Use of 4-pyrimidine sulfamide derivatives for the treatment of hypertension

Abstract

The present invention relates to a compound, aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yl-oxy)-ethoxy]-pyrimidin-4-yl}-sulfamide; and its use as an endothelin receptor antagonist in a method of treating hypertension, including resistant hypertension in a subject, the use comprising administering to a subject in need thereof a pharmaceutical composition comprising a clinically effective amount of aprocitentan or a pharmaceutically acceptable salt thereof. 【Chemical 1】 TIFF2025519101000003.tif76153

Description

Technical Field

[0001] The present invention relates to a compound, aprocitentan, and its use as a clinically proven endothelin receptor antagonist for the treatment of hypertension, including treatment-resistant and refractory hypertension.

Background Art

[0002] Aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide (hereinafter also referred to as "compound"), has the formula I.

[0003]

Chemical Formula

[0004] The compound of formula I, also known by the above name and designated as ACT-132577, is an endothelin receptor antagonist. The compound of formula I is a member of a structural family that was comprehensively disclosed previously in WO02 / 053557. In particular, the compound of formula I exhibits endothelin receptor antagonist activity while showing a much longer half-life and a much shorter clearance in vivo compared to the corresponding alkylated derivatives. Therefore, the compound of formula I is particularly suitable for long-acting pharmaceutical compositions, as disclosed in WO2009 / 024906.

[0005] By virtue of its ability to inhibit endothelin binding, the compounds of formula I can be used for the treatment of endothelin-related diseases associated with increased vasoconstriction, proliferation or inflammation caused by endothelin that occurs in many cardio-renal-metabolic diseases. Examples of such endothelin-related diseases are hypertension, particularly including difficult-to-control hypertension and resistant hypertension. Further examples of endothelin-related diseases disclosed in, for example, WO2009 / 024906, WO2018 / 153513 or WO2018 / 154101 are pulmonary hypertension; coronary artery disease; heart failure; renal and myocardial ischemia; chronic kidney disease (CKD) [particularly, CKD at stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (particularly, stage 3 or 4 CKD), especially CKD caused by / associated with hypertension or diabetes (particularly CKD at these stages) (including diabetic kidney disease (DKD) associated with hypertension); diabetes and diabetes-related diseases such as diabetic arterial disease, diabetic nephropathy, diabetic retinopathy or diabetic vasculopathy; having diabetes Reducing the risk of major cardiovascular events (such as heart failure (HF), myocardial infarction, stroke or cardiovascular death) in patients being treated, particularly in patients with diabetes associated with at least one other cardiovascular risk factor (e.g., hypertension, dyslipidemia, thrombotic events); treatment and prevention of diabetic complications; (acute and chronic) renal insufficiency; glomerulonephritis; connective tissue diseases; atherosclerosis; obliterative arterial diseases including chronic obliterative (atherosclerotic) arteriopathy; digital ulcers; reducing the risk of lower limb / extremity amputation in patients with diabetes and / or smokers and / or having atherosclerosis; heart failure (HF) defined as particularly including, among others, HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%) and HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%) and particularly chronic HF; reducing the risk of major cardiovascular events (such as heart failure (HF), myocardial infarction, stroke or cardiovascular death) in patients with cardiovascular risk (e.g., patients with coronary artery disease and / or patients presenting clinical signs of congestive heart failure); angina; and diastolic dysfunction. The compound of formula I can also be used for the treatment or prevention of cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, portal hypertension; restenosis after balloon or stent angioplasty; inflammation; gastric ulcer and duodenal ulcer; cancer; melanoma; prostate cancer; prostatic hyperplasia; erectile dysfunction; eclampsia; hearing loss; cataract; chronic bronchitis; asthma; pulmonary fibrosis; gram-negative sepsis; shock; sickle cell anemia; renal colic; glaucoma; complications after vascular or cardiac surgery or after organ transplantation; complications of cyclosporine treatment or equivalent treatments showing a nephrotoxic profile; pain; hyperlipidemia; and other diseases currently known to be related to endothelin.

[0006] 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., BP cannot be lowered to a pre-determined threshold) despite the simultaneous administration of three antihypertensive therapies from different pharmacological classes, including diuretics, at maximum or optimal doses. That is, patients with resistant hypertension include those whose blood pressure is controlled by the use of more than three medications. That is, patients whose blood pressure is controlled but who require four or more medications for this purpose should be considered treatment-resistant (see, for example, Mancia et al., J. Hypertens. (2013)).

[0007] Clinical trials have shown that endothelin receptor antagonists (ERAs) may have significant therapeutic effects in patients with hypertension and / or kidney disease, regardless of whether diabetes is associated. Through the effects of endothelin-1 (ET-1) in mediating plaque formation, thrombosis, vasoconstriction and vascular hypertrophy, and since ET-1 enhances the actions of other systems, particularly the renin-angiotensin and sympathetic nervous systems and / or insulin signaling, ET-1 probably plays a role in the pathological mechanism of chronic diabetic arteriopathy. Therefore, ERAs may be beneficial in the treatment of obliterative arterial occlusive diseases including diabetic arteriopathy by having acute (peripheral vasodilation) and chronic (vasodilation, improvement of vascular structure, regulation of sympathetic action, antithrombotic, anti-inflammatory) effects. In a clinical network meta-analysis of trials conducted on adults with diabetes and CKD (157 trials including 43,256 patients), ERAs were ranked as the most effective drugs for the prevention of end-stage kidney disease (S.C. Palmer et al., Lancet (2015), 385(9982):2047-2056). However, the beneficial effects of treatment need to outweigh the potential side effects such as the potential risk of the paradoxical effects commonly associated with ERAs. Additionally, and more importantly, selective ET antagonists as well as dual antagonists of both ET A and ET A and ET B receptors may cause fluid retention, a common side effect associated with many ERAs that have been tested in the past, and sometimes (e.g., when not treatable with diuretics) cause serious (exaggerated) major adverse cardiac events such as heart failure or death. The risk-benefit balance is (e.g., for the dual antagonists bosentan and macitentan, ET AAs reflected in the successive past approvals for ERAs such as ambrisentan, a selective antagonist, for indications such as pulmonary hypertension, in most cases, it is advantageous to use ERAs for treatment, but it has been stated that ERAs are not suitable for the treatment of primary hypertension (Laffin et al., Seminars in Nephrology 2015, 35, 168 - 175). Also, when considering the possibility of treating difficult - to - control hypertension and resistant hypertension (rHT) or other hypertension - related diseases with ERAs, problems with side effects such as fluid retention will remain.

[0008] ET A Darusentan, a selective endothelin receptor antagonist, is under development for the treatment of resistant hypertension (rHT) (see also Bakris et al., Hypertension 2010, 56, 824 - 830, WO2007 / 098390). In a 14 - week phase 3 trial in patients with rHT, darusentan showed efficacy for the reduction of ambulatory blood pressure, but was unable to show significant treatment efficacy for systolic blood pressure, the primary endpoint. Patients were eligible to participate if they had treatment - resistant hypertension (systolic blood pressure higher than 140 mmHg) despite treatment at optimal doses with more than three antihypertensive drugs from different drug classes, including diuretics. A minimum dose of 25 mg per day of hydrochlorothiazide (or an equivalent other thiazide diuretic) was required. Although diuretic treatment could be intensified at the discretion of the study investigators during the trial to manage fluid retention, the most frequent adverse event associated with darusentan was fluid retention / edema, which was 28% compared to 12% in each of the other groups. More patients discontinued the trial due to adverse events with darusentan compared to placebo.

[0009] ET AAvosentan, a selective ERA, showed a significant treatment effect in a trial examining the effect of avosentan on the progression of overt diabetic nephropathy in patients with type 2 diabetes, but was associated with a significant increase in trial drug discontinuation due to adverse events mainly related to fluid overload and congestive heart failure (Mann et al., "Avosentan for Overt Diabetic Nephropathy" J Am Soc Nephrol. 2010, 21(3):527-535.). The composite primary outcome was time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in the albumin / creatinine ratio (ACR) and cardiovascular outcomes. The trial did not detect a difference in the frequency of primary outcomes between groups. Avosentan significantly reduced the ACR. After a median follow-up period of 4 months (maximum 16 months), the trial was terminated due to excess cardiovascular events with avosentan, and the authors stated that, "At doses of 25-50 mg, the selectivity of avosentan for the ET A receptor is lower, and thus, potential fluid shifts from the intravascular to the extravascular space may have caused sodium and water retention and peripheral vasodilation." Concluded. Mixed-type ET A / B receptor antagonists have previously been found to be weak or ineffective against proteinuria, so the effect on albuminuria was presumably due to inhibition of renal ET A receptors. According to the authors, the hypothesis that avosentan blocks ET B receptors at higher doses is further supported by data showing the natriuretic effect of selective ET A receptor blockade in people treated with ACE inhibitors. Thus, the natriuretic effect / fluid retention that presumably ultimately led to trial discontinuation was likely due to blockade of both ET A and ET B receptors, which discourages the use of ERAs that act on both in such clinical situations.

[0010] Additional preclinical data showed that the combination of enalapril, an ACE inhibitor, with ET A The synergistic effect of selective ERAs on blood pressure was abolished by co-blockade of the ET B receptor (Goddard et al., J. Am. Soc. Nephrol. 2004, 15, 2601 - 2610), thus discouraging the use of dual-acting ERAs in clinical situations where an ACE inhibitor is required as background therapy.

[0011] In a review in "Endothelin antagonists for diabetic and non-diabetic chronic kidney disease" (Br J Clin Pharmacol (2012), 76:4, 573 - 579), D.E. Kohan et al. stated that "In general, in contrast to binding ET A / B receptor antagonists, there is a strong opinion that ET A receptor antagonists are preferable for the treatment of CKD." Three years later, regarding a study published in Clin J Am Soc Nephrol (2015), 10:1568 - 1574, Kohan et al. concluded that "The fluid retention effect of ERAs is probably related to a direct effect on sodium transport in the renal tubules, while the anti-proteinuric effect of ERAs is likely related to an action on the vasculature and / or glomeruli. Ultimately, the reduction in proteinuria itself by ERAs is expected to favorably affect renal fluid excretion; however, ERAs can still promote fluid retention via another effect on sodium and water reabsorption in the tubules."

[0012] A general summary of testing ERA for various indications including diabetic and non-diabetic CKD and rHT is described in WO2016 / 073846. WO2016 / 073846 describes further examples where fluid retention may have caused an increase in side effects of ERAs bosentan, tezosentan, ambrisentan and atrasentan. WO2016 / 073846 concludes by using predictors of fluid retention to treat CKD with an ERA, particularly an ET A selective ERA, atrasentan; the method comprising determining the risk of fluid retention when administering an ERA to a subject; and administering an ERA to the subject when the risk is at an acceptable level. The detailed test protocol of the Phase 3 clinical trial (SONAR) to evaluate the effect of atrasentan, a test compound for the progression of kidney disease in patients with stage 2-4 chronic kidney disease and type 2 diabetes when added to standard treatment, was published by Heerspink et al., Diabetes Obes.Metab. 2018, 1-8. This protocol reflects the importance of dose optimization and co-control of sodium retention / fluid retention in the test design, and as a result, the test design requires "selection of individuals with a high risk of the disease (prognostic enrichment) and, in addition, showing a good response to the test treatment (predictive enrichment)". However, on December 1, 2017, AbbVie announced a strategic decision to discontinue the SONAR trial. The press release states that "ongoing monitoring of renal events observed in the trial has shown that the endpoints are considerably fewer than expected to date and are considered to have an adverse impact on verifying the hypothesis of the SONAR trial. Therefore, AbbVie has determined that it is not justifiable to continue patients' participation in the trial." The decision to prematurely discontinue the SONAR trial is unrelated to any safety concerns.

[0013] ​Contrary to the conclusions drawn from the avosentan trials, preclinical and clinical data show that the ET A selective antagonists sitaxentan and ambrisentan have a higher risk of fluid retention than the dual ERAs bosentan and macitentan (Vercauteren et al., JPET 2017, 361, 322-333). The authors state that their findings "suggest that in rats, the stimulation of the ET A receptor itself by functional antagonism is not the case, but rather that the stimulation of the non-blocked ET A receptor in the presence of an ET B receptor antagonist may be harmful and that blockade of both receptors does not necessarily cause more water retention than blockade of one receptor." They then speculate that "combining an increase in plasma volume with an increase in vascular permeability would explain the observations obtained with ET A selective antagonists." The authors conclude that "while there has been an increase in mortality related to fluid retention in some clinical trials using ET A selective antagonists, this has not been observed with dual ERAs. However, under conditions of existing fluid retention or increased arginine vasopressin (AVP), such as in chronic heart failure or chronic kidney disease, dual ERAs caused significant fluid retention."

[0014] Aprosartan, an ERA that effectively blocks both endothelin receptors, has been shown in a Phase 2 clinical trial to effectively control blood pressure in subjects with essential hypertension (Aprosartan was administered as monotherapy, i.e., without background antihypertensive therapy.) (Actelion Pharmaceuticals Ltd, press release dated May 22, 2017; P. Verweij et al., 2020: https: / / www.ahajournals.org / doi / full / 10.1161 / HYPERTENSIONAHA.119.14504). In this trial, the efficacy, safety, and tolerability of a once-daily oral regimen of four dose levels of aprosartan (5, 10, 25, and 50 mg) were evaluated to identify the optimal dose for further testing. In this trial, 490 randomized patients were given aprosartan, 5, 10, 25, 50 mg, placebo, or lisinopril 20 mg once daily. After 8 weeks of treatment, the mean decrease in diastolic blood pressure from baseline - measured at trough using a novel automated office blood pressure device - was statistically significantly and dose-dependently in the range of 6.3 mmHg to 12.0 mmHg for the aprosartan groups, compared with a 4.9 mmHg decrease in the placebo group and an 8.4 mmHg decrease in the lisinopril group (in the per-protocol population consisting of 410 patients). The decrease in systolic blood pressure was statistically significantly and dose-dependently in the range of 10.3 mmHg to 18.5 mmHg for the aprosartan groups, and 7.7 mmHg and 12.8 mmHg in the placebo and lisinopril groups, respectively. These findings were confirmed in all randomized patients (by the Intent-to-Treat principle) and by 24-hour ambulatory blood pressure monitoring under free-living conditions. 327 patients were included in the safety population in the aprosartan group, 82 patients in the placebo group, and 81 patients in the lisinopril group.Aprositen tan showed good tolerance at all four doses in this patient population. The discontinuation of the test treatment due to adverse events ranged from 1.2% to 3.7% in the aprositentan group, compared with 6.1% in the placebo group and 3.7% in the lisinopril group. The overall frequency of adverse events was similar to that observed in the placebo group. In two cases, liver enzymes increased above three times the upper limit of the normal range, one case in the placebo group and one case in the aprositentan 5m. g group. Peripheral edema was observed in four cases, two cases in the aprositentan 25 mg group and two cases in the aprositentan 50 mg group. The mean body weight showed no change from baseline in the aprositentan 5 and 10 mg groups, increased by 0.4 kg in the aprositentan 25 and 50 mg groups, increased by 0.3 kg in the placebo group, and decreased by 0.3 kg with lisinopril. As expected, in the aprositentan group, there was a dose-correlated decrease in hemoglobin concentration (an indicator of haemodilution) from baseline (ranging from 1.3 to 6.7 g / L), while in the placebo and lisinopril groups, there were increases of 2.2 and 0.1 g / L, respectively (see also P. Gueneau de Mussy et al.; Clin Pharm & Therapeutics 2020; doi:10.1002 / cpt.2043).

