EA044958B1 - PHARMACEUTICAL COMPOSITION FOR TREATMENT OF PULMONARY ARTERIAL HYPERTENSION - Google Patents

Description

Scope of the invention

The present invention relates to high doses of macitentan (INN), i.e. [5-(4-bromophenyl)-6-[2(5-bromopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl]propylsulfamic acid amide or its pharmaceutically acceptable salts, solvates, hydrates or morphological forms, for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH). In addition, the present invention relates to the use of high doses of macitentan for the production of a medicament for the treatment and/or prevention of PAH, as well as a method for the treatment and/or prevention of PAH, comprising administering high doses of macitentan to a patient. In addition, the present invention relates to a dosage regimen for the treatment and/or prevention of PAH, as well as a combination of macitentan with one or more phosphodiesterase type 5 (PDE5) inhibitors, prostacyclin analogues, prostacyclin receptor agonists or soluble guanylate cyclase stimulators. Here, PAH is preferably mild or moderate PAH. Moreover, the present invention relates to a pharmaceutical composition for the treatment of PAH, which contains a high dose of macitentan.

Prerequisites for creating the invention

The first reports of pulmonary hypertension (PH) appeared in 1891, when an autopsy of a patient following sudden death revealed right ventricular hypertrophy and pulmonary artery sclerosis without any obvious cause. Pulmonary arterial hypertension (PAH) is a subgroup of PH and is a progressive disease with increased pulmonary vascular resistance (PVR) as the underlying cause of increased afterload and right ventricular hypertrophy, which ultimately progresses to right ventricular dilatation and failure and premature death. According to the World Health Organization (WHO) classification, PH is clinically divided into five groups: pulmonary arterial hypertension (PAH) (group 1); PH associated with left heart disease (group 2); PH associated with pulmonary disease and/or hypoxia (group 3); chronic thromboembolic RP and other pulmonary artery obstructions (group 4); and ROP with unclear and/or multifactorial mechanisms (group 5) (Roger Hullin, Cardiovascular Medicine (2018), 21(7-8):195-199; Simonneau et al., Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J. (2018), Dec. 13. pii: 1801913, doi: 10.1183/13993003.01913-2018 [Epub ahead of print]).

The present invention focuses on PAH, which is hemodynamically characterized by a mean pulmonary artery pressure (PAP) >20 mmHg. Art., pulmonary artery wedge pressure (PAWP) <15 mm Hg. Art. and a PVR that is equal to or greater than 3 Wood units, alternatively >2 Wood units, all measured at rest.

In particular, the present invention focuses on PAH, which is hemodynamically characterized by a mean pulmonary artery pressure (PAP) >25 mmHg. Art., pulmonary artery wedge pressure (PAWP) <15 mm Hg. Art. and a PVR that is equal to or greater than 3 Wood units, alternatively >2 Wood units, all measured at rest.

The pathophysiology of PAH is characterized by an imbalance between molecules that mediate vasoconstriction (eg, endothelin or thromboxane) and/or molecules that mediate vasodilation (eg, prostacyclin and nitric oxide). Moreover, the mitogenic effects of these molecules with specific pathomorphological changes in the pulmonary circulation are one of the factors in the progression of the disease.

Currently available compounds approved for the specific treatment of PAH are divided into three different groups: a) endothelin receptor antagonists, b) phosphodiesterase type 5 inhibitors (PDE5is) and soluble guanylate cyclase stimulators, and c) molecules that block the prostacyclin pathway. Treatment with these compounds in combination with general supportive measures has resulted in an increase in 3-year survival after first diagnosis of idiopathic PAH from 48% in the 1980s. up to 74% in the last two decades, as evidenced by data from the REVEAL Registry (Benza et al., An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. CHEST (2012), 142(2), 448-456 and CHEST (2012), 141(2):354-362).

Summary of the invention

The object of the present invention is to provide a drug and/or regimen for the treatment of pulmonary arterial hypertension (PAH). In particular, the purpose of the present invention is to provide a drug and/or regimen for the treatment of mild to moderate forms of RAS. A further object of the present invention is to provide a combination drug and/or therapy for RAS.

Brief description of graphic materials

The figure shows a dose-response curve demonstrating the change

- 1 044958 hemoglobin (HGB) depending on the dose of macitentan administered to a person.

Detailed description

The present inventors have found that, despite concerns regarding clinically significant decreases in hemoglobin levels, drops in blood pressure, and/or edema or increased fluid retention, it is possible to safely and effectively treat patients with PAH with high doses of macitentan. In particular, the progression of the disease can be inhibited or even the disease status can be improved.

In the present invention, macitentan refers to propylsulfamic acid [5-(4-bromophenyl)-6-[2-(5bromopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl]amide, i.e. compound of formula (I)

Vg

(I).

or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof.

Macitentan is an endothelin receptor antagonist (ERA) that acts as an antagonist of two endothelin receptor (ET) subtypes ET _A and ET _B (Kholdani et al., Macitentan for the treatment of pulmonary arterial hypertension. Vasc. Health Risk Manag. (2014) , 10, 665-673). Its half-life in humans is approximately 16 hours, and steady-state concentrations are reached on the third day of administration (Bruderer et al., Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica (2012), 42(9), 901-910). It is slowly absorbed into the plasma (Sidharta et al., Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur. J. Clin. Pharmacol. (2011), 67, 977-984). Macitentan is dealkylated to the active metabolite ACT-132577, which reaches peak plasma concentrations approximately 30 hours after the first dose and has a half-life of approximately 48 hours. Although the affinity of ACT-132577 for ET receptors is lower than that of its parent compound (Iglarz et al., Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J. Pharmacol. Exp. Ther. (2008), 327(3), 736-745), its steady-state plasma concentration is higher than that of macitentan. Both compounds can be excreted from the body in urine or feces.

