Alpoxivan for treatment of hypertension

Abstract

The present invention relates to the compound alpoxivan, {5-(4-bromophenyl)-6 [2 (5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide: # imgabs0 # and their use as an endothelin receptor antagonist in a method of treating hypertension, including refractory hypertension, in a subject in need thereof, the method comprises administering to the subject a pharmaceutical composition comprising a clinically proved effective amount of alpoxivan or a pharmaceutically acceptable salt thereof.

Description

[0001] The present invention relates to a compound aprocitentan and its verified clinical effect as an endothelin receptor antagonist for treating hypertension (including uncontrollable hypertension and refractory hypertension).

[0002] Aprecitentan, {5-(4-bromophenyl)-6-[2-(5-bromo-pyrimidin-2-oxy)-ethoxy]-pyrimidin-4-yl}-sulfamide (hereinafter also referred to as "the compound"), has the formula I The compound of formula I, also known as ACT-132577, is an endothelin receptor antagonist. The compound of formula I is a member of the structural family previously disclosed in WO02 / 053557. In particular, compared with the corresponding alkylated derivatives, the compound of formula I exhibits endothelin receptor antagonist activity while exhibiting a longer half-life and a shorter clearance rate in vivo. This makes the compound of formula I particularly suitable for the long-acting pharmaceutical composition disclosed in WO2009 / 024906.

[0003] Due to their ability to inhibit endothelin binding, compounds of formula I are useful for treating endothelin-related diseases that are associated with increased endothelin-induced vasoconstriction, proliferation or inflammation that occurs in many cardiorenal metabolic diseases. Examples of such endothelin-related diseases include hypertension, particularly difficult-to-control hypertension and refractory hypertension. Further examples of endothelin-related diseases disclosed, for example, in WO2009 / 024906, WO2018 / 153513 or WO2018 / 154101 include pulmonary hypertension, coronary heart disease, heart failure, renal and myocardial ischemia; chronic kidney disease (CKD) [especially CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (especially stage 3 or 4 CKD), especially CKD caused by / associated with hypertension or diabetes (diabetic nephropathy (DKD), including DKD that is also associated with hypertension) (especially CKD at these stages); diabetes and diabetes-related diseases such as diabetic arterial disease, diabetic nephropathy, diabetic retinopathy or diabetic vasculopathy; reducing the risk of major cardiovascular events (such as heart failure (HF), myocardial infarction, stroke or death from cardiovascular causes) in diabetic patients, especially those with at least one other cardiovascular risk factor (such as hypertension diabetic patients with diabetes (including those with idiopathic, dyslipidemia, thrombotic phenomena); treatment and prevention of diabetic complications; renal failure (acute and chronic); glomerulonephritis; connective tissue disease; atherosclerosis; peripheral arterial disease, including chronic peripheral (occlusive) arterial disease; fingertip ulcers; diabetic foot ulcers and / or reducing the risk of lower limb / limb amputation in patients with diabetes, smokers or patients with atherosclerosis; heart failure (HF), defined as specifically including chronic HF, especially including systolic HF / HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction less than about 40%), and diastolic HF / HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%); reducing the risk of major cardiovascular events (such as heart failure (HF), myocardial infarction, stroke or death from cardiovascular causes) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with clinical manifestations of congestive heart failure); angina pectoris; and diastolic dysfunction. The compounds of formula I may also be used to treat or prevent cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, portal hypertension, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, eclampsia, hearing loss, Alzheimer's disease, chronic bronchitis, asthma, pulmonary fibrosis, Gram-negative sepsis, shock, sickle cell anemia, renal colic, glaucoma, complications after vascular or cardiac surgery or organ transplantation, complications of cyclosporine therapy or equivalent therapies that exhibit nephrotoxicity, pain, dyslipidemia, and other diseases currently known to be associated with endothelin.

[0004] According to the 2014 joint statement of the American Society of Hypertension and the International Society of Hypertension [Weber et al., "Clinical Practice Guidelines for the Management of Hypertension in the Community. A Statement by the American Society of Hypertension and the International Society of Hypertension." J Clin Hypertens (2014), 16(1), 14-26], the 2013 joint guidelines of the European Society of Hypertension and the European Society of Cardiology [Mancia et al., J. Hypertens. (2013), 31, 1281-1357], and several national guidelines [Denolle et al., J Hum Hypertens. (2016), 30(11), 657-663; McCormack et al., Br J Cardiol (2013), 20(suppl 1), S1–S16], resistant hypertension (rHT) is defined as uncontrolled blood pressure (BP) (i.e., failure to reduce BP to a predetermined threshold) despite concurrent use of three antihypertensive therapies from different pharmacological classes (including diuretics). Therefore, patients with resistant hypertension include patients whose blood pressure is controlled with more than three drugs. That is, patients whose blood pressure is controlled but require four or more drugs to control should be considered to be resistant to treatment (see, e.g., Mancia et al., J. Hypertens. (2013)).

[0005] Clinical studies have shown that endothelin receptor antagonists (ERAs) have significant therapeutic effects on patients with hypertension and / or kidney disease (regardless of whether they have diabetes or not). Endothelin 1 (ET-1) may play a role in the pathogenesis of chronic diabetic arterial disease because it mediates plaque formation, thrombosis, vasoconstriction and vascular hypertrophy, and because it can enhance the effects of other systems, especially renin angiotensin and the sympathetic nervous system and / or insulin signaling. Therefore, ERA can treat peripheral arterial obstructive diseases, including diabetic arterial disease, through acute (peripheral vasodilation) and chronic (vasodilation, improvement of vascular structure, regulation of sympathetic nerve activity, anti-thrombosis, anti-inflammatory) effects. In a clinical network meta-analysis of adult patients with diabetes and chronic kidney disease (157 studies, including 43,256 patients), ERA was listed as the most effective drug for preventing end-stage renal disease (SCPalmer et al., Lancet (2015), 385(9982): 2047-2056). However, the therapeutic benefits need to be weighed against potential side effects, such as the potential teratogenicity associated with ERA. Furthermore, and more importantly, selective ET A Antagonists and ET A With E.T. B Both dual antagonists of the ERA receptor can cause fluid retention, a common side effect of many previously studied ERAs and can sometimes (for example, if diuretics are uncontrolled) lead to serious adverse cardiac events such as heart failure or death. Although in most cases the risk-benefit balance of ERAs in conditions such as pulmonary hypertension favors treatment with ERAs (as in the past with the dual ERA antagonists bosentan and macitentan and ET A However, some people point out that ERA does not play a role in the treatment of essential hypertension (Laffin et al. Seminars in Nephrology 2015, 35, 168-175). When considering the use of potential ERAs to treat difficult-to-control hypertension and resistant hypertension (rHT) or other hypertension-related diseases, side effects such as fluid retention may still be a problem.

[0006] Currently developing ET ADarusentan, a selective endothelin receptor antagonist, is used to treat resistant hypertension (rHT) (Bakris et al., Hypertension 2010, 56, 824-830, see also WO2007 / 098390). In a 14-week phase 3 trial in patients with rHT, the drug showed efficacy in reducing ambulatory blood pressure, but failed to show a significant therapeutic effect in the primary endpoint of systolic blood pressure. Patients were eligible to participate in the trial if they had resistant hypertension (systolic blood pressure above 140 mmHg) despite being treated with three or more antihypertensive drugs from different classes (including one diuretic) at optimal doses. The minimum dose of hydrochlorothiazide was 25 mg per day (or the equivalent dose of other thiazide diuretics). Although during the trial, the investigators could intensify the trial diuretic therapy at their discretion to control fluid retention, the most common adverse event associated with darusentan was fluid retention / edema, which was 28% and 12% in the other groups. More patients withdrew from treatment due to adverse events with darusentan than with placebo.

[0007] ET A Avosentan, a selective ERA, showed a significant treatment effect in a trial investigating the effect of avosentan on the progression of overt diabetic nephropathy in patients with type 2 diabetes, but at the same time, the number of discontinuations of the trial drug due to adverse events (primarily related to fluid overload and congestive heart failure) was significantly increased (Mann et al., "Avosentan for Overt Diabetic Nephropathy", J Am Soc Nephrol. 2010, 21(3): 527–535.). The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in the albumin-creatinine ratio (ACR) and cardiovascular outcomes. The study did not detect differences in the frequency of the primary outcome between the groups. Avosentan significantly reduced the ACR. The trial was terminated early after a median follow-up of 4 months (maximum 16 months) because avosentan caused too many cardiovascular events, and the authors concluded: "It is possible that the 25 to 50 mg dose of avosentan has a negative effect on ET. A The receptors are less selective, thus leading to sodium and water retention and peripheral vasodilation causing fluid shifts from the intravascular to the extravascular space." The effect on albuminuria is thought to be due to inhibition of renal ET A Receptors, because mixed ET was previously found A / B The data suggest that selective ET antagonists may have little or no effect on proteinuria in people receiving ACE inhibitors. A The natriuretic effect of receptor blockers further supports the possibility that higher doses of avosentan can block ET BTherefore, the natriuretic effect / fluid retention that may ultimately lead to trial termination is attributed to ET A and E.T. B Dual blockade of the ER receptors is therefore discouraged from use in such clinical settings.

[0008] Further preclinical data showed that the synergistic effect of ETA-selective ERAs combined with the ACE inhibitor enalapril on blood pressure was abolished by simultaneous blockade of the ETB receptor (Goddard et al., J. Am. Soc. Nephrol. 2004, 15, 2601-2610), and therefore, the use of dual-acting ERAs is discouraged in clinical settings where ACE inhibitors may be required as background therapy.

[0009] In a review on "endothelin antagonists for the treatment of diabetic and non-diabetic chronic kidney disease" (Br J Clin Pharmacol (2012), 76:4, 573-579), DE Kohan et al. pointed out that "in general, the mainstream view is that ET is the first choice for the treatment of CDK A Receptor antagonists, not ET A / B Three years later, Kohan et al. concluded in a study published in Clin JAm Soc Nephrol (2015), 10:1568–1574: "The fluid-retaining effect of ERA is likely related to direct effects on tubular sodium transport, while the antiproteinuric effect of ERA is likely related to effects on blood vessels and / or glomeruli. Finally, it is foreseeable that the alleviation of proteinuria by ERA will itself be beneficial for renal fluid excretion; however, ERA may still promote fluid retention through its separate effects on tubular sodium and water reabsorption."

[0010] WO2016 / 073846 provides a comprehensive summary of ERAs tested for various indications, including diabetic and non-diabetic CDK and rHT. WO2016 / 073846 provides further examples, where it is shown that fluid retention may lead to increased side effects of the ERAs bosentan, tezosentan, ambrisentan and atrasentan. WO2016 / 073846 summarizes and proposes a method of using ERAs, especially using ET AA method for treating CKD with atrasentan, a selective ERA, which uses a predictor of fluid retention; the method includes: if a subject is administered an ERA, determining the risk of fluid retention; if the risk is at an acceptable level, administering the ERA to the subject. A detailed study protocol for a Phase III clinical study (SONAR) has been published (Heerspink et al, Diabetes Obes. Metab. 2018, 1-8), which evaluates the effect of the investigational compound atrasentan - on top of standard treatment - on the progression of renal disease in patients with stage 2 to 4 chronic kidney disease and type 2 diabetes. The protocol reflects the importance of dose optimization and simultaneous control of sodium retention / fluid retention in the study design, resulting in a study design that requires "selecting individuals who are at high risk for disease (prognostic enrichment) and who also show a good response to the study therapy (predictive enrichment)". However, on December 1, 2017, AbbVie announced a strategic decision to close the SONAR study. The news release stated, "Ongoing monitoring of the renal events observed in the study has identified significantly fewer endpoints than expected at this time, which is likely to impact the ability to test the hypotheses of the SONAR study. Therefore, AbbVie does not see reason to continue to enroll patients in the study. The decision to prematurely end the SONAR study is not related to any safety concerns."

[0011] Contrary to the conclusions drawn from the avosentan trials, preclinical and clinical data suggest that ET A The selective antagonists sitaxsentan and ambrisentan pose a greater risk of fluid retention than the dual ERAs bosentan and macitentan (Vercauteren et al., JPET 2017, 361, 322-333). The authors note that their results “suggest that in rats, in the presence of ET A In the absence of receptor antagonists, ET is stimulated without blocking B Receptors may be harmful, but ET A Functional antagonism of the receptors themselves is not harmful, and blocking both receptors is less likely to cause sodium and water retention than blocking a single receptor," and went on to speculate that "plasma volume expansion combined with increased vascular permeability may explain the use of ET A selective antagonists". The authors conclude: "The use of ET A Multiple clinical studies with selective antagonists have found that fluid retention is associated with increased mortality, whereas this has not been found with dual ERA. However, dual ERA can lead to significant fluid retention in conditions with pre-existing fluid retention or increased arginine vasopressin (AVP), such as chronic heart failure or chronic renal failure."

[0012] A phase 2 clinical trial showed that aprexitentan (an ERA that effectively dual-blocks endothelin receptors) can effectively control blood pressure in patients with essential hypertension (aprexitentan is administered as a monotherapy, i.e., without background antihypertensive treatment) (Actelion Pharmaceuticals Ltd, press release May 22, 2017; P. Verweij et al. 2020: https: / / www.ahajournals.org / doi / full / 10.1161 / HYPERTENSIONAHA.119.14504). The study evaluated the efficacy, safety, and tolerability of a once-daily oral regimen of aprexitentan at four dose levels (5, 10, 25, and 50 mg) to confirm the optimal dose for further study. In this study, 490 patients were randomly assigned to receive one of the following treatments: aprexitentan 5, 10, 25, 50 mg, placebo, or lisinopril 20 mg once daily. After 8 weeks of treatment, diastolic blood pressure decreased from baseline in a mean range of 6.3 to 12.0 mmHg (measured at trough with an unattended automated office blood pressure device) in the aprecistentan group in a statistically significant dose-dependent manner, compared with a reduction of 4.9 mmHg in the placebo group and 8.4 mmHg in the lisinopril group (in the per-protocol treated population of 410 patients). Systolic blood pressure decreased in a mean range of 10.3 to 18.5 mmHg in the aprecistentan group in a statistically significant dose-dependent manner, with reductions of 7.7 mmHg in the placebo group and 12.8 mmHg in the lisinopril group. These results were confirmed in all randomized patients (intention-to-treat principle) and in 24-hour ambulatory blood pressure monitoring. The safety population included 327 patients in the aprecistentan group, 82 patients in the placebo group, and 81 patients in the lisinopril group. In these patient populations, aprecistentan was well tolerated at all four doses. Discontinuation of study treatment due to adverse events ranged from 1.2% to 3.7% in the aprexitentan group, compared with 6.1% in the placebo group and 3.7% in the lisinopril group. The overall incidence of adverse events was similar to that in the placebo group. There were two cases of liver enzyme elevations greater than three times the upper limit of the normal range, one in the placebo group and one in the aprexitentan 5 mg group. Four cases of peripheral edema were observed, two each in the aprexitentan 25 mg group and the aprexitentan 50 mg group. Mean body weight was unchanged from baseline in the aprexitentan 5 mg and 10 mg groups, with an increase of 0.4 kg in the aprexitentan 25 mg and 50 mg groups, an increase of 0.3 kg in the placebo group, and a decrease of 0.3 kg in the lisinopril group.Hemoglobin concentrations (a measure of blood dilution) showed the expected dose-related decrease from baseline in the apremilast group (ranging from 1.3 g / L to 6.7 g / L), whereas they increased by 2.2 g / L and 0.1 g / L in the placebo and lisinopril groups, respectively (see also P. Gueneau de Mussy et al; Clin Pharm & Therapeutics 2020; doi:10.1002 / cpt.2043).