[0015] Therefore, unlike the method of WO2016 / 073846, for aprositentan, when used for the treatment of hypertension-related diseases, especially resistant hypertension, a risk assessment for fluid retention and / or dose reduction to reduce side effects may not be necessary. Therefore, aprositentan has a pharmacological profile that may be different from that of the mainly ET A selective antagonists tested so far in resistant hypertension or chronic kidney disease in diabetic and non-diabetic patients. Following the positive results of the Phase 2 clinical trial, aprositentan advanced to a Phase 3 clinical trial (NCT03541174): "A Research Study to "Show the Effect of Aprocitentan in the Treatment of Difficult to Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its Safety」(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 also refer to; both documents are incorporated by reference). The results of the PRECISION trial were announced in a press release by Idorsia Pharmaceuticals on May 23, 2022 (https: / / www.idorsia.com / media / news - details?newsId = 2758691). Subsequently, the results were published in a peer - reviewed journal on November 7, 2022 (Schlaich et al., Lancet 2022; 400:1927 - 37 and associated supplementary material, both of which are incorporated by reference herein), and the above publication was covered in a press release dated November 8, 2022 (https: / / www.idorsia.com / media / news - details?newsId = 2869821) and a webcast presentation.

[0016] Furthermore, in a hypertensive rat model, aprosartan has been found to have a synergistic pharmacological effect when combined with an angiotensin receptor blocker (ARB) such as valsartan, and to have a synergistic pharmacological effect in certain models when combined with an angiotensin-converting enzyme (ACE) inhibitor such as enalapril, and to have an additive pharmacological effect when combined with a calcium channel blocker (CCB) such as amlodipine (F. Trensz et al., 2019: https: / / doi.org / 10.1124 / jpet.118.253864). In particular , when combined with three antihypertensive therapies of different pharmacological classes (i.e., a fixed dose combination of valsartan / amlodipine / hydrochlorothiazide) containing valsartan, amlodipine, and a thiazide-class diuretic such as the commercially available Exforge HCT (registered trademark), aprosartan may provide an effect superior to, for example, spironolactone, which is an available standard add-on therapy. Furthermore, aprosartan has mainly been tested for ET in resistant hypertension and other endothelin-related diseases AIt may have a pharmacological profile different from that of selective antagonists. Therefore, when prescribed in combination with a standard background therapy generally having one or more antihypertensive therapies of different pharmacological classes, including angiotensin receptor blockers such as valsartan, calcium channel blockers such as amlodipine, and / or diuretics, particularly thiazide-class diuretics (thiazide-like diuretics) such as chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide or metolazone, aprocitentan, an ERA that causes effective dual blockade of endothelin receptors, may be particularly suitable for the treatment of (resistant) hypertension (WO2018 / 153513, WO2018 / 154101). Such combination therapy maintains a favorable side effect profile even at the optimal effective dose of aprocitentan and may provide superior blood pressure control compared to treatment with such antihypertensive therapy alone without the need for the risk assessment method of WO2016 / 073846 and / or dose reduction, for example, to reduce side effects associated with fluid retention.

[0017] A further standard background therapy, particularly for the treatment of patients with a history of hypertension, involves having a beta blocker (a sympathetic beta receptor blocker that blocks the effects of the hormone epinephrine (adrenaline)). Beta blockers cause the heart to beat more slowly with less force, thereby lowering blood pressure, assisting in the dilation of blood vessels, and improving blood flow in arteries.

[0018] Additional standard background therapies for the treatment of patients with a history of diabetes or diabetic kidney disease or patients with established cardiovascular disease include SGLT-2 inhibitors such as atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, tianagliflozin or tofogliflozin, which block glucose reabsorption in the kidney, increase glucose excretion, and lower blood glucose concentration. In addition to this well-characterized mechanism of action, SGLT-2 inhibitors lower blood pressure, reduce vascular stiffness, improve endothelial function, and have anti-inflammatory and anti-fibrotic properties similar to ERA (H.J. Heerspink et al., Circulation (2016), 134(10):752-772). This unique mechanism of action has led to the development and approval of several SGLT-2 inhibitors, including canagliflozin, dapagliflozin, and empagliflozin, all of which are indicated for the improvement of glycemic control in adults with type 2 diabetes. In addition, empagliflozin is indicated for the reduction of the risk of cardiovascular death in patients with established cardiovascular disease. For sotagliflozin, a dual SGLT-1 and SGLT-2 inhibitor, it has been reported that it is in clinical trials for type 1 diabetes.

[0019] Diabetes is often associated with heart failure (HF) and can contribute to its development. SGLT-2 inhibitors such as empagliflozin are also effective in HFpEF, where treatment options are very limited. May be appropriate for the treatment of chronic HF. 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 therapy. The results suggested improvements in cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for HF, and death from any cause. A post hoc analysis of patients who received a diagnosis of HF at baseline suggested a significant reduction in cardiovascular death, hospitalization for HF, 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 mechanism of action of SGLT-2 causes simultaneous inhibition of glucose and sodium uptake in the proximal renal tubule of the nephron, which is thought to result in a resetting of tubuloglomerular feedback that triggers the phenomenon of glomerular hyperfiltration. The effects of SGLT-2 inhibitors are thought to decrease with a reduction in plasma glucose levels or a decrease in glomerular filtration rate (GFR), and thus, SGLT-2 inhibitors inherently have a low risk of causing hypoglycemia. As a result, the properties of SGLT-2 inhibitors may open the way to treat HF, including HFpEF, in non-diabetic patients (P. Martens et al., “Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond” Curr Treat Options Cardio Med (2017) 19:23). Side effects associated with the pharmacological effects of SGLT-2 inhibitors can be volume loss / intravascular volume contraction, which may lead to symptoms of dehydration, hypovolemia, orthostatic hypotension or hypotension. Therefore, SGLT-2 inhibitors generally may induce an increase in hematocrit (Hct), an indicator of blood concentration, and an increase in blood viscosity, which is the supposed cause of vascular damage associated with atherosclerotic disease. Furthermore, data from large-scale clinical trials suggest that SGLT2 inhibitors may induce acute kidney injury and renal insufficiency, especially in patients prone to acute kidney injury, where hypovolemia, chronic kidney disease, congestive heart failure and concomitant drug therapy (diuretics, ACE inhibitors, ARBs and NSAIDs) should be considered. The pharmacological effects of SGLT-2 inhibitors on the kidney include an increase in serum creatinine and a decrease in eGFR.

[0020] The combination of apocynin and an SGLT-2 inhibitor would be of particular interest (WO2019 / 106066). The preliminary data obtained in the above PRECISION trial show that this available data, even considering the small size of the available trials: (a) confirm the significant effect of the treatment with apocynin on blood pressure data points (the clinical endpoint of this trial), whether alone in addition to standard antihypertensive background therapy or as background therapy in subjects receiving an SGLT-2 inhibitor and the said standard antihypertensive background therapy; (b) (i) improvement in the anti-proteinuric effect associated with kidney disease, CKD / DKD of this combination therapy; and (ii) It has been shown that it can be considered that it shows a slight decrease in hemoglobin value from baseline until week 36, indicating further potential clinical benefit of this combination therapy.

[0021] Hypertension is one of the most common cardiovascular risk factors, and its prevalence continues to increase. According to recent research, there are more than one billion people worldwide with hypertension, and this number has almost doubled in the past 40 years [Bin Zhou et al., The Lancet; 2017; 389(10064): 37-55]. While many patients with hypertension are successfully treated with various existing antihypertensive therapies, 10-20% of the hypertensive population still has high blood pressure despite using at least three antihypertensive agents (including diuretics) from different pharmacological classes at optimal doses, and hypertension guidelines [R.M. Carey et al., Hypertension, 2018; 72, pp.e53-e90; Noubiap, J.J. et al., He In the medical community, those with resistant hypertension are classified as such [Noubiap, J. J. et al., Heart 2019;105:98 - 105; Carey R. M. et al., Hypertension. 2019;73(2):424 - 431]. Certain populations are at particularly high risk of developing resistant hypertension in old age; these include 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, D. R. et al., Curr Opin Cardiol, 2012;27, 386 - 91; Khan, A. et al., Int J Hypertens, 2013;193010 - 193010]. By 2025, it is estimated that approximately 10 million patients in the United States and a similar number in Europe will be classified as having resistant hypertension [Noubiap, J. J. et al., Heart 2019;105:98 - 105; Carey R. M. et al., Hypertension. 2019;73(2):424 - 431; Lu Y et al., Hypertension. 2022;79(1):207 - 217]. Uncontrolled hypertension causes a variety of cardiovascular and renal adverse outcomes, including stroke, heart disease, and kidney failure. These co - morbidities increase the vulnerability of patients and the complexity of their treatment [Daugherty, S. L. et al., Circulation. 2012;125(13):1635 - 42; Kumbhani, D. J. 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 towards controlling blood pressure earlier, lower, and over 24 hours, including night and morning time periods. Management of nocturnal blood pressure is particularly important for preventing cardiovascular events, especially heart failure (K. Kario, Hypertension. 2018;71:997 - 1009). E. Dolan et al. found that the hazard ratio for nocturnal ambulatory blood pressure remained significant after adjustment for daytime ambulatory blood pressure.From these results, the authors conclude two important clinical messages: ambulatory measurement of blood pressure is superior to clinic measurement in predicting cardiovascular mortality, and nocturnal blood pressure best predicts outcome (E Dolan et al., Hypertension 2005, 46(1):156-161).

[0022] (Incorporated herein by reference) According to K. Kario, Hypertension. 2018;71:997-1009, the pattern of the circadian rhythm of BP can be evaluated, for example, by ambulatory BP monitoring (ABPM). In healthy subjects, nocturnal BP decreases by 10% - 20% compared to daytime BP (normal dipper pattern). This circadian rhythm of BP is determined in part by neurohumoral factors and the inherent rhythms of the central and peripheral clock genes that control the cardiovascular system, and in part by the sleep-wake behavioral pattern. Hypertensive patients without organ damage also show a dipper pattern; patients with organ damage tend to show a nondipper pattern (or a riser pattern where nocturnal BP is rather higher than daytime BP) with a small nocturnal BP decrease. Nocturnal BP decline is classified into four groups: riser, nondipper, dipper, and extreme dipper patterns. The definitions of these groups are based on nocturnal BP decline. Kario has shown that nocturnal hypertension and the nondipper / riser pattern of nocturnal BP are associated with psychocognitive dysfunction (cognitive impairment, apathy, falls and sedentary lifestyle, and stroke), hypertensive heart disease (left ventricular hypertrophy, reduced diastolic function), vascular damage (carotid It has been stated that it is a predisposing factor for the increase in carotid intima-media thickness, pulse wave velocity, and cardio ankle vascular index, and for the development of chronic kidney disease (CKD; decrease in glomerular filtration rate and urinary albumin / creatinine excretion ratio).

[0023] Burnier and Damianaki have stated that in patients with CKD, a reduced or reversed dipping pattern or masked and resistant hypertension is frequently seen and is also associated with poor cardiovascular and renal prognosis. Today's antihypertensive treatment options have been broadened by new drugs such as SGLT-2 inhibitors and novel non-steroidal mineralocorticoid receptor antagonists that can reduce existing renal and cardiovascular risks (Burnier and Damianaki; Circulation Research. 2023;132:1050-1063; incorporated herein by reference). The authors concluded that: "Hypertension is a major cardiovascular risk factor in the general population, but even more so in patients with CKD who have several other risk factors including reduced renal function. Patients with CKD are characterized by several specific BP characteristics and hypertensive phenotypes that should be accurately diagnosed to avoid misdiagnosis. For this purpose, out-of-office BP measurement, including during the night-time hours, is currently strongly recommended, and by using this more widely, it should be confirmed that BP is controlled during the day as well as at night. Today, BP is poorly controlled in a high percentage of patients with CKD, mainly due to elevated nocturnal BP."

Summary of the Invention

[0024] Therefore, aprocitentan, an ERA that causes effective dual blockade of endothelin receptors, is considered particularly suitable for the clinically proven and safe long-term treatment of (chronic) hypertension, especially (chronic) resistant hypertension. The treatment of resistant hypertension is generally understood to be carried out in combination with standard background therapies, such as, in particular, regulators of the renin-angiotensin system, such as ARBs or ACE inhibitors; CCBs; diuretics; and / or beta-blockers. Furthermore, the patient population diagnosed with such difficult-to-control or resistant hypertension is generally understood to be a frail patient population that generally has one or more comorbidities, particularly including diabetes, ischemic heart disease, stroke, congestive heart failure, and / or sleep apnea syndrome. In addition, additional comorbidities (associated or not associated with the above-mentioned comorbidities) can be CKD (e.g., CKD or CKD related to diabetes (DKD)). Therefore, in the case of specific comorbidities, particularly including diabetes, ischemic heart disease, congestive heart failure, and / or CKD (including DKD related to diabetes), additional background therapies, such as, in particular, SGLT-2 inhibitors, will be of particular interest in combination with different classes of antihypertensive agents that have been clinically proven to be safe and clinically effective, such as aprocitentan.

[0025] Aprocitentan or a pharmaceutically acceptable salt thereof is particularly useful for providing a clinically proven treatment for specific endothelin-related disorders, particularly hypertension, including difficult-to-control and resistant hypertension, which requires a significant and long-lasting reduction in systolic and diastolic blood pressure. In particular, it has been found to be useful when used in combination (in combination) with a standard background therapy for such hypertensive disorders or other active ingredients or therapeutic agents that are standard background therapies for diseases or disorders generally associated with hypertension, in subjects having one or more comorbidities.

[0026] Detailed Description of the Invention 1) A first aspect of the present invention is a method for treating an endothelin-related disorder, comprising administering to a subject in need of said treatment a pharmaceutical composition comprising an amount of aprocitentan or a pharmaceutically acceptable salt thereof that has been proven clinically effective, and hypertension including difficult-to-control and

[0027] resistant hypertension; chronic kidney disease (CKD) [in particular, CKD at stages 1 to 4 as defined in the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (in particular, CKD at stage 3 or 4)], and, in particular, CKD (diabetic kidney disease (DKD)) caused by / associated with and / or caused by / associated with diabetes (in particular at these stages); or a method for treating an endothelin-related disorder particularly including diabetes.

[0028] UACR is a biomarker of renal dysfunction and is monitored in patients with kidney disorders (Levey et al., Uses of GFR and albuminuria level in acute and chronic kidney disease. N Engl J Med. 2022;386(22):2120-28).

[0029] Such a method for treating CKD caused by / associated with hypertension and optionally further associated with diabetes (diabetic kidney disease (DKD)) (in particular CKD at stage 3 or 4) also means treating hypertension including difficult-to-control and resistant hypertension, said hypertension including the hypertension causing / associated with such CKD, and said CKD being optionally further associated with diabetes in addition to said hypertension.

[0030] 2) A further aspect relates to a method according to aspect 1), wherein the subject in need of the treatment method is a subject receiving standard background therapy (such standard background therapy is considered appropriate for the treatment of hypertension).

[0031] 3) A further aspect relates to a method according to aspect 2), wherein the standard background therapy is appropriate for the prevention or treatment of hypertension and is a first line therapy, particularly an angiotensin receptor blocker (ARB) or an ACE inhibitor as a treatment for hypertension, especially (furthermore) a calcium channel blocker (CCB) and / or a diuretic (particularly a thiazide-like diuretic) in combination (used in combination); optionally (furthermore) an angiotensin receptor blocker (ARB) or an ACE inhibitor in combination (used in combination) with a beta blocker.

