-C compared with statin alone. This sample size with an assumed 10% (SD 15%) greater decrease in LDL-C for the investigational product compared with placebo was expected to provide a power of 80% for a successful study. All tests were 2-sided tests with a significance of 0.Math.05. To allow for a 10-15% drop-out rate, 42 randomised patients per group were planned.

Results

[0083] The results of this clinical study are provided in table 1 and FIG. 1 below and reference is also made to Hovingh G.H, et al., Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomized, double-blind, placebo controlled phase 2 trial. Lancet. 2015., which article is herewith incorporated by reference .

[0084] From this table it is apparent that Compound A already at a relatively low dose significantly increases HDL-C concentration, decreases LDL-C concentrations and Lp(a) concentrations. It is further clear from these results that the administration of both Compound A and atorvastatin or rosuvastatin results in a synergistic effect with respect to the lowering of LDL-C concentrations. Furthermore, the combination of Compound A with a statin also showed a markedly increase of HDL-C and a remarkable decrease of Lp(a). Hence, the administration of Compound A in combination with a statin appears to be very beneficial for patients suffering from cardiovascular diseases, in particular dyslipidemia.

TABLE-US-00001 TABLE 1 results of the clinical study 1 mg of 2.5 mg of 5 mg of 10 mg of Compound Compound Compound Compound Placebo A A A A n 40 39 41 40 40 HDL- 1.80 76.04 122.28 160.90 180.64 C LDL- 0.18 −27.05 −34.38 −47.49 −47.26 C Lp(a) −5.06 −28.81 −26.69 −37.33 −34.86 Atorvastatin + Rosuvastatin + Ator- 10 mg of 10 mg of vastatin Compound A Rosuvastatin Compound A Total n 40 40 41 41 362 HDL-C 1.27 154.19 6.16 159.86 LDL-C −46.73 −69.56 −47.36 −65.58 Lp(a) −4.46 −25.29 −7.79 −24.16

[0085] It has further been found that Compound A alone and in combination with statins, such as rosuvastatin, enhanced the ability of serum to promote cholesterol efflux. The ability of serum to promote cholesterol efflux was increased by 16.9% (p<0.0001) in patients given 1mg of Compound A, whereas treatment with the 10 mg dose of Compound A resulted in a 36.7% increase in serum-mediated cholesterol efflux (p<0.0001; FIG. 1).

[0086] In this Figure baseline andweek 12 data for serum-driven cholesterol efflux is shown. Bars are means and error bars are standard deviations. The baseline data only includes patients who had both baseline and week 12 data. The changes from baseline for all active treatments showed significant differences from placebo at week 12.

Checmical Name and Formula of a Compound A

[0087] ##STR00004##

[0088] {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}