Treatment of HIS low responders

Abstract

The present invention relates to the treatment of cardiovascular disease, more particularly to the treatment of subjects suffering from or at risk of suffering from atherosclerotic cardiovascular disease who are hyporesponsive to HIS treatment. The inventors have found that HIS hypo-responders show a marked improvement in their blood lipid profile when their statin therapy is combined with treatment with the CETP inhibitor obiscetrapib. Thus, in a general aspect, the present invention provides a method for treating subjects who are hyporesponsive to high-intensity statin (HIS) therapy, comprising administering a composition comprising obiscetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Description

[Technical field]

[0001] The present invention relates to the treatment of cardiovascular disease, more particularly to the treatment of subjects suffering from or at risk of suffering from atherosclerotic cardiovascular disease who do not respond adequately to high-intensity statin (HIS) therapy, particularly subjects who are hyporesponsive to HIS therapy. The present invention provides a novel treatment modality in which HIS is combined with newly discovered add-on therapies that, in conjunction with HIS, provide major improvements in plasma LDL-C, apoB and non-HDL-C, resulting in amelioration of associated symptoms and risks. [Background technology]

[0002] Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide. In 2015, up to 31% of global deaths were attributable to ASCVD. ASCVD is the leading cause of death in the EU, and in the United States, the burden of disease attributable to ASCVD is greater than the burden of any other chronic disease.

[0003] It is generally recognized that there is a strong association between low-density lipoprotein-cholesterol (LDL-C) levels and ASCVD risk. Inhibition of HMG CoA reductase by HMG CoA reductase inhibitors, commonly referred to as "statins," has been shown to reduce LDL-C levels in the blood by reducing cholesterol production and promoting hepatic uptake of cholesterol from the circulation. The application of such statin therapy to lower these LDL-C levels in the blood has resulted in a significant reduction in ASCVD-related morbidity and mortality since their commercial introduction. Since then, statins have become the cornerstone of lipid-lowering pharmacotherapy for the prevention and management of ASCVD. Evidence from clinical trials has shown a consistent linear relationship between the degree of low-density lipoprotein cholesterol (LDL-C) reduction with statins and the relative reduction in risk of ASCVD events. Furthermore, the low cost of statins also means that their treatment is cost-effective even for low-risk patients (such as those with a 10-year calculated cardiovascular disease risk of 7.5%).

[0004] Despite progress in ASCVD treatment and prevention with statin therapy, there are limitations to what can be achieved with statins due to tolerability and safety issues. Particularly at high doses, statins can cause increased liver enzymes and myopathy, and sometimes rhabdomyolysis, which can lead to acute renal failure and death. Furthermore, even at the maximum tolerated doses of the most effective statins, LDL-C goals cannot be achieved in a significant subpopulation of patients, especially those at high ASCVD risk. For example, the CEPHEUS study in over 35,000 patients (mean age 60 years) enrolled in 29 countries across Asia, Western and Eastern Europe, the Middle East and Africa found that only 50% of patients at high cardiovascular risk and 20% of patients at very high risk achieved guideline-recommended LDL-C target levels. Furthermore, EUROASPIRE, a pan-European survey of coronary patient care, found that although there was improvement in statin uptake, less than 1 in 5 patients reached LDL-C goals of less than 1.8 mmol / L. As shown by evidence from EUROASPIRE, the variability of patient response to statin therapy, for example due to genetic factors, is a factor that cannot be ignored. Indeed, evidence from the JUPITER study highlights the wide variability of statin response. In this secondary analysis, while the median LDL-C lowering response was 50%, more than half showed a lower response; 43% had an LDL-C reduction of <50%, and 11% showed no reduction or even an increase in LDL-C with rosuvastatin 20 mg. The magnitude of response was an important determinant of clinical benefit from statins, since the incidence of first cardiovascular events was about two times higher in patients who did not respond to statins compared to patients who showed at least a 50% reduction in LDL-C. Evidence from real-world situations demonstrates the magnitude of statin hyporesponsiveness, with 60% of high-risk patients showing less than a 30% reduction in LDL-C levels with statin therapy.

[0005] Patient responsiveness to statins is even more relevant when considering its impact on the progression of ASCVD. This was clearly demonstrated with intravascular ultrasound in patients with angiographic coronary artery disease. Patients with inadequate response to statins (i.e., <15% reduction in LDL-C levels with the recommended statin dose) had significantly higher atherosclerosis progression, as assessed by percent atheroma volume, than statin responders. This association remained even after adjusting for baseline characteristics and plaque burden. The study showed that 20% of patients were inadequate responders to statins and therefore at higher risk for advanced ASCVD.

[0006] As can be seen from the above, there remains an unmet need in the clinical implementation of safe and effective pharmacological treatment modalities for poor responders to (high-intensity) statin therapy. Summary of the Invention [Problem to be solved by the invention]

[0007] It is an object of the present invention to provide such a novel treatment modality. [Means for solving the problem]

[0008] The inventors have found that HIS low-responders show a significant improvement in their blood lipid profile when their statin therapy is combined with treatment with the CETP inhibitor obiscetrapib. In particular, as described in the experimental part of this specification, obiscetrapib administered in addition to high-intensity statin therapy has a similar safety profile to placebo (in addition to HIS therapy) and was newly shown to be well tolerated in our Phase 2b clinical trial. In the group of HIS low-responders, obiscetrapib reduced median LDL-C levels to levels of -41.5% from baseline at a dose of 5 mg and -50.8% at a dose of 10 mg. Significant improvements in apoB, non-HDL-C and HDL-C levels were also demonstrated in the study.

[0009] The obiscetrapib compound itself was first described as one of a number of novel CETP inhibitors in EP 1730152 and U.S. Pat. No. 7,872,126, the entireties of which are incorporated herein by reference.

[0010] WO 2016 / 032324 and US 10,300,059, the entireties of which are incorporated herein by reference, report synergistic effects in the treatment of subjects suffering from or at risk of suffering from (AS)CVD with a combination of obiscetrapib and an HMG CoA reductase inhibitor, with a favorable safety profile, in terms of lowering blood LDL-C levels. According to WO 2016 / 032324, the combination allows for a reduction in the dose of the HMG CoA reductase inhibitor, thereby overcoming / reducing tolerability issues sometimes associated with HMG CoA reductase inhibitors.

[0011] As explained in WO 2016 / 032324, despite clear evidence supporting the potential of CETP inhibition in reducing cardiovascular morbidity, the clinical development of CETP inhibitors has not been straightforward. Several promising CETP inhibitors have already been withdrawn from development. When used in conjunction with the HMG CoA reductase inhibitor atorvastatin, the CETP inhibitor torcetrapib resulted in an unexpected increase in cardiovascular events and mortality. Another CETP inhibitor, dalcetrapib, which has proven to be a weak inhibitor in vivo, increasing HDL-C by 30-40% with minimal effects on LDL-C concentrations and development, was discontinued on grounds of futility in a phase 3 trial in which the drug was administered at 600 mg. An accelerated trial with evacetrapib at a daily dose of 130 mg failed to show a CV benefit but showed a nominally significant benefit on all-cause mortality. The 6.4-year follow-up of the REVEAL study with anacetrapib at a daily dose of 100 mg confirmed the CETP inhibitor class for CV protection and suggested that lowering of LDL-C or apoB was responsible for the CV benefits observed. The dosages of evacetrapib and anacetrapib shown to be of therapeutic value are relatively high. This may present tolerability issues when used in combination therapy.

[0012] WO 2016 / 032324 shows that in the general population of patients with or at risk of (AS)CVD, obiscetrapib has a significantly more favorable safety and efficacy profile than other CETP inhibitors, even in combination with statins. However, the beneficial effects of obiscetrapib in the population of non-responders and / or poor responders to HIS therapy are not disclosed or predicted in WO 2016 / 032324.