[0032] Preferably, such standard background therapy, if present, has only one active ingredient which is a regulator of the renin-angiotensin system, i.e., either an ARB or an ACE inhibitor.

[0033] Furthermore, it is assumed that the beta blocker is a standard background therapy recommended for subjects with a history of cardiac comorbidities such as ischemic heart disease and / or congestive heart failure.

[0034] 4) A further aspect is that the standard background therapy is: - an angiotensin receptor blocker (particularly valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or, an ACE inhibitor (particularly enalapril, ramipril, quinapril (q quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril), or a pharmaceutically acceptable salt thereof; and / or, - a calcium channel blocker (in particular, amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; and / or, - a diuretic including a loop diuretic such as furosemide, bumetanide, ethacrynic acid, torsemide; a potassium-sparing diuretic including an aldosterone antagonist or an aldosterone synthase inhibitor such as spironolactone, eplerenone or finerenone; a carbonic anhydrase inhibitor including acetazolamide and methazolamide; in particular, a diuretic of the thiazide class (thiazide-like diuretic) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone; (a preferred diuretic is a thiazide-like diuretic, in particular chlorthalidone or hydrochlorothiazide.); and / or, - Beta blockers (sympathetic beta receptor blockers), in particular, acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); Regarding the method of embodiment 2) having; Such standard background therapy has at least one (particularly 1 to 4 kinds) of the above standard background therapy agents, and in addition, may have the above further background therapy agents. Such further background therapy agents shall have different pharmacological actions, such as further diuretics with different pharmacological actions.

[0035] 4a) Therefore, the first sub - embodiment of this embodiment 4) is that the standard background therapy is: - An angiotensin receptor blocker (particularly valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or, An ACE inhibitor (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril,trandolapril, cilazapril), or a pharmaceutically acceptable salt thereof; and / or, - A calcium channel blocker (particularly amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; and / or, - An aldosterone antagonist such as spironolactone, eplerenone or finerenone; or, an aldosterone synthase inhibitor (such as baxdrostat, etc.); and / or - A diuretic selected from the following: -- A loop diuretic containing furosemide, bumetanide, ethacrynic acid or torsemide; -- A carbonic anhydrase inhibitor containing acetazolamide or methazolamide; -- In particular, a diuretic of the thiazide class (thiazide-like diuretic) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide-like diuretics, especially chlorthalidone or hydrochlorothiazide); or, -- A potassium-sparing diuretic that is not an aldosterone antagonist or an aldosterone synthase inhibitor (an example is amiloride); - A beta-blocker (sympathetic nerve beta-receptor blocker), in particular, acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); Relates to the method of embodiment 2) having [in particular, the standard background therapy having at least two (especially three or four) other antihypertensive drugs selected from the group consisting of the above].

[0036] 4b) Therefore, the second sub-aspect of this aspect 4) is that the standard background therapy is: - An angiotensin receptor blocker (in particular, valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or, An ACE inhibitor (in particular, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril,trandolapril, cilazapril), or a pharmaceutically acceptable salt thereof; and / or, - A calcium channel blocker (in particular, amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; and / or, - A loop diuretic including furosemide, bumetanide, ethacrynic acid, torsemide; and / or, - A further diuretic selected from the following: -- A potassium-sparing diuretic (e.g., amiloride) that is not an aldosterone antagonist or an aldosterone synthase inhibitor; -- An aldosterone antagonist such as spironolactone, eplerenone or finerenone; or, an aldosterone synthase inhibitor (such as baxdrostat, etc.); -- A carbonic anhydrase inhibitor including acetazolamide and methazolamide; or, -- In particular, a thiazide-class diuretic (thiazide-like diuretic) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (a preferred diuretic is a thiazide-like diuretic, in particular chlorthalidone or hydrochlorothiazide); and / or, - A beta blocker (sympathetic beta-receptor blocker), in particular, acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); Relates to the method of embodiment 2) having [in particular, the standard background therapy having at least two (in particular 3 or 4) other antihypertensive drugs selected from the group consisting of the above].

[0037] 5) A further embodiment relates to a method according to any one of embodiments 1) to 3), wherein the subject in need of the above treatment method is a subject administered with at least three other antihypertensive drugs independently selected from the group consisting of the following; - An angiotensin receptor blocker (especially valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; - An ACE inhibitor (especially enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril,trandolapril, cilazapril), or a pharmaceutically acceptable salt thereof; - A calcium channel blocker (especially amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; - A loop diuretic including furosemide, bumetanide, ethacrynic acid, torsemide; A potassium-sparing diuretic including an aldosterone antagonist or an aldosterone synthase inhibitor such as spironolactone, eplerenone or finerenone; A carbonic anhydrase inhibitor including acetazolamide and methazolamide; Especially a diuretic of the thiazide class (thiazide-like diuretic) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone; A diuretic (a preferred diuretic is a thiazide-like diuretic, especially chlorthalidone or hydrochlorothiazide); and - A beta blocker (sympathetic beta receptor blocker), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); Preferably, when present, the at least three other antihypertensive drugs have only one regulator of the renin-angiotensin system, i.e., either an ARB or an ACE inhibitor.

[0038] ​6) A further aspect relates to a method according to any one of aspects 1) to 3), wherein apocynin is administered in combination (co-administered) with at least three other antihypertensive drugs independently selected from the group consisting of: - an angiotensin receptor blocker (in particular valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or, an ACE inhibitor (in particular enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril,trandolapril, cilazapril), or a pharmaceutically acceptable salt thereof; - a calcium channel blocker (in particular amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; - loop diuretics including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics including aldosterone antagonists or aldosterone synthase inhibitors such as spironolactone, eplerenone or finerenone; carbonic anhydrase inhibitors including acetazolamide and methazolamide; diuretics including, in particular, diuretics of the thiazide class (thiazide-like diuretics) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide-like diuretics, in particular chlorthalidone or hydrochlorothiazide); and - beta blockers (sympathetic beta-receptor blockers), in particular acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); In particular, one regulator of the renin-angiotensin system selected from ARB and ACE inhibitors is administered in such combination therapy; it is assumed that only one regulator of the renin-angiotensin system, i.e., either ARB or ACE inhibitor, is administered.

[0039] 7) A further aspect relates to a method according to any one of aspects 1) to 6), wherein the subject has a history of co-existing diseases including diabetes (especially diabetes mellitus), ischemic heart disease, stroke and / or congestive heart failure.

[0040] 8) A further aspect is that when the subject has a history of diabetes (especially diabetes mellitus), the subject is (in addition to the standard background therapy appropriate for the treatment of hypertension) - to reduce the risk of cardiovascular death and hospitalization due to heart failure in adults with heart failure; and / or, - to 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 therapy to improve glycemic control in adults with type 2 diabetes; and / or, - for the treatment of diabetes (especially type 2 diabetes); relates to a method according to any one of aspects 1) to 7), wherein the subject is receiving an appropriate standard background therapy; In particular, the subject is a subject receiving an appropriate standard background therapy for the treatment of diabetes (especially type 2 diabetes) (in addition to the standard background therapy appropriate for the treatment of hypertension).

[0041] 9) A further aspect is that the subject is a subject receiving, in addition to standard hypertensive background therapy, a further standard background therapy, especially an appropriate standard background therapy for the treatment of diabetes; the additional standard background therapy is - An SGLT-2 inhibitor (especially atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof; particularly bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, sotagliflozin or tofogliflozin; especially canagliflozin, or dapagliflozin, or empagliflozin) or a pharmaceutically acceptable salt thereof; and / or, - Metformin; and / or, - Insulin; and / or, - A sulfonylurea (especially glibenclamide) or a pharmaceutically acceptable salt thereof; and / or; - A DPP-4 inhibitor (especially sitagliptin, vildagliptin, saxagliptin or linagliptin) or a pharmaceutically acceptable salt thereof; and / or, - A GLP-1 receptor agonist (especially exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide); or a dual GLP-1 / GIP agonist such as trizepatide); and / or, - A thiazolidinedione or a pharmaceutically acceptable salt thereof; having; In particular, such additional standard background therapy is an SGLT-2 inhibitor; metformin and / or a DPP-4 inhibitor; Particularly having an SGLT-2 inhibitor, and the SGLT-2 inhibitor (especially, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, sotagliflozin or tofogliflozin; especially, canagliflozin or dapagliflozin or empagliflozin) is particularly - To reduce the risk of cardiovascular death and hospitalization due to heart failure in adults with heart failure; and / or, - To reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease; and / or, - As an adjunct to diet therapy and exercise therapy for improving blood glucose control in adults with type 2 diabetes; It relates to a method according to any one of aspects 1) to 8) which is adapted.

[0042] Such a method according to any one of aspects 1) to 9) is similarly related to aprocitentan or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension including difficult-to-control hypertension and resistant hypertension, in which aprocitentan is administered in combination with such standard background therapy.

[0043] Furthermore, such a method according to any one of aspects 1) to 9) is similarly intended to be used in such a method, particularly in hypertension including difficult-to-control hypertension and resistant hypertension, or in chronic kidney disease (CKD) [especially stage 1 to 4 CKD as defined in the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (especially stage 3 or 4 CKD)], particularly caused by / related to hypertension and / or caused by / related to diabetes (especially such stages of) CKD (diabetic kidney disease (DKD)); - Having one or more such standard background therapies as additional active ingredients; or, - To be administered in combination with one or more such standard background therapies; It relates to a pharmaceutical composition containing aprositentan or a pharmaceutically acceptable salt thereof.

[0044] In this application, the term "angiotensin receptor blocker" or "ARB" specifically means valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt of one of these. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

[0045] In this application, the term "angiotensin-converting enzyme inhibitor" or "ACE inhibitor" specifically means captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril or a pharmaceutically acceptable salt of one of these.

[0046] In this application, the term "calcium channel blocker" or "CCB" specifically means amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil or diltiazem or a pharmaceutically acceptable salt of one of these. A preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.

[0047] The term "SGLT-2 inhibitor" specifically means inhibitors of sodium-glucose cotransporter 2 such as atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, remogliflozin , sotagliflozin, tianagliflozin or tofogliflozin (especially canagliflozin or dapagliflozin or empagliflozin).

[0048] The term "DPP-4 inhibitor" or "DPP-IV inhibitor" means, in particular, sitagliptin, vildagliptin, saxagliptin and linagliptin, and inhibitors of dipeptidyl peptidase 4 such as gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin and dutogliptin.

[0049] The term "GLP-1 receptor agonist" means, in particular, agonists of the glucagon-like peptide-1 receptor such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide.

[0050] The term "dual GLP-1 / GIP agonist" means, in particular, dual agonists of the glucagon-like peptide-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor such as trizepatide.

[0051] The term "sulfonylurea" means, in particular, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, glipizide, glisoxepide, glyclopyramide or glimepiride.

[0052] The term "thiazolidinedione", abbreviated as TZD and also known as glitazones, means an agonist of PPARγ (peroxisome proliferator-activated receptor gamma), and in particular, pioglitazone, rosiglitazone or lobeglitazone.

[0053] As used in this application, the term "diuretic" means loop diuretics including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics including, for example, amiloride, and in particular, aldosterone antagonists (or mineralocorticoid receptor antagonists (MRAs) such as spironolactone, eplerenone or finerenone); or aldosterone synthase inhibitors (such as baxdrostat); carbonic anhydrase inhibitors including acetazolamide and methazolamide; and, in particular, thiazide-class diuretics (thiazide-like diuretics) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferred thiazide-like diuretics are chlorthalidone or hydrochlorothiazide. To avoid doubt, SGLT-2 inhibitors are not included in the term "diuretic" as used herein, even if they have a diuretic pharmacological effect. Further, certain potassium-sparing diuretics may be regarded as mineralocorticoid receptor antagonists (MRAs) / aldosterone antagonists (such as finerenone) or aldosterone synthase inhibitors (such as baxdrostat) mainly by their pharmacological actions rather than by their diuretic actions. Such potassium-sparing diuretics are included in the definition of diuretics herein. Further, standard background therapy may have a combination of several diuretics as defined herein. Specific combinations of diuretics are (i) combination of an aldosterone antagonist with a thiazide-like diuretic; (ii) combination of an aldosterone antagonist with a loop diuretic; (iii) combination of an aldosterone synthase inhibitor with a thiazide-like diuretic; (iv) combination of an aldosterone synthase inhibitor with a loop diuretic; and (v) combination of a loop diuretic with a thiazide-like diuretic. (iv) combination of an aldosterone synthase inhibitor with a loop diuretic; and (v) combination of a loop diuretic with a thiazide-like diuretic.

[0054] The term "beta blocker" means such a sympathetic beta receptor blocking agent, in particular acebutolol, atenolol, bisoprolol, metoprolol (including immediate release or sustained release formulations), nadolol, nebivolol and propranolol (including immediate release or sustained release formulations); in particular, it means atenolol, bisoprolol, metoprolol, nebivolol and propranolol.

[0055] The standard background therapy should preferably be administered at a dose corresponding to the resistant effective dose of each active ingredient when administered, for example, as monotherapy. In particular, valsartan or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 160 mg or 320 mg of valsartan per day; losartan or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 50 mg or 100 mg of losartan per day; irbesartan or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 75 mg, 150 mg or 300 mg of irbesartan per day; amlodipine or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 5 mg or 10 mg of amlodipine per day; enalapril or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of enalapril per day; lisinopril or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of lisinopril per day; ramipril or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 mg to 20 mg of ramipril per day; metformin, if present, should be administered in a dosage form suitable for oral administration of 500 mg to 2000 mg of metformin per day; glibenclamide, if present, should be administered in a dosage form suitable for oral administration of 1.25 mg to 5 mg of glibenclamide per day; sitagliptin, if present, should be administered in a dosage form suitable for oral administration of 25 mg to 100 mg of sitagliptin per day; vildagliptin, if present, should be administered in a dosage form suitable for oral administration of 50 mg of vildagliptin twice a day; saxagliptin, if present, should be administered 2. per day.It should be administered in a dosage form suitable for oral administration of 5 mg or saxagliptin at 5 mg; linagliptin, if present, should be administered in a dosage form suitable for twice-daily oral administration of 5 mg of linagliptin per day; bexagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 5 to 50 mg (especially 20 mg) of bexagliflozin per day; canagliflozin or a pharmaceutically acceptable salt thereof, if present, should 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; particularly 100 mg or 300 mg; especially 100 mg) of canagliflozin per day; dapagliflozin or a pharmaceutically acceptable salt thereof, if present, should 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 a pharmaceutically acceptable salt thereof, if present, should 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; ertugliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 to 50 mg (especially 5 mg or 15 mg) of ertugliflozin per day; henaagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 5 to 100 mg (especially 25 mg) of henaagliflozin per day; ipragliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 10 to 100 mg (especially 25 mg or 50 mg). It should be administered in a dosage form suitable for oral administration of ipragliflozin; lesoglitazone or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of lesoglitazone at 1 to 10 mg per day (in particular, 2.5 mg or 5 mg); sotagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of sotagliflozin at 50 to 500 mg per day (in particular, 75 mg, 200 mg or 400 mg), and tofogliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of tofogliflozin at 10 to 50 mg per day (in particular 20 mg).