[0013] Therefore, unlike the approach of WO2016 / 073846, when aprexitentan is used to treat hypertension-related conditions, particularly resistant hypertension, risk assessment and / or dose reduction to mitigate side effects associated with fluid retention may not be necessary. AAprexitentan may have different pharmacological properties compared with selective antagonists. Following the positive results of the Phase 2 clinical trial, aprocitentan has entered a Phase 3 clinical trial (NCT03541174): “a study designed to show the effectiveness of aprocitentan in treating difficult-to-control (refractory) high blood pressure (hypertension) and to further understand its safety” (see also Danaietash P et al; Identifying and treating resistant hypertension in PRECISION–a randomized long-term clinical trial with Aprocitentan. J Clin Hypertension 2022, 24(7):804-813; https: / / doi.org / 10.1111 / jch.14517; M. Clozel, Aprocitentan and the endothelin system in resistant hypertension; Can. J. Physiol. Pharmacol. 2022; https: / / doi.org / 10.1139 / cjpp-2022-0010; both documents are incorporated as references). On May 23, 2022, Idorsia Pharmaceuticals announced the results of the PRECISION trial in the media (https: / / www.idorsia.com / media / news-details?newsId=2758691). The results were subsequently published in a peer-reviewed journal on November 7, 2022 (Schlaich et al., Lancet 2022;400:1927–37 and related supplementary materials, both of which are incorporated herein by reference), and the publication was reported in a media press release (https: / / www.idorsia.com / media / news-details?newsId=2869821) and a webcast presentation on November 8, 2022.

[0014] In addition, in a rat hypertension model, it was found that aprexitentan may have a synergistic pharmacological effect when combined with angiotensin receptor blockers (ARBs) (such as valsartan), angiotensin converting enzyme (ACE) inhibitors (such as enalapril) in some models, and may have an additive pharmacological effect when combined with calcium channel blockers (CCBs) (such as amlodipine) (F.Trensz et al.2019:https: / / doi.org / 10.1124 / jpet.118.253864). In particular, when aprexitentan is combined with three different pharmacological classes including valsartan, amlodipine and commercially available Aprexitentan may be superior to standard add-on therapy, such as spironolactone, when used in combination with antihypertensive therapy with a thiazide diuretic (i.e., a fixed-dose combination of valsartan / amlodipine / hydrochlorothiazide). In addition, the pharmacology of aprexitentan may differ from that of the ETs that have been primarily tested to date in resistant hypertension and other endothelin-related diseases. A Selective antagonists. Therefore, aprexitentan, as an ERA that effectively dual-blocks endothelin receptors, may be particularly suitable for the treatment of (refractory) hypertension when used in combination with standard background therapy (generally including antihypertensive therapy of one or more different pharmacological classes, especially including angiotensin receptor blockers (such as valsartan), calcium channel blockers (such as amlodipine), and / or diuretics, (especially thiazide diuretics (thiazide-like diuretics) (such as chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide or metolazone (WO2018 / 153513, WO2018 / 154101)). Compared with the use of such antihypertensive therapy alone, this combination therapy can achieve better blood pressure control while maintaining a benign side effect profile even at the optimal therapeutic dose of aprexitentan, without the need for risk assessment methods such as WO2016 / 073846 and / or dose reduction to alleviate side effects, such as side effects related to fluid retention.

[0015] Further standard background therapy, especially for those with a history of high blood pressure, includes beta-blockers (beta-adrenergic blockers, which block the effects of the hormone adrenaline (epinephrine). Beta-blockers make the heart beat slower and less forcefully, which lowers blood pressure, and help widen veins and arteries, improving blood flow.

[0016] Further standard background therapy, especially for the treatment of patients with a history of diabetes or diabetic nephropathy, or patients with established cardiovascular disease, includes SGLT-2 inhibitors such as atigliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, repagliflozin, sogliflozin, tabagliflozin or togliflozin, which block the reabsorption of glucose in the kidneys, increase glucose excretion, and reduce blood glucose concentrations. In addition to this well-characterized mode of action, SGLT-2 inhibitors can also lower blood pressure, reduce vascular stiffness, improve endothelial function, and have anti-inflammatory and anti-fibrotic properties similar to ERA (HJ Heerspink et al., Circulation (2016), 134(10): 752-772). This unique mechanism of action has led to the development and marketing approval of several SGLT-2 inhibitors, including canagliflozin, dapagliflozin and empagliflozin, all of which are indicated for improving glycemic control in adult patients with type 2 diabetes, and empagliflozin is also indicated for reducing the risk of cardiovascular death in such patients who already have cardiovascular disease. Sogliflozin is reportedly a dual SGLT-1 and SGLT-2 inhibitor that is currently undergoing clinical trials for type 1 diabetes.

[0017] Diabetes is often complicated by heart failure (HF) and may contribute to its development. SGLT-2 inhibitors (such as empagliflozin) may be suitable for the treatment of chronic HF, especially HFpEF, where treatment options are very limited. The EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes) randomized patients with type 2 diabetes at high cardiovascular risk to empagliflozin or standard care. Results showed improvements in cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for HF, and death from any cause. A post hoc study of patients with a baseline diagnosis of HF showed a significant reduction in the proportion of cardiovascular death, HF hospitalization, and hospitalization for any cause (D. H. Kim et al., "Pharmacologic Management for Heart Failure and Emerging Therapies" Curr Cardiol. Rep (2017) 19:94). The mode of action of SGLT-2 is to simultaneously inhibit the uptake of glucose and sodium by the proximal glomerular tubule, which is believed to lead to a reset of tubular-glomerular feedback, thereby causing glomerular hyperfiltration. The efficacy of SGLT-2 inhibitors is thought to decrease with decreasing plasma glucose levels or decreased glomerular filtration rate (GFR), and therefore, SGLT-2 inhibitors have a lower risk of hypoglycemia. Therefore, the properties of SGLT-2 inhibitors may open up a way to treat HF, including HFpEF, and even HF in non-diabetic patients (P.Martens et al., "Promise ofSGLT2Inhibitors in Heart Failure:Diabetes and Beyond", Curr Treat Options Cardio Med (2017) 19:23). Side effects associated with the pharmacological actions of SGLT-2 inhibitors may be volume depletion / intravascular volume contraction, which may lead to dehydration, hypovolemia, positive hypotension, or hypotension. Therefore, SGLT-2 inhibitors often cause an increase in hematocrit (Hct), which is a sign of increased hemoconcentration and blood viscosity, which may be the cause of vascular damage in peripheral vascular disease. In addition, data from large clinical trials suggest that SGLT2 inhibitors may induce acute kidney injury and renal impairment, especially in patients who are susceptible to acute kidney injury in the setting of hypovolemia, chronic renal insufficiency, congestive heart failure, and concurrent medications (diuretics, ACE inhibitors, ARBs, and NSAIDs). The pharmacological effects of SGLT-2 inhibitors on the kidney include increases in serum creatinine and decreases in eGFR.

[0018] The combination of aprecitentan and an SGLT-2 inhibitor may be of particular interest (WO2019 / 106066). Preliminary data from the PRECISION trial described above indicate that, given the small sample size available, the available data (a) confirm that aprecitentan treatment has a significant effect on blood pressure data points (the clinical endpoint of the study), both with standardized antihypertensive background therapy alone and in subjects receiving an SGLT-2 inhibitor as background therapy and the standardized antihypertensive background therapy; and (b) indicate that (i) the combination therapy has an improved antiproteinuric effect in CKD / DKD; and (ii) the decrease in hemoglobin values ​​from baseline to week 36 is smaller, indicating that the combination therapy has further potential clinical benefits.

[0019] Hypertension is one of the most common cardiovascular risk factors, and its incidence continues to rise. According to a recent study, more than 1 billion people worldwide suffer from hypertension, a number that has nearly doubled in the past 40 years. [Bin Zhou, et al. The Lancet; 2017; 389(10064): 37-55]. Although many hypertensive patients have been successfully treated with various existing antihypertensive therapies, 10-20% of the hypertensive population still maintains hypertension after receiving optimal doses of at least three different pharmacological classes of antihypertensive drugs (including diuretics). Hypertension guidelines [RM Carey, et al. Hypertension, 2018; 72, pp. e53-e90; Noubiap, JJ, et al., Heart 2019; 105: 98-105; Carey RM, et al. Hypertension. 2019; 73(2): 424-431] and the medical community classify these patients as suffering from refractory hypertension. Certain populations are at particularly high risk for developing resistant hypertension later in life, including patients with a high body mass index (BMI), African Americans, postmenopausal women, and patients with obstructive sleep apnea. [Coylewright, M., et al. Hypertension, 2008; 51, 952-9; Roberie, DR, et al. Curr Opin Cardiol, 2012; 27, 386-91; Khan, A., et al. Int J Hypertens, 2013; 193010-193010]. It is estimated that by 2025, approximately 10 million patients in the United States may be classified as having resistant hypertension, and a similar number in Europe. [Noubiap, JJ, et al., Heart 2019; 105: 98-105; Carey RM, et al. Hypertension. 2019; 73(2): 424-431; Lu Y, et al. Hypertension. 2022; 79(1): 207-217]. Uncontrolled hypertension can lead to a variety of adverse cardiovascular and renal consequences, including stroke, heart disease, and renal failure. These complications increase patient vulnerability and complexity of treatment. [Daugherty, SL, et al. Circulation. 2012; 125(13): 1635-42; Kumbhani, DJ, et al. Eur Heart J. 2013; 34(16): 1204-14; Muntner, P., et al. Hypertension. 2014; 64: 1012–1021].The current direction of hypertension management is to control BP earlier and lower within 24 hours (including nighttime and early morning). Nighttime blood pressure management is particularly important for preventing cardiovascular events, especially heart failure (K. Kario, Hypertension. 2018; 71: 997–1009). E. Dolan et al. found that after adjusting for daytime ambulatory blood pressure, the hazard ratio of nighttime ambulatory blood pressure remained significant. From these results, the author summarized two important clinical messages: ambulatory blood pressure measurement is superior to outpatient blood pressure measurement in predicting cardiovascular mortality, and nighttime blood pressure is the most powerful indicator for predicting results ((EDolan et al, Hypertension 2005, 46(1): 156-161).

[0020] According to K. Kario, Hypertension. 2018; 71: 997–1009, hereby incorporated by reference, for example, the circadian pattern of blood pressure can be assessed by ambulatory BP monitoring (ABPM). In healthy subjects, the nighttime BP decreases by 10% to 20% of the daytime BP (normal dipper pattern). This circadian rhythm of BP is determined in part by the intrinsic rhythms of central and peripheral clock genes that regulate neurohumoral factors and the cardiovascular system, and in part by sleep-wake behavior patterns. Hypertensive patients without organ damage also show a dipper pattern; however, hypertensive patients with organ damage tend to show a non-dipper pattern with a reduced amplitude of the nighttime BP decrease (even showing an ascending pattern in which the nighttime BP is higher than the daytime BP). The nighttime BP decrease pattern can be divided into four categories: ascending, non-dipper, dipper, and super-dipper patterns. The definition of these groups is based on the nocturnal BP drop. Kario pointed out that nocturnal hypertension and a non-dipping / rising pattern of nighttime BP predispose to psychocognitive dysfunction (cognitive dysfunction, apathy, falls and sedentary lifestyle, and stroke), hypertensive heart disease (left ventricular hypertrophy, decreased diastolic function), vascular damage (increased carotid intima-media thickness, pulse wave velocity, and cardio-ankle vascular index), and chronic kidney disease (CKD, decreased glomerular filtration rate and urinary albumin / creatinine excretion).

[0021] Burnier and Damianaki noted that in CDK patients, a descending or reverse dipping pattern or masked and resistant hypertension is common and is associated with adverse cardiovascular and renal outcomes. Current antihypertensive medications have been augmented by newer agents that reduce existing renal and cardiovascular risks, such as SGLT-2 inhibitors and newer nonsteroidal mineralocorticoid receptor antagonists. (Burnier and Damianaki; Circulation Research. 2023;132:1050–1063, incorporated herein by reference). The authors concluded, "Hypertension is a major cardiovascular risk factor in the general population and even more so in CDK patients, who also accumulate several other risk factors, including decreased renal function. CDK patients are characterized by several specific BP profiles and hypertension phenotypes that require accurate diagnosis to avoid misdiagnosis. For this reason, out-of-office BP measurement, including nighttime BP, is now strongly recommended and should be used more widely to verify that daytime and nighttime BP is controlled. Today, a high proportion of CDK patients have poor BP control, mainly because of elevated nighttime BP."

[0022] Therefore, as an ERA that can effectively double block endothelin receptors, aprexitentan may be particularly suitable for the long-term treatment of (chronic) hypertension, especially (chronic) refractory hypertension, which is clinically proven to be effective and safe, wherein it is understood that the treatment of refractory hypertension usually includes combining with standard background therapy; for example, regulators of the renin-angiotensin system, such as in particular ARBs or ACE inhibitors, CCBs, diuretics, and / or beta-blockers. It is further understood that the patient population diagnosed with such difficult-to-control or refractory hypertension is a frail patient population, who usually have one or more comorbidities, in particular including diabetes, ischemic heart disease, stroke, congestive heart failure and / or sleep apnea syndrome. In addition, another comorbidity (related or unrelated to the above comorbidities) may be CDK (such as CDK, or CDK associated with diabetes (DKD)). Therefore, (additional) background therapy, such as in particular SGLT-2 inhibitors, in combination with antihypertensive drugs from different classes that have been clinically proven to be safe and effective, such as apremilast, may be of particular interest, especially in the presence of certain comorbidities, including in particular diabetes mellitus, ischemic heart disease, congestive heart failure and / or CKD, including CKD associated with diabetes mellitus (DKD).

[0023] Studies have found that apremilast or a pharmaceutically acceptable salt thereof is particularly suitable for providing proven effective clinical treatment for certain endothelin-related diseases, particularly hypertension (including difficult-to-control hypertension and resistant hypertension), which require a significant and long-term sustained reduction in systolic and diastolic blood pressure, especially when used in subjects with one or more comorbidities and in combination with other active ingredients or therapeutic agents that are standard background therapies for such hypertension or diseases or disorders typically associated with hypertension. DETAILED DESCRIPTION

[0024] 1) The first embodiment of the present invention relates to a method for treating an endothelin-related disease in a subject in need thereof, the disease particularly including hypertension including uncontrolled hypertension and resistant hypertension, chronic kidney disease (CKD) [particularly stage 1 to 4 CKD (particularly stage 3 or 4 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines] and particularly CKD caused / associated with hypertension and / or caused / associated with diabetes (particularly CKD at these stages) (diabetic kidney disease (DKD)), or diabetes, the method comprising administering to the subject a pharmaceutical composition comprising a clinically proven effective amount of apremilast or a pharmaceutically acceptable salt thereof.