[0013] Kastelein et al. ("Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study". THE LANCET,vol.385,no.9983,1 May 2015(2015-05-01),pages 2153-2161) discuss the results of the phase 3 REALIZE trial, in which patients with heterozygous familial hypercholesterolemia (heFH) were treated with the CETP inhibitor anacetrapib in addition to stable statin doses of atorvastatin ranging from 10 to 80 mg and rosuvastatin ranging from 5 to 40 mg. Heterozygous familial hypercholesterolemia is a common autosomal dominant disorder that results in significantly elevated LDL-C levels from birth, causing early-onset CAD. HeFH is generally recognised as treatable with statins. For example, McGowan et al. (Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia. J Am Heart Assoc. 2019 Dec 17;8(24)) explain that high-intensity statin therapy can lower LDL-C by 50%-60%, and a cohort observational study following 1950 adults with FH for 8.5 years reported a 76% reduction in cardiovascular events in statin-treated patients versus untreated patients. Subjects with heFH are not considered HIS non-responders and / or low-responders.

[0014] In a general aspect, the invention provides a method of treating a subject who does not adequately respond to statin therapy, in particular high-intensity statin (HIS) therapy, said method comprising administration of a composition comprising obiscetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0015] More specifically, the present invention relates to the following aspects:

[0016] A first aspect of the present invention relates to a method for the prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, said method comprising the administration of a pharmaceutical composition comprising obicetrapib or a pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein the subject is a poor responder to HIS therapy, and the method further comprises concomitant statin therapy, in particular HIS therapy.

[0017] A further aspect of the invention relates to a pharmaceutical composition comprising obiscetrapib or a pharma- ceutically acceptable salt, hydrate or solvate thereof for use in a method for prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, wherein the subject is a poor responder to HIS therapy, and the method further comprises concomitant statin therapy, in particular HIS therapy.

[0018] A further aspect of the invention relates to the use of obiscetrapib or a pharma- ceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for use in a method for prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from CVD, in particular ASCVD, wherein the subject is a poor responder to HIS therapy, and the method further comprises concomitant statin therapy, in particular HIS therapy.

[0019] Another aspect of the invention relates to a pharmaceutical composition comprising obiscetrapib or a pharma- ceutically acceptable salt, hydrate or solvate thereof, preferably in unit dosage form, optionally in combination with an HMG CoA reductase inhibitor; and a kit comprising a package containing a plurality of unit dosage forms of such agents and a leaflet with printed instructions to repeatedly self-administer said unit dosage forms to treat and / or prevent CVD, particularly SCVD, by combined obiscetrapib therapy and statin therapy, particularly HIS therapy, in case of inadequate response to said HIS therapy alone.

[0020] It will be understood that, unless specifically stated otherwise, all of these aspects of the invention involve the same compositions, the same methods of treatment, the same subject matter, etc. Specific details and preferred embodiments of the above-described methods and compositions and pharmaceutical kits used therein will be apparent to those of skill in the art based on the following detailed description and supplemental experimental part.

[0021] Pharmaceutical Compositions The pharmaceutical compositions according to the present invention comprise, as an active pharmaceutical ingredient ("API"), obiscetrapib, or a pharma- ceutically acceptable salt, hydrate or solvate thereof. Obicetrapib has the IUPAC name (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and the following structural formula: [ka] The compound INN has the formula:

[0022] The term "pharmacologically acceptable" as used herein has its conventional meaning and means those compounds, substances, compositions and / or dosage forms within the scope of sound medical judgment, suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic response and other problematic complications commensurate with a reasonable benefit / risk ratio.

[0023] As used herein, "pharmaceutically acceptable salt" includes any salt that maintains the activity of the active agent and is acceptable for pharmaceutical use. Pharmaceutically acceptable salt also refers to a salt that may form in vivo as a result of administration of an acid, another salt, or a prodrug that is converted to an acid or salt. Pharmaceutically acceptable salts of the disclosed compounds may be prepared by methods well known to those skilled in the art. Synthetic routes are described in EP 1730152 and U.S. Pat. No. 7,872,126, which are incorporated herein by reference in their entirety; EP 2007728 and U.S. Pat. No. 8,084,611, which are incorporated herein by reference in their entirety; EP 3180314 and U.S. Pat. No. 10,112,904, which are incorporated herein by reference in their entirety.

[0024] Additionally, the compositions may contain obiscetrapib in a solvated form with a pharma- ceutically acceptable solvent such as water ("hydrate"), ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0025] The term "pharmaceutical composition" as used herein means a composition comprising obiscetrapib or a salt or solvate thereof, and optionally one or more additional non-toxic ingredients, in a form suitable for administration to a (human) subject via any route of administration, and which is physiologically tolerable for such administration.

[0026] Thus, the composition of the present invention may include one or more additional components. In a preferred embodiment, the composition includes one or more carriers and / or excipients. As known to those skilled in the art, the appropriate selection of excipients depends on several factors, such as the physicochemical properties of the API, the preferred pharmaceutical form, the preferred route of administration, and the desired release rate. The composition of the present invention may be formulated for various routes of administration, with oral administration being particularly preferred. It is within the scope of those skilled in the art to devise and develop suitable formulations by relying on ordinary general knowledge and routine development efforts as reflected in textbooks such as Remington's Pharmaceutical Sciences (Meade Publishing Co., Easton, Pa., 20th Ed., 2000), the disclosure of which is incorporated herein in its entirety by reference.

[0027] According to various aspects of the present invention, the composition is preferably provided in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary administration to a human subject, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect in association with any suitable pharmaceutical carrier and / or excipient. Exemplary, non-limiting unit dosage forms include tablets, caplets, capsules (e.g., hard or soft capsules), troches, films, strips, gel caps, and metered volumes of solutions, suspensions, syrups or elixirs, etc., which may be contained in vials, syringes, applicator devices, sachets, sprays, micropumps, etc. According to a particularly preferred embodiment of the present invention, the unit dosage form is a unit dosage form suitable for oral administration. Most preferably, it is a solid unit dosage form, such as a tablet, for oral ingestion.

[0028] According to various aspects of the invention, the compositions are provided in unit dosage forms comprising obistrapib in a dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg or at least 9 mg, for example about 10 mg; or an equipotent dose of a salt, solvate or hydrate of obistrapib. According to various aspects of the invention, the compositions are typically provided in unit dosage forms comprising obistrapib in a dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less or 11 mg; or an equipotent dose of a salt, solvate or hydrate of obistrapib. According to various aspects of the invention, the compositions are preferably provided in unit dosage forms comprising obiscetrapib in a dose range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg, or 5-10 mg; or an equipotent dose of a salt, solvate, or hydrate of obiscetrapib. In certain preferred embodiments, the compositions are provided in unit dosage forms comprising obiscetrapib in a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg; or an equipotent dose of a salt, solvate, or hydrate of obiscetrapib. In certain preferred embodiments, the compositions are provided in unit dosage forms comprising obicetrapib in doses of 5, 7.5, 10, 12.5 or 15 mg; or an equipotent dose of a salt, solvate or hydrate of obicetrapib.

[0029] The term "equipotent" as used herein means equally capable or equally capable of producing a pharmacological effect of a particular intensity. It is also common in the art to mean an amount of a given compound that is "equivalent" to a specified amount of a reference compound. For example, if a composition contains a salt of obiscetrapib, the amount of said salt administered and / or incorporated into a unit dosage form must be adjusted to take into account the molecular weight difference between the free base and the salt form. For example, when expressing dosage amounts on the label and / or product information of an approved pharmaceutical product that contains a salt form of an active compound that can also be used in free base form, it is conventional practice to specify the dose of the free base to which the dose of the salt used is equivalent. In this context, the term "equipotent" is considered synonymous with the term "equivalent".