[0056] 10) A further aspect of the present invention is that administration of an amount of aprocitentan that has been clinically proven to be effective is - After 4 weeks of treatment, a decrease in systolic blood pressure of at least about 12 mmHg (in particular, at least about 15 mmHg) from baseline (the decrease is measured by unattended Automated Office Blood Pressure Measurement (uAOBPM) at trough without accompaniment); and / or, - After 4 weeks of treatment, a mean placebo corrected reduction in systolic blood pressure of at least 3.5 mmHg (the decrease is measured by unattended Automated Office Blood Pressure Measurement (uAOBPM) at trough); relates to a method according to any one of aspects 1) to 9) that results in

[0057] 11) A further aspect relates to a method according to any one of aspects 1) to 10) in which administration of an amount of aprocitentan that has been clinically proven to be effective results in a decrease in diastolic blood pressure of at least about 8 mmHg (in particular, at least about 10 mmHg) from baseline after 4 weeks of treatment (the decrease is measured by unattended Automated Office Blood Pressure Measurement (uAOBPM) at trough).

[0058] 12) A further aspect relates to a method according to any one of aspects 1) to 11), wherein administration of the clinically proven amount of aprositantan for an additional 32 weeks after the initial 4-week treatment results in at least maintaining the mean reduction in systolic blood pressure and / or diastolic blood pressure from baseline during such additional 32 weeks.

[0059] 13) A further aspect relates to a method according to any one of aspects 1) to 9), wherein the clinical effect on blood pressure reduction (in particular on systolic blood pressure reduction according to aspect 10)) is confirmed after a 4-week withdrawal period (starting 32 weeks after the initial 4-week treatment), and the mean systolic blood pressure increases in subjects administered placebo compared to the mean systolic blood pressure of subjects who continued to receive aprositantan at a dose of 25 mg per day (i.e., by measuring the difference in mean SBP between weeks 36 and 40 for placebo and aprositantan, respectively, and comparing the mean SBP); the increase is at least about 5 mmHg, particularly at least about 6 mmHg (the increase is measured by unattended automated office blood pressure measurement (uAOBPM) at trough).

[0060] 14) A further aspect relates to a method according to any one of aspects 10) to 12), wherein the clinical effect on blood pressure reduction is confirmed by the mean reduction from baseline blood pressure after 4 weeks of treatment, the reduction being measured by ambulatory 24-hour blood pressure measurement (24h ABPM); in particular, - the systolic blood pressure is reduced by at least about 6 mmHg and / or, the diastolic blood pressure is reduced by at least about 6 mmHg, and the clinically proven amount of aprositantan is 12.5 mg per day; or, - the systolic blood pressure is reduced by at least about 8 mmHg and / or, the diastolic blood pressure is reduced by at least about 7 mmHg, and the clinically proven amount of aprositantan is 25 mg per day.

[0061] 15) A further aspect is that administration of the clinically proven effective amount of aprocitentan results in a mean placebo-corrected decrease in blood pressure after 4 weeks of treatment, and this decrease is measured by ambulatory 24-hour blood pressure measurement (24h ABPM) (the BP is expressed as the least squares mean value); in particular, - the systolic blood pressure decreases by at least about 4 mmHg, and / or the diastolic blood pressure decreases by at least about 5.5 mmHg, and the clinically proven effective amount of aprocitentan is 12.5 mg per day; or, - the systolic blood pressure decreases by at least about 4 mmHg, and / or the diastolic blood pressure decreases by at least about 5.5 mmHg, and the clinically proven effective amount of aprocitentan is 25 mg per day; relating to a method according to any one of aspects 1) to 14).

[0062] 16) A further aspect is that the clinical effect on blood pressure reduction is confirmed by the mean reduction from baseline blood pressure after 4 weeks of treatment, and this reduction is measured by nocturnal ambulatory blood pressure measurement (nocturnal ABPM); in particular, - the systolic blood pressure decreases by at least about 6 mmHg, particularly at least about 8 mmHg, and / or the diastolic blood pressure decreases by at least about 6 mmHg, particularly at least about 7 mmHg, and the clinically proven effective amount of aprocitentan is 12.5 mg per day; or, - the systolic blood pressure decreases by at least about 8 mmHg, particularly at least about 10 mmHg, and / or the diastolic blood pressure decreases by at least about 7 mmHg, particularly at least about 8 mmHg, and the clinically proven effective amount of aprocitentan is 25 mg per day; relating to a method according to any one of aspects 10) to 12).

[0063] 17) A further aspect is that administration of the clinically proven effective amount of aprocitentan results in a mean placebo-corrected reduction in blood pressure after 4 weeks of treatment, and the reduction is measured by ambulatory blood pressure measurement at night (nocturnal ABPM) (the BP is expressed as the least squares mean value); in particular, - the systolic blood pressure is reduced by at least about 4 mmHg, particularly at least about 5 mmHg, and / or, the diastolic blood pressure is reduced by at least about 4 mmHg, particularly at least about 5 mmHg, the clinically proven effective amount of aprocitentan is 12.5 mg per day; or, - the systolic blood pressure is reduced by at least about 4 mmHg, particularly at least about 7 mmHg, and / or, the diastolic blood pressure is reduced by at least about 5.5 mmHg, particularly at least about 6 mmHg, the clinically proven effective amount of aprocitentan is 25 mg per day; relates to a method according to any one of aspects 1) to 16).

[0064] 18) A further aspect is that the above reduction in blood pressure (e.g., as defined in aspect 10) or 11)) is confirmed after a 4-week drug withdrawal period (starting 32 weeks after the initial 4-week treatment), and the mean blood pressure increases in subjects administered placebo compared to the mean blood pressure of each subject who continued administration of aprocitentan at a dose of 25 mg per day (i.e., by measuring the difference in the mean BP between weeks 36 and 40 for placebo and aprocitentan, respectively, and comparing the mean BPs); the increase is measured by ambulatory 24-hour blood pressure measurement (24h ABPM) (the BP is expressed as the least squares mean value); - the systolic blood pressure is increased by at least about 6 mmHg, particularly at least about 6.5 mmHg, and / or, the diastolic blood pressure is increased by at least about 6 mmHg, particularly at least about 6.5 mmHg; relates to a method according to any one of aspects 1) to 9).

[0065] 19) A further aspect is that the above-mentioned decrease in blood pressure (defined, for example, in aspect 10) or 11)) is confirmed after a 4-week drug withdrawal period (starting 32 weeks after the first 4 weeks of treatment), and the mean blood pressure increases in subjects administered placebo compared to the mean blood pressure of each subject who continued administration of aprocitentan at a dose of 25 mg per day (i.e., by measuring the difference in each mean BP between weeks 36 and 40 for placebo and aprocitentan, respectively, and comparing each mean BP); the increase is measured by ambulatory blood pressure measurement at night (nocturnal ABPM) (the BP is expressed as the least squares mean value). - The systolic blood pressure increases by at least about 8 mmHg, particularly at least about 8.5 mmHg, and / or The diastolic blood pressure increases by at least about 7 mmHg, particularly at least about 7.5 mmHg; Relates to a method according to any one of aspects 1) to 9).

[0066] 20) A further aspect of the invention relates to a method according to any one of aspects 1) to 19), which comprises administering to a subject in need of the treatment method a pharmaceutical composition comprising an amount of aprocitentan that has been clinically proven to be safe and clinically proven to be effective for the treatment of hypertension, including resistant hypertension.

[0067] 21) A further aspect relates to a method according to any one of aspects 1) to 20), wherein the amount clinically proven to be effective (and, respectively, the amount clinically proven to be safe according to aspect 20) is 10 to 50 mg per day; particularly 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg; especially 12.5 mg or 25 mg of aprocitentan.

[0068] 22) A further aspect relates to a method according to any one of aspects 1) to 20), wherein the amount clinically proven to be effective (and, respectively, the amount clinically proven to be safe according to aspect 20) is 12.5 mg of aprocitentan per day.

[0069] 23) A further aspect relates to a method according to any one of aspects 1) to 20), wherein the clinically proven effective amount (and, respectively, the clinically proven safe amount according to aspect 20) is 25 mg of aprocitentan per day.

[0070] 23) A further aspect relates to a method according to any one of aspects 21) to 23), wherein, mutatis mutandis, the pharmaceutical composition comprises aprocitentan or a pharmaceutically acceptable salt thereof in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg of aprocitentan 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; form).

[0071] 24) A further aspect relates to a method according to any one of aspects 1) to 23), wherein the pharmaceutical composition comprising aprocitentan or a pharmaceutically acceptable salt thereof is administered in the morning (assuming that aprocitentan is suitable for once-daily administration).

[0072] When not used with respect to temperature, the term "about" placed before the numerical value "X" means, in the present application, between X - 10% of X and X + 10% of X, preferably between X - 5% of X and X + 5% of X. In the specific case of temperature, the term "about" placed before the temperature "Y" means, in the present application, between Y - 10°C and Y + 10°C, preferably between Y - 5°C and Y + 5°C, especially between Y - 3°C and Y + 3°C. Room temperature means a temperature of about 25°C. In the present application, when the term n equivalents (where n is a number) is used, within the scope of the present application, n means about n, and preferably n means exactly n.

[0073] When the terms "between" or "from (... ) to" are used to describe a numerical range, the end points of the indicated range are always understood to be explicitly included in that range. This means, for example, that when a temperature range is described as being between 40°C and 80°C (or from 40°C to (~) 80°C), the end points 40°C and 80°C are included in the range; or, when a variable is defined as being an integer between 1 and 4 (or from 1 to (~) 4), the variable is meant to be the integer 1, 2, 3, or 4.

[0074] The manufacture of the pharmaceutical composition can be carried out by methods well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by formulating the crystalline form of the present invention, optionally in combination with other therapeutically beneficial substances, together with a suitable non-toxic, inert, pharmaceutically acceptable solid or liquid carrier material and, if necessary, conventional pharmaceutical adjuvants, into a dosage form for administration.

[0075] Examples of solid pharmaceutical compositions (especially in the form of tablets) include pharmaceutically acceptable excipients such as inert microcrystalline cellulose, lactose, hydroxypropyl cellulose, croscarmellose sodium, and magnesium stearate.

[0076] In particular, such a solid pharmaceutical composition comprises aprocitentan in an amount of 5 to 25% by weight, based on the total weight of the pharmaceutical composition, microcrystalline cellulose in an amount of 20 to 30% by weight, based on the total weight of the pharmaceutical composition, lactose in an amount of 40 to 65% by weight, based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in an amount of 1 to 3% by weight, based on the total weight of the pharmaceutical composition, croscarmellose sodium in an amount of 2 to 8% by weight, based on the total weight of the pharmaceutical composition, and magnesium stearate in an amount of 0.2 to 2% by weight, based on the total weight of the pharmaceutical composition, and the total weight percentage of the solid pharmaceutical composition is always 100; the solid pharmaceutical composition is in the form of tablets in particular.

[0077] A further aspect of the present invention relates to such a pharmaceutical composition in the form of tablets. In a secondary aspect, the pharmaceutically active ingredient is contained in the granules before tableting the tablets. The tablets may optionally be coated with a suitable protective pellicle. The protective pellicle in particular prevents the pharmaceutical composition from coming into direct contact with moisture; and also facilitates an imprint that is preferably used to distinguish the above pharmaceutical composition from others. The coating material forming such a protective pellicle may comprise a low water vapor permeability polymer such as polyvinyl alcohol (for example, Aquapolish® white PVA manufactured by Biogrund or dimethylaminoethyl methacrylate (for example, EUDRAGIT® E PO, etc.). The coating material may further comprise a plasticizer (for example, propylene glycol, triacetyne, dibutyl phthalate or dibutyl sebacate), a surfactant (for example, sodium lauryl sulfate or a polysorbate such as Tween®) and / or a lubricant / slipping agent (for example, stearic acid, magnesium stearate or calcium or talc). Further, the coating material may comprise a pigment (for example, iron(II) oxide, iron(III) oxide or titanium oxide) for coloring the tablets.

[0078] In the context of the present invention, an endothelin-related disease is - Essential hypertension, and hypertension including particularly difficult-to-control and resistant hypertension; - Pulmonary hypertension and pulmonary arterial hypertension; - Chronic kidney disease (CKD) [particularly CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (particularly stage 3 or 4 CKD)], and in particular CKD (diabetic kidney disease, DKD) caused by / associated with hypertension and / or caused by / associated with diabetes (particularly in these stages); and (acute and particularly chronic) renal insufficiency, where said (acute and chronic) renal insufficiency may be related to hypertension and / or diabetes (acute and particularly chronic) renal insufficiency; diabetic nephropathy where said diabetic nephropathy may be related to hypertension; and glomerulonephritis where said glomerulonephritis may be related to hypertension and / or diabetes; (To avoid ambiguity, the term CKD (diabetic kidney disease, DKD) caused by / associated with diabetes may additionally include such DKD associated with hypertension; in particular, the diabetes is type 2 diabetes.) In a secondary aspect, the previously defined DKD particularly means DKD in patients diagnosed with type 2 diabetes; in particular, for example, it means a reduction in the progression rate of DKD in patients diagnosed with type 2 diabetes, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage kidney disease (ESKD) events or a reduction in kidney death events; in particular, the patient additionally shows a history of hypertension; In a further secondary aspect, the previously defined DKD particularly means diabetic nephropathy related to an increase in serum creatinine and / or proteinuria in patients with type 2 diabetes, particularly in such patients who additionally show a history of hypertension, [corresponding particularly to CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (particularly stage 3 or 4 CKD)]; In a further secondary aspect, the previously defined DKD particularly means such DKD additionally related to hypertension; in particular, the diabetes is type 2 diabetes; - Diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic retinopathy or diabetic angiopathy; and the treatment and prevention of diabetic complications; and reducing the risk of developing major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients with diabetes, particularly in patients with diabetes accompanied by at least one other cardiovascular risk factor (e.g., especially hypertension); and reducing the risk of diabetic foot ulcers and / or lower limb amputations in patients with diabetes; and - Heart failure (HF) defined as including particularly chronic HF, especially including HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%) and HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%) accompanied by a reduction in systolic HF / ejection fraction; and reducing the risk of developing major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients with cardiovascular risk (e.g., patients with coronary artery disease and / or patients showing clinical signs of congestive HF); angina pectoris; coronary artery disease; cardiac insufficiency; and diastolic dysfunction; including.

[0079] In particular, in the context of the present invention, an endothelin-related disease means hypertension, particularly difficult-to-control or resistant hypertension.

[0080] In particular, in the context of the present invention, an endothelin-related disease means resistant hypertension.

[0081] Essential hypertension (also called primary or idiopathic hypertension) is, by definition, a form of hypertension without an identifiable cause. This is a major global public health concern affecting vascular and renal disease rates and cardiovascular mortality. When the average of multiple systolic blood pressure measurements in two or more consecutive visits consistently equals or exceeds a specific threshold value T SBP it is diagnosed as essential hypertension. Individuals with high normal blood pressure tend to maintain blood pressure above the average of the general population and have a greater risk of developing definite hypertension and cardiovascular events than the general population. The threshold value T above which treatment is recommended SBPThis is regularly discussed among clinicians (see, for example, Mancia et al., J. Hypertens. (2013), 31, 1281 - 1357); thus, depending on the patient's overall condition and age, T SBP can be 140 or 130 mmHg, or another appropriate value.

[0082] The term "difficult - to - control hypertension" is defined in the present invention as blood pressure that remains above target despite the concurrent use of standard background therapy, which has treatment with at least one, particularly at least two, and especially at least three (in this case, the term is used equivalently to resistant hypertension as defined below) different classes of antihypertensive agents. When the standard background therapy has more than one therapeutic agent, one of the therapeutic agents should be a diuretic, and all agents should be prescribed at optimal / maximal doses.