[0025] In particular, the above CDKs may be associated with heavy proteinuria (defined as UACR>300 mg / g).

[0026] UACR is a biomarker of renal insufficiency monitored in patients with impaired renal function (Levey et al., Uses of GFR and albuminuria level in acute and chronic kidney disease. N Engl J Med. 2022; 386(22): 2120–28).

[0027] It will be appreciated that this method of treating CKD (particularly stage 3 or stage 4 CKD) caused by / associated with hypertension and optionally additionally associated with diabetes (diabetic nephropathy (DKD)) also refers to the treatment of hypertension including difficult-to-control and refractory hypertension, wherein the hypertension includes the hypertension causing / associated with such CKD, and wherein the CKD is optionally associated with diabetes in addition to the hypertension.

[0028] 2) Another embodiment relates to the method according to embodiment 1), wherein the subject in need thereof is a subject receiving standard background treatment (wherein it can be understood that such standard background treatment is treatment applicable to hypertension).

[0029] 3) Another embodiment relates to the method according to embodiment 2), wherein the standard background therapy includes first-line therapy suitable for the prevention or treatment of hypertension, such as angiotensin receptor blockers (ARBs) or ACE inhibitors, especially (further) in combination with calcium channel blockers (CCBs) and / or diuretics (especially thiazide-like diuretics) as treatment of hypertension; and optionally (further) in combination with beta-blockers.

[0030] It will be appreciated that preferably such standard background therapy, if any, will include only one renin-angiotensin system modulator, ie, an ARB or an ACE inhibitor.

[0031] It is further understood that beta-blockers are recommended standard background therapy for subjects with a history of cardiac comorbidities, such as, in particular, ischemic heart disease and / or congestive heart failure.

[0032] 4) Another embodiment relates to the method of embodiment 2), wherein the standard background therapy comprises: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan), or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; and / or calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine), or pharmaceutically acceptable salts thereof; and / or diuretics, including loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including aldosterone antagonists, such as spironolactone, eplerenone or finerenone, or aldosterone synthase inhibitors; carbonic anhydrase inhibitors, including acetazolamide and mesotrione; in particular thiazide diuretics (thiazide-like diuretics), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferably thiazide diuretics, in particular chlorthalidone or hydrochlorothiazide); and / or beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release);

[0033] It is understood that such standard background therapy may include at least one (especially one to four) of the above-mentioned standard background therapy agents and, in addition, another background therapy preparation listed above, wherein this other background therapy preparation has a different pharmacological effect, for example, an additional diuretic with a different pharmacological effect.

[0034] 4a) Therefore, the first sub-embodiment of this embodiment 4) relates to the method of embodiment 2), wherein the standard background therapy includes [wherein it is worth noting that the standard background therapy includes at least two (especially including three or four) other antihypertensive drugs selected from the following groups]: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan), or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; and / or calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine), or pharmaceutically acceptable salts thereof; and / or an aldosterone antagonist, such as spironolactone, eplerenone, or finerenone; or an aldosterone synthase inhibitor (such as baxdrostat); and / or A diuretic selected from the following: Loop diuretics, including furosemide, bumetanide, ethacrynic acid, or torsemide; Carbonic anhydrase inhibitors, including acetazolamide or sulfazolamide; In particular, a thiazide diuretic (thiazide-like diuretic), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide-like diuretics, in particular chlorthalidone or hydrochlorothiazide); or Potassium-sparing diuretics that are not aldosterone antagonists or aldosterone synthase inhibitors (e.g., amiloride); Beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release).

[0035] 4b) Therefore, the second sub-embodiment of this embodiment 4) relates to the method of embodiment 2), wherein the standard background therapy includes [wherein it is worth noting that the standard background therapy includes at least two (especially including three or four) other antihypertensive drugs selected from the following group]: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan), or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; and / or calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine), or pharmaceutically acceptable salts thereof; and / or Loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; and / or A diuretic further selected from the group consisting of: Potassium-sparing diuretics that are not aldosterone antagonists or aldosterone synthase inhibitors (e.g., amiloride); an aldosterone antagonist, such as spironolactone, eplerenone, or finerenone; or an aldosterone synthase inhibitor (such as baxdrostat); Carbonic anhydrase inhibitors, including acetazolamide or sulfazolamide; In particular, a thiazide diuretic (thiazide-like diuretic), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide-like diuretics, in particular chlorthalidone or hydrochlorothiazide); and / or Beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release).

[0036] 5) Another embodiment relates to the method according to any one of embodiments 1) to 3), wherein the subject in need is a subject who is receiving at least three other antihypertensive drugs, which are independently selected from the group consisting of: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan), or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; Calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine), or pharmaceutically acceptable salts thereof; diuretics, including loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including aldosterone antagonists, such as spironolactone, eplerenone or finerenone, or aldosterone synthase inhibitors; carbonic anhydrase inhibitors, including acetazolamide and mesotrione; in particular thiazide diuretics (thiazide-like diuretics), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferably thiazide diuretics, in particular chlorthalidone or hydrochlorothiazide); and beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release);

[0037] It is to be understood that, preferably, the at least three other antihypertensive drugs, if any, preferably only include one renin-angiotensin system regulator, ie, ARB or ACE inhibitor.

[0038] 6) Another embodiment relates to the method according to any one of embodiments 1) to 3), wherein aprexitentan is administered in combination with at least three other antihypertensive drugs independently selected from the group consisting of: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan), or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; Calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine), or pharmaceutically acceptable salts thereof; diuretics, including loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including aldosterone antagonists, such as spironolactone, eplerenone or finerenone, or aldosterone synthase inhibitors; carbonic anhydrase inhibitors, including acetazolamide and mesotrione; in particular thiazide diuretics (thiazide-like diuretics), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferably thiazide diuretics, in particular chlorthalidone or hydrochlorothiazide); and beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release);

[0039] In this combination therapy, in particular, one renin-angiotensin system regulator selected from ARB and ACE inhibitor is administered; in this case, it can be understood that only one renin-angiotensin system regulator, namely ARB or ACE inhibitor, is administered.

[0040] 7) Another embodiment relates to the method according to any one of embodiments 1) to 6), wherein the subject has a history of comorbidities including polyuria (especially diabetes), ischemic heart disease, stroke and / or congestive heart failure.

[0041] 8) Another embodiment relates to the method according to any one of embodiments 1) to 7), wherein, in case the subject has a history of polyuria (especially diabetes), the subject is a subject receiving (in addition to the standard background therapy for the treatment of hypertension) the following standard background therapy: Reduce the risk of cardiovascular death and heart failure-related hospitalization in adults with heart failure, and / or Reducing the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease; and / or As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes; and / or Used to treat diabetes (especially type 2 diabetes);

[0042] Therein, in particular, the subject is a subject receiving (in addition to a standard background therapy for the treatment of hypertension) a standard background therapy for the treatment of diabetes (in particular type 2 diabetes).

[0043] 9) Another embodiment relates to a method according to any one of embodiments 1) to 8), wherein the subject is a subject who, in addition to receiving standard hypertension background therapy, is also receiving further standard background therapy, in particular a standard background therapy suitable for treating diabetes; wherein the additional standard background therapy includes SGLT-2 inhibitors (especially atigliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, repagliflozin, sogliflozin or togliflozin; or pharmaceutically acceptable salts thereof); in particular bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, sogliflozin or togliflozin; in particular canagliflozin or dapagliflozin or empagliflozin), or pharmaceutically acceptable salts thereof; and / or Metformin; and / or Insulin; and / or Sulfonylureas (especially glibenclamide), or pharmaceutically acceptable salts thereof; and / or a DPP-4 inhibitor (particularly sitagliptin, vildagliptin, saxagliptin or linagliptin) or a pharmaceutically acceptable salt thereof; and / or GLP-1 receptor agonists (especially exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tapoglutide, semaglutide; or GLP-1 / GIP dual agonists such as telportide); and / or · a thiazolidinedione or a pharmaceutically acceptable salt thereof;

[0044] Among them, such additional standard background therapy includes, in particular, SGLT-2 inhibitors, metformin and / or DPP-4 inhibitors;

[0045] In particular, SGLT-2 inhibitors, wherein the SGLT-2 inhibitor (especially bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliptin, rupagliflozin, soglipflozin or topagliflozin; especially canagliflozin or dapagliflozin or empagliflozin) especially refers to Reduce the risk of cardiovascular death and heart failure-related hospitalization in adults with heart failure, and / or Reducing the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease; and / or As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

[0046] It is to be understood that the method according to any one of embodiments 1) to 9) also refers to aprexitentan or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension, including uncontrolled hypertension and resistant hypertension, wherein aprexitentan is to be administered in combination with such standard background therapy.

[0047] It is further understood that this method according to any one of embodiments 1) to 9) also refers to a pharmaceutical composition comprising apremitentan or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is used in this method, in particular for the treatment of hypertension, including difficult-to-control hypertension and refractory hypertension, or chronic kidney disease (CKD) [in particular CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (in particular CKD stage 3 or 4)], in particular CKD caused / associated with hypertension and / or caused / associated with diabetes (diabetic nephropathy (DKD)) (in particular CKD at these stages); wherein the pharmaceutical composition as a further active ingredient, in combination with such standard background therapy; or • Administered in conjunction with such standard background treatments.

[0048] The term "angiotensin receptor blocker" or "ARB" in the present application refers in particular to valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt thereof. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

[0049] The term "angiotensin converting enzyme inhibitor" or "ACE inhibitor" in the present application refers in particular to captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril, or a pharmaceutically acceptable salt of one of them.

[0050] The term "calcium channel blocker" or "CCB" in the present application refers in particular to amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil or diltiazem or a pharmaceutically acceptable salt thereof. A preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.

[0051] The term "SGLT-2 inhibitor" refers to inhibitors of the sodium-glucose co-transporter 2, such as in particular atigliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, repagliflozin, sopagliflozin, tabagliflozin or topagliflozin (in particular canagliflozin or dapagliflozin or empagliflozin).

[0052] The term "DPP-4 inhibitor" or "DPP-IV inhibitor" refers to inhibitors of dipeptidyl peptidase 4, such as in particular sitagliptin, vildagliptin, saxagliptin and linagliptin, as well as gemagliptin, anagliptin, tenagliptin, alogliptin, trelagliptin, omagliptin, ivogliptin and dulagliptin.

[0053] The term "GLP-1 receptor agonist" refers to an agonist of the glucagon-like peptide-1 receptor, in particular exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tapoglutide, semaglutide.

[0054] The term "GLP-1 / GIP dual agonist" refers to a dual agonist of the glucagon-like peptide-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as in particular telportide.

[0055] The term "sulfonylurea" refers in particular to glyburide, glibenclamide, gliclazide, glipizide, gliquidone, glipiride, glypyruvide or glimepiride.

[0056] The term "thiazolidinediones", abbreviated to TZD, also known as glitazones, refers to agonists of PPARγ (peroxisome proliferator-activated receptor γ), in particular pioglitazone, rosiglitazone or lobeglitazone.

[0057] The term "diuretic" in this application refers to loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including, for example, amiloride, especially including aldosterone antagonists (or alternative names: mineralocorticoid receptor antagonists (MRA)): or aldosterone synthase inhibitors (such as baxdrostat); carbonic anhydrase inhibitors, including acetazolamide and mesosulfazolamide; especially thiazide diuretics (thiazide-like diuretics), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferred thiazide-like diuretics are chlorthalidone or hydrochlorothiazide. For the avoidance of doubt, SGLT-2 inhibitors, even if they have a pharmacological effect of diuresis, are not included in the term "diuretic" used herein. In addition, certain potassium-sparing diuretics may be considered primarily for their pharmacological effects as mineralocorticoid receptor antagonists (MRAs) / aldosterone antagonists (e.g., finerenone) or aldosterone synthase inhibitors (e.g., baxdrostat), rather than for their diuretic effects as potassium-sparing diuretics. The definition of diuretics herein includes such potassium-sparing diuretics. It is further understood that standard background therapy may include a combination of several diuretics as defined herein. Specific diuretic combinations include: (i) a combination of an aldosterone antagonist and a thiazide-like diuretic; (ii) a combination of an aldosterone antagonist and a loop diuretic; (iii) a combination of an aldosterone synthase inhibitor and a thiazide-like diuretic; (iv) a combination of an aldosterone synthase inhibitor and a loop diuretic; and (v) a combination of a loop diuretic and a thiazide-like diuretic.

[0058] The term "beta-blocker" refers to beta-adrenergic blocking agents, in particular acebutolol, atenolol, bisoprolol, metoprolol (including immediate release or extended release formulations), nadolol, nebivolol and propranolol (including immediate release or extended release formulations); in particular atenolol, bisoprolol, metoprolol, nebivolol and propranolol.

[0059] The dosage of the standard background therapy is preferably equivalent to the tolerated effective dose of the corresponding active ingredient, for example when administered as a monotherapy. In particular, valsartan or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 160 mg or 320 mg of valsartan per day; losartan or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 50 mg or 100 mg of losartan per day; irbesartan or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 75 mg, 150 mg or 300 mg of irbesartan per day; amlodipine or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 5 mg or 10 mg of amlodipine per day; enalapril or its pharmaceutically acceptable salt (such as If present, enalapril will be administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg per day; lisinopril or a pharmaceutically acceptable salt thereof, if present, will be administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg per day; ramipril or a pharmaceutically acceptable salt thereof, if present, will be administered in a dosage form suitable for oral administration of 2.5 mg to 20 mg per day; metformin, if present, will be administered in a dosage form suitable for oral administration of 500 mg to 2000 mg per day of metformin; glibenclamide, if present, will be administered in a dosage form suitable for oral administration of 1.25 mg to 5 mg per day of glibenclamide; sitagliptin, if present, will be administered in a dosage form suitable for oral administration of 1.25 mg to 5 mg per day of glibenclamide; and sinagliflozin, if present, will be administered in a dosage form suitable for oral administration of 1.5 mg to 2000 mg per day of glibenclamide. In the present invention, 25 mg to 100 mg of sitagliptin per day will be administered in a dosage form suitable for oral administration; vildagliptin (if present) will be administered in a dosage form suitable for oral administration of 50 mg of vildagliptin twice a day; saxagliptin (if present) will be administered in a dosage form suitable for oral administration of 2.5 mg or 5 mg of saxagliptin per day; linagliptin (if present) will be administered in a dosage form suitable for oral administration of 5 mg of linagliptin twice a day; bepagliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 5 to 50 mg (especially 20 mg) of bepagliflozin per day; canagliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 50 to 400 mg (especially 50 mg, 100 mg, 150 mg or 300 mg; note that it is 100 mg or 300 mg; especially 100 mg) of canagliflozin will be administered per day; dapagliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 1 to 20 mg (especially 5 mg or 10 mg) of dapagliflozin per day; empagliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 5 to 50 mg (especially 10 mg or 25 mg) of empagliflozin per day; ertogliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 2.5 to 50 mg (especially 5 mg or 15 mg) of ertogliflozin will be administered in a dosage form suitable for oral administration of 5 to 100 mg (especially 25 mg) of henggliflozin per day; ipragliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 10 to 100 mg (especially 25 mg or 50 mg) of ipragliflozin per day; rupagliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 10 to 100 mg (especially 25 mg or 50 mg) of ipragliflozin per day; In the present invention, 1 to 10 mg (especially 2.5 mg or 5 mg) of rugliflozin per day will be administered in a dosage form suitable for oral administration; sogliaflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 50 to 500 mg (especially 75 mg, 200 mg or 400 mg) of sogliaflozin per day; togliflozin or its pharmaceutically acceptable salt (if present) will be administered in a dosage form suitable for oral administration of 10 to 50 mg (especially 20 mg) of togliflozin per day.