[0030] In a particular embodiment of the present invention, the pharmaceutical composition further comprises an HMG CoA reductase inhibitor, preferably a statin, in particular selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin and pitavastatin, most preferably selected from the group consisting of atorvastatin and rosuvastatin. As will be understood by the skilled artisan based on the teachings of the present invention, the present invention relates to a combination treatment in which a subject receives an obiscetrapib-based therapy and a statin therapy, in particular an HIS therapy, simultaneously, and therefore an embodiment is envisaged in which the composition is a fixed dose combination product comprising both obiscetrapib or a pharma- ceutically acceptable salt, solvate or hydrate thereof and an HMG CoA reductase inhibitor. Thus, the present invention provides a composition as defined herein, provided in a unit dosage form comprising said HMG CoA reductase inhibitor in an amount typically ranging from 1 to 80 mg. Preferably, the dose of the HMG CoA reductase inhibitor is safe and at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% and / or less than 120%, less than 115%, less than 110%, less than 105%, less than 103%, less than 102% or less than 101% of the maximum (daily) dose approved for the treatment of (AS)CVD. In some embodiments, the invention provides a composition as defined herein provided in unit dosage form comprising atorvastatin in a dose of 70-90 mg, 75-85 mg, 77.5-82.5 mg, for example 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 mg, most preferably about 40 mg or 80 mg; or an equipotent dose of a salt, solvate or hydrate of atorvastatin.In some embodiments, the invention provides a composition as defined herein provided in unit dosage form comprising rosuvastatin in a dose of 30-50 mg, 35-45 mg, 37.5-42.5 mg, such as 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg, most preferably about 20 mg or 40 mg; or an equipotent dose of a salt, solvate or hydrate of rosuvastatin.

[0031] In a further embodiment of the present invention, the composition according to the present invention comprises polyunsaturated fatty acids (PUFAs), preferably omega-3 polyunsaturated fatty acids, more preferably PUFAs selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA) or combinations thereof. PUFAs, especially omega-3 PUFAs, have specific ability on lipoproteins rich in glycerides, remnant cholesterol and very bad cholesterol, whereas HMG CoA reductase inhibitors have no effect on remnant cholesterol and little effectiveness on lipoproteins rich in triglycerides, and CETP inhibitors have no or little effect on lipoproteins rich in triglycerides and remnant cholesterol. Therefore, the combination of HMG CoA reductase inhibitors, CETP inhibitors and PUFAs in a pharmaceutical composition makes the composition particularly suitable for the treatment of subjects suffering from or at high risk of cardiovascular disease. PUFA exists in its free acid form, that is, PUFA species exists substantially in esterified form, preferably in ethyl ester form.When PUFA is used in this form, HMG CoA reductase inhibitor has good solubility in said PUFA.In this regard, reference is made to WO2013 / 169797, the document of which is incorporated herein by reference.

[0032] Treatment indications As explained herein above, the present invention provides a method for therapeutic and / or prophylactic treatment of a subject that does not respond adequately or at all to statin therapy, particularly high intensity statin (HIS) therapy. In particular, the present invention also provides a method for the treatment and / or prevention of cardiovascular disease, particularly atherosclerotic cardiovascular disease, in such a subject using a composition as defined herein. The present invention further provides a method for the treatment and / or prevention of one or more symptoms associated with (atherosclerotic) cardiovascular disease in such a subject using a composition as defined herein. The present invention further provides a method for the treatment and / or prevention of one or more pathologies associated with and / or caused by (atherosclerotic) cardiovascular disease in such a subject using a composition as defined herein. The present invention further provides a method for the treatment and / or prevention of one or more pathogenic factors associated with (atherosclerotic) cardiovascular disease, such as high LDL-C levels and / or high apo B levels, in such a subject using a composition as defined herein. The present invention further provides methods of alleviating and / or ameliorating resistance or hyporesponsiveness to statin therapy, particularly high-intensity statin therapy, in such subjects using the compositions defined herein.

[0033] When used in conjunction with a specific disease or condition, the terms "treat", "treating" or "treatment" (e.g., "methods of treating a disease") refer to curing, alleviating or arresting the disease and / or associated symptoms, reducing the severity of symptoms, stabilizing (i.e., not worsening) the disease state, delaying or slowing progression, improving the disease state, prolonging survival (compared to expected survival without treatment), and the like. As used herein, the terms "prevent", "preventing" or "prevention" refer to reducing the risk of a subject acquiring a disease and / or associated symptoms, delaying the time when a subject acquires a disease, and the like. When used in reference to a patient or subject, the terms "treat", "treating" or "treatment" (e.g., "methods of treating a disease") generally refer to the act of administering a therapeutic compound to the patient or subject, whether for therapeutic and / or prophylactic purposes.

[0034] The term "cardiovascular disease" as used herein has its conventional meaning of referring to a disease or condition in which the function of the circulatory system of a subject becomes impaired. Examples of cardiovascular disease include thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the atrioventricular chambers of the heart); atherosclerosis; hypertensive heart disease; coronary artery disease; carotid artery disease; stroke; peripheral arterial disease, including atherosclerosis; restenosis; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); refractory arterial disease (ROD); and vascular endothelial dysfunction (VEHD). These include chronic unstable angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction (AMI); myocardial infarction; ischemic heart disease; cardiac ischemia; ischemia; sudden ischemic death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary artery thrombosis; cerebral artery thrombosis, cerebral embolism; renal embolism; pulmonary embolism, etc.

[0035] The term "atherosclerotic cardiovascular disease" as used herein refers to a specific subset of cardiovascular disease that includes atherosclerosis as a component or precursor to a particular type of cardiovascular disease. Atherosclerosis is a chronic inflammatory reaction that occurs in the arterial vessel wall, associated with the retention of LDL-C. It is accompanied by the formation of atherosclerotic plaques that can cause narrowing ("stenosis") of the artery and ultimately cause partial or complete closure of the arterial opening and / or plaque rupture. Thus, atherosclerotic disease or disorder includes the consequences of the formation and rupture of atherosclerotic plaques, including but not limited to narrowing or narrowing of arteries, heart failure, aneurysm formation, e.g., aortic aneurysm, arterial dissection, and ischemic events such as myocardial infarction or stroke.

[0036] In particularly preferred embodiments, the atherosclerotic cardiovascular disease and / or pathologies associated with atherosclerotic cardiovascular disease which may be advantageously treated and / or prevented in accordance with the present invention are selected from the group consisting of arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia betalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and stroke.

[0037] As is evident from the teachings of the present invention, the method of the present invention is effective and / or intended to reduce and / or normalize LDL-C plasma levels even in subjects with low responsiveness to HIS therapy. More particularly, the method is effective and / or intended to reduce LDL-C plasma levels by at least 5%, more preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50% from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In a further embodiment, the method is effective and / or intended to reduce LDL-C plasma levels by at least 5 mg / dL, more preferably at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, at least 30 mg / dL, at least 35 mg / dL or at least 40 mg / dL from baseline defined as initiation of treatment with obiscetrapib as an add-on to HIS therapy. In a further embodiment, the method is effective and / or intended to reduce LDL-C plasma levels to a level of less than 85 mg / dL, preferably to a level of less than 80 mg / dL, less than 75 mg / dL, less than 70 mg / dL, less than 65 mg / dL, less than 60 mg / dL, less than 55 mg / dL or less than 50 mg / dL.

[0038] In a preferred embodiment of the invention, the method is effective and / or intended to reduce and / or normalize apoB plasma levels. More particularly, the method is effective and / or intended to reduce apoB plasma levels by at least 5%, more preferably at least 10%, at least 15%, at least 20%, at least 22.5%, at least 25% or at least 27.5% from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In a further embodiment, the method is effective and / or intended to reduce apoB plasma levels by at least 5 mg / dL, more preferably at least 5 mg / dL, at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 22.5 mg / dL, at least 25 mg / dL or at least 27.5 mg / dL from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In further embodiments, the method is effective and / or intended to reduce apo B plasma levels to levels below 80 mg / dL, preferably below 75 mg / dL, below 70 mg / dL, below 65 mg / dL, below 60 mg / dL, below 57.5 mg / dL or below 55 mg / dL.