[0083] The term "resistant hypertension" is defined in the present invention as blood pressure that remains above target despite the concurrent use of three different classes of antihypertensive agents. One of the three therapeutic agents should be a diuretic, and all agents should be prescribed at optimal / maximal doses. As defined, patients with resistant hypertension include those whose blood pressure is controlled by the use of more than three medications. That is, patients whose blood pressure is controlled but who require four or more medications for this purpose should be considered treatment - resistant (see, for example, Mancia et al., J. Hypertens. (2013), 31, 1281 - 1357).

[0084] The term "diabetes" as used herein means all types of diabetes, particularly type 2 diabetes; as well as type 1 diabetes, and the form of type 1 diabetes that develops in adulthood, which often has a more indolent onset process than type 1 diabetes diagnosed in youth, i.e., latent autoimmune diabetes in adults.

[0085] 25) A further aspect of the present invention relates to a method according to any one of aspects 1) to 24) with the necessary modifications, the method being intended to: - CKD [especially CKD in stages 1 to 4, particularly CKD in stage 3 or 4]; and in particular, the treatment of CKD (DKD) caused by / associated with hypertension and / or diabetes (especially in these stages); and the prevention or treatment of acute or chronic renal insufficiency; diabetic nephropathy; or glomerulonephritis; In a first sub-aspect, such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, especially where apocynum venetum reduces the rate of progression of DKD, and such reduced rate of progression may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; In a second sub-aspect, such use is for the treatment of such DKD in patients with type 2 diabetes, especially in such patients who additionally show a history of hypertension, [especially corresponding to CKD in stages 1 to 4 (especially such CKD in stage 3 or 4) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines] and includes the treatment of diabetic nephropathy associated with an increase in serum creatinine and / or proteinuria; In a variation, the method according to any one of aspects 1) to 24) is diagnosed with CKD [especially CKD stages 1 to 4, particularly CKD stage 3 or 4]; in particular, it is intended for the treatment of hypertension in subjects diagnosed with CKD [especially CKD stages 1 to 4, particularly CKD stage 3 or 4] and diabetes (especially type 2 diabetes) (DKD); in particular, in addition to reducing blood pressure according to any one of aspects 10) to 19), an amount of aprocitentan or a pharmaceutically acceptable salt thereof that has been clinically proven effective; reduces the progression rate of CKD or DKD, and such reduced progression rate may be particularly represented by a reduction in the urinary albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline in eGFR, reduction in end-stage kidney disease (ESKD) events, and / or reduction in kidney death events; - The treatment of diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic retinopathy or diabetic vasculopathy; and the treatment of diabetic complications; reducing the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients with diabetes, especially those with diabetes accompanied by at least one other cardiovascular risk factor (e.g., especially hypertension); and use in the prevention or treatment of diabetic foot ulcers and / or reducing the risk of lower limb amputation in patients with diabetes; - The treatment of heart failure (HF), especially chronic HF including systolic HF and diastolic HF; reducing the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients with a cardiovascular risk (e.g., patients with coronary artery disease and / or patients showing clinical signs of congestive HF); and use in the prevention or treatment of ischemic heart diseases including angina pectoris, coronary artery disease and myocardial ischemia; heart dysfunction; or diastolic dysfunction; - The treatment of atherosclerosis; and obliterative atherosclerotic diseases including chronic obliterative arteriopathy; - The treatment of finger ulcers; or, - The treatment of connective tissue diseases.

[0086] 26) A further aspect of the invention relates to a method according to any one of aspects 1) to 24) with the necessary modifications, the method being intended to: - the treatment of CKD caused by / associated with hypertension [especially CKD stages 1 to 4, particularly CKD stage 3 or 4]; and / or, - the treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, particularly CKD stage 3 or 4] (DKD); Such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, in particular where apocynin reduces the rate of progression of DKD, and such reduced rate of progression may be particularly represented by a reduction in eGFR, a reduction in end-stage kidney disease (ESKD) events or a reduction in kidney death events; in particular, the patient additionally shows a history of hypertension; In a variant, the method according to any one of aspects 1) to 24) is intended for the treatment of hypertension in subjects diagnosed with CKD [especially CKD stages 1 to 4, particularly CKD stage 3 or 4]; in particular, in addition to reducing blood pressure according to any one of aspects 10) to 19), a clinically effective amount of apocynin or a pharmaceutically acceptable salt thereof is; CKD, a or DKD to reduce the rate of progression, and such reduced rate of progression may be particularly represented by a reduction in the urinary albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline in eGFR, reduction in end-stage kidney disease (ESKD) events, and / or reduction in kidney death events; and / or, - reducing the risk of occurrence of major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients with diabetes, particularly patients with diabetes accompanied by at least one other cardiovascular risk factor (e.g., particularly hypertension).

[0087] 27) A further aspect of the invention relates to a method according to any one of aspects 1) to 24) with the necessary modifications, the method being: - The treatment of CKD caused by / associated with hypertension [especially CKD stages 1 to 4, particularly CKD stage 3 or 4]; and / or, - The treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, particularly CKD stage 3 or 4] (DKD); is intended for; such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage kidney disease (ESKD) events, or a reduction in kidney death events; in particular, the patient additionally shows a history of hypertension; In a variant, the method according to any one of aspects 1) to 24) is diagnosed with CKD [especially CKD stages 1 to 4, particularly CKD stage 3 or 4]; in particular, it is intended for the treatment of hypertension in subjects diagnosed with CKD [especially CKD stages 1 to 4, particularly CKD stage 3 or 4] and diabetes (especially type 2 diabetes) (DKD); in particular, in addition to reducing blood pressure according to any one of aspects 10) to 19), an amount of apocynin or a pharmaceutically acceptable salt thereof, which has been proven to be clinically effective, reduces the progression rate of CKD or DKD, and such reduced progression rate may be particularly represented by a reduction in the urinary albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline in eGFR, reduction in end-stage kidney disease (ESKD) events, and / or reduction in kidney death events.

[0088] 27) A further aspect of the present invention relates to a method according to any one of aspects 1) to 24), with necessary modifications, the method being: - The treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, particularly CKD stage 3 or 4] (DKD); is intended for; In a first sub-aspect, such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynum tannin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events, or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; In a second sub-aspect, such use is for patients with type 2 diabetes, and in particular, for such patients who additionally show a history of hypertension, [in particular, corresponding to stage 1-4 CKD (especially stage 3 or 4 of such CKD) defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines] the treatment of diabetic nephropathy associated with an increase in serum creatinine and / or proteinuria, including the treatment of such DKD, is particularly intended; In a variant, the method according to any one of aspects 1)-24) is diagnosed with CKD [especially stage 1-4 CKD, especially stage 3 or 4 CKD]; in particular, it is intended for the treatment of hypertension in subjects diagnosed with CKD [especially stage 1-4 CKD, especially stage 3 or 4 CKD] and diabetes (especially type 2 diabetes) (DKD); in particular, in addition to reducing blood pressure according to any one of aspects 10)-19), an amount of apocynum tannin or a pharmaceutically acceptable salt thereof that has been proven to be clinically effective; reduces the progression rate of CKD or DKD, and such reduced progression rate may be particularly represented by a reduction in the urinary 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.

[0089] 28) A further aspect of the present invention relates to a method according to any one of aspects 1)-24), with necessary modifications, the method being: - To reduce the risk of developing major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients with diabetes, particularly those with diabetes accompanied by at least one other cardiovascular risk factor (e.g., particularly hypertension). It is intended to be.

[0090] Unless otherwise stated, the term "clinically proven" as used herein (either independently or to modify the terms "safety" and / or "efficacy") means proven by clinical trials that are in compliance with the approval criteria of the U.S. Food and Drug Administration, EMA or the corresponding domestic regulatory authorities. For example, the above clinical trials may be randomized, double-blind trials of an appropriate scale used to clinically prove the effect of a drug.

[0091] As used herein, the terms "clinically proven effect" and "clinically demonstrated efficacy" in connection with a dosage, dosing regimen, treatment or method mean the efficacy of a particular dosage, administration or treatment regimen. The effect can be measured based on changes in the course of a disease in response to the agent of the present invention. For example, the dual endothelin receptor antagonists of the present invention (particularly aprocitentan) are administered to a subject in an amount and for a period sufficient to cause an improvement, preferably a sustained improvement, in at least one parameter reflecting the severity of the disorder being treated. Various parameters reflecting the condition, disease or degree of symptoms of the subject can be evaluated to determine whether the amount and duration of treatment are sufficient. Such parameters include clinically recognized indicators of disease severity, symptoms or manifestations of the disorder in question. The degree of improvement is generally determined by a physician and can be based on signs, symptoms, bioresearch or other test results, and questionnaires administered to the subject, such as quality-of-life questionnaires developed for a particular disease, can also be used. For example, the compounds of the present invention can be administered to improve the symptoms of a subject associated with hypertension, including resistant hypertension. The improvement can be indicated by an improvement in the indicators of disease activity, either by improvement in clinical symptoms or by any other measurement of disease activity.

[0092] In certain embodiments, such indicators of a disease are measured by uAOBPM and / or ABPM (including 24h ABPM and nocturnal ABPM), according to any one of embodiments 10) to 19), respectively, and compared to a baseline or to a placebo, and are the blood pressure, including systolic and diastolic blood pressure, or a decrease thereof.

[0093] In certain embodiments, the clinically proven safe amount of aprocitentan is an amount that results in a decrease in blood pressure as shown by Example A or by clinical trials having the protocol described below, for example, according to any one of embodiments 10) to 19), for example, measured by uAOBPM and / or ABPM (including 24h ABPM and nocturnal ABPM), each compared to a baseline or compared to a placebo.

[0094] Nocturnal hypertension is defined as nocturnal BP ≧ 120 / 70 mmHg ( > 110 / 65 mmHg according to the new 2017 ACC / AHA guidelines) according to K. Kario, Hypertension. 2018;71:997 ~1009. When clinic and morning home BP are < 130 / 80 mmHg, it is defined as masked nocturnal hypertension and masked uncontrolled nocturnal hypertension under drug treatment. Nocturnal BP is calculated as the average of nocturnal BP (from bedtime to wake-up) measured by ABPM or by a recently developed HBPM system with an automatic nocturnal BP measurement function (nocturnal HBPM). The number of nocturnal BP measurements required may be ≧ 6. Nocturnal systolic BP dipping (%) is calculated as (1 - average nocturnal systolic BP / average daytime systolic BP) × 100, and based on this percentage, the following four nocturnal BP dipping patterns are defined: extreme dipper: > 20%; dipper: ≦ 20% - > 10%; non-dipper: ≦ 10% - > 0%; riser: ≦ 0%. This classification is usually based on ABPM data.

[0095] 29) Accordingly, a further aspect of the present invention relates to a method for treating an endothelin-related disorder, including hypertension including treatment-resistant and resistant hypertension according to any one of aspects 1) to 24); chronic kidney disease (CKD) [in particular, CKD at stages 1 to 4 defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (in particular, CKD at stage 3 or 4)], and in particular, CKD (diabetic kidney disease (DKD)) caused by and / or related to hypertension and / or diabetes (in particular at these stages); the endothelin-related disorder particularly includes hypertension including treatment-resistant and resistant hypertension; the method comprises administering to the subject a pharmaceutical composition comprising an amount of aprocitentan or a pharmaceutically acceptable salt thereof that has been clinically proven to be safe and clinically proven to be effective; the amount of aprocitentan that has been clinically proven to be safe and clinically proven to be effective is an amount that results in a decrease in blood pressure; the amount of aprocitentan that has been clinically proven to be safe and clinically proven to be effective results in an average placebo-corrected decrease in blood pressure after 4 weeks of treatment, the decrease being measured by ambulatory blood pressure measurement (24h ABPM) under free-living conditions according to aspect 15) (the BP is expressed as the least-squares mean value), and / or the amount of aprocitentan that has been clinically proven to be safe and clinically proven to be effective results in an average placebo-corrected decrease in blood pressure after 4 weeks of treatment, the decrease being measured by nocturnal ambulatory blood pressure measurement (nocturnal ABPM) under free-living conditions according to aspect 17) (the BP is expressed as the least-squares mean value).); In particular, the treated subject has nocturnal hypertension, especially a dipper, non-dipper or riser measured by ABPM; in particular, nocturnal hypertension associated with a nocturnal systolic BP dipping pattern that can be defined as a non-dipper or riser; in particular, the subject shows nocturnal hypertension associated with a nocturnal systolic BP dipping pattern that can be defined as a non-dipper or riser; in particular, the subject is diagnosed with CKD [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD]; and, in particular, the subject is diagnosed with CKD [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD] associated with diabetes (especially type 2 diabetes) (DKD); the clinically proven safe and clinically proven effective amount additionally reduces the progression rate of CKD or DKD, and such reduced progression rate may be particularly represented by a reduction in the urinary albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline in eGFR, reduction in end-stage kidney disease (ESKD) events, and / or reduction in kidney death events; the pharmaceutical composition has aprocitentan or a pharmaceutically acceptable salt thereof in a pharmaceutical unit dosage form suitable for oral administration of 12.5 mg or 25 mg (especially 25 mg) of aprocitentan per day.

[0096] 30) A further aspect of the present invention relates to a method for treating an endothelin-related disorder according to any one of aspects 1) to 24); the endothelin-related disorder particularly includes hypertension including difficult-to-control and resistant hypertension in a subject in need of such treatment, and the method comprises administering to the subject a pharmaceutical composition comprising an amount of aprocitentan or a pharmaceutically acceptable salt thereof that has been clinically proven to be safe and clinically proven to be effective; the clinically proven safe and clinically proven effective amount of aprocitentan is (for example, in the Examples A or as shown by a clinical trial having the protocol described below, for example, according to any one of embodiments 10) to 19); when compared to baseline or when compared to placebo) an amount that results in a decrease in blood pressure measured by nocturnal ABPM; the subject so treated has nocturnal hypertension, particularly, a dipper, non-dipper or riser measured by ABPM; particularly nocturnal hypertension associated with a nocturnal systolic BP dipping pattern that can be defined as a non-dipper or riser; particularly, the subject is diagnosed with CKD [particularly CKD stages 1 to 4, especially stage 3 or 4 CKD]; especially the subject is diagnosed with CKD [particularly CKD stages 1 to 4, especially stage 3 or 4 CKD] associated with diabetes (particularly type 2 diabetes) (DKD); the amount that has been clinically proven to be safe and clinically proven to be effective, in addition, reduces the progression rate of CKD or DKD, and such reduced progression rate may be particularly represented by a reduction in urinary albumin-creatinine ratio (UACR), maintenance of eGFR / prevention of further decline of eGFR, reduction of end-stage renal disease (ESKD) events, and / or reduction of renal death events; the pharmaceutical composition has aprocitentan or a pharmaceutically acceptable salt thereof in a pharmaceutical unit dosage form suitable for oral administration of 12.5 mg or 25 mg (especially 25 mg) of aprocitentan per day.