[0060] 10) Another aspect of the invention relates to the method according to any one of embodiments 1) to 9), wherein the administration of the clinically proven effective amount of aprexitentan results in: a reduction in systolic blood pressure from baseline of at least about 12 mmHg (particularly at least about 15 mmHg) after 4 weeks of treatment (wherein the reduction is measured by unattended automated office blood pressure measurement (uAOBPM) at trough values); and / or A placebo-corrected mean reduction in systolic blood pressure of at least 3.5 mmHg after 4 weeks of treatment (where the reduction was measured by unattended automated office blood pressure measurement (uAOBPM) at trough values).

[0061] 11) Another embodiment relates to the method according to any one of embodiments 1) to 10), wherein administration of the clinically proven effective amount of apremitentan results in a reduction in diastolic blood pressure from baseline of at least about 8 mmHg (in particular at least about 10 mmHg) after 4 weeks of treatment (wherein the reduction is measured by unattended automated office blood pressure measurement (uAOBPM) at trough values).

[0062] 12) Another embodiment relates to the method according to any one of embodiments 1) to 11), wherein, after the initial 4 weeks of treatment, the clinically proven effective amount of aprexitentan is administered for an additional 32 weeks, resulting in at least maintaining the mean reduction in systolic and / or diastolic blood pressure from baseline for these additional 32 weeks.

[0063] 13) Another embodiment relates to a method according to any one of embodiments 1) to 9), wherein a clinical effect on blood pressure reduction (especially a clinical effect of systolic blood pressure reduction according to embodiment 10) is confirmed after a 4-week rest period (starting from 32 weeks after the initial 4-week treatment), wherein the mean systolic blood pressure of subjects taking placebo is increased compared to the mean systolic blood pressure of subjects who continue to be administered apremilast at a dose of 25 mg per day (i.e. by measuring the difference in mean SBP between placebo and apremilast at week 36 and week 40, respectively, and comparing the mean SBP); wherein the increase is at least about 5 mmHg, in particular at least about 6 mmHg (wherein the increase is measured by unattended automated office blood pressure measurement (uAOBPM) at trough values).

[0064] 14) Another embodiment relates to the method according to any one of embodiments 10) to 12), wherein the clinical effect of the blood pressure reduction is confirmed by a mean reduction in blood pressure from baseline after 4 weeks of treatment, wherein the reduction is measured by 24-hour ambulatory blood pressure monitoring (24hABPM); wherein in particular A decrease in systolic blood pressure of at least about 6 mmHg, and / or Diastolic blood pressure drops by at least about 6 mmHg, wherein the clinically proven effective amount of aprexitentan is 12.5 mg per day; or A decrease in systolic blood pressure of at least about 8 mmHg, and / or Diastolic blood pressure drops by at least about 7 mmHg, The clinically proven effective amount of aprexitentan is 25 mg per day.

[0065] 15) Another embodiment relates to the method according to any one of embodiments 1) to 14), wherein the administration of the clinically proven effective amount of aprexitentan results in a placebo-corrected mean reduction in blood pressure after 4 weeks of treatment, wherein the reduction is measured by 24-hour ambulatory blood pressure monitoring (24hABPM) (wherein the BP is expressed as a least squares mean); wherein, in particular A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, The clinically proven effective dose of aprexitentan is 12.5 mg per day; or A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, The clinically proven effective dose of apremilast is 25 mg per day.

[0066] 16) Another embodiment relates to the method according to any one of embodiments 10) to 12), wherein the clinical effect of the blood pressure reduction is confirmed by the mean reduction in blood pressure from baseline after 4 weeks of treatment, wherein the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM); wherein in particular a decrease in systolic blood pressure of at least about 6 mmHg, in particular at least about 8 mmHg, and / or a decrease in diastolic blood pressure of at least about 6 mmHg, in particular at least about 7 mmHg, The clinically proven effective dose of aprexitentan is 12.5 mg per day; or a reduction in systolic blood pressure of at least about 8 mmHg, in particular at least about 10 mmHg, and / or a decrease in diastolic blood pressure of at least about 7 mmHg, in particular at least about 8 mmHg, The clinically proven effective dose of apremilast is 25 mg per day.

[0067] 17) Another embodiment relates to the method according to any one of embodiments 1) to 16), wherein the administration of the clinically proven effective amount of aprexitentan results in a placebo-corrected mean reduction in blood pressure after 4 weeks of treatment, wherein the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM) (wherein the BP is expressed as a least squares mean); wherein in particular a decrease in systolic blood pressure of at least about 4 mmHg, in particular at least about 5 mmHg, and / or a decrease in diastolic blood pressure of at least about 4 mmHg, in particular at least about 5 mmHg, The clinically proven effective dose of aprexitentan is 12.5 mg per day; or a reduction in systolic blood pressure of at least about 4 mmHg, in particular at least about 7 mmHg, and / or a decrease in diastolic blood pressure of at least about 5.5 mmHg, in particular at least about 6 mmHg, The clinically proven effective dose of apremilast is 25 mg per day.

[0068] 18) Another embodiment relates to a method according to any one of embodiments 1) to 9), wherein a reduction in blood pressure (e.g. as defined in embodiment 10) or 11)) is confirmed after a 4-week rest period (starting 32 weeks after the initial 4 weeks of treatment), wherein the mean blood pressure of subjects administered placebo is increased compared to subjects who continue to be administered aprexitentan at a dose of 25 mg per day (i.e. by measuring the difference between the corresponding mean BP of placebo and aprexitentan at week 36 and week 40, respectively, and comparing the corresponding mean BP); wherein the increase is measured by 24-hour ambulatory blood pressure monitoring (24h ABPM) (wherein the BP is expressed as a least squares mean); wherein an increase in systolic blood pressure of at least about 6 mmHg, in particular at least about 6.5 mmHg, and / or The diastolic blood pressure is increased by at least about 6 mmHg, in particular at least about 6.5 mmHg.

[0069] 19) Another embodiment relates to a method according to any one of embodiments 1) to 9), wherein a reduction in blood pressure (e.g. as defined in embodiment 10) or 11)) is confirmed after a 4-week rest period (starting 32 weeks after the initial 4 weeks of treatment), wherein the mean blood pressure of subjects administered placebo is increased compared to subjects who continue to be administered aprexitentan at a dose of 25 mg per day (i.e. by measuring the difference in the corresponding mean BP between placebo and aprexitentan at week 36 and week 40, respectively, and comparing the corresponding mean BP); wherein the increase is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM) (wherein the BP is expressed as a least squares mean); wherein an increase in systolic blood pressure of at least about 8 mmHg, in particular at least about 8.5 mmHg, and / or The diastolic blood pressure is increased by at least about 7 mmHg, in particular at least about 7.5 mmHg.

[0070] 20) Another aspect of the present invention relates to a method according to any one of embodiments 1) to 19), wherein the method of treating hypertension (including resistant hypertension) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of apremilast.

[0071] 21) Another embodiment relates to a method according to any one of embodiments 1) to 20), wherein the clinically proven effective amount (and the clinically proven safe amount according to embodiment 20, respectively) is 10 to 50 mg per day; in particular 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg; especially 12.5 mg or 25 mg of aprexitentan.

[0072] 22) Another embodiment relates to the method according to any one of embodiments 1) to 20), wherein the clinically proven effective amount (and the clinically proven safe amount according to embodiment 20, respectively) is 12.5 mg of aprexitentan per day.

[0073] 23) Another embodiment relates to the method according to any one of embodiments 1) to 20), wherein the clinically proven effective amount (and the clinically proven safe amount according to embodiment 20, respectively) is 25 mg of aprexitentan per day.

[0074] 23) Another embodiment relates to a method according to any one of embodiments 21) to 23), wherein, as applicable, the pharmaceutical composition comprises aprexitentan or a pharmaceutically acceptable salt thereof in a unit dosage form suitable for oral administration of 10 to 50 mg of aprexitentan per day, in particular 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg, especially 12.5 mg or 25 mg of aprexitentan.

[0075] 24) Another embodiment relates to a method according to any one of embodiments 1) to 23), wherein the pharmaceutical composition comprising aprexitentan or a pharmaceutically acceptable salt thereof is administered in the morning (it can be understood that aprexitentan is suitable for administration once a day).

[0076] Unless used in relation to temperature, the term "about" before a numerical value "X" in this application refers to the interval from X minus 10% of X to X plus 10% of X, preferably to the interval from X minus 5% of X to X plus 5% of X. In the special case of temperature, the term "about" before a temperature "Y" in this application refers to the interval from temperature Y minus 10°C to Y plus 10°C, preferably to the interval from temperature Y minus 5°C to Y plus 5°C, and especially to the interval from temperature Y minus 3°C to Y plus 3°C. Room temperature refers to a temperature of about 25°C. In this application, when the term n equivalents is used, wherein n is a number, within the scope of this application, n refers to approximately the number n, preferably the exact number n.

[0077] Whenever "between" or "to" is used to describe a numerical range, it should be understood that the endpoints of the range are explicitly included in the range. For example: if the temperature range is described as between 40°C and 80°C (or 40°C to 80°C), it means that the endpoints of 40°C and 80°C are included in the range; or, if a variable is defined as an integer between 1 and 4 (or 1 to 4), it means that the variable is an integer 1, 2, 3 or 4.

[0078] The production of the pharmaceutical composition of the present invention can be carried out in a manner familiar to those skilled in the art (for example, see Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by preparing the crystalline form of the present invention (optionally in combination with other therapeutically valuable substances) together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and (if necessary) commonly used pharmaceutical adjuvants into a galenical administration form.

[0079] Solid pharmaceutical compositions, especially in tablet form, are exemplified by inert microcrystalline cellulose, lactose, hydroxypropylcellulose, sodium aminomethylcellulose and magnesium stearate as pharmaceutically acceptable excipients.

[0080] In particular, such a solid pharmaceutical composition will contain aprexitentan, in a total amount of 5% to 25% of the total weight of the pharmaceutical composition; microcrystalline cellulose, in a total amount of 20% to 30% of the total weight of the pharmaceutical composition; lactose, in a total amount of 40% to 65% of the total weight of the pharmaceutical composition; hydroxypropyl cellulose, in a total amount of 1% to 3% of the total weight of the pharmaceutical composition; tranexamic acid, in a total amount of 2% to 8% of the total weight of the pharmaceutical composition; and magnesium stearate, in a total amount of 0.2% to 2% of the total weight of the pharmaceutical composition, wherein the total weight percentage of the solid pharmaceutical composition is always 100; in particular, the above-mentioned solid pharmaceutical composition is in the form of a tablet.

[0081] A further embodiment of the invention relates to such a pharmaceutical composition, wherein the pharmaceutical composition is in the form of a tablet. In a sub-embodiment, the pharmaceutically active ingredient is contained in the form of particles before being pressed into the tablet. Optionally, the tablet can be coated with a suitable protective film. The protective film can significantly prevent the pharmaceutical composition from coming into direct contact with moisture; it can also easily leave an imprint that may be needed to distinguish the pharmaceutical composition from other pharmaceutical compositions. The coating material used to make such a protective film can include a low water vapor permeability polymer (such as polyvinyl alcohol (such as Biogrund's White PVA) or dimethylaminoethyl methacrylate (such as E PO)). The coating material may also include a plasticizer (such as propylene glycol, triacetylene, dibutyl phthalate or dibutyl sebacate), a surfactant (such as sodium lauryl sulfate or polysorbate, such as ) and / or lubricant / glidant (such as stearic acid, magnesium stearate or calcium stearate or talc). In addition, the coating material can also include a pigment (such as iron oxide (II), iron oxide (III) or titanium oxide) to make the tablet appear colorful.

[0082] In the present invention, diseases associated with endothelin include Hypertension, including essential hypertension, especially difficult-to-control hypertension and refractory hypertension; Pulmonary hypertension and arterial pulmonary hypertension; Chronic kidney disease (CKD) [especially CKD stages 1 to 4 (especially CKD stage 3 or 4) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], especially CKD caused by / associated with hypertension (especially CKD at these stages), and / or CKD caused by / associated with diabetes (diabetic nephropathy (DKD)); and (acute and especially chronic) renal failure, wherein the (acute and chronic) renal failure may be associated with hypertension and / or diabetes; diabetic nephropathy, wherein the diabetic nephropathy may be associated with hypertension; and glomerulonephritis, wherein the glomerulonephritis may be associated with hypertension and / or diabetes; For the avoidance of doubt, the term CKD (diabetic nephropathy, DKD) caused by / associated with diabetes may also include such DKD associated with hypertension; wherein in particular type 2 diabetes. In a sub-embodiment, the DKD defined above refers in particular to DKD in patients diagnosed with type 2 diabetes; in particular to a reduction in the rate of progression of DKD, such as a reduction in the rate of progression of DKD in patients diagnosed with type 2 diabetes, wherein such a reduction in the rate of progression may in particular be represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein in particular the patient also has a history of hypertension; In another sub-embodiment, DKD as defined above refers in particular to diabetic nephropathy in patients with type 2 diabetes accompanied by elevated serum creatinine and / or proteinuria [in particular equivalent to stage 1 to 4 CKD (in particular stage 3 or 4 CKD) as defined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], especially such patients also have a history of hypertension; In another sub-embodiment, the DKD as defined above particularly refers to such DKD being also associated with hypertension; wherein particularly, the diabetes is type 2 diabetes; Diabetes and diabetes-related diseases such as diabetic arteropathy, diabetic retinopathy or diabetic vasculopathy; and treatment and prevention of diabetic complications; reduction of the risk of major cardiovascular events (such as heart failure, myocardial infarction, stroke or cardiovascular death) in patients with diabetes, especially those with at least one other cardiovascular risk factor (especially hypertension); and diabetic foot ulcers and / or reduction of the risk of lower limb amputation in patients with diabetes; as well as Heart failure (HF), defined as including specifically chronic HF, especially including systolic HF / HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%) and diastolic HF / heart failure with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%); and reducing the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or cardiovascular death) in patients at cardiovascular risk (e.g., patients with coronary artery disease and / or clinical symptoms of congestive HF); angina, coronary artery disease, cardiac insufficiency, and diastolic dysfunction.

[0083] It should be noted that, in the present invention, endothelin-related diseases refer to hypertension, especially difficult-to-control hypertension or refractory hypertension.

[0084] In particular, in the present invention, the endothelin-related disease refers to refractory hypertension.