[0039] In a preferred embodiment of the invention, the method is effective and / or intended to reduce and / or normalize non-HDL-C plasma levels. More particularly, the method is effective and / or intended to reduce non-HDL-C plasma levels by at least 5%, more preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 42.5% from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In a further embodiment, the method is effective and / or intended to reduce non-HDL-C plasma levels by at least 5 mg / dL, more preferably at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, at least 30 mg / dL, at least 35 mg / dL or at least 40 mg / dL from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In further embodiments, the method is effective and / or intended to reduce non-HDL-C plasma levels to levels below 110 mg / dL, preferably below 100 mg / dL, below 90 mg / dL, below 80 mg / dL, below 75 mg / dL, below 70 mg / dL or below 65 mg / dL.

[0040] In a preferred embodiment of the invention, the method is effective and / or intended to increase HDL-C plasma levels. More particularly, the method is effective and / or intended to increase HDL-C plasma levels by at least 25%, more preferably at least 50%, at least 75%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130% or at least 140% from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In a further embodiment, the method is effective and / or intended to increase non-HDL-C plasma levels by at least 25 mg / dL, more preferably at least 40 mg / dL, at least 50 mg / dL, at least 55 mg / dL, at least 60 mg / dL, at least 65 mg / dL or at least 70 mg / dL from baseline defined as initiation of treatment with obiscetrapib as add-on to HIS therapy. In further embodiments, the method is effective and / or intended to reduce HDL-C plasma levels to levels greater than 50 mg / dL, preferably greater than 60 mg / dL, greater than 70 mg / dL, greater than 80 mg / dL, greater than 90 mg / dL, greater than 100 mg / dL or greater than 110 mg / dL.

[0041] In a further embodiment of the present invention, the method is effective and / or intended to alleviate and / or improve resistance or responsiveness to statin therapy, particularly high-intensity statin therapy. High-intensity statin therapy is a term conventionally used in the art to indicate a regimen based on the highest tolerated dose of statin with the highest efficacy in reducing LDL-C, particularly a regimen that typically exhibits a LDL-C reduction of ≧50% in normally responding subjects. Among the statins currently used in clinical practice, only rosuvastatin 20 mg (daily dose) or 40 mg (daily dose) and atorvastatin 40 mg (daily dose) or 80 mg (daily dose) meet the criteria. In the context of the present invention, hyporesponsiveness to HIS therapy means that a patient undergoing HIS therapy does not reach a 35% LDL-C reduction, preferably that a patient undergoing HIS therapy does not reach a 30% LDL-C reduction, a 25% LDL-C reduction, a 20% LDL-C reduction, a 15% LDL-C reduction or a 10% LDL-C reduction. Alleviating and / or improving hyporesponsiveness to HIS therapy means that the difference between the subject's response (LDL-C reduction) and the (average) response of normally responsive subjects is reduced. In a further embodiment of the present invention, the method is effective and / or intended for normalizing the response to statin therapy.

[0042] Subjects to be treated As explained herein above, the method of the present invention relates to the treatment and / or prevention of a subject suffering from or at risk of suffering from CVD, in particular ASCVD.

[0043] The term "subject" refers to an organism, generally a mammal, particularly a human subject, suffering from or prone to suffering from a disease or condition that can be treated by using the compositions provided herein.

[0044] In a particularly preferred embodiment of the invention, the subject is one who has been diagnosed with CVD, in particular ASCVD.

[0045] In a further preferred embodiment of the invention, the subject is one who is generally considered to be at risk, above the average risk, of developing CVD, particularly ASCVD, as may be determined, for example, by a health care professional.

[0046] In a preferred embodiment of the invention, the subject is a subject suffering from one or more conditions that have a causal and / or epidemiological correlation with the occurrence of (AS)CVD, such as diabetes, hypertension, hypercholesterolemia, including weight / obesity, metabolic syndrome, etc. In a further preferred embodiment of the invention, the subject is a subject with a genetic predisposition to developing (AS)CVD. In a further preferred embodiment of the invention, the subject is a subject prone to developing (AS)CVD as a result of lifestyle / habitual factors, such as an unhealthy diet, lack of exercise, alcohol intake, smoking, etc.

[0047] Moreover, as is clear from the above, the subject treated according to the present invention is usually already undergoing statin therapy, particularly HIS therapy. Moreover, the subject treated according to the present invention is usually hyporesponsive to statin therapy, particularly HIS therapy. As described elsewhere herein, high-intensity statin therapy is a term conventionally used in the art to refer to a regimen based on the highest tolerated dose of statin with the highest efficacy in reducing LDL-C, particularly a regimen that typically exhibits ≧50% LDL-C reduction in normally responsive subjects. In clinical practice, only rosuvastatin 20mg / day or 40mg / day, or atorvastatin 40mg / day or 80mg / day are considered HIS therapy.

[0048] In a preferred embodiment of the invention, the subject is a subject undergoing HIS therapy and not achieving a 35% LDL-C reduction, preferably a subject undergoing HIS therapy not achieving a 30% LDL-C reduction, a 25% LDL-C reduction, a 20% LDL-C reduction, a 15% LDL-C reduction or a 10% LDL-C reduction.

[0049] According to a preferred embodiment of the present invention, the treated subject has an elevated plasma level of LDL-C, despite undergoing HIS therapy, generally an LDL-C plasma level of at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Furthermore, according to a preferred embodiment of the present invention, the subject has an LDL-C plasma level that is at least 125%, such as at least 150%, at least 175% or at least 200% of the average LDL-C plasma level in healthy subjects. Normal LDL-C (reference) values ​​usually vary depending on gender and age.

[0050] According to a preferred embodiment of the invention, the treated subject has an elevated plasma level of apoB, despite undergoing HIS therapy, usually an apoB plasma level of at least 70 mg / dL, more preferably at least 75 mg / dL, at least 80 mg / dL, at least 85 mg / dL, at least 90 mg / dL, at least 95 mg / dL or at least 100 mg / dL. Furthermore, according to a preferred embodiment of the invention, the subject has an apoB plasma level that is at least 125%, such as at least 150%, at least 175% or at least 200% of the average apoB plasma level in healthy subjects. Normal apoB (reference) values ​​usually vary depending on sex and age.

[0051] According to a preferred embodiment of the present invention, the treated subject has an elevated plasma level of non-HDL-C, despite receiving HIS therapy, usually a non-HDL-C plasma level of at least 100 mg / dL, more preferably at least 105 mg / dL, at least 110 mg / dL, at least 115 mg / dL, at least 120 mg / dL, at least 125 mg / dL or at least 130 mg / dL. Furthermore, according to a preferred embodiment of the present invention, the subject has a non-HDL-C plasma level that is at least 125%, such as at least 150%, at least 175% or at least 200% of the average non-HDL-C plasma level in healthy subjects. Normal non-HDL-C (reference) values ​​usually vary depending on gender and age.

[0052] In a preferred embodiment of the invention, the subject's hypo-responsiveness to statin therapy, in particular HIS therapy, is established after at least 1 month, more preferably after at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months of (continuous) HIS therapy.

[0053] In one embodiment of the invention, the subject is a male human. In another embodiment of the invention, the subject is a female human.

[0054] In a further preferred embodiment of the invention, the subject has an increased risk based on age, such as the subject being over 35 years of age, over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age or over 70 years of age, generally in conjunction with one or more other factors defined herein.

[0055] Treatment regimen All the various embodiments defined herein relate to a method of treatment comprising the administration, generally repeated administration, of a composition comprising obiscetrapib or a salt or solvate / hydrate thereof, preferably any of the compositions defined herein above.