[0097] 31) A further aspect relates to a method according to any one of aspects 1) to 30), the method comprising administering to the subject a pharmaceutical composition comprising an amount of aprocitentan or a pharmaceutically acceptable salt thereof that has been clinically proven to be safe and clinically proven to be effective; the administration of the amount of aprocitentan that has been clinically proven to be safe and clinically proven to be effective results in a mean placebo-corrected decrease in blood pressure after 4 weeks of treatment, the decrease being measured by ambulatory 24-hour blood pressure measurement (24h ABPM) (the BP is expressed as the least squares mean value); particularly, - the systolic blood pressure decreases by at least about 4 mmHg, and / or, the diastolic blood pressure decreases by at least about 5.5 mmHg, The clinically proven safe and effective amount of aprocitentan is 12.5 mg per day; or, - The systolic blood pressure is reduced by at least about 4 mmHg and / or, The diastolic blood pressure is reduced by at least about 5.5 mmHg, The clinically proven safe and effective amount of aprocitentan is 25 mg per day; In each case, preferably, the subject has stage 3 or 4 CKD (optionally related to diabetes), and the mean placebo-corrected UACR after 4 weeks of treatment is reduced by at least about 25% (in particular, at least about 30%); In particular, when the subject has macroalbuminuria (defined as UACR > 300 mg / g), - The mean placebo-corrected UACR after 4 weeks of treatment is reduced by at least about 40% (in particular about 45%), and the clinically proven safe and effective amount of aprocitentan is 12.5 mg per day; or, - The mean placebo-corrected UACR after 4 weeks of treatment is reduced by at least about 50% (in particular about 60%), and the clinically proven safe and effective amount of aprocitentan is 25 mg per day; Preferably, the clinically proven safe and effective amount of aprocitentan is 25 mg per day (preferably, the amount should be administered once daily in the morning).

[0098] 32) A further aspect relates to a method according to any one of aspects 1) to 30), the method comprising administering to the subject a pharmaceutical composition comprising a clinically proven safe and effective amount of aprocitentan or a pharmaceutically acceptable salt thereof; The administration of the clinically proven safe and clinically proven effective amount of aprocitentan results in a mean placebo-corrected reduction in blood pressure after 4 weeks of treatment, which reduction is measured by ambulatory blood pressure measurement during sleep (nocturnal ABPM) (the BP is expressed as the least-squares mean value); in particular, - the systolic blood pressure is reduced by at least about 4 mmHg, in particular at least about 5 mmHg, and / or the diastolic blood pressure is reduced by at least about 4 mmHg, in particular at least about 5 mmHg, The clinically proven safe and clinically proven effective amount of aprocitentan is 12.5 mg per day; or - the systolic blood pressure is reduced by at least about 4 mmHg, in particular at least about 7 mmHg, and / or the diastolic blood pressure is reduced by at least about 5.5 mmHg, in particular at least about 6 mmHg, The clinically proven safe and clinically proven effective amount of aprocitentan is 25 mg per day; In each case, preferably, the subject has stage 3 or 4 CKD (optionally related to diabetes), and the mean placebo-corrected UACR after 4 weeks of treatment is reduced by at least about 25% (in particular at least about 30%); In particular, when the subject has macroalbuminuria (defined as UACR > 300 mg / g measured at baseline), - the mean placebo-corrected UACR after 4 weeks of treatment is reduced by at least about 40% (in particular about 45%), and the clinically proven safe and clinically proven effective amount of aprocitentan is 12.5 mg per day; or - the mean placebo-corrected UACR after 4 weeks of treatment is reduced by at least about 50% (in particular about 60%), and the clinically proven safe and clinically proven effective amount of aprocitentan is 25 mg per day; Preferably, the amount of aprocitentan that has been clinically proven to be safe and clinically proven to be effective is 25 mg per day (preferably, such amount should be administered once a day in the morning).

[0099] When the subject has a history of CKD and / or diabetes (e.g., a subject diagnosed with DKD (i.e., CKD and diabetes)), such subject always - to reduce the risk of cardiovascular death and hospitalization due to heart failure in adults with heart failure, and / or - to 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 for improving glycemic control in adults with type 2 diabetes; and / or - for the treatment of diabetes (especially type 2 diabetes); may receive standard background therapy; In particular, such subject may receive standard background therapy appropriate for the treatment of diabetes (especially type 2 diabetes) (in addition to standard background therapy appropriate for the treatment of hypertension); such standard background therapy is in particular an SGLT-2 inhibitor (especially atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof; especially bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, sotagliflozin or tofogliflozin; particularly canagliflozin or dapagliflozin or empagliflozin) or a pharmaceutically acceptable salt thereof.

[0100] The term "clinically proven safe", when referring to the compounds of the invention, the dosage of aprositantan, the dosing regimen, the treatment or method, means a favorable risk:benefit ratio where treatment-emergent adverse events (described as AE or TEAE) occur at an acceptable frequency and / or severity. As used herein, the terms "adverse event", "treatment-emergent adverse event" and "adverse reaction" mean any adverse, undesirable, unintended or unwanted sign or outcome related to or resulting from the administration or treatment with the pharmaceutical composition. It is an untoward medical occurrence in the subject to whom the pharmaceutical is administered.

[0101] Accordingly, aprositantan or a pharmaceutically acceptable salt thereof according to the invention encompasses the above use in combination with (or in combination therapy with) such further pharmaceutically active ingredients, particularly including standard background therapies.

[0102] Combined treatment (or co-therapy) may be carried out simultaneously, separately or over a period of time (in particular, simultaneously).

[0103] When related to the dosage form, "simultaneously" in the present application means that the related dosage form is the administration of two or more active ingredients and / or treatments that are administered substantially simultaneously; it is understood that by simultaneous administration, the subject will be simultaneously exposed to the two or more active ingredients and / or treatments described above. When administered simultaneously, the two or more active ingredients may be administered as a fixed-dose combination, or as an equivalent non-fixed dose combination (e.g., by using two or more different pharmaceutical compositions that should be administered substantially simultaneously by the same route of administration), or by a non-fixed dose combination using two or more different routes of administration, and by such administration, the subject will be essentially simultaneously exposed to the two or more active ingredients and / or treatments described above. When used in combination with (administered concomitantly with) standard background therapy, aprocitentan will preferably be used "simultaneously".

[0104] When related to the dosage form, "fixed-dose combination" in the present application means that the related dosage form is the administration of a single pharmaceutical composition having two or more active ingredients.

[0105] When related to the dosage form, the term "separately" in the present application means that the related dosage form is the administration of two or more active ingredients and / or treatments at different times; separate administrations lead to a treatment phase in which the subject is simultaneously exposed to the two or more active ingredients and / or treatments described above (e.g., for at least 1 hour, particularly at least 6 hours, especially at least 12 hours), but separate administrations may also lead to a treatment phase in which the subject is exposed to only one of the two or more active ingredients and / or treatments for a certain period of time (e.g., for at least 12 hours, particularly at least 1 day). Separate administrations particularly mean a situation where at least one active ingredient and / or treatment is administered at a cycle that is substantially different from consecutive daily administrations (e.g., one active ingredient and / or treatment is administered, for example, once or twice a day, and another is administered, for example, every other day, or once a week, or at longer intervals).

[0106] "For a period of time" administration means, in the present application, administering two or more active ingredients and / or treatments successively at different times. This term particularly means an administration method in which, after the entire administration of one active ingredient and / or treatment is completed, the administration of one or two or more other administrations is started. In this case, after administering one of the above active ingredients and / or treatments for several months, it is possible to administer other active ingredients and / or treatments.

[0107] Aprositant can be used as a medicine according to the present invention, for example, in the form of a pharmaceutical composition for enteral or parenteral administration in particular.

[0108] Dosage forms suitable for enteral administration may be tablets or capsules (particularly tablets) having a pharmaceutical composition containing an effective amount of aprositant or a pharmaceutically acceptable salt thereof.

[0109] To avoid doubt, for the present invention, any amount / unit dose of aprositant means an amount / unit dose suitable for administration of aprositant in the free base form of such amount / unit dose. When aprositant is present in such a composition in a form different from the anhydrous free base, such as in the form of a pharmaceutically acceptable salt; and / or a solvate such as a hydrate, such amount / unit dose may need to be adjusted in the pharmaceutical composition.

[0110] When a certain dose means a unit dose of a specific amount expressed in mg, such unit dose shall always mean such amount expressed in mg of the aprositant active ingredient in the free base form. When the above active ingredient is administered, for example, in the form of a pharmaceutically acceptable salt, each amount of the active pharmaceutical ingredient (for example, such pharmaceutically acceptable salt) in the pharmaceutical composition shall be adapted accordingly.

[0111] To avoid any ambiguity, of course, any pharmaceutical composition having a pharmaceutically effective amount of aprocitentan may further have additional conventional excipients and / or additives, and the above conventional excipients and / or additives may be used alone or in combination (quantum satis, i.e., the maximum amount of such additional conventional components and / or additives may need to be reduced to make the total ww% equal to 100). The total amount represented by "ww%" of a composition shall be 100.

[0112] Extensive literature on the subject of these and other pharmaceutically acceptable excipients and techniques referred to herein is cited, for example, see R.C. Rowe, P.J. 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].

[0113] The expression "ww%" (or, %(w / w)) means the weight percentage relative to the total weight of the composition under consideration. In the absence of an explicit statement, the total weight under consideration is the total weight of the pharmaceutical composition.

[0114] The expression (wt / wt) regarding ratios means the weight ratio of each component.

[0115] If a value is described as a % value and there is no further explanation, such a value means ww% or, in the case of purity, the area % measured by HPLC.

[0116] Unless otherwise specified, any reference to aprocitentan means aprocitentan or a pharmaceutically acceptable salt form of aprocitentan, preferably aprocitentan in free base form.

[0117] The term "pharmaceutical composition" is interchangeable with the terms "formulation" or "composition". Yes.

[0118] The terms "treat", "treatment", or "treating" as used in connection with a disease mean either that the disease is cured in a patient or animal; or that, although the animal or patient continues to be adversely affected by the disease, some or all of the symptoms of the disease are alleviated or eliminated.

[0119] The terms "subject", and likewise "patient", mean a mammal, particularly a human. In particular, the term "subject" means a human patient.

[0120] To avoid any doubt, any method of treating a particular disease or disorder such as RHT, which involves administering aprocitentan or a pharmaceutically acceptable salt thereof as described in any one of aspects 1) to 24) of this specification, - aprocitentan or a pharmaceutically acceptable salt thereof for use in the treatment of the disease or disorder described in any one of aspects 1) to 24) of this specification; - the use of aprocitentan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of the disease or disorder described in any one of aspects 1) to 24) of this specification; - aprocitentan or a pharmaceutically acceptable salt thereof for use in the method of treating the disease or disorder described in any one of aspects 1) to 24) of this specification; - a medicament for the treatment of the disease or disorder described in any one of aspects 1) to 24) of this specification, which medicament comprises aprocitentan or a pharmaceutically acceptable salt thereof; etc. are also disclosed.

[0121] Similarly, when aprocitentan or a pharmaceutically acceptable salt thereof is described as being useful for the treatment of certain diseases or disorders such as RHT described herein, aprocitentan or a pharmaceutically acceptable salt thereof is similarly: - for use in the manufacture of a medicament for the treatment of said disease or disorder described herein; - for use in a method of treating said disease or disorder, said method comprising administering aprocitentan or a pharmaceutically acceptable salt thereof as described herein; - as a medicament for the treatment of said disease or disorder described herein, comprising aprocitentan or a pharmaceutically acceptable salt thereof; etc. is suitable for.

[0122] Certain embodiments of the present invention are described in the following examples, which are provided to explain the present invention in more detail and are not intended to limit its scope in any way.

[0123] Abbreviations: ABP Blood pressure during free activity ABPM Blood pressure measurement during free activity ACE Angiotensin-converting enzyme in ACE inhibitors (ACEI), etc. ARB Angiotensin receptor blocker BP Blood pressure BMI Body mass index CCB Calcium channel blocker DB(-WD) Double-blind (-withdrawal) DBP Diastolic blood pressure ET Endothelin RHT or rHT Resistant hypertension SB Single-blind SBP Systolic blood pressure SBT Standardized background therapy SiDBP Sitting diastolic blood pressure SiSBP Sitting systolic blood pressure UACR Urinary albumin / creatinine ratio uAOBP Automated office blood pressure without attendant uAOBPM Automated office blood pressure measurement without attendant

[0124] Example 1: The method for producing aprocitentan is described, for example, in WO2018 / 154101. Aprocitentan was used in the following clinical trial example in the form of its stable crystalline form A disclosed therein.

[0125] Example A): A research study (PRECISION) to show the effect of aprocitentan in the treatment of difficult to control (resistant) high blood pressure (hypertension) and to find out more about its safety and Find Out More About Its Safety)(PRECISION) A single, randomized trial with three consecutive treatment parts was designed. This trial design was directed at both the 4-week placebo-controlled efficacy (Part 1) of 12.5 and 25 mg of apocitentan, and the subsequent 32-week long-term active treatment with 25 mg of apocitentan (Part 2), followed by the persistence of its effect during a 12-week placebo-controlled washout period (Part 3) in patients re-randomized to 25 mg or placebo (for example, see Danaietash P et al; Identifying and treating hypertension in PRECISION - a randomized long-term clinical trial with Aprocitentan. J Clin Hypertension 2022 (in press)). Patients with uncontrolled BP (measured as untethered automated ambulatory BP) despite the use of 3 or more antihypertensive agents for at least 1 year were screened. These patients were switched to single-tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo run-in period. This 4-week placebo run-in period further excluded placebo responders. The randomized period consisted of three consecutive parts: 1) A 4-week double-blind part with 12.5 mg, 25 mg of apocitentan or placebo (in a 1:1:1 ratio); 2) A 32-week single-blind part with 25 mg of apocitentan; and 3) A 12-week randomized washout part with 25 mg of apocitentan or placebo (in a 1:1 ratio).

[0126] The objectives were to demonstrate the BP-lowering effect of apocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3) in chronic treatment.

[0127] Standard background therapy (SBT) is a fixed combination of three drugs in a single tablet of CCB (amlodipine), ARB (valsartan), and diuretic (hydrochlorothiazide); two dose strengths of 5 / 160 / 25 mg and 10 / 160 / 25 mg are available respectively. The maximum tolerated dose strength is selected at the discretion of the investigator during the treatment period of this trial and must be maintained stably from at least one week before randomization through the end of the double-blind (DB) part and again during the DB-washout (DB-WD) part. Patients receiving β-blocker treatment at the time of screening continue that treatment throughout the trial.

[0128] The investigational treatment and SBT are taken every morning except on the morning of the study visit day. On the morning of the study visit day, treatment is administered after the completion of the visit assessment and BP measurement.

[0129] Compliance with the investigational treatment and SBT is evaluated throughout the trial based on tablet counts. In addition, intake of SBT is monitored by detecting valsartan in the participant's urine by liquid chromatography with tandem mass spectrometry and by directly observing treatment administration before the start of ambulatory blood pressure monitoring (ABPM).

[0130] At each visit, the patient rests quietly alone (without accompaniment) for 5 minutes in a quiet place, and trough uAOBP is measured using the same oscillometric sphygmomanometer (Microlife® WatchBP Office), which records 5 seated BP readings (one per minute, excluding the first value from the average).

[0131] ABPM is performed over a 24-hour period using a Mobil-O-Graph NG device at baseline and at weeks 4, 36, and 40. Systolic BP and diastolic BP are measured every 20 minutes from 06:00 to 23:00 and every 30 minutes from 23:00 to 06:00. Monitoring starts between 06:00 and 11:00.

[0132] Trial treatment Part 1: 4-week double-blind, randomized parallel-group comparison and placebo-controlled. Subjects received either 25 or 12.5 mg of ambrisentan or placebo (in a 1:1:1 ratio).