[0085] Essential hypertension (also called primary hypertension or spontaneous hypertension) is a type of hypertension for which no cause can be identified by definition. It is a major global public health problem, causing vascular and renal morbidity and cardiovascular mortality. If the average of multiple measurements of systolic blood pressure is persistently equal to or above a certain threshold T on 2 or more subsequent visits, the patient is considered to have a high blood pressure. SBP , then it can be diagnosed as essential hypertension. People with normal to high blood pressure tend to maintain blood pressure higher than the average level of the general population, and they are at greater risk of developing definite hypertension and cardiovascular events compared with the general population. Clinicians often discuss the T that is recommended for treatment when it exceeds SBP critical value (see Mancia et al, J. Hypertens. (2013), 31, 12811357); therefore, according to the patient's general condition and age, T SBP It may be 140 or 130 mmHg, or other suitable value.

[0086] In the present invention, the term "hard-to-control hypertension" is defined as blood pressure that is still above the target value despite the simultaneous use of standard background therapy, wherein the standard background therapy includes treatment with at least one, particularly at least two, and especially at least three (in this case, the use of the term is equivalent to resistant hypertension as defined below) different categories of antihypertensive drugs. If the standard background therapy includes more than one therapeutic agent, one of the therapeutic agents should be a diuretic, and all agents should be prescribed at the optimal / maximum dose.

[0087] "Refractory hypertension" in the present invention means that blood pressure is still above the target value despite the simultaneous use of three different types of antihypertensive drugs. One of the three therapeutic agents should be a diuretic, and all agents should be prescribed at the optimal / maximum dose. By definition, patients with refractory hypertension include patients who use more than three drugs to control their blood pressure. In other words, patients whose blood pressure is controlled but require four or more drugs to control should be considered as treatment-resistant patients (see Mancia et al, J. Hypertens. (2013), 31, 1281 1357).

[0088] As used herein, the term "diabetes" refers to all types of diabetes, particularly type 2 diabetes; as well as type 1 diabetes and latent autoimmune diabetes of adulthood, a form of type 1 diabetes that develops in adulthood and tends to develop more slowly than type 1 diabetes diagnosed in adolescence.

[0089] 25) Another aspect of the present invention relates to a method according to any one of embodiments 1) to 24), wherein the method is used Treatment of CDKs [particularly phase 1 to 4 CDKs, especially phase 3 or 4 CDKs]; especially CDKs caused / associated with hypertension and / or caused / associated with diabetes mellitus (DKD) (particularly these phases); and prevention / prevention or treatment of acute or chronic renal failure, diabetic nephropathy or glomerulonephritis; Wherein, in a first sub-embodiment, this use is particularly for treating such DKD in patients diagnosed with type 2 diabetes, wherein aprexitentan particularly reduces the rate of progression of DKD, and this reduction in the rate of progression can be particularly reflected by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events, or a reduction in renal death events; wherein it is noted that the patient also has a history of hypertension; Wherein, in the second sub-embodiment, the use is particularly for treating such DKD in patients diagnosed with type 2 diabetes, including treating diabetic nephropathy associated with elevated serum creatinine and / or proteinuria [especially corresponding to stage 1 to 4 CKD (especially stage 3 or 4 CKD) defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], especially such patients also have a history of hypertension; wherein in a variant, the method according to any one of embodiments 1) to 24) is for treating hypertension in a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD]; especially a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] and diabetes (especially type 2 diabetes) (DKD); wherein, it is noted that in addition to reducing blood pressure according to any one of embodiments 10) to 19), the clinically proven effective amount of aprexitentan or a pharmaceutically acceptable salt thereof; reduces the rate of progression of CKD (corresponding to DKD), wherein such reduction in the rate of progression can be particularly reflected by reducing urine albumin-creatinine ratio (UACR), maintaining eGFR / preventing further decline in eGFR, reducing end-stage renal disease (ESKD) events and / or reducing renal death events; Treatment of diabetes and diabetes-related diseases, such as diabetic arteropathy, diabetic retinopathy, or diabetic vasculopathy; and complications of diabetes; for reducing the risk of major cardiovascular events (such as HF, myocardial infarction, stroke, or cardiovascular death) in patients with diabetes, especially those with at least one other cardiovascular risk factor (such as hypertension); and for the prophylaxis / prevention or treatment of diabetic foot ulcers and / or reduction of the risk of lower limb amputation in patients with diabetes; Treatment of heart failure (HF), especially chronic heart failure, especially systolic HF and diastolic HF; reduction of the risk of major cardiovascular events (such as HF, myocardial infarction, stroke or cardiovascular death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with clinical symptoms of congestive heart failure); and for the prevention / prevention or treatment of ischemic heart disease, including angina pectoris, coronary heart disease and myocardial ischemia; heart failure or diastolic dysfunction; Treatment of atherosclerosis; and peripheral arterial occlusive disease, including chronic peripheral arterial disease; Treating fingertip ulcers; or Treat connective tissue diseases.

[0090] 26) Another aspect of the present invention relates to a method according to any one of embodiments 1) to 24), wherein the method is used Treatment of CDKs caused by / associated with hypertension [particularly phase 1 to 4 CDKs, especially phase 3 or 4 CDKs]; and / or Treatment of CKD caused by / associated with diabetes mellitus (DKD) [particularly stages 1 to 4 CKD, especially stage 3 or 4 CKD]; Wherein this use is particularly for treating DKD in patients diagnosed with type 2 diabetes, wherein in particular aprexitentan can reduce the progression rate of DKD, and this reduction in progression rate can be particularly reflected by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is noted that the patient also has a history of hypertension; wherein in a variant, the method according to any one of embodiments 1) to 24) is used to treat hypertension in a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD]; especially a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] and diabetes (especially type 2 diabetes) (DKD); wherein, it is noted that in addition to reducing blood pressure according to any one of embodiments 10) to 19), the clinically proven effective amount of aprexitentan or a pharmaceutically acceptable salt thereof; reduces the progression rate of CKD (especially DKD), wherein such reduction in progression rate can be particularly reflected by reducing urine albumin-creatinine ratio (UACR), maintaining eGFR / preventing further decline in eGFR, reducing end-stage renal disease (ESKD) events and / or reducing renal death events; and / or To reduce the risk of major cardiovascular events (such as heart failure, myocardial infarction, stroke, or cardiovascular death) in patients with diabetes, especially those with at least one other cardiovascular risk factor (such as hypertension).

[0091] 27) Another aspect of the present invention relates to a method according to any one of embodiments 1) to 24), wherein the method is used Treatment of CDKs caused by / associated with hypertension [particularly phase 1 to 4 CDKs, especially phase 3 or 4 CDKs]; and / or Treatment of CKD caused by / related to diabetes (DKD) [especially stages 1 to 4 CKD, especially stage 3 or 4 CKD]; The use is particularly for treating DKD in patients diagnosed with type 2 diabetes, wherein aprexitentan can particularly reduce the rate of progression of DKD, and the reduction in the rate of progression can be particularly reflected by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events, or a reduction in renal death events; it is worth noting that the patient also has a history of hypertension; wherein in a variant, the method according to any one of embodiments 1) to 24) is used to treat hypertension in a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD]; especially a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] and diabetes (especially type 2 diabetes) (DKD); wherein It is noteworthy that in addition to lowering blood pressure according to any one of embodiments 10) to 19), the clinically proven effective amount of apremitentan or a pharmaceutically acceptable salt thereof reduces the progression rate of CKD, especially the corresponding DKD, wherein this reduction in progression rate can be particularly reflected by reducing urine albumin-creatinine ratio (UACR), maintaining eGFR / preventing further decline in eGFR, reducing end-stage renal disease (ESKD) events and / or reducing renal death events.

[0092] 27) Another aspect of the present invention relates to a method according to any one of embodiments 1) to 24), wherein the method is used For the treatment of CKD caused by / associated with diabetes mellitus (DKD) [particularly CKD stages 1 to 4, especially CKD stage 3 or 4]; In a first sub-embodiment, the use is particularly for treating DKD in patients diagnosed with type 2 diabetes, wherein aprexitentan can particularly reduce the rate of progression of DKD, and the reduction in the rate of progression can be particularly reflected by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events, or a reduction in renal death events; it is worth noting that the patient also has a history of hypertension; Wherein in the second sub-embodiment, the use is particularly for the treatment of such DKD in patients with type 2 diabetes, including the treatment of diabetic nephropathy associated with elevated serum creatinine and / or proteinuria [especially corresponding to stage 1 to 4 CKD (especially stage 3 or 4 CKD) defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], especially such patients also have a history of hypertension; wherein in a variant, the method according to any one of embodiments 1) to 24) is for treating hypertension in a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD]; especially a subject diagnosed with CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] and diabetes (especially type 2 diabetes) (DKD); It is worth noting that, in addition to lowering blood pressure according to any one of embodiments 10) to 19), the clinically proven effective amount of apremilast or a pharmaceutically acceptable salt thereof reduces the progression rate of CKD (corresponding to DKD), wherein the reduction in the progression rate can be particularly reflected by reducing the urine albumin-creatinine ratio (UACR), maintaining eGFR / preventing further decline in eGFR, reducing end-stage renal disease (ESKD) events and / or reducing renal death events.

[0093] 28) Another aspect of the present invention relates to a method according to any one of embodiments 1) to 24), wherein the method is used To reduce the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or cardiovascular death) in patients with diabetes, particularly those with at least one other cardiovascular risk factor (e.g., hypertension).

[0094] As used herein, the term "clinically proven (clinically confirmed)" (used independently or as a modification of the term "safety" and / or "effectiveness") means that it has been proven through clinical trials, where the clinical trials have met the approval standards of the U.S. Food and Drug Administration, the European Medicines Agency, or the corresponding national regulatory authorities, unless otherwise specified. For example, a clinical study can be a properly sized, randomized, double-blind study used to clinically demonstrate the efficacy of a drug.

[0095] The terms "clinically demonstrated efficacy" and "clinically demonstrated effectiveness" as used herein with respect to a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage or treatment regimen. Efficacy can be measured based on the course of the disease in response to the formulation of the invention. For example, the dual endothelial receptor antagonist of the invention (particularly aprexetine) is administered to a subject in sufficient amounts and for sufficient time to promote improvement, preferably sustained improvement, of at least one indicator reflecting the severity of the disease being treated. Various indicators reflecting the extent of the subject's condition, disease or condition can be evaluated to determine whether the treatment dose and duration are sufficient. For example, these indicators include clinically recognized indicators of disease severity, symptoms or manifestations of related diseases. The degree of improvement is generally determined by a physician, who can determine it based on signs, symptoms, biopsy or other test results, or by using a questionnaire administered to the subject, such as a quality of life questionnaire developed for a specific disease. For example, administration of the compounds of the invention can improve the condition of a subject associated with hypertension (including refractory hypertension). Improvement of the condition can be represented by an improvement in a disease activity index, an improvement in clinical symptoms, or any other indicator of disease activity.

[0096] In a specific embodiment, the disease index is blood pressure (including systolic and diastolic blood pressure) or a reduction thereof measured by uAOBPM and / or ABPM (including 24-hour ABPM and nighttime ABPM), each compared to baseline or compared to placebo; for example, according to any one of embodiments 10) to 19).

[0097] In certain embodiments, a clinically demonstrated effective amount of aprexitentan is an amount that results in a reduction in blood pressure [e.g., as measured by uAOBPM and / or ABPM (including 24-hour ABPM and nocturnal ABPM), each compared to baseline or compared to placebo; e.g., according to any one of Embodiments 10) to 19)]; as shown by a clinical trial having a protocol as described in Example A or below.

[0098] According to K. Kario, Hypertension. 2018; 71: 997–1009, nighttime BP ≥ 120 / 70 mmHg (according to the new ACC / AHA guidelines in 2017, > 110 / 65 mmHg). Outpatient and morning home BP < 130 / 80 mmHg were defined as masked nocturnal hypertension and masked refractory nocturnal hypertension under drug treatment. Nighttime BP was calculated as the average of nighttime BP (from going to bed to getting up) measured by ABPM or the recently developed HBPM system with automatic nighttime BP measurement function (nighttime HBPM). The number of nighttime BP measurements required may be ≥ 6 times. The formula for calculating the nighttime systolic BP decrease rate (%) was (1-nighttime average systolic BP / daytime average systolic BP) × 100. Based on this percentage, the following 4 nocturnal BP decrease patterns can be defined: superdipper: > 20%; dipper: ≤ 20% -> 10%; non-dipper: ≤ 10% -> 0%; elevated: ≤ 0%. This classification is usually based on ABPM data.

[0099] 29) Therefore, another embodiment of the present invention relates to a method for treating endothelin-related diseases, in particular hypertension including difficult-to-control and refractory hypertension; chronic kidney disease (CKD) [in particular CKD stages 1 to 4 (especially stage 3 or 4 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], in particular CKD caused by / associated with hypertension and / or caused by / associated with diabetes (diabetic kidney disease (DKD)); the endothelin-related diseases especially include hypertension, including difficult-to-control hypertension and refractory hypertension; the method comprises administering to a subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective apremitentan or a pharmaceutically acceptable salt thereof; wherein the clinically proven safe and clinically proven effective amount of apremitentan is an amount that results in a reduction in blood pressure; wherein the clinically proven safe and clinically proven effective amount of apremitentan results in a reduction in placebo-corrected mean blood pressure after 4 weeks of treatment, wherein according to embodiment 15) the reduction is measured by 24-hour ambulatory blood pressure monitoring (24h wherein the subject is a patient who has been diagnosed with CKD [particularly stage 1 to 4 CKD, particularly stage 3 or 4 CKD]; and / or wherein the clinically proven safe and clinically proven effective amount of aprexitentan results in a placebo-corrected mean blood pressure reduction after 4 weeks of treatment, wherein according to Example 17) the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM) (wherein the BP is expressed as mean least squares values); wherein in particular the treated subject exhibits nocturnal hypertension, in particular nocturnal hypertension associated with a dipping pattern of nocturnal systolic BP, which pattern can be defined as dipping, non-dipping or rising; in particular as non-dipping or rising as determined by ABPM; wherein in particular the subject is diagnosed with CKD [particularly stage 1 to 4 CKD, particularly stage 3 or 4 CKD]; in particular The subject is diagnosed with CKD associated with diabetes (especially type 2 diabetes) (DKD) [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD]; wherein the clinically proven safe and clinically proven effective amount can also reduce the progression rate of CKD (corresponding to DKD), and this reduction in progression rate is particularly manifested in a reduction in urine albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline in eGFR, reduction in end-stage renal disease (ESKD) events and / or reduction in renal death events; wherein the pharmaceutical composition comprises apremitentan or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical unit dosage form suitable for daily oral administration of 12.5 mg or 25 mg (especially 25 mg) of apremitentan.

[0100] 30) Another embodiment of the present invention relates to a method for treating an endothelin-related disease according to any one of embodiments 1) to 24); comprising in a hypertensive subject in need thereof, particularly including difficult-to-control and refractory hypertension, comprising administering to the subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of aprexitentan or a pharmaceutically acceptable salt thereof; wherein the amount of the clinically proven safe and clinically proven effective amount of aprexitentan is an amount that results in a reduction in blood pressure measured by nocturnal ABPM (compared to baseline or compared to placebo; i.e., according to any one of embodiments 10) to 19), for example as shown by a clinical trial having a protocol as described in Example A or below); wherein the subject receiving treatment exhibits nocturnal hypertension, particularly nocturnal hypertension associated with a nocturnal systolic blood pressure drop pattern, which pattern can be defined as a dipper, non-dipper or rise; wherein wherein, in particular, the subject is diagnosed with CKD [in particular, stage 1 to 4 CKD, in particular, stage 3 or 4 CKD]; in particular, the subject is diagnosed with CKD associated with diabetes (in particular, type 2 diabetes) (DKD) [in particular, stage 1 to 4 CKD, in particular, stage 3 or 4 CKD]; wherein the clinically proven safe and clinically proven effective amount can also reduce the progression rate of CKD (corresponding to DKD), and this reduction in progression rate is particularly manifested in a reduction in urine albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline in eGFR, reduction in end-stage renal disease (ESKD) events and / or reduction in renal death events; wherein the pharmaceutical composition comprises aprexitentan or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical unit dosage form suitable for daily oral administration of 12.5 mg or 25 mg (in particular, 25 mg) of aprexitentan.