[0056] Thus, in a particularly preferred embodiment of the invention, the method comprises administration of obicetrapib in a dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg or at least 9 mg, for example about 10 mg; or a salt, solvate or hydrate of obicetrapib in an equipotent dose. According to various aspects of the invention, the method comprises administration of obicetrapib in a dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less or 11 mg; or a salt, solvate or hydrate of obicetrapib in an equipotent dose. According to various aspects of the invention, the method comprises administration of obicetrapib at a dose in the range of 1-100 mg, 2-50 mg, 3-50 mg, 4-25 mg, 4.5-15 mg, or 5-10 mg; or an equipotent dose of a salt, solvate, or hydrate of obicetrapib. In certain preferred embodiments, the method comprises administration of obicetrapib at a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg; or an equipotent dose of a salt, solvate, or hydrate of obicetrapib. In certain particularly preferred embodiments, the method comprises administration of obicetrapib at a dose of 5, 7.5, 10, 12.5, or 15 mg; or an equipotent dose of a salt, solvate, or hydrate of obicetrapib.

[0057] In a particularly preferred embodiment of the invention, the treatment comprises repeated administration of a composition containing obicetrapib or a salt, hydrate or solvate thereof, preferably in a dose within the ranges defined herein above. In a particularly preferred embodiment of the invention, the treatment comprises repeated administration of the composition at a frequency of at least once every two days or at least once a day, preferably in a dose within the ranges defined herein above. In a particularly preferred embodiment of the invention, the treatment comprises repeated administration of the composition at a frequency of 1 to 4 times a day, preferably in a dose within the ranges defined herein above. In a particularly preferred embodiment of the invention, the method comprises once or twice a day administration of a composition containing obicetrapib or a salt, hydrate or solvate thereof, most preferably twice a day, in a dose within the ranges defined herein above.

[0058] Thus, in a particularly preferred embodiment of the invention, the method comprises administering obicetrapib in a daily dose of at least 1 mg, preferably at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg or at least 9 mg, for example about 10 mg; or a salt, solvate or hydrate of obicetrapib in an equipotent dosage. According to various aspects of the invention, the method comprises administering obicetrapib in a daily dose of 100 mg or less, more preferably 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 15 mg or less, 12.5 mg or less, 12 mg or less or 11 mg; or a salt, solvate or hydrate of obicetrapib in an equipotent dosage. According to various aspects of the invention, the method comprises administering obicetrapib in a daily dose ranging from 1 to 100 mg, 2 to 50 mg, 3 to 50 mg, 4 to 25 mg, 4.5 to 15 mg, or 5 to 10 mg; or an equipotent dose of a salt, solvate, or hydrate of obicetrapib. In certain preferred embodiments, the method comprises administering obicetrapib in a daily dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg; or an equipotent dose of a salt, solvate, or hydrate of obicetrapib. In certain particularly preferred embodiments, the methods comprise administering obicetrapib in a daily dose of 4, 5, 7.5, 10, 12.5 or 15 mg; or an equipotent dose of a salt, solvate or hydrate of obicetrapib.

[0059] As will be apparent to those skilled in the art based on the teachings of the present invention, the daily doses shown herein can be contained in a single unit dosage form and in multiple unit dosage forms. In the most preferred embodiment of the present invention, the method includes administering obiscetrapib once a day in the dosage amounts described herein. However, it is also contemplated that the method includes administration of two unit dosage forms each containing approximately half of the daily doses shown above at specific predetermined times during the day, for example, once in the morning, such as immediately after the subject wakes up, and once in the evening, such as around the time the subject eats dinner or goes to bed. Also contemplated are embodiments in which a unit dosage form containing a higher dose of obiscetrapib than the daily doses shown herein is used. This includes, for example, the use of sustained release dosage forms that remain in the body for a sufficiently long time to maintain release of the active ingredient.

[0060] In an embodiment of the invention, there is provided a method comprising the administration of a composition for use according to the invention, comprising administering, preferably repeatedly administering, the composition to a subject at a dose and frequency that is effective to reduce the subject's LDL-C plasma level, the subject's Apo B plasma level and / or the subject's total non-HDL-C plasma level, more preferably effective to achieve a reduction in one or more of the subject's LDL-C plasma level, the subject's Apo B plasma level and / or the subject's non-HDL-C plasma level, within the scope described elsewhere herein.

[0061] In particularly preferred embodiments of the invention, the treatment comprises repeated administration of a composition containing obiscetrapib or a salt, hydrate or solvate thereof, preferably according to a regimen defined above, for a period of at least 1 month, at least 3 months, at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, at least 10 years, at least 20 years, at least 30 years. There is no particular upper limit, and the treatment may continue for as long as it is deemed beneficial for the subject's overall health and well-being (as determined by an appropriately qualified health care professional), e.g. for the rest of the subject's life.

[0062] As will be apparent to those skilled in the art based on the teachings of the present invention, the method of the present invention further includes combination treatment, preferably combination HIS therapy, with an HMG CoA reductase inhibitor. For this purpose, the HMG CoA reductase inhibitor and obiscetrapib (or an acceptable salt, solvate or hydrate thereof) can be administered simultaneously or at about the same time, sequentially or in parallel, or at different times. In a preferred embodiment of the present invention, the frequency and administration interval of obiscetrapib and the HMG CoA reductase inhibitor are equal, more preferably once a day, respectively, and more preferably at the same time of the day, sequentially or in parallel as two separate unit dosage forms or in the form of a fixed dose combination product. In a preferred embodiment, the method of the invention comprises administering rosuvastatin at a daily dose of 20 to 30 mg, 30 to 50 mg, 35 to 45 mg, 37.5 to 42.5 mg, for example 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg, most preferably about 20 mg or 40 mg; or an equipotent dose of a salt, solvate or hydrate of rosuvastatin. In a preferred embodiment, the method comprises administering atorvastatin in a daily dose of 40 to 70 mg, 70 to 90 mg, 75 to 85 mg, 77.5 to 82.5 mg, for example 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 mg, most preferably about 40 mg or 80 mg; or an equipotent dosage of a salt, solvate or hydrate of atorvastatin.

[0063] Medicine kit Another aspect of the present invention relates to a pharmaceutical kit comprising a package comprising a plurality of unit dosage forms and a leaflet, said unit dosage forms containing a pharmaceutical composition according to the present invention, said leaflet comprising printed instructions for repeatedly self-administering said unit dosage forms to achieve any of the therapeutic goals defined herein, such as for treating and / or preventing a cardiac disease or dysfunction as defined herein.

[0064] According to an embodiment of the present invention, the pharmaceutical kit comprises a container, such as a cardboard box, housing one or more blister packs, said one or more blister packs comprising a plurality of solid unit dosage forms as defined herein above, preferably a plurality of tablets as defined herein above. In a particularly preferred embodiment of the present invention, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 or at least 15 of said unit dosage forms, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In one embodiment of the present invention, the pharmaceutical kit comprises only unit dosage forms as defined herein, containing obiscetrapib as the sole active ingredient. In one embodiment of the invention, the pharmaceutical kit simply comprises a plurality of unit dosage forms as defined herein containing obistrapib as the sole active ingredient, generally in dosages as described elsewhere herein, and a plurality, preferably an equal number, of unit dosage forms containing an HMG CoA reductase inhibitor, preferably atorvastatin or rosuvastatin, as the sole active ingredient. In one embodiment of the invention, the pharmaceutical kit simply comprises a plurality of unit dosage forms as defined, each unit dosage form containing obistrapib and an HMG CoA reductase inhibitor.