[0133] Part 2: 32-week single-blind and single-arm. All subjects received 25 mg of ambrisentan.

[0134] Part 3: Double-blind drug withdrawal. All subjects who completed Part 2 and entered Part 3 were re-randomized to either 25 mg of ambrisentan or placebo (in a 1:1 ratio).

[0135] Main inclusion criteria: Screening period: (i) Signed and dated the ICF prior to the study-mandated procedure.

[0136] (ii) Male and female subjects; 18 years of age or older (or the country-specific age of majority).

[0137] (iii) Medical history documentation in the subject's medical record regarding having uncontrolled BP despite at least 3 background antihypertensive agents within 1 year prior to screening visit.

[0138] (iv) Having been treated with at least 3 antihypertensive therapies of different pharmacological classes for at least 4 weeks prior to the screening visit (Visit 1).

[0139] (v) The mean SiSBP measured by uAOBPM ≥ 140 mmHg.

[0140] (vi) Information in the medical records of the subjects regarding the diagnosis of RHT according to the medical practice of the facility: - Exclusion of secondary causes of hypertension (e.g., serum aldosterone, plasma renin activity, duplex / doppler ultrasonography, angiographic evaluation by computed tomography are performed to exclude secondary causes of hypertension), - Adherence to medication to exclude apparent RHT (e.g., how adherence was checked and / or monitored), (e.g., how adherence was checked and / or monitored), (vii) Women who may be pregnant are eligible only if the following apply: - The pregnancy test at the time of screening and at baseline (i.e., before randomization) is negative.

[0141] - Agree to undergo pregnancy tests during the study period and up to 30 days after the end of the randomized trial treatment.

[0142] - Agree to use contraception from screening until at least 30 days after the end of the randomized trial treatment.

[0143] (viii) When switching from background antihypertensive agents (i.e., at least three drug treatments of different pharmacological classes) to standard background antihypertensive treatment, the mean trough SiSBP measured by AOBPM ≥ 140 mmHg.

[0144] Run-in period (RI): Switch to standard background antihypertensive treatment at least 4 weeks before the first RI visit.

[0145] The mean trough SiSBP measured by uAOBPM ≥ 140 mmHg.

[0146] Randomization period: Standard background antihypertensive treatment at a stable dose for at least 1 week before the end of the RI period.

[0147] Mean trough SiSBP measured by uAOBPM ≥ 140 mmHg.

[0148] Subjects showing ≥ 80% compliance (tablet count) with the test treatment (i.e., placebo), and ≥ 80% compliance (tablet count) with the standard background antihypertensive treatment during the RI period.

[0149] Main exclusion criteria: White coat effect, clinical inertia, poor treatment adherence, or apparent / pseudo RHT due to secondary causes of hypertension (other than sleep apnea).

[0150] Severe hypertension (grade 3) defined as SiSBP ≥ 180 mmHg and / or SiDBP ≥ 110 mmHg measured by uAOBPM is confirmed at two different time points.

[0151] Subjects who are pregnant or lactating.

[0152] If the investigator considers that there is clinically significant unstable cardiac disease at the time of screening or in the past (exclusion of participants with significant or potential unstable cardiac disease).

[0153] Severe renal insufficiency.

[0154] Any known factor, disease, or clinically relevant medical or surgical condition that the investigator considers may pose a risk to the subject and interfere with treatment compliance, conduct of the study, or interpretation of the results.

[0155] Treatment with any agent that may adversely affect BP, and / or treatment with high-dose loop diuretics (i.e., furosemide exceeding 80 mg per day, or other loop diuretics at equivalent doses).

[0156] Endpoint The primary efficacy endpoint is the change from baseline in mean trough SiSBP measured as uAOBP up to week 4 of DB treatment, where baseline is defined as the last available measurement before the start of DB treatment.

[0157] The key secondary efficacy endpoint is the change from the DB-WD baseline (the last available measurement at or before week 36) in mean trough SiSBP measured as uAOBP up to week 40.

[0158] Other secondary efficacy endpoints include - Changes in mean trough seated diastolic blood pressure (SiDBP) measured as uAOBP from baseline up to week 4 and from the DB-WD baseline up to week 40, - Changes in 24-h mean SBP and DBP from baseline up to week 4 of DB treatment, changes in daytime and nighttime mean SBP and DBP from baseline up to week 4 of DB treatment, changes in 24-h mean SBP and DBP from the DB-WD baseline (week 36) up to week 40, and changes in daytime and nighttime mean SBP and DBP from the DB-WD baseline (week 36) up to week 40, including changes in systolic / diastolic BP measured by ABPM. are included.

[0159] For safety evaluation, TEAEs that lead to early termination of the test treatment; adverse events of special interest (AESIs): liver impairment, anemia (or hemodilution), edema / fluid retention, and decompensation / aggravation of heart failure; major adverse cardiovascular events (MACE) / MACE-plus defined as cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke or heart failure requiring hospitalization, as approved by the Central Adjudication Committee (CAC) and occurring during treatment; are included (TEAEs occurring during treatment), as well as vital signs, body weight, clinical laboratory evaluations, and 12-lead electrocardiograms.

[0160] Statistical analysis In this design report, continuous endpoints were summarized by descriptive statistics in terms of numbers and percentages and categorical variables. Categorical variables were compared using the Cochran-Mantel-Haenszel test for ordinal variables and the Chi-square test for nominal variables. In addition, stepwise multivariable logistic regression was performed to identify predictors of pseudo-RHT from among the patient characteristics at screening for patients with pseudo-RHT and randomized patients (p < 0.05 for inclusion in the model).

[0161] In the final analysis, three null hypotheses were tested (see Figure S1 in the Data Supplement). The first two null hypotheses specify that there is no difference between aliskiren and placebo in the DB part with respect to the mean change from baseline of the mean trough SiSBP measured as uAOBP up to week 4 (H10 for aliskiren 25 mg and H20 for aliskiren 12.5 mg).

[0162] Results: In this study, aliskiren was found to lower blood pressure compared to placebo after 4 weeks of treatment, and this effect persisted and was confirmed over 48 weeks. Also, aliskiren generally showed good tolerability and no major safety concerns were identified. The primary and key secondary endpoints met statistical significance and clinically meaningful results were obtained - the above effects were consistent across multiple endpoints and methods of blood pressure monitoring.

[0163] To confirm the diagnosis of resistant hypertension and exclude pseudo-resistant hypertension, 1965 patients were screened. During the 12-week screening period, eligible patients were switched to standard background antihypertensive treatment with a fixed-dose combination of a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan), and a diuretic (hydrochlorothiazide) for at least 4 weeks before entering a 4-week single-blind run-in period. During this period, placebo was added to the background antihypertensive treatment. Then, patients with consistently elevated systolic blood pressure above 140 mmHg were randomized for the first treatment part. Out of the 1965 screened patients, 730 were randomized, and the overall inclusion failure rate was 63%. The most common exclusion reason (44.4% of all screened patients) was not meeting the BP selection criteria. These results imply that a high proportion of pseudo-resistant hypertension exists among patients diagnosed with RHT. The randomized patients had a history of comorbidities such as diabetes (about 53%), ischemic heart disease (about 30%), stroke (about 23%), congestive heart failure (about 19%), and / or sleep apnea syndrome (about 14%). At the time of screening, patients who were later randomized had received 3 (about 37%), 4 (about 46%), or 5 or more (about 17%) of the major antihypertensive therapies. These antihypertensive therapies included ACEI or ARB (about 98% overall: about 37% ACEI and about 61% ARB); diuretics (about 86% overall, of which about 11% were mineralocorticoid receptor antagonists (MRA)); CCB (about 83%); and beta-blockers (about 61%).

[0164] In the first 4-week double-blind treatment period, Part 1, a total of 730 patients were randomized to take tablets of ambrisentan 12.5 mg (N = 243), 25 mg (N = 243), or placebo (N = 244) once daily. After 4 weeks of treatment, a statistically significant and clinically meaningful decrease in systolic blood pressure measurements, the primary endpoint, measured at trough with an automated office blood pressure (uAOBP) device without adjuncts, compared to placebo, was observed in both the 12.5 mg (p < 0.005) and 25 mg (p < 0.005) ambrisentan groups.

[0165] Following the 4-week double-blind, placebo-controlled treatment period, patients entered the single-blind treatment period, Part 2, and all patients were treated with 25 mg of ambrisentan for an additional 32 weeks. In patients who received ambrisentan in Part 1, the mean decrease in systolic blood pressure from baseline was maintained during this treatment period. In patients who switched from placebo to ambrisentan, the same blood pressure decrease as seen in Part 1 was rapidly achieved.

[0166] This was followed by a double-blind, placebo-controlled, randomized withdrawal treatment period, Part 3, in which 614 patients were re-randomized to 12 weeks of ambrisentan 25 mg or placebo. Four weeks after entering the withdrawal period, systolic blood pressure measurements, a key secondary endpoint, increased significantly in placebo compared to 25 mg ambrisentan (p < 0.0001). This reproduced the treatment effect of ambrisentan and confirmed its sustained antihypertensive effect.

[0167] The decreases in systolic and diastolic blood pressure evaluated by measurement of automated office blood pressure without adjuncts in this trial were confirmed by ambulatory blood pressure monitoring (ABPM) under free-living conditions, showing a BP decrease over 24 h (especially during the night).

[0168] Aprosartan generally had good tolerability, with no major safety concerns for either dose in this patient population, and few discontinuations of study treatment due to adverse events during the first 4-week double-blind study period: 0.8% in the placebo group, compared with 2.5% and 2.0% in the 12.5 mg and 25 mg aprosartan groups, respectively. During this 4-week double-blind study period, treatment-emergent adverse events (TEAEs) were reported in 27.6% and 36.7% of patients treated with 12.5 and 25 mg aprosartan, respectively, compared with 19.4% in the placebo group. The most frequently reported TEAE was edema / fluid retention, which occurred more than 3% higher compared with placebo. Over the entire 48-week treatment period, no additional safety findings emerged subsequently. Importantly, the overall incidence of major adverse cardiovascular events (MACE) reflected the incidence expected in this patient population. Approximately 30% of patients developed edema / fluid retention at some point during the entire study period, and >95% of these were mild to moderate in intensity. Two of these adverse events (<1%) were severe (both in the 25 mg aprosartan group). Only 7 patients (<1%) discontinued treatment due to edema / fluid retention. Most of the edema / fluid retention was reported by patients during the first 4-week double-blind study period (2.1% in the placebo group, compared with 9.1% and 18.4% in the 12.5 mg and 25 mg aprosartan groups, respectively).

[0169] The results of the PRECISION trial are published in more detail as follows by Schlaich et al., Lancet 2022;400:1927-37 and the related supplementary material (both of which are incorporated herein by reference): Patient characteristics were similar across all treatment groups at the time of randomization and re - randomization. These patients were typical of those affected by resistant hypertension related to age and comorbidities. Black and African - American patients accounted for 11% of all randomly assigned participants and 37% (78 out of 211) of participants born in the United States, which is higher than the distribution of blacks in the United States. As previously described, at screening, 63% of all randomly assigned patients were prescribed 4 or more antihypertensive medications and 63% were taking a β - blocker. At the time of randomization, 516 (71%) of the 730 patients were taking the maximum dose of standard background therapy (amlodipine 10mg), and 423 (58%) of the 730 patients continued β - blocker therapy.

[0170] The time course of changes in clinic SBP and DBP between the three study parts represents the short - term (4 - week) and sustained blood pressure - lowering effects of aprocitentan (up to 48 weeks). After 4 weeks of treatment in double - blind part 1, the primary endpoint was achieved. The change in the least - squares mean (SE) of clinic SBP at week 4 was - 15.3(0.9) mmHg for aprocitentan 12.5mg, - 15.2(0.9) mmHg for aprocitentan 25mg, and - 11.5(0.9) mmHg for placebo. The differences from placebo were - 3.8(1.3) mmHg (97.5% CI - 6.8~ - 0.8, p = 0.0042) and - 3.7(1.3) mmHg (- 6.7~ - 0.8, p = 0.0046), respectively. Clinic DBP also decreased compared to placebo at both doses of aprocitentan ( - 3.9 mmHg for the 12.5mg dose, 95% CI -5.6 to -2.3; for the 25 mg dose, -4.5 mmHg, 95% CI -6.1 to -2.9). In patients who had taken ambrisentan previously, office SBP and DBP were maintained during Part 2, and in patients who had taken placebo previously, they decreased during the first 2 weeks of Part 2 and then stabilized. In Part 3, office SBP (a key secondary endpoint) after 4 weeks of drug withdrawal was significantly higher in placebo compared with ambrisentan (5.8 mmHg, 95% CI 3.7 to 7.9, p < 0.0001). Office DBP also increased in placebo compared with ambrisentan (5.2 mmHg, 95% CI 3.8 to 6.6, p < 0.0001). The difference between the two groups was maintained until week 48.

[0171] The robustness of the main analysis was confirmed by the results of all sensitivity and secondary analyses. In particular, early termination of double-blind treatment, or addition or increase in dose of diuretics, or exclusion of patients due to use of rescue medication for elevated blood pressure did not affect the results for the primary and key secondary endpoints.

[0172] The results of ambulatory blood pressure measurements confirmed the results from office measurements. At the end of Part 1, ambrisentan (after placebo correction) decreased both 24-hour ambulatory SBP (-4.2 mmHg, 95% CI -6.2 to -2.1 for the 12.5 mg dose; -5.9 mmHg, 95% CI -7.9 to -3.8 for the 25 mg dose) and DBP (-4.3 mmHg, 95% CI -5.7 to -3.0 for the 12.5 mg dose; -5.8 mmHg, 95% CI -7.1 to -4.5 for the 25 mg dose). The placebo-corrected SBP reduction effect was -5.1 mmHg and -7.4 mmHg at night and -3.8 mmHg and -5.3 mmHg during the day for the 12.5 mg and 25 mg doses, respectively.

[0173] In Part 3, after 4 weeks of drug withdrawal (week 40), both 24-h ambulatory SBP and DBP increased in placebo compared with aprocitentan (6.5 mmHg, 95% CI 4.6–8.5; 6.8 mmHg, 95% CI 5.5–8.0, respectively).

[0174] For the primary and key secondary efficacy analyses, treatment effects consistent with those obtained in the full study population were observed in most subgroups. In particular, significant decreases in SBP were seen at week 4 in elderly patients (age ≥75 years) and in patients with macroalbuminuria (urinary albumin / creatinine ratio [UACR] >300 mg / g) and stage 3–4 chronic kidney disease (estimated glomerular filtration rate [eGFR], 1.73 m 2 per 1.73 m² 15–<60 mL / min). No difference in treatment effect was detected between patients on β-blocker treatment at screening and those not. With respect to race, black or African American patients had a lower response to aprocitentan at week 4 compared with other patients and tended to have a stronger response at week 40 after 4 weeks of placebo-controlled drug withdrawal. Results of ambulatory blood pressure measurements in black or African American patients were consistent with those observed in the overall population throughout the study parts.

[0175] At the end of Part 1, decreases in urinary albumin / creatinine ratio (UACR) of -28% and -31% were observed in the 12.5 mg and 25 mg aprocitentan groups, respectively, and a 5% increase was observed in the placebo group. In Part 2, this decrease was maintained in all patients. In Part 3, after 4 weeks of drug withdrawal, this ratio increased in placebo compared with aprocitentan. This anti-proteinuric effect of aprocitentan tended to be stronger in patients with stage 3–4 chronic kidney disease than in patients with eGFR of 1.73 m 2 per 1.73 m² 60 mL / min or more.