[0101] 31) Another embodiment relates to a method according to any one of embodiments 1) to 30), comprising administering to a subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of aprexitentan or a pharmaceutically acceptable salt thereof; wherein administration of the clinically proven safe and clinically proven effective amount of aprexitentan results in a placebo-corrected reduction in mean blood pressure after 4 weeks of treatment, wherein the reduction is measured by 24-hour ambulatory blood pressure monitoring (24hABPM) (wherein the BP is expressed as a least squares mean); wherein in particular A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, wherein the clinically proven safe and clinically proven effective amount of aprexitentan is 12.5 mg per day; or A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, The clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg per day;

[0102] and wherein, in each case, preferably the subject is CKD stage 3 or 4 (optionally with diabetes), wherein the placebo-corrected mean UACR is reduced by at least about 25% (especially by at least about 30%) after 4 weeks of treatment;

[0103] It is worth noting that if the subject suffers from heavy proteinuria (defined as UACR>300 mg / g), a placebo-corrected mean UACR reduction of at least about 40% (particularly about 45%) after 4 weeks of treatment, wherein the clinically proven safe and clinically proven effective amount of aprexitentan is 12.5 mg per day; or a reduction in the placebo-corrected mean UACR of at least about 50% (particularly about 60%) after 4 weeks of treatment, The clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg per day;

[0104] And wherein preferably the clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg per day (wherein preferably the amount is administered once per day in the morning).

[0105] 32) Another embodiment relates to a method according to any one of embodiments 1) to 30), comprising administering to a subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of aprexitentan or a pharmaceutically acceptable salt thereof; wherein administration of the clinically proven safe and clinically proven effective amount of aprexitentan results in a placebo-corrected reduction in mean blood pressure after 4 weeks of treatment, wherein the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM) (wherein the BP is expressed as mean least squares value); wherein in particular a decrease in systolic blood pressure of at least about 4 mmHg, in particular at least about 5 mmHg, and / or a decrease in diastolic blood pressure of at least about 4 mmHg, in particular at least about 5 mmHg, wherein the clinically proven safe and clinically proven effective amount of aprexitentan is 12.5 mg per day; or a reduction in systolic blood pressure of at least about 4 mmHg, in particular at least about 7 mmHg, and / or a decrease in diastolic blood pressure of at least about 5.5 mmHg, in particular at least about 6 mmHg, The clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg per day;

[0106] and wherein, in each case, preferably the subject is CKD stage 3 or 4 (optionally with diabetes), wherein the placebo-corrected mean UACR is reduced by at least about 25% (especially by at least about 30%) after 4 weeks of treatment;

[0107] and wherein in particular in the case where the subject suffers from macroalbuminuria (defined as UACR>300 mg / g, e.g., baseline measurement), a placebo-corrected mean UACR reduction of at least about 40% (particularly about 45%) after 4 weeks of treatment, wherein the clinically proven safe and clinically proven effective amount of aprexitentan is 12.5 mg per day; or a reduction in the placebo-corrected mean UACR of at least about 50% (particularly about 60%) after 4 weeks of treatment, The clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg per day;

[0108] And wherein preferably the clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg per day (wherein preferably the amount is administered once per day in the morning).

[0109] It is understood that as long as the subject has / had a history of CKD and / or diabetes, for example, the subject has been diagnosed with DKD (i.e., CKD and diabetes), the subject can receive standard background treatment Reduce the risk of cardiovascular death and heart failure-related hospitalization in adults with heart failure, and / or Reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease; and / or As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes; and / or Used to treat diabetes (especially type 2 diabetes);

[0110] In addition to the standard background therapy for the treatment of hypertension, the subject may also receive a standard background therapy for the treatment of diabetes (especially type 2 diabetes); wherein such standard background therapy especially includes SGLT-2 inhibitors (especially atigliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, repagliflozin, sogliflozin or togliflozin; or a pharmaceutically acceptable salt thereof; especially bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, repagliflozin, sogliflozin or togliflozin; especially canagliflozin or dapagliflozin or empagliflozin), or a pharmaceutically acceptable salt thereof.

[0111] The term "clinically proven safety" in relation to the dose, dosage regimen, treatment or method of the compound aprexetine of the present invention refers to a favorable risk / benefit ratio of treatment-emergent adverse events (AEs or TEAEs for short) with an acceptable frequency and / or acceptable severity. "Adverse event", "treatment-emergent adverse event" and "adverse reaction" as used herein refer to any harmful, unfavorable, unexpected or undesirable sign or result associated with or caused by the administration of a composition or treatment. It refers to an unexpected medical event that occurs in a subject who is administered a drug product.

[0112] Therefore, according to the present invention, aprexitentan or a pharmaceutically acceptable salt thereof includes combined use (or co-therapy) with further pharmaceutically active ingredients as described above, especially including standard background therapeutic drugs.

[0113] The combined treatment (or co-treatment) may be performed simultaneously, separately or over a period of time (especially simultaneously).

[0114] In this application, "simultaneous" when referring to a mode of administration, refers to a mode of administration related to the administration of two or more active ingredients and / or therapies at approximately the same time; it is understood that simultaneous administration will result in the subject being exposed to the two or more active ingredients and / or therapies at the same time. When administered simultaneously, the two or more active ingredients can be administered in a fixed dose combination, or in an equivalent non-fixed dose combination (e.g., using two or more different pharmaceutical compositions, administered by the same administration route at approximately the same time), or in a non-fixed dose combination using two or more different administration routes; wherein the administration will result in the subject being exposed to the two or more active ingredients and / or therapies substantially at the same time. When used in combination with standard background therapy, it is best to use apremilast "simultaneously".

[0115] In the present application, "fixed dose combination" when referring to a mode of administration refers to a related mode of administration of a single pharmaceutical composition comprising two or more active ingredients.

[0116] In the present application, "single" when referring to a mode of administration refers to a related mode of administration of two or more active ingredients and / or therapies at different time points; wherein it is understood that single administration will result in the subject being exposed to two or more active ingredients and / or therapies simultaneously during a treatment period (such as at least 1 hour, in particular at least 6 hours, and in particular at least 12 hours); however, single administration may also result in the subject being exposed to only one of the two or more active ingredients and / or therapies during a certain treatment period (such as at least 12 hours, in particular at least one day). Single administration refers in particular to a situation where at least one active ingredient and / or therapy is administered in a manner substantially different from daily administration (such as once or twice a day) (for example, one active ingredient and / or therapy is administered once or twice a day, and another active ingredient and / or therapy is administered every other day, or once a week, or at a longer interval).

[0117] In the present application, administration "over a period of time" refers to the subsequent use of two or more active ingredients and / or therapies at different times. The term refers in particular to an administration method according to which the entire administration of one of the active ingredients and / or therapies is completed before the administration of another or other active ingredients and / or therapies is started. In this way, one active ingredient and / or therapy can be administered several months before another active ingredient and / or therapy is administered.

[0118] According to the invention, aprexitentan can be used as a medicament, for example in the form of a pharmaceutical composition, in particular for enteral or parenteral administration.

[0119] The dosage form suitable for enteral administration may be a tablet or a capsule (especially a tablet), which contains a pharmaceutical composition comprising an effective amount of aprexitentan or a pharmaceutically acceptable salt thereof.

[0120] For the avoidance of doubt, for the purposes of the present invention, any amount / unit dose of aprexitentan refers to an amount / unit dose of aprexitentan suitable for administration in the form of the free base. If aprexitentan is present in the pharmaceutical composition in a form other than the anhydrous free base, such as in the form of a pharmaceutically acceptable salt; and / or in the form of a solvate such as a hydrate, the amount / unit dose may need to be adjusted.

[0121] When a dose refers to a unit dose in mg, it is understood that the unit dose refers to the free base form of the active ingredient of aprexitentan in mg. If the active ingredient is administered in the form of a pharmaceutically acceptable salt, etc., the corresponding amount of the active pharmaceutical ingredient (such as the pharmaceutically acceptable salt) in the pharmaceutical composition will be adjusted accordingly.

[0122] For the avoidance of doubt, it is understood that any pharmaceutical composition comprising a pharmaceutically effective amount of aprexitentan may additionally comprise more conventional excipients and / or additives, which may be used alone or in combination (in appropriate amounts, i.e., the maximum amount of the more conventional ingredients and / or additives may need to be reduced so that the total ww% reaches 100). It is understood that the total amount of a certain composition expressed as "ww%" is 100.

[0123] For these and other pharmaceutical excipients and procedures mentioned herein, please refer to a large number of relevant literature, such as RC Rowe, PJ Seskey, S C Owen, Handbook of Pharmaceutical Excipients, 5th edition, Pharmaceutical Press 2006; Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins].

[0124] "ww %" (or % (w / w)) refers to the percentage by weight compared to the total weight of the composition under consideration. If not explicitly stated, the total weight under consideration is the total weight of the pharmaceutical composition.

[0125] Ratio-related expressions (wt / wt) refer to the weight ratio of the individual components.

[0126] If a value is given as a % value, this refers to ww% unless otherwise stated and in the case of purity to area% determined by HPLC.

[0127] Unless otherwise specified, any reference to aprexetentan refers to aprexetentan or a pharmaceutically acceptable salt form of aprexetentan, preferably to aprexetentan in the free base form.

[0128] The term "pharmaceutical composition" is interchangeable with the term "formulation" or "composition".

[0129] The terms "treat" or "treatment" or "cure" are used to refer to a disease, or to a patient or animal being cured of a disease; or to an animal or patient still being affected by the disease, but some or all of the symptoms of the disease are alleviated or eliminated.

[0130] The terms "subject" and "patient" also refer to mammals, especially humans. Note that the term "subject" refers to a human patient.

[0131] For the avoidance of doubt, any method of treating a disease or disorder such as RHT, said method comprising administering aprexitentan or a pharmaceutically acceptable salt thereof, as set forth in any one of embodiments 1) to 24), is also disclosed herein. Aprexitentan or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder as listed in any one of embodiments 1) to 24), Aprexitentan or a pharmaceutically acceptable salt thereof for use in the preparation of a therapeutic agent as in embodiments 1) to 24) Use in medicine for any of the diseases or disorders listed in ; Aprexitentan or a pharmaceutically acceptable salt thereof for use in a method for treating a disease or disorder as listed in any one of embodiments 1) to 24); A medicament for treating a disease or disorder as listed in any one of Embodiments 1) to 24) herein, comprising aprexitentan or a pharmaceutically acceptable salt thereof, and the like.

[0132] Likewise, if aprexitentan or a pharmaceutically acceptable salt thereof is described as being useful for treating a disease or disorder, such as RHT as listed herein, then aprexitentan or a pharmaceutically acceptable salt thereof is also applicable: · for use in the preparation of a medicament for treating a disease or disorder listed herein; Use in a method of treating said disease or disorder, said method comprising administering aprexitentan or a pharmaceutically acceptable salt thereof as described herein; As a medicament for treating the diseases or disorders listed herein, the medicament comprises aprexitentan or a pharmaceutically acceptable salt thereof, and the like.

[0133] The following examples describe specific embodiments of the present invention. These examples are used to illustrate the present invention in more detail but are not intended to limit the scope of the present invention in any way.

[0134] abbreviation:

[0135] ABP dynamic blood pressure

[0136] ABPM ambulatory blood pressure monitoring

[0137] ACE angiotensin converting enzyme, such as ACE inhibitors (ACEI)

[0138] ARB angiotensin receptor blocker

[0139] BP

[0140] BMI body mass index

[0141] CCB calcium channel blockers

[0142] DB(-WD) double-blind(-unblind)

[0143] DBP diastolic blood pressure

[0144] ET

[0145] RHT or rHT resistant hypertension

[0146] SB single blind

[0147] SBP Systolic blood pressure

[0148] SBT standardized background therapy

[0149] SiDBP Sitting Diastolic Blood Pressure

[0150] SiSBP Sitting Systolic Blood Pressure

[0151] UACR urine albumin-creatinine ratio

[0152] uAOBP unattended automated clinic blood pressure

[0153] uAOBPM unattended automated clinic blood pressure measurement ARB Example 1

[0154] For example, a method for manufacturing aprexitentan is described in WO2018 / 154101. In the following clinical trial example, aprexitentan is used in the form of the stable crystalline form A disclosed therein. Example A): A study aimed to show the efficacy of apremilast in the treatment of difficult to control (refractory) high blood pressure (hypertension). to further understand its effectiveness and safety (PRECISION).

[0155] A single randomized study with three sequential treatment parts was designed. The study design involved a 4-week placebo-controlled efficacy of aproxitentan 12.5 mg and 25 mg (part 1) and the durability of efficacy of long-term active treatment with 25 mg aproxitentan for an additional 32 weeks (part 2), followed by a 12-week placebo-controlled withdrawal period with patients re-randomized to 25 mg or placebo (part 3) (e.g., see Danaietash P et al; Identifying and treating resistant hypertension in PRECISION–a randomized long-term clinical trialwith Aprocitentan. J Clin Hypertension 2022 (in press)). Patients who had been on three or more antihypertensive medications for at least one year but still could not control their BP (as measured by unattended automated office BP) were screened. They would switch to a single-tablet triple fixed-combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo trial period. Placebo responders were further excluded during the 4-week placebo trial period. The randomization period consisted of 3 sequential parts: 1) A 4-week double-blind portion using aprexitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); 2) a 32-week single-blind portion of aprexitentan 25 mg; and 3) A 12-week randomized discontinuation phase with either apremilast 25 mg or placebo (1:1 ratio).

[0156] The aim was to demonstrate the BP-lowering effect of aprexitentan in RHT (Part 1) and the sustained effect in long-term treatment (Parts 2 and 3).

[0157] Standardized background therapy (SBT) is a single-tablet triple fixed combination of a CCB (amlodipine), an ARB (valsartan), and a diuretic (hydrochlorothiazide); two dose strengths are available: 5 / 160 / 25 mg and 10 / 160 / 25 mg, respectively. The maximum tolerated dose intensity is determined by the investigator at the discretion of the treatment period of the study and must be stable for at least 1 week before randomization, until the end of the DB part, and again during the DB-WD part. Patients who are receiving beta-blocker therapy at screening will continue to receive their treatment throughout the study.

[0158] Study treatment and SBT will be administered each morning, except on the morning of study visit days, when treatment will be administered after visit assessments and BP measurement are completed.