[0065] In accordance with the present invention, the pharmaceutical kit comprises a leaflet to be inserted into the container, typically a patient information leaflet containing printed information, which may include a description of the form and composition of the unit dosage forms contained in the kit, indications for the therapeutic indications for which the product is intended, instructions on how to use the product, information and warnings regarding adverse effects and contraindications associated with use. Based on the information provided herein, it will be understood by the skilled artisan that the leaflet that is part of the kit according to the present invention will typically contain information regarding the therapeutic indications, uses, treatment regimens, etc., as described above with respect to the treatment method of the present invention. In a particularly preferred embodiment of the present invention, the leaflet comprises printed instructions for repeated (self-)administration of the unit dosage form for treating and / or preventing CVD, particularly ASCVD, with combined obiscetrapib and HIS therapy in case of insufficient response to said HIS therapy alone.

[0066] others It is to be understood that many or most of the pharmacologically and / or physiologically active ingredients contained in the compositions defined herein may be present in the form of a pharma- ceutically acceptable salt or solvate, and such forms will typically be equally suitable for use in the present invention.

[0067] Unless otherwise defined, all terms used in the disclosure of the present invention, including technical and scientific terms, have the meanings commonly understood by one of ordinary skill in the art to which the present invention belongs. By way of further guidance, definitions of terms are included to better understand the teachings of the present invention.

[0068] As used herein, "a," "an," and "the" refer to both the singular and the plural, unless the context clearly dictates otherwise. By way of example, "a section" means one or more sections.

[0069] As used herein, "about" referring to a measurable value such as a parameter, amount, duration, and the like, is meant to encompass a variation of no more than + / - 10% from the specified value, more preferably no more than + / - 5%, and even more preferably no more than + / - 1%, so long as such variation is appropriate for the practice of the disclosed invention. However, it is to be understood that the value referred to by the modifier "about" is itself specifically disclosed.

[0070] As used herein, "comprise," "including," "comprises," and "composed of" are synonymous with "include," "comprising," "includes," or "contain," "containing," "contains," and are inclusive or open-ended terms specifying the presence of, for example, components, and do not exclude or preclude the presence of additional, unrecited components, features, elements, members, steps that are known in the art or disclosed therein.

[0071] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints.Those of skill in the art will appreciate that the present invention may incorporate many of the specific features described above. [Brief description of the drawings]

[0072] [Figure 1] Patient flow chart. 1 AE was moderate arthralgia. Subjects were excluded from the PP population due to missing low-density lipoprotein cholesterol (LDL-C) assessment at week 28 (n=1 each in the placebo and obicetrapib 5 mg groups) or because LDL-C assessment at week 8 (n=1 in the obicetrapib 10 mg group) was performed >5 days after obicetrapib administration. Abbreviations: AE, adverse event; ITT, intention to treat; mITT, modified intention to treat; PK, pharmacokinetics; PP, protocol adherence. [Figure 2a] Median lipoprotein lipid concentrations. LDL-C concentrations measured by the Friedewald formula, apoB (Fig. 2b) and HDL-C (Fig. 2c) for placebo (●), obiscetrapib 5 mg (■) and obiscetrapib 10 mg (▲) groups (n=40 each) administered on a background of high-intensity statins at baseline, and after 4 and 8 weeks of treatment (for Lp(a) only after 8 weeks of treatment). Abbreviations: Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. [Figure 2b] Median lipoprotein lipid concentrations. LDL-C concentrations measured by the Friedewald formula, apoB (Fig. 2b) and HDL-C (Fig. 2c) for placebo (●), obiscetrapib 5 mg (■) and obiscetrapib 10 mg (▲) groups (n=40 each) administered on a background of high-intensity statins at baseline, and after 4 and 8 weeks of treatment (for Lp(a) only after 8 weeks of treatment). Abbreviations: Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. [Figure 2c]Median lipoprotein lipid concentrations. LDL-C concentrations measured by the Friedewald formula, apoB (Fig. 2b) and HDL-C (Fig. 2c) for placebo (●), obiscetrapib 5 mg (■) and obiscetrapib 10 mg (▲) groups (n=40 each) administered on a background of high-intensity statins at baseline, and after 4 and 8 weeks of treatment (for Lp(a) only after 8 weeks of treatment). Abbreviations: Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] Example 1: A placebo-controlled, double-blind, randomized, phase 2 study of obiscetrapib as an adjunct to HIS therapy A placebo-controlled, double-blind, randomized, phase 2 study was conducted to evaluate the efficacy, safety, and tolerability of obiscetrapib as an adjunct to intensive statin therapy.

[0074] High LDL-C is the major modifiable risk factor for developing CVD. Lowering LDL-C has been shown to reduce the risk of CV events, with risk reduction linearly proportional to absolute LDL-C reduction. LDL-C reduction is the primary therapeutic lipid target in ASCVD and HeFH patients. Published patient-level meta-analyses have found that each 1 mmol / L reduction in LDL-C is associated with a 22% reduction in the 5-year incidence of major CV events. Strong versus moderate reductions in LDL-C reductions confer greater benefit to patients at high CV risk.

[0075] Statins are generally the first-choice drugs in the treatment of dyslipidemia. Statins are considered the most potent, most effective and best tolerated drugs for reducing LDL-C levels. However, two-thirds of patients do not reach acceptable levels of LDL-C with statins alone, even with high-intensity statin therapy (HIS). Therefore, when used adjunctively to high-intensity statin therapy, long-term therapy is needed to ensure high LDL-C levels are reduced.

[0076] Obicetrapib is a selective CETP inhibitor undergoing clinical development to reduce both LDL-C and major cardiovascular event rates. CETP Inhibition with Obicetrapib in Patients with Mild Lipid Metabolism (TULIP), a 364-subject study conducted in Denmark and the Netherlands, found that a daily dose of 10 mg of Obicetrapib in combination with a moderate-intensity statin (atorvastatin 20 mg or rosuvastatin 10 mg) for 12 weeks resulted in up to 50% incremental LDL-C reduction compared to statin monotherapy.

[0077] In contrast to the results seen in TULIP, results from Mendelian randomization analyses suggested that combined exposure to variants in genes encoding targets of CETP inhibitors and statins was associated with a retrograde reduction in LDL-C and apoB levels, and that the corresponding risk reduction was proportional to apoB but less proportional to LDL-C. Thus, there was concern that the potential clinical benefit of obi-cetrapib might be weakened, especially when used in conjunction with intensive statins. Another concern relates to the fact that some data suggest that LDL-C reduction with CETP inhibitors cannot be reliably assessed by the Friedewald formula, but instead requires preparative ultracentrifugation.

[0078] Therefore, this study was set up to test the efficacy of 8 weeks of obicetrapib 5 mg and 10 mg compared to placebo as an adjunct to high-intensity statin therapy to reduce LDL-C and apoB in subjects with an inadequate response to HIS therapy. The study consisted of three arms: 1) obicetrapib 5 mg as adjunct therapy; 2) obicetrapib 10 mg as adjunct therapy, and 3) a placebo arm. Secondary goals were to evaluate other lipoprotein lipid and apolipoprotein responses, safety and tolerability profile, and plasma concentrations of obicetrapib during weeks of treatment and follow-up. Finally, the study aimed to determine whether different quantitative measurements of LDL-C levels would result in differences in the therapeutic effect of CETP inhibition.

[0079] Study Participants This randomized, double-blind, placebo-controlled, parallel-group, phase 2 study was conducted in male and female patients (ages 18-75 years) treated with high-intensity statin therapy and with DL-C levels >70 mg / dL and TG levels <400 mg / dL. Major exclusion criteria were patients with BMI >40 kg / m; significant cardiovascular disease; HbA1c >10%; uncontrolled hypertension; active myopathy; GFR <60 ml / min; hepatic insufficiency; anemia; history of malignant disease; alcoholism; treatment with an investigational product; treatment with a PCSK9 inhibitor; clinically significant symptoms; and / or previous exposure to a CETP inhibitor. Patients were recruited at 19 sites in the United States. The study was approved by the Independent Ethics Committees, and each patient provided written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, and the protocol was registered at ClinicalTrials.gov (NCT04753606).