[0176] Aprosartan showed good tolerability. The most frequent adverse event was oedema or fluid retention, which mainly occurred during the first 4 weeks of treatment. Before randomization, 70 out of 730 patients (10%) showed symptoms of ongoing oedema or fluid retention, and 35 out of 730 (5%) had experienced an adverse event of oedema or fluid retention. Oedema or fluid retention was reported more frequently in aprosartan than in placebo and was dose-dependent (in part 1 of 4 weeks, 9.1%, 18.4% and 2.1% of patients taking aprosartan, 12.5 mg, 25 mg and placebo respectively; in part 2 of 32 weeks, 18.2% of patients taking aprosartan 25 mg; in part 3 of 12 weeks, 2.6% and 1.3% of patients taking aprosartan 25 mg and placebo respectively). Oedema or fluid retention was generally mild to moderate and diuretic treatment was added as needed. The frequency of oedema or fluid retention was higher in patients with stage 3 - 4 chronic kidney disease. Discontinuation due to oedema or fluid retention was reported for 7 patients taking aprosartan 25 mg during parts 1 - 3 (1 out of 245 patients in part 1, 5 out of 704 patients in part 2, 1 out of 310 patients in part 3).

[0177] A total of 13 deaths were reported, 2 of which were not considered to have occurred under treatment. Of the 11 treatment-emergent deaths, none were considered by the trialists to be related to the trial treatment; 5 were cardiovascular deaths, 5 were COVID-19 related, and 1 patient died due to procedural intestinal perforation.

[0178] Eleven patients were hospitalized due to heart failure (in Part 1, 2 out of 245 [0.8%] taking ambrisentan 25 mg; in Part 2, 6 out of 704 [0.9%]; in Part 3, 2 out of 310 [0.6%] taking ambrisentan 25 mg and 1 out of 303 [0.3%] taking placebo); none of them died. All patients had a high-risk cardiovascular history, including diabetes (11 out of 11 [100%]), stage 3 - 4 chronic kidney disease (6 out of 11 [55%]), and pre-existing heart failure (5 out of 11 [45%]). Two out of 11 patients (18%) discontinued the trial treatment due to heart failure. The major cardiovascular events included 5 cardiovascular deaths.

[0179] No signs of hepatotoxicity were observed. In Part 1, hemoglobin concentration decreased and estimated plasma volume increased to a similar extent at both ambrisentan doses (hemoglobin was -8.0 g / L, -8.5 g / L, and -0.4 g / L in ambrisentan 12.5 mg, ambrisentan 25 mg, and placebo respectively; estimated plasma volume was 10.5%, 11.2%, and 0.51%), stabilized in Part 2, and returned to baseline upon drug withdrawal in Part 3. In Part 1, a slight increase in N-terminal pro-brain natriuretic peptide (NT-proBNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) was observed for ambrisentan, stabilized in Part 2, and returned to baseline in Part 3. In Part 1, moderate weight gain was observed at both ambrisentan doses and weight loss was observed with placebo. With ambrisentan, in Part 1, eGFR decreased slightly compared to placebo, stabilized in Part 2, and further decreased in the ambrisentan group in Part 3 while remaining stable in the placebo group. A slight decrease in heart rate was seen in all treatment groups in Part 1 and was maintained in Part 2.

[0180] Schlaich et al. discuss in double-blind part 1 that while the urinary albumin / creatinine ratio increased by 5% in the placebo, substantial decreases of 28% and 31% in the urinary albumin / creatinine ratio were observed at apocynetant doses of 12.5 mg and 25 mg, respectively. This anti-proteinuric effect of apocynetant was stronger in patients with stage 3-4 chronic kidney disease (-46% vs -26%) than in patients with an eGFR of 60 mL / min / 1.73 m 2 or more, which would probably emphasize the potential of apocynetant to reduce organ damage even in patients with moderate to severe chronic kidney disease where blood pressure control is particularly difficult. Importantly, this anti-proteinuric effect was maintained in single-blind part 2 where all participants received 25 mg of apocynetant.

[0181] Additional data from the PRECISION trial: Between-treatment analyses of the changes from baseline in 24-hour daytime and nighttime SBP / DBP at week 4 and week 40 showed a significant and consistent decrease in SBP / DBP in the apocynetant group compared to placebo. Clinically particularly important is the difference from placebo in the mean nighttime SBP (-6.6 mmHg) observed at week 4 with 25 mg of apocynetant.

[0182] The anti-proteinuric effect of apocynetant (i.e., decrease in UACR: -30% and -34% in the apocynetant 12.5 mg and 25 mg groups, respectively) was shown early at week 4 in this trial and maintained over 48 weeks of treatment, while no change was observed with placebo. This effect was more prominent in subjects with stage 3-4 CKD (-26% with 12.5 mg of apocynetant and -45% with 25 mg); it was also more prominent in subjects with baseline microalbuminuria (-43% with 12.5 mg and -45% with 25 mg). The greatest effects (-48% with 12.5 mg and -61% with 25 mg) were observed in subjects with macroalbuminuria.

[0183] Taking into account all available data in the overall population and in particular the subgroups of interest, an exposure- and dose-response relationship is observed between 12.5 mg and 25 mg for all Week 4 secondary BP efficacy endpoints: - In the overall population, apocynum venetum 25 mg achieved numerically greater decreases (than 12.5 mg) in all BP endpoints except the primary endpoint; - The benefit of 25 mg over 12.5 mg was particularly evident in nocturnal BP (collected by ABPM), which is a well-known major predictor of cardiovascular outcomes; - The difference between 25 mg and 12.5 mg was particularly prominent in subgroups of patients with stage 3-4 CKD and black or African American patients, who have a high medical need when hypertension becomes difficult to control.

[0184] Dose-response in subpopulations: Consistent dose-response was observed for all of the above endpoints, including the % increase in BP reduction at the 25 mg dose compared to the 12.5 mg dose, in two sub-population groups: (i) stage 3-4 CKD, and (ii) black or African American patients.

[0185] In black or African American patients, the least-squares (LS) mean reduction in BP from baseline to Week 4 was consistently greater with apocynum venetum 25 mg than with apocynum venetum 12.5 mg for all endpoints. An additional effect (64% - 145%) for 25 mg vs 12.5 mg on ABPM was observed in this subpopulation, with the difference being up to -5.90 mmHg (i.e., nocturnal SBP decreased by >100% more with 25 mg compared to 12.5 mg).

[0186] In subjects with stage 3-4 CKD, the least-squares (LS) mean reduction in BP from baseline up to week 4 was consistently greater with apocynatan 25 mg than with apocynatan 12.5 mg for all endpoints, with the largest difference being -5.88 mmHg for SiSBP, the primary endpoint (a further 44% reduction compared with 12.5 mg).

[0187] Dose-response relationship in UACR: In a population with resistant hypertension (mean age 62 years, obesity [69.3% of subjects], >50% with diabetes, 22% with stage 3-4 CKD), assessment of UACR is important. The PRECISION trial did not have any selection criteria for UACR. The geometric mean UACR at baseline was 26.6 mg / g in the overall population. At week 4, the placebo-corrected reduction in UACR was 30% and 34% for apocynatan 12.5 mg and 25 mg, respectively. However, in a subgroup of subjects with macroproteinuria (>300 mg / g UACR; 12.6% of subjects), a clear dose-response relationship was observed, with a placebo-corrected reduction of 48% at 12.5 mg and 61% at 25 mg.

Claims

1. A therapeutic agent for uncontrolled or resistant hypertension in human patients who require it, The aforementioned therapeutic agent, Aprocitentan in free or pharmaceutically acceptable salt form: 【Chemistry 1】 It contains as an active ingredient, The therapeutic agent is intended to be administered in the form of a pharmaceutical composition containing a clinically effective amount of aprocitentan in free or pharmaceutically acceptable salt form. The clinically effective dose of aprocitentan is 12.5 mg or 25 mg of aprocitentan per day. Here, if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the amount means the amount of aprocitentan in a free base form.

2. The therapeutic agent according to claim 1, wherein the human patient is a subject receiving standard background therapy, and the standard background therapy includes a first-line treatment appropriate for the prevention or treatment of hypertension.

3. The therapeutic agent is combined with at least three other antihypertensive drugs independently selected from the group consisting of the following. The therapeutic agent according to claim 1, which is intended to be administered in combination: - Angiotensin receptor blockers or pharmaceutically acceptable salts thereof; or, ACE inhibitors or pharmaceutically acceptable salts thereof; - Calcium channel blockers or pharmaceutically acceptable salts thereof; - Diuretics; and - Beta-blockers (sympathetic beta-receptor blockers).

4. The therapeutic agent according to claim 1, wherein administration of the therapeutic agent results in a decrease of at least 12 mmHg of systolic blood pressure from baseline after 4 weeks of treatment, the decrease being measured at trough by unassisted automated room blood pressure monitoring (uAOBPM).

5. The therapeutic agent according to claim 4, wherein an additional 32 weeks of administration of the therapeutic agent following the initial 4 weeks of treatment results in at least the maintenance of a mean reduction in systolic blood pressure from baseline during such additional 32 weeks.

6. The above clinical effect on systolic blood pressure is confirmed after a four-week drug-free period, and the mean systolic blood pressure is elevated in the placebo-treated subjects compared to the mean systolic blood pressure of subjects who continued to receive the therapeutic agent containing aprocitentan at a dose of 25 mg per day; the elevation is at least 6 mmHg; the elevation is measured at trough by an unassisted automated room blood pressure monitor (uAOBPM); and if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, the amount means the amount of aprocitentan in free base form; the therapeutic agent according to claim 4.

7. The clinical effect of blood pressure reduction was confirmed by the mean decrease from baseline blood pressure after 4 weeks of treatment, and this decrease was measured by ambulatory 24-hour blood pressure monitoring (24h ABPM); - Systolic blood pressure decreases by at least 6 mmHg, and / or, Diastolic blood pressure decreased by at least 6 mmHg, If the clinically effective dose of aprocitentan is 12.5 mg per day, and the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose means the amount of aprocitentan in its free base form; Or, - Systolic blood pressure decreases by at least 8 mmHg, and / or, Diastolic blood pressure decreased by at least 7 mmHg, The clinically effective amount of aprocitentan is 25 mg per day, and if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the amount means the amount of aprocitentan in a free base form; the therapeutic agent according to claim 4.

8. The clinical effect of blood pressure reduction was confirmed by the mean decrease from baseline blood pressure after 4 weeks of treatment, and this decrease was measured by nocturnal ambulatory blood pressure monitoring (nocturnal abPM); - Systolic blood pressure decreases by at least 6 mmHg, and / or, Diastolic blood pressure decreased by at least 6 mmHg, If the clinically effective dose of aprocitentan is 12.5 mg per day, and the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose means the amount of aprocitentan in its free base form; Or, - Systolic blood pressure decreases by at least 8 mmHg, and / or, Diastolic blood pressure decreased by at least 7 mmHg, The clinically effective dose of aprocitentan is 25 mg per day, and if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose is This refers to the amount of aprositentan in its separate base form; The therapeutic agent according to claim 4.

9. The therapeutic agent results in an average placebo-corrected reduction in blood pressure after four weeks of treatment, and the reduction is measured by ambulatory 24-hour blood pressure monitoring (24h ABPM); - Systolic blood pressure decreases by at least 4 mmHg, and / or, Diastolic blood pressure decreased by at least 5.5 mmHg, If the clinically effective dose of aprocitentan is 12.5 mg per day, and the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose means the amount of aprocitentan in its free base form; Or, - Systolic blood pressure decreases by at least 4 mmHg, and / or, Diastolic blood pressure decreased by at least 5.5 mmHg, The clinically effective amount of aprocitentan is 25 mg per day, and if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the amount means the amount of aprocitentan in a free base form; the therapeutic agent according to any one of claims 1 to 8.

10. The therapeutic agent results in an average placebo-corrected reduction in blood pressure after four weeks of treatment, and the reduction is measured by nocturnal ambulatory blood pressure monitoring (nocturnal abpm); - Systolic blood pressure decreases by at least 4 mmHg, and / or, Diastolic blood pressure decreased by at least 4 mmHg, If the clinically effective dose of aprocitentan is 12.5 mg per day, and the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose means the amount of aprocitentan in its free base form; or, - Systolic blood pressure decreases by at least 4 mmHg, and / or, Diastolic blood pressure decreased by at least 5.5 mmHg, If the clinically effective dose of aprocitentan is 25 mg per day, and the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose means the amount of aprocitentan in its free base form; A therapeutic agent according to any one of claims 1 to 8.

11. The above-mentioned decrease in blood pressure was confirmed after a four-week drug-free period, and the mean blood pressure was elevated in the placebo-treated subjects compared to the mean blood pressure of each subject who continued to receive aprocitentan at a dose of 25 mg per day; the elevation of mean blood pressure in the placebo-treated subjects was measured by nocturnal ambulatory blood pressure monitoring (nocturnal abpm); and if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, the amount refers to the amount of aprocitentan in its free base form; - Systolic blood pressure increases by at least 8.5 mmHg, and / or, Diastolic blood pressure rises by at least 7.5 mmHg; The therapeutic agent according to any one of claims 4 to 6.

12. The therapeutic agent is intended to be administered in the form of a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of aprocitentan in free or pharmaceutically acceptable salt form, and the therapeutic agent is intended to be administered once daily in the morning; the therapeutic agent according to any one of claims 1 to 8.

13. The clinically safe and clinically effective dose is 12.5 mg of aprocitentan per day; if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, the dose means the amount of aprocitentan in free base form. The therapeutic agent according to claim 12.

14. The amount for which the clinically proven safety and clinically proven efficacy is 25 mg of aprocitentan per day; if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, the amount means the amount of aprocitentan in a free base form; the therapeutic agent according to claim 12.

15. The therapeutic agent is a therapeutic agent for uncontrolled hypertension or resistant hypertension that lowers blood pressure in a human patient in need thereof, The therapeutic agent is intended to be administered in the form of a pharmaceutical composition containing a clinically safe and clinically effective amount of aprocitentan in free or pharmaceutically acceptable salt form. The clinically safe and clinically effective dose is 12.5 mg or 25 mg of aprocitentan per day, and if the therapeutic agent contains aprocitentan in a pharmaceutically acceptable salt form, then the dose refers to the amount of aprocitentan in free base form. The aforementioned therapeutic agent is intended to be administered orally once a day. The aforementioned human patient had stage 3 or 4 chronic kidney disease (CKD) prior to treatment with the therapeutic agent. A therapeutic agent according to any one of claims 1 to 8.

16. The human patient has also been treated with at least three antihypertensive drugs prior to treatment with the therapeutic agent. Regardless, the therapeutic agent according to any one of claims 1 to 8, wherein the patient has a systolic blood pressure of 140 mmHg or higher.

17. A pharmaceutical composition for the treatment of uncontrolled or resistant hypertension in human patients requiring the same, The aforementioned pharmaceutical composition Aprocitentan in free or pharmaceutically acceptable salt form: 【Chemistry 2】 It contains as an active ingredient, The pharmaceutical composition comprises a clinically effective amount of aprocitentan in free or pharmaceutically acceptable salt form, and at least one pharmaceutically inactive excipient. The clinically effective dose of aprocitentan is 12.5 mg or 25 mg of aprocitentan per day. Herein, if the pharmaceutical composition contains aprocitentan in a pharmaceutically acceptable salt form, the amount means the amount of aprocitentan in a free base form.

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