[0159] Adherence to study treatment and SBT will be assessed throughout the study based on pill counts. In addition, SBT intake will be monitored by testing participants' urine by liquid chromatography-tandem mass spectrometry for valsartan and by direct observation of treatment intake before initiation of ambulatory BP monitoring (ABPM).

[0160] The same automatic oscillometric blood pressure monitor ( Trough uAOBP was measured by the sphygmomanometer WatchBP Office, which records five sitting BP readings (one per minute, the first value not included in the average) while the patient is undisturbed and alone (unattended) resting in a quiet place for 5 minutes.

[0161] 24-hour ABPM was performed using a Mobil-O-Graph NG device at baseline, week 4, week 36, and week 40. Systolic and diastolic blood pressures were measured every 20 minutes between 06:00 and 23:00, and every 30 minutes between 23:00 and 06:00. Monitoring began between 06:00 and 11:00. Study Therapy

[0162] Part 1: Double-blind, randomized, parallel-group, placebo-controlled, 4-week trial. Subjects received (1:1:1 ratio) 25 or 12.5 mg of apremilast or placebo.

[0163] Part 2: Single-blind, single-arm, 32 weeks. All subjects received 25 mg of apremilast.

[0164] Part 3: Double-blind discontinuation. All subjects who completed Part 2 and entered Part 3 were re-randomized in a 1:1 ratio to receive either apremilast 25 mg or placebo. Main inclusion criteria:

[0165] Screening period:

[0166] (i) An ICF signed and dated prior to any study-mandated proceedings.

[0167] (ii) Male and female subjects; 18 years (or the year of majority in the specific country) or older.

[0168] (iii) The subject's medical records showed that BP was not controlled despite taking at least three background antihypertensive medications within 1 year before the screening visit.

[0169] (iv) Receipt of antihypertensive treatment from 3 different pharmacological classes at least 4 weeks before the screening visit (Visit 1).

[0170] (v) Mean SiSBP measured by uAOBPM ≥ 140 mmHg.

[0171] (vi) A diagnosis of RHT according to local medical practice is documented in the subject's medical record: Exclude secondary causes of hypertension (eg, serum aldosterone, plasma renin activity, biphasic / Doppler ultrasound, computed tomography angiography evaluation to exclude secondary causes of hypertension), Adherence to medication (e.g., checking and / or monitoring adherence to medication) to eliminate overt RHT.

[0172] (vii) Women of childbearing age are eligible for treatment only if they meet the following conditions: Negative screening and baseline (i.e., before randomization) pregnancy tests. ·Agree to undergo pregnancy testing during the study and within 30 days after termination of randomized study treatment. Agree to use contraceptive methods from the start of screening until at least 30 days after termination of randomized study treatment.

[0173] (viii) mean trough SiSBP measured by AOBPM ≥ 140 mmHg when switching from background antihypertensive medications (i.e., drugs from at least 3 different pharmacological classes) to standardized background antihypertensive therapy.

[0174] Run-in period (RI):

[0175] Switch to standard background antihypertensive therapy at least 4 weeks before the first RI visit.

[0176] The mean trough SiSBP measured by uAOBPM was ≥140 mmHg.

[0177] During randomization:

[0178] Standardized background antihypertensive therapy doses were stabilized for at least 1 week before the end of the RI period.

[0179] The mean trough SiSBP measured by uAOBPM was ≥140 mmHg.

[0180] Subjects had compliance (pill count) ≥ 80% to study treatment (ie, placebo) and compliance (pill count) ≥ 80% to standardized background antihypertensive therapy during the RI period. Main exclusion criteria :

[0181] Overt / pseudohypertension due to white coat effect, medical inertia, poor treatment compliance, or secondary causes of hypertension (except sleep apnea).

[0182] Confirmed severe hypertension (grade 3), defined as SiSBP ≥ 180 mmHg and / or SiDBP ≥ 110 mmHg measured by uAOBPM at two different time points.

[0183] Pregnant or lactating subjects.

[0184] Subjects were considered by the investigator to have clinically severe unstable heart disease at screening or in the past (subjects with severe or potential unstable heart disease were excluded).

[0185] Severe renal insufficiency.

[0186] Any known factor, disease, or clinically relevant medical or surgical condition that, in the opinion of the investigator, may pose a risk to the subject or interfere with treatment compliance, study conduct, or interpretation of the results.

[0187] Receiving any medication that may affect BP and / or receiving high-dose loop diuretic therapy (i.e., furosemide greater than 80 mg / day, or equivalent doses of other loop diuretics). end

[0188] The primary efficacy endpoint was the change in mean trough SiSBP measured as uAOBP from baseline to Week 4 of DB treatment, where baseline was defined as the last available measurement before the start of DB treatment.

[0189] The key secondary efficacy endpoint was the change in mean trough SiSBP measured as uAOBP from DB-WD baseline (last available measurement on or before Week 36) to Week 40.

[0190] Other secondary efficacy endpoints included Changes in mean trough sitting diastolic blood pressure (SiDBP) measured as uAOBP from baseline to Week 4 and from baseline to Week 40 for DB-WD. and changes in systolic / diastolic blood pressure as measured by ABPM, including changes in 24-h mean SBP and DBP from baseline to Week 4 of DB treatment, changes in daytime and nighttime mean SBP and DBP from baseline to Week 4, changes in 24-h mean SBP and DBP from DB-WD baseline (Week 36) to Week 40, and changes in daytime and nighttime mean SBP and DBP from DB-WD baseline (Week 36) to Week 40.

[0191] Safety assessments included (treatment-emergent) adverse events (TEAEs), including those leading to premature discontinuation of study treatment; adverse events of special interest (AESI): liver dysfunction, anemia (or hemodilution), edema / fluid retention, heart failure decompensation / exacerbation; treatment-emergent major adverse cardiovascular events (MACE) / MACE-plus, defined as cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke, or heart failure leading to hospitalization as confirmed by a central adjudication committee (CAC); as well as vital signs, weight, clinical laboratory assessments, and 12-lead electrocardiogram. Statistical analysis

[0192] In this design report, continuous endpoints were summarized by descriptive statistics, and categorical variables were summarized by numbers and percentages. For ordinal variables, stratified chi-square tests were used to compare categorical variables; for ordinal variables, chi-square tests were used to compare categorical variables. In addition, stepwise multivariable logistic regression was performed on patients with pseudo-RHT and randomized patients to identify predictors of pseudo-RHT among patient characteristics at screening (inclusion in the model when p < 0.05).

[0193] In the final analysis, three null hypotheses were tested (see Fig. S1 in the Data Supplement). The first two null hypotheses stated that there was no difference between aprecitentan and placebo in the mean change from baseline to week 4 in the mean trough SiSBP measured as uAOBP in the DB portion (H10 for aprecitentan 25 mg and H20 for aprecitentan 12.5 mg). result

[0194] The study found that compared with placebo, apremilast lowered blood pressure after 4 weeks of treatment, the efficacy was maintained and verified for 48 weeks, and was generally well tolerated with no major safety issues. Both the primary and key secondary endpoints achieved statistically significant and clinically meaningful results - the efficacy was consistent across multiple endpoints and blood pressure monitoring methods.

[0195] A total of 1965 patients were screened to confirm resistant hypertension and exclude pseudo-resistant hypertension. During the 12-week screening period, eligible patients were switched to standardized background antihypertensive therapy, i.e., a fixed-dose combination of a calcium channel blocker (amlodipine), angiotensin receptor blocker (valsartan), and a diuretic (hydrochlorothiazide) for at least 4 weeks and then entered a 4-week single-blind trial period. During this period, placebo was added to the background antihypertensive therapy. Patients with systolic BP persistently above 140 mmHg were then randomized to treatment part 1. Of the 1965 screened patients, 730 were randomized to treatment, with an overall failure rate of 63%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results suggest that the proportion of pseudo-resistant hypertension is high in patients with RHT. Randomized patients had a history of comorbidities such as diabetes (approximately 53%), ischemic heart disease (approximately 30%), stroke (approximately 23%), congestive heart failure (approximately 19%), and / or sleep apnea syndrome (approximately 14%). At screening, the subsequently randomized patients were receiving 3 (approximately 37%), 4 (approximately 46%), or equal to or more than 5 (approximately 17%) major antihypertensive therapies. These antihypertensive therapies included ACE inhibitors or ARBs (total approximately 98%: ACE inhibitors approximately 37% and ARBs approximately 61%); diuretics (total approximately 86%, of which approximately 11% were mineralocorticoid receptor antagonists (MRAs)); CCBs (approximately 83%); and beta-blockers (approximately 61%).

[0196] In Part 1, the first double-blind treatment period of 4 weeks, a total of 730 patients were randomly assigned to receive one tablet of aprexitentan 12.5 mg (N=243), 25 mg (N=243) or placebo (N=244) once daily. After 4 weeks of treatment, the primary endpoint of systolic blood pressure (trough value measured by unattended automated office blood pressure (uAOBP) device) was statistically and clinically meaningfully reduced in both the aprexitentan 12.5 mg group (p<0.005) and the 25 mg group (p<0.005) compared with placebo.

[0197] After a 4-week double-blind, placebo-controlled treatment period, patients entered Part 2, a single-blind treatment period in which all patients received 25 mg of aprexitentan for 32 weeks. During this treatment period, the mean reduction in systolic blood pressure from baseline was maintained in patients taking aprexitentan during Part 1. Patients who switched from placebo to aprexitentan rapidly achieved the same blood pressure reduction as in Part 1.

[0198] This was followed by a double-blind, placebo-controlled, randomized off-treatment period in Part 3, where 614 patients were re-randomized to receive either aprecitentan 25 mg or placebo for 12 weeks. After the 4-week off-treatment period, the key secondary endpoint of systolic blood pressure was significantly higher on placebo compared with aprecitentan 25 mg (p<0.0001). This replicated the treatment effect of aprecitentan and confirmed its durable blood pressure-lowering effect.

[0199] During the study period, reductions in systolic and diastolic blood pressure were assessed by unattended automated office blood pressure measurement, which was confirmed by 24-hour ambulatory blood pressure monitoring (ABPM), showing a reduction in BP throughout the entire 24-hour period, especially during the night.

[0200] Aprexitentan was generally well tolerated, with no major safety issues at either dose in this patient population, and discontinuation of study treatment due to adverse events was low during the first 4-week double-blind study period: 2.5% and 2.0% for aprexitentan 12.5 mg and 25 mg, respectively, compared with 0.8% for placebo. During the 4-week double-blind study period, treatment-emergent adverse events (TEAEs) occurred in 27.6% and 36.7% of patients treated with aprexitentan 12.5 mg and 25 mg, respectively, compared with 19.4% for placebo. Edema / fluid retention was the most common TEAE, occurring at an incidence of more than 3%, which was higher than placebo. No other additional safety findings were observed during the subsequent treatment period of a total of 48 weeks. Importantly, the overall incidence of major adverse cardiac events (MACEs) reflected the expected incidence in this patient population. During the entire study period, approximately 30% of patients experienced edema / fluid retention at some point, of which more than 95% were mild to moderate. Two of these adverse events (<1%) were serious (both for aprexitentan 25 mg). Only seven patients (<1%) discontinued treatment due to edema / fluid retention. Most of the edema / fluid retention occurred during the first 4 weeks of the double-blind study (9.1% and 18.4% in the aprexitentan 12.5 mg and 25 mg groups, respectively, and 2.1% in the placebo group).

[0201] Schlaich et al., Lancet 2022;400:1927–37 published detailed results of the PRECISION trial and provided relevant supplementary materials (both documents are incorporated herein by reference), as follows:

[0202] Patient characteristics were similar in all treatment groups at randomization and rerandomization. They were representative of patients with resistant hypertension with respect to age and comorbidities. Black or African American patients comprised 11% of all randomly assigned participants and 37% of U.S. participants (78 of 211), a higher than average distribution of black patients in the U.S. As previously reported, 63% of the randomly assigned patients were taking four or more antihypertensive medications at screening, and 63% were taking a beta-blocker. At randomization, 516 of 730 patients (71%) were receiving the highest dose of standardized background therapy (amlodipine 10 mg), and 423 of 730 patients (58%) continued to receive a beta-blocker.

[0203] The temporal course of office SBP and DBP in the three study parts illustrates the short-term (4 weeks) and sustained (up to 48 weeks) antihypertensive effects of aprexitentan. The primary endpoint was met after 4 weeks of treatment in double-blind part 1. At 4 weeks, the least square mean (SE) changes in office SBP were -15.3 (0.9) mmHg for aprexitentan 12.5 mg, -15.2 (0.9) mmHg for aprexitentan 25 mg, and -11.5 (0.9) mmHg for placebo, respectively, with differences from placebo of -3.8 (1.3) mmHg (97.5% CI, -6.8 to -0.8, p=0.0042) and -3.7 (1.3) mmHg (-6.7 to -0.8, p=0.0046), respectively. Both doses of aprexitentan reduced office DBP compared with placebo (-3.9 mmHg, 95% CI, -5.6 to -2.3, for the 12.5 mg dose; -4.5 mmHg, 95% CI, -6.1 to -2.9, for the 25 mg dose). Office SBP and DBP remained unchanged during part 2 in patients who had previously received aprexitentan, whereas SBP and DBP decreased during the first 2 weeks of part 2 in patients who had previously received placebo and then stabilized. In part 3, office SBP was significantly increased with placebo compared with aprexitentan after 4 weeks of treatment cessation (a key secondary endpoint) (5.8 mmHg, 95% CI, 3.7 to 7.9, p<0.0001). Office DBP was also increased with placebo compared with aprexitentan (5.2 mmHg, 95% CI, 3.8 to 6.6, p<0.0001). The difference between the two groups was maintained until week 48.

[0204] Results from all sensitivity and supportive analyses confirmed the robustness of the primary analysis. In particular, exclusion of patients for premature discontinuation of double-blind treatment, increased or escalated diuretic doses, or use of rescue medication for elevated blood pressure did not affect the primary and key secondary outcomes.

[0205] Results from ambulatory blood pressure monitoring confirmed those from office measurements. At the end of Part 1, aprecitentan reduced 24-hour ambulatory SBP (-4.2 mmHg, 95% CI, -6.2 to -2.1 at 12.5 mg; -5.9 mmHg, -7.9 to -3.8 at 25 mg) and DBP (-4.3 mmHg, 95% CI, -5.7 to -3.0 at 12.5 mg; -5.8 mmHg, 95% CI, -7.1 to -4.5 at 25 mg) after placebo correction. The placebo-corrected SBP-lowering effects at night were -5.1 mmHg and -7.4 mmHg at 12.5 mg and 25 mg, respectively, and during the day were -3.8 mmHg and -5.3 mmHg, respectively.

[0206] In part 3, 4 weeks after treatment discontinuation (week 40), 24-hour ambulatory SBP and DBP increased with placebo compared with apremilast (6.5 mmHg, 95% CI, 4.6 to 8.5; and 6.8 mmHg, 95% CI, 5.5 to 8.0, respectively).