[0080] Study design The screening period for this study lasted up to 2 weeks. Patients were then randomized to placebo, obiscetrapib 5 mg, or obiscetrapib 10 mg for an 8-week treatment period. After the treatment period, patients continued with a 4-week safety follow-up and a 15-week PK follow-up.

[0081] Patients were randomly assigned to receive one of three treatment study treatments. All treatments were taken once daily with a meal for 8 weeks. Safety was assessed throughout the study by monitoring adverse events and use of concomitant medications, 12-lead electrocardiograms (ECGs), vital signs, laboratory safety assessments, and physical examinations. Other assessments included salivary cortisol, plasma aldosterone, high-sensitivity C-reactive protein (hsCRP), and endothelin-1.

[0082] Efficacy assessments included fasting lipid profile such as total cholesterol (TC), HDL-C, LDL-C, triglycerides, apolipoprotein B (apoB) and derived parameters.

[0083] The safety and tolerability profile of obiscetrapib will be assessed by clinical laboratory values ​​and the incidence of adverse events (AEs).

[0084] Analysis method Total cholesterol and triglycerides were measured by homogeneous enzymatic assays using the modular analyzer (cholesterol oxidase peroxidase-peroxidase aminophenazone phenol [CHOP-PAP]) and glycerol phosphate oxidase [GPO-PAP] methods, respectively. Apolipoprotein B was measured by immunoturbidimetry using commercially available reagents from Rolf Greiner Biochemica (Germany) and N-apoprotein standard serum from Siemens (Germany). LDL particle size was determined by gradient gel electrophoresis. HDL fractions were separated (β quantification) using a combined ultracentrifugation-sedimentation method. HDL-2 and HDL-3 fractions were then separated by further ultracentrifugation. Total cholesterol in the HDL, HDL2 and HDL-3 fractions, free cholesterol in the HDL fraction, triglycerides in the HDL fraction and phospholipids in plasma and HDL fractions were measured using enzymatic methods and commercially available reagents from Diasys Diagnostics (Germany). Measurements were performed on an Olympus AU600 automated analyzer and calibrated with secondary standards from Roche Diagnostics (total cholesterol, triglycerides) and Diasys Diagnostics (free cholesterol, phospholipids), respectively.

[0085] statistical analysis The primary endpoint measure was LDL-C (percent change). Secondary endpoint measures included apoB, non-HDL-C, and HDL-C (percent change). The intention to treat (ITT) population included all participants randomized into the study. The modified ITT (mITT) population included all participants in the ITT population who received at least one dose of any study drug and had a baseline value for LDL-C assessment. The safety population included all participants receiving at least one dose of any study drug. The mITT population was the primary population for efficacy analyses. The primary efficacy analysis of percent change in LDL-C was performed using a mixed model for repeated measures (MMRM) approach. Secondary efficacy endpoints were tested sequentially according to a prespecified hierarchical order at a significance level of 0.05 to maintain an overall type I error rate. All safety endpoints were summarized descriptively. No statistical inference was applied to the safety endpoints. Plasma obicetrapib concentrations were summarized with descriptive statistics based on the PK population.

[0086] result Topline results of the clinical trials are summarized below in Tables 1-8. Tables 9 and 10 and Figures 1 and 2 provide other specific details.

[0087] [Table 1]

[0088] [Table 2]

[0089] [Table 3]

[0090] [Table 4]

[0091] [Table 5]

[0092] [Table 6]

[0093] [Table 7]

[0094] [Table 8]

[0095] Of the 120 randomized subjects, 119 (99.2%) completed treatment; the modified intention to treat (mITT) population included all 120 subjects (Figure 1). Subjects were mean age 61.8 years, 55.8% male, 76.7% white, and had a mean body mass index (BMI) of 31.1 kg / m2. 2 All patients were treated with high-intensity statins. The majority received atorvastatin 40 mg (54.2%), whereas 24.2%, 8.3%, and 13.3% of subjects received atorvastatin 80 mg, rosuvastatin 20 mg, and rosuvastatin 40 mg, respectively.

[0096] LDL-C, apoB and HDL-C concentrations at baseline and after 4 and 8 weeks of treatment are shown in Figure 2, and lipoprotein, lipid, apolipoprotein and lipoprotein(a) [Lp(a)] concentrations at baseline and percentage change from baseline to end of treatment are shown in Table 9. Obicetrapib 5 mg and 10 mg each significantly reduced LDL-C compared to placebo (p<0.0001). In the primary analysis, where LDL-C was calculated using the Friedewald formula, LDL-C was reduced by 42.9% and 45.7% from baseline for obistrapib 5 mg and 10 mg, respectively, compared to 0.0% for placebo. Results for LDL-C measured by preparative ultracentrifugation (also called β-quantification), performed to assess possible discrepant results using this "gold standard" method of determining LDL-C, were comparable to those from the Friedewald formula: -41.5% and -50.8% for 5 mg and 10 mg obiscetrapib, respectively, compared with -6.50% for placebo. Furthermore, we calculated LDL-C reductions for doses of 5 mg and 10 mg obiscetrapib using the recently published Martin-Hopkins formula instead of the Friedewald formula,18 which were again comparable to the results from β-quantification; 42.5% and -49.2%, respectively. Other sensitivity analyses, including mixed model repeated measures (MMRM) with imputation and analysis of covariance (ANCOVA), yielded similar results to the analysis of the per-protocol (PP) population (n=117).

[0097] Obicettrapib 5 mg and 10 mg also significantly reduced apoB by 24.4% and 29.8%, non-HDL-C by 38.9% and 44.4%, and Lp(a) by 33.8% and 56.5%, respectively, compared to placebo (p<0.0001), and significantly increased HDL-C by 135% and 165%, and apoA1 by 44.6% and 47.8%, respectively (p<0.0001). Both TG and VLDL-C (measured by preparative ultracentrifugation) were modestly but significantly reduced by obistrapib 5 mg compared to placebo (-11.0% and -11.5%, respectively) (p<0.05), but there were no significant differences between placebo and obistrapib 10 mg (Table 9). Post-hoc analysis showed that in individuals with baseline apoB >100 mg / dL, bicetrapib 10 mg resulted in a median apoB reduction of 39% from baseline.

[0098] [Table 9]

[0099] [Table 10]

[0100] [Table 11]

[0101] Treatment-emergent adverse events were reported by a total of 42 (35.0%) of 120 subjects in the safety population: 15 (37.5%) and 8 (20.0%) subjects in the obiscetrapib 5 mg and 10 mg groups, respectively, compared with 19 (47.5%) subjects in the placebo group. Adverse events reported by at least two subjects in the treatment groups are shown in Table 10. The most common adverse events were gastrointestinal disorders (mainly nausea) and nervous system disorders (mainly headache). The majority of events were classified as mild or moderate in severity; one subject (2.5%) in the placebo group had a severe adverse event (Covid-19 pneumonia). Six events reported by 4 subjects (10.0%) in the placebo group, 2 events reported by 2 subjects (5.0%) in the obicetrapib 5 mg group, and 1 event reported by 1 subject (2.5%) in the obicetrapib 10 mg group were considered to be study drug related. Two subjects (5.0%) in the placebo group had serious adverse events (one had Covid-19 pneumonia [above] and the other had a transient ischemic attack). None were considered to be study drug related. One subject (2.5%) in the placebo group had moderate arthralgia that caused him to discontinue study drug, but was not considered to be study drug related. There were no signals in any laboratory parameters, i.e., no clinically significant shifts in chemistry, hematology, or urinalysis parameters in the obicetrapib-treated group compared to placebo, and no changes in vital signs.

[0102] [Table 12]

[0103] Post-treatment PK assessments showed nearly complete clearance of the drug from the circulation 4 to 8 weeks after treatment. Plasma obiscetrapib levels were reduced by 92%, 98%, and 99% (median) at 4, 8, and 15 weeks after the end of treatment in the obiscetrapib 5 mg group and by 93%, 98%, and 99%, respectively, in the obiscetrapib 10 mg group.

[0104] Consideration In this study of subjects with dyslipidemia (LDL-C>70 mg / dL) receiving high-intensity statin therapy (atorvastatin 40 mg or 80 mg or rosuvastatin 20 mg or 40 mg), 8 weeks of add-on treatment with obiscetrapib 5 mg and 10 mg significantly reduced LDL-C, apoB, non-HDL-C and Lp(a) and significantly increased HDL-C and apoA1. Maximum LDL-C reduction was already present after 4 weeks of treatment. In the TULIP study, patients with mild dyslipidemia who received obiscetrapib 1, 2.5, 5 or 10 mg for 12 weeks had LDL-C reductions of 27%, 33%, 45% and 45%, respectively, and patients who received obiscetrapib 10 mg + atorvastatin 20 mg or + rosuvastatin 10 mg had LDL-C reductions of 68% and 63%, respectively. However, the study design made it impossible to calculate the additional LDL-C reduction that could be achieved with a given dose of obiscetrapib in addition to a statin, and did not examine the combination of obiscetrapib with a high-intensity statin. Thus, the present results go beyond previous findings of obiscetrapib administered as monotherapy and in conjunction with a medium-intensity statin, demonstrating its lipid-altering efficacy at both the 5 mg and 10 mg doses in combination with a high-intensity statin.

[0105] Evidence from randomized clinical trials of lipid-modifying therapy and Mendelian randomization studies indicates a causal relationship between LDL-C reduction and reduced ASCVD risk. Further Mendelian randomization analysis further explored the relationship between lipoprotein changes associated with variants in the CETP gene alone and in conjunction with variants in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) gene and the risk of major cardiovascular events. This analysis demonstrated that when evaluated alone, CETP score is associated with higher HDL-C and lower LDL-C, correspondingly lower apoB and correspondingly lower risk of major cardiovascular events, and the relationship between HMGCR score and the risk of major cardiovascular events per unit of LDL-C (and apoB) change is approximately the same magnitude. However, when CETP score and HMGCR score are combined, CETP score is associated with the same LDL-C reduction, but with attenuated apoB response and corresponding attenuated non-significant cardiovascular risk. These results suggest that combined exposure to gene variants that reduce both CETP and HMG CoA reductase is associated with discordant LDL-C and apoB reductions, and that the risk reduction of cardiovascular events is proportional to the effect on apoB and less so for LDL-C. The results of this study are inconsistent with the hypothesis that the combination of moderate- and high-intensity statins with obiscetrapib could significantly attenuate apoB reduction.

[0106] conclusion As can be seen from the data presented, obiscetrapib 5 mg and 10 mg added to intensive statin therapy was well tolerated and had a safety profile similar to placebo.Obicetrapib 5 mg and 10 mg added to intensive statin therapy reduced median LDL-C levels to -41.5% and -50.8% from baseline at PUC, respectively.

[0107] This study demonstrates the efficacy of obiscetrapib 5 mg and 10 mg as an adjunct to high-intensity statins in robustly reducing LDL-C, apoB, non-HDL-C, and Lp(a) and increasing HDL-C and apoA1 compared to placebo, thus disproving the theory that such inhibitor-induced effects are attenuated when used in conjunction with high-intensity statins. Given the unmet medical need for additional therapies that substantially reduce LDL-C in patients at high cardiovascular risk, the results from ROSE are encouraging.

[0108] Obicetrapib is a valuable addition to high-risk ASCVD patients who do not reach their target LDL-C guideline goals despite the use of high-intensity dose statin therapy. In particular, obiscetrapib is a valuable addition to ASCVD patients who are poorly responsive to HIS therapy.

Claims

1. A pharmaceutical composition for use in a prophylactic and / or therapeutic treatment method for a subject suffering from or at risk of suffering from cardiovascular disease (CVD), the pharmaceutical composition comprising obicetrapib, a compound having the structural formula: 【Chemical 1】 or a pharmaceutically acceptable salt, hydrate or solvate of obicetrapib, wherein the subject is a low responder to high-intensity statin (HIS) therapy, wherein low responsiveness to HIS therapy means that a subject receiving HIS therapy does not achieve a 35% LDL-C reduction established at least one month after the start of HIS therapy, wherein high-intensity statin therapy refers to a statin regimen selected from the group consisting of rosuvastatin at 20 mg per day; rosuvastatin at 40 mg per day; atorvastatin at 40 mg per day; and atorvastatin at 80 mg per day, and wherein the method further comprises an accompanying statin therapy.

2. The pharmaceutical composition for use according to claim 1, wherein the subject is a subject who has received HIS therapy and has not achieved a 35% LDL-C reduction.

3. The pharmaceutical composition for use according to claim 1, wherein the method comprises oral administration of obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The pharmaceutical composition for use according to claim 1, wherein the method comprises oral administration of obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof at a dose of 4 to 25 mg, or oral administration of a salt, solvate or hydrate of obicetrapib at an equipotent dose.

5. The pharmaceutical composition for use according to claim 1, wherein the method comprises oral administration of obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof at a dose of 5 mg, or oral administration of a salt, solvate or hydrate of obicetrapib at an equipotent dose.

6. The pharmaceutical composition for use according to claim 1, wherein the method comprises oral administration of obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof at a dose of 10 mg, or oral administration of a salt, solvate or hydrate of obicetrapib at an equipotent dose.

7. The pharmaceutical composition for use according to claim 1, wherein the method comprises once-daily administration of obicetrapib or a salt, solvate or hydrate thereof.

8. The pharmaceutical composition for use according to claim 1, wherein the method comprises administration of atorvastatin at a daily dose within the range of 70 to 90 mg.

9. The pharmaceutical composition for use according to claim 1, wherein the method comprises administration of rosuvastatin at a daily dose in the range of 30 to 50 mg.

10. The pharmaceutical composition for use according to claim 1, wherein the subject has a plasma level of LDL-C elevated by at least 70 mg / dL at least 3 months after continuous HIS therapy.

11. The pharmaceutical composition for use according to claim 1, wherein the method is effective to and / or is intended to reduce the LDL-C plasma level by at least 25 mg / dL from baseline, which is defined as the start of treatment with obicetrapib as an add-on to HIS therapy.

12. The pharmaceutical composition for use according to claim 1, wherein the subject to be treated has a plasma level of apo B elevated by at least 70 mg / dL at least 3 months after continuous HIS therapy.

13. The pharmaceutical composition for use according to claim 1, wherein the method is effective to and / or is intended to reduce the apo B plasma level by at least 25 mg / dL from baseline, which is defined as the start of treatment with obicetrapib as an add-on to HIS therapy.

14. The pharmaceutical composition for use according to claim 1, wherein the method comprises repeated administration of the composition containing obicetrapib or a salt, hydrate or solvate thereof for a period of at least 6 months.

15. The pharmaceutical composition for use according to claim 1, wherein the subject is a subject suffering from diabetes, hypertension, hypercholesterolemia, overweight / obesity and / or metabolic syndrome.

16. The pharmaceutical composition for use according to claim 1, wherein the subject is a subject suffering from or at risk of suffering from atherosclerotic cardiovascular disease (ASCVD).

17. Use of obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for use in a method for prophylactic and / or therapeutic treatment of a subject suffering from or at risk of suffering from cardiovascular disease (CVD), wherein the subject is a low responder to high-intensity statin (HIS) therapy, wherein the method further comprises an accompanying statin therapy, Low responsiveness to HIS therapy means that subjects undergoing HIS therapy do not achieve a 35% LDL-C reduction, High-intensity statin therapy is used to denote a statin regimen that exhibits a ≥50% LDL-C reduction in subjects who respond normally.

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