[0207] In the primary and key secondary efficacy analyses, treatment effects consistent with those in the overall study population were observed in most subgroups. Notably, elderly patients (age ≥75 years), patients with macroalbuminuria (urine albumin-creatinine ratio (UACR) >300 mg / g), and patients with chronic kidney disease stages 3-4 (estimated glomerular filtration rate [eGFR] 15 to <60 mL / min per 1.73 m 2 ) had a greater reduction in SBP at week 4. There was no difference in treatment effect between patients who did or did not receive beta-blocker therapy at screening. With respect to race, black or African American patients tended to have a lower response to aprexitentan at week 4 and a greater response at week 40, 4 weeks after the placebo control was discontinued, compared with other patients. The ambulatory BP monitoring results in black or African American patients were consistent with those observed in the overall population in all parts of the study.

[0208] At the end of part 1, the urine albumin-to-creatinine ratio (UACR) decreased by 28% and 31% in the 12.5 mg and 25 mg apremilast groups, respectively, and increased by 5% in the placebo group. In part 2, blood pressure continued to decrease in all patients. In part 3, after 4 weeks of treatment discontinuation, the ratio increased in the placebo group compared with the apremilast group. 2 Compared with patients with CKD stages 3-4 or above, aprexitentan has a greater antiproteinuric effect in patients with CKD stages 3-4.

[0209] Aprexitentan was well tolerated. The most common adverse event was edema or fluid retention, which occurred mainly in the first four weeks of treatment. Before randomization, 70 of 730 patients (10%) had edema or fluid retention, and 35 of 730 patients (5%) had an adverse event of edema or fluid retention. The incidence of edema or fluid retention was higher with aprexitentan than with placebo and was dose-related (9.1%, 18.4%, and 2.1% of patients receiving aprexitentan 12.5 mg, 25 mg, and placebo, respectively, in the 4-week Part 1; 18.2% of patients receiving aprexitentan 25 mg in the 32-week Part 2; and 2.6% and 1.3% of patients receiving aprexitentan 25 mg and placebo, respectively, in the 12-week Part 3). Edema or fluid retention was generally mild to moderate and was treated with diuretics as needed. Edema or fluid retention was more common in patients with chronic kidney disease stages 3-4. Discontinuation of apremilast 25 mg due to edema or fluid retention was reported in seven patients in Parts 1-3 (1 of 245 patients in Part 1, 5 of 704 patients in Part 2, and 1 of 310 patients in Part 3).

[0210] A total of 13 deaths were reported, 2 of which were not treatment-emergent. Of the 11 treatment-emergent deaths, none were considered by the investigators to be related to study treatment; 5 were cardiovascular, 5 were related to COVID-19, and 1 patient died from procedural intestinal perforation.

[0211] Eleven patients required hospitalization for heart failure (2 of 245 patients [0.8%] who received apremilast 25 mg in part 1; 6 of 704 patients [0.9%] who received apremilast 25 mg in part 2; and 2 of 310 patients [0.6%] who received apremilast 25 mg in part 3 and 1 of 303 patients [0.3%] who received placebo); none of these events was fatal. All patients had a history of high-risk cardiovascular disease, including diabetes (11 of 11 [100%]), chronic kidney disease stages 3 to 4 (6 of 11 [55%]), and preexisting heart failure (5 of 11 [45%]). Two of 11 patients (18%) discontinued study treatment because of heart failure. Major cardiovascular events included five cardiovascular deaths.

[0212] No signs of hepatotoxicity were observed. Decreases in hemoglobin concentrations and increases in estimated plasma volume were similar for both doses of aprexitentan in part 1 (hemoglobin concentrations -8.0 g / L, -8.5 g / L, and -0.4 g / L for aprexitentan 12.5 mg, aprexitentan 25 mg, and placebo, respectively; estimated plasma volume 10.5%, 11.2%, and 0.51%, respectively), stabilized in part 2, and reversed after discontinuation of the drug in part 3. N-terminal pro-natriuretic peptide (NT-proBNP) and mid-pro-atrial natriuretic peptide (MR-proANP) increased slightly in part 1 with aprexitentan, then stabilized in part 2 and reversed in part 3. In part 1, both doses of aprexitentan resulted in a modest increase in body weight, whereas placebo resulted in a decrease in body weight. Compared with placebo, eGFR decreased slightly in the aprecitentan group in part 1, stabilized in part 2, and decreased further in the aprecitentan group in part 3, whereas it remained stable in the placebo group. Heart rate decreased slightly in part 1, which was evident in all treatment groups, and remained the same in part 2.

[0213] Schlaich et al. further discussed that in the double-blind part 1, a significant reduction in the urine albumin-to-creatinine ratio of 28% and 31% was observed with the 12.5 mg and 25 mg apremilast doses, respectively, whereas the urine albumin-to-creatinine ratio increased by 5% with the placebo dose. 2 The antiproteinuria effect of aprexitentan tended to be greater in patients with CKD stages 3-4 compared with patients with CKD ≥50 mg (-46% vs -26%), perhaps highlighting the potential of aprexitentan to reduce organ damage even in patients with moderate to severe CKD, in whom blood pressure control is particularly difficult to achieve. Importantly, the antiproteinuria effect was sustained during the single-blind part 2, during which all participants received 25 mg of aprexitentan. Additional data from the PRECISION trial:

[0214] Between-treatment analyses of changes from baseline in 24-hour, daytime, and nighttime SBP / DBP at Weeks 4 and 40 demonstrated significant and consistent reductions in SBP / DBP with aprexitentan compared with placebo. The difference in mean nighttime SBP (-6.6 mmHg) observed with aprexitentan 25 mg at Week 4 was particularly clinically meaningful compared with placebo.

[0215] The antiproteinuric effect of aprexitentan (i.e., UACR reduction of 30% and 34% in the aprexitentan 12.5 mg and 25 mg groups, respectively) was demonstrated as early as Week 4 in this study and was maintained through Week 4 of treatment, whereas no change was observed with placebo. This effect was more pronounced in subjects with Stage 3-4 CKD (-26% in the aprexitentan 12.5 mg group and -45% in the 25 mg group) and in subjects with microalbuminuria at baseline (-43% in the 12.5 mg group and -45% in the 25 mg group). The greatest effect was observed in subjects with macroalbuminuria (-48% for 12.5 mg and -61% for 25 mg).

[0216] Considering all available data for the overall population and subgroups of special interest, there was an exposure and dose-response relationship between 12.5 mg and 25 mg for all secondary BP efficacy endpoints at Week 4: In the overall population, aprecitentan 25 mg resulted in greater reductions in all BP endpoints (compared with aprecitentan 12.5 mg) except for the primary endpoint. The advantage of 25 mg over 12.5 mg was particularly evident in nighttime blood pressure (collected by ABPM). And nighttime blood pressure is a well-known major predictor of cardiovascular prognosis; The difference between 25 mg and 12.5 mg was particularly pronounced in the subpopulations of patients with stage 3-4 CDK and black or African American patients, who require a high level of medical care when their hypertension is difficult to control. Dose response in subpopulations:

[0217] Consistent dose responses were observed for all of the above endpoints, including an increase in percent BP reduction with the 25 mg dose compared with the 12.5 mg dose, in both subpopulation groups: (i) CKD stages 3-4 and (ii) blacks or African Americans.

[0218] In blacks or African Americans, aprexitentan 25 mg resulted in greater least squares (LS) mean reductions in BP from baseline to week 4 for all endpoints compared with aprexitentan 12.5 mg. Additional gains in ABPM (64% to 145%) were observed with 25 mg compared with 12.5 mg in this subpopulation, with differences as high as -5.90 mmHg (i.e., >100% further reduction in nocturnal SBP with 25 mg compared with 12.5 mg).

[0219] In subjects with stage 3-4 CKD, apremilast 25 mg resulted in greater least squares (LS) mean reductions in blood pressure from baseline to week 4 for all endpoints compared with apremilast 12.5 mg, with a difference of up to -5.88 mmHg for the primary endpoint, SiSBP (representing a further 44% reduction compared with 12.5 mg). Dose-response relationship of UACR:

[0220] In a population with uncontrolled hypertension (mean age 62 years, obesity [69.3% of subjects], >50% of subjects with diabetes, 22% of subjects with stage 3-4 CKD), it is important to assess UACR. The PRECISION trial did not impose any inclusion criteria for UACR. The geometric mean UACR at baseline in the overall population was 26.6 mg / g. At week 4, placebo-corrected reductions in UACR were 30% and 34% with aprecitentan 12.5 mg and 25 mg, respectively. However, in the subgroup of subjects with macroalbuminuria (UACR >300 mg / g, 12.6% of subjects), a clear dose-response relationship was observed, with placebo-corrected reductions of 48% and 61% with 12.5 mg and 25 mg, respectively.

Claims

1. A method for treating hypertension, including uncontrolled and refractory hypertension, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a clinically effective amount of aprexitentan or a pharmaceutically acceptable salt thereof.

2. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to claim 1, wherein the subject in need is a subject receiving standard background therapy, wherein the background therapy includes first-line therapy suitable for the prevention or treatment of hypertension, such as angiotensin receptor blockers (ARBs) or ACE inhibitors, especially further combined with calcium channel blockers (CCBs) and / or diuretics, and optionally further combined with beta-blockers, as hypertension treatment.

3. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to claim 1 or 2, wherein aprexitentan is administered in combination with at least three other antihypertensive drugs independently selected from the following group: - angiotensin receptor blockers (in particular valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan), or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; - calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, pranidipine), or pharmaceutically acceptable salts thereof; - diuretics, including loop diuretics such as furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including aldosterone antagonists such as spironolactone, eplerenone or finerenone, or aldosterone synthase inhibitors; carbonic anhydrase inhibitors, including acetazolamide and mesotrione; in particular thiazide diuretics (thiazide-like diuretics), such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferably thiazide diuretics, in particular chlorthalidone or hydrochlorothiazide); and - beta-blockers (beta-adrenergic blockers), particularly acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release).

4. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method of any one of claims 1 to 3, wherein administration of the clinically demonstrated effective amount of aprexitentan results in a reduction in systolic blood pressure of at least about 15 mmHg from baseline after 4 weeks of treatment, wherein the reduction is measured at trough by unattended automated office blood pressure measurement (uAOBPM).

5. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to any one of claims 1 to 4, wherein after said initial 4 weeks of treatment, said clinically demonstrated effective amount of aprexitentan is administered for an additional 32 weeks such that at least the mean reduction in systolic blood pressure from baseline is maintained for such additional 32 weeks.

6. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method of claim 4, wherein a clinical effect on systolic blood pressure is demonstrated after a 4-week rest period, wherein the mean systolic blood pressure of subjects administered a placebo is increased compared to the mean systolic blood pressure of subjects who continue to be administered aprexitentan at a dose of 25 mg per day; wherein, The increase is at least about 6 mmHg; wherein the increase is measured at trough values ​​by unattended automated office blood pressure measurement (uAOBPM).

7. Aprexitentan or a pharmaceutically acceptable salt thereof for use according to any one of claims 4 to 6, wherein the clinical effect of blood pressure reduction is demonstrated by a mean reduction in blood pressure from baseline after 4 weeks of treatment, wherein the reduction is measured by 24-hour ambulatory blood pressure monitoring (24hABPM); - a decrease in systolic blood pressure of at least about 6 mmHg, and / or Diastolic blood pressure drops by at least about 6 mmHg, wherein the clinically proven effective amount of aprexitentan is 12.5 mg per day; or - a decrease in systolic blood pressure of at least about 8 mmHg, and / or Diastolic blood pressure drops by at least about 7 mmHg, The clinically proven effective amount of aprexitentan is 25 mg per day.

8. Aprexitentan or a pharmaceutically acceptable salt thereof for use according to any one of claims 4 to 6, wherein the clinical effect of blood pressure reduction is demonstrated by a mean reduction in blood pressure from baseline after 4 weeks of treatment, wherein the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM); - a decrease in systolic blood pressure of at least about 6 mmHg, and / or Diastolic blood pressure drops by at least about 6 mmHg, wherein the clinically proven effective amount of aprexitentan is 12.5 mg per day; or - a decrease in systolic blood pressure of at least about 8 mmHg, and / or Diastolic blood pressure drops by at least about 7 mmHg, The clinically proven effective amount of aprexitentan is 25 mg per day.

9. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to any one of claims 1 to 8, wherein administration of the clinically demonstrated effective amount of aprexitentan results in a placebo-corrected mean reduction in blood pressure after 4 weeks of treatment, wherein the reduction is measured by 24-hour ambulatory blood pressure monitoring (24hABPM); wherein - A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, wherein the clinically proven effective amount of aprexitentan is 12.5 mg per day; or - A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, The clinically proven effective amount of aprexitentan is 25 mg per day.

10. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to any one of claims 1 to 8, wherein administration of the clinically demonstrated effective amount of aprexitentan results in a placebo-corrected mean reduction in blood pressure after 4 weeks of treatment, wherein the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM); wherein - A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 4 mmHg, The clinically proven effective amount of aprexitentan is 12.5 mg per day; in, In particular, the clinically proven effective amount of aprexitentan is administered once daily in the morning; or - A decrease in systolic blood pressure of at least about 4 mmHg, and / or Diastolic blood pressure drops by at least about 5.5 mmHg, The clinically proven effective amount of aprexitentan is 25 mg per day; In particular, the clinically proven effective amount of the aprexitentan is administered once a day in the morning.

11. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method of any one of claims 4 to 6, wherein the reduction in blood pressure is demonstrated after a 4-week rest period, wherein the mean blood pressure of subjects administered a placebo is increased compared to the corresponding mean blood pressure of subjects who continue to be administered aprexitentan at a dose of 25 mg per day; wherein the increase in mean blood pressure of subjects administered a placebo is measured by nocturnal ambulatory blood pressure monitoring (nocturnal ABPM); wherein - An increase in systolic blood pressure of at least about 8.5 mmHg, and / or An increase in diastolic blood pressure of at least about 7.5 mmHg; in, In particular, aprexitentan is administered once daily in the morning.

12. Aprexitentan or a pharmaceutically acceptable salt thereof for use in a method according to any one of claims 1 to 11, wherein the method for treating hypertension in a subject in need thereof comprises administering to the subject a pharmaceutical composition of aprexitentan in a clinically proven safe and clinically proven effective amount, wherein the hypertension includes refractory hypertension; In particular, the clinically proven safe and clinically proven effective amount of aprexitentan is administered once daily in the morning.

13. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to any one of claims 1 to 12, wherein the clinically proven effective amount of aprexitentan, respectively the clinically proven safe and clinically proven effective amounts of aprexitentan, is 12.5 mg or 25 mg of aprexitentan per day; wherein, In particular, the clinically proven effective amount of aprexitentan, respectively the clinically proven safe and clinically proven effective amount of aprexitentan, is administered once a day in the morning.

14. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to any one of claims 1 to 12, wherein the clinically proven effective amount, respectively the clinically proven safe and clinically proven effective amount of aprexitentan is 12.5 mg of aprexitentan per day; wherein, In particular, the clinically proven effective amount of aprexitentan, respectively the clinically proven safe and clinically proven effective amount of aprexitentan, is administered once a day in the morning.

15. Aprexitentan or a pharmaceutically acceptable salt thereof for use in the method according to any one of claims 1 to 12, wherein the clinically proven effective amount, respectively the clinically proven safe and clinically proven effective amount of aprexitentan is 25 mg of aprexitentan per day; wherein, In particular, the clinically proven effective amount of aprexitentan, respectively the clinically proven safe and clinically proven effective amount of aprexitentan, is administered once a day in the morning.

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