It was previously reported that the maximum or near maximum effect of macitentan in rats was achieved at 10 mg/kg. (European Medicines Agency, European Public Assessment Report for Opsumit, Procedure No. EMEA/H/C/002697/0000 (2013) see 20 (hereinafter EMA Assessment Report)). The maximum effective dose of macitentan in rats has also been previously reported to be 30 mg/kg (Id.; e.g., Iglarz et al., Comparison of Pharmacological Activity of Macitentan and Bosentan in Preclinical Models of Systemic and Pulmonary Hypertension. Life Sci. (2014) , 118, 333-339; see also Kunita-Takanezawa et al., Novel Dual Endothelin Receptor Antagonist Macitentan Reverses Severe Pulmonary Arterial Hypertension in Rats. J. Cardiovasc. Pharmacol. (2014), 64(5), 473-480) .

In a multiple dose escalation study evaluating macitentan doses of 1, 3, 10, and 30 mg in healthy subjects, steady-state plasma concentrations of ET-1 showed a dose-dependent increase with no further increase after the 10 mg oral dose, indicating blockade at this level. dosage. (Id. see 40). The researchers concluded that the 10 mg dose appeared to be close to a plateau of pharmacological effect. (Id. see 48). The European Medicines Agency and the US Food and Drug Administration have approved the use of a daily oral dose of 10 mg of macitentan for the treatment of patients with pulmonary arterial hypertension. (EMA, Summary of Product Characteristics for Opsumit (Oct. 29, 2019) see 2; FDA, Prescribing Information for Opsumit (April 2019) see 1).

Several aspects of the present invention will be explained in detail below.

(a) One aspect of the present invention relates to macitentan for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH) in humans, wherein the dose of macitentan is from more than 20 to 300 mg per day or less, for example from more than 20 to less than 250 mg in a day. Preferably the dose is from 25 to 200 mg.

In a more preferred aspect, such doses are administered once daily.

In the present invention, PAH refers to pulmonary arterial hypertension in humans.

The present invention focuses on PAH, which is hemodynamically characterized by a mean pulmonary artery pressure (PAP) >20 mmHg. Art., pulmonary artery wedge pressure (PAWP) <15 mm Hg. Art. and a PVR that is equal to or greater than 3 Wood units, alternatively >2 Wood units, all measured at rest. In addition to the hemodynamic parameters of PAH listed above

- 2 044958 is clinically characterized by the absence of significant left-sided heart disease, severe pulmonary disease or known chronic thromboembolic disease.

In particular, the present invention focuses on PAH, which, during right-sided cardiac catheterization, is characterized by the following hemodynamic parameters:

mean pulmonary artery pressure (mPAP) >25 mm Hg. Art., pulmonary artery occlusion/wedge pressure (PAWP) <15 mm Hg. Art., pulmonary vascular resistance equal to or greater than 3 Wood units, in an alternative embodiment >2 Wood units.

In addition to the hemodynamic parameters listed above, PAH is clinically characterized by the absence of significant left-sided heart disease, severe pulmonary disease, or known chronic thromboembolic disease.

As described above, macitentan is currently administered orally at a dose of 10 mg once daily. However, the present invention proposes to administer a high dose of macitentan to improve disease status, prevent disease exacerbations, improve or maintain WHO functional class, and improve long-term survival and/or reduce hospitalization rates. Compared with bosentan, the advantages are reduced or absent side effects affecting liver function and little or no hepatotoxicity.

Additional benefits include no further clinically significant drop in hemoglobin, no further clinically significant decrease in blood pressure, and/or no further clinically significant increase in edema/fluid retention.

(b) Another aspect of the present invention relates to the use of macitentan for the treatment and/or prevention of pulmonary arterial hypertension (PAH) in accordance with aspect (a), wherein PAS is a mild or moderate form of PAS, preferably a moderate form of PAS.

Surprisingly, it has been found that in cases of mild to moderate PAH, the disease status can be improved or stabilized; in particular, WHO functional class can be improved in patients with mild to moderate disease. It is also possible to improve functional capacity using the 6-minute walk test.

The term mild PAH roughly corresponds to WHO functional classes I and II.

The term moderate PAH roughly corresponds to WHO functional class III.

In contrast, WHO functional class IV corresponds to severe PAH.

WHO functional classes (FC WHO) are well known and are defined as follows.

WHO FC I: no symptoms of pulmonary arterial hypertension during exercise or at rest. The diagnosis is rarely made if the patient is still Class I. Patients screened for high risk factors for RAS, such as patients with scleroderma or a family history of RAS, are rarely diagnosed with Class I. This classification is more commonly used. to describe patients who had a marked response to therapy, previously classified as class II or III, but improved to class I.

WHO FC II: No symptoms at rest, but discomfort, fatigue, or shortness of breath during normal activities, such as climbing a flight of stairs, grocery shopping, or preparing a bed.

WHO FC III: Patients may be asymptomatic at rest, but usual activities are significantly limited due to shortness of breath, fatigue, or lightheadedness. Patients in this class have difficulty performing normal household chores and are forced to take breaks from daily activities.

WHO FC IV: symptoms at rest or severe symptoms during any activity. Patients in this class may lose consciousness during normal activities or when bending over with their head down. Many patients in this class also have increased swelling of the feet and ankles due to right-sided heart failure.

According to a more detailed assessment, mild RAS is defined as follows:

(dmild): meeting at least 3 of the following criteria:

WHO FC I or II;

six-minute walk distance (6MWD) >440 m;

B-type natriuretic peptide (BNP) <50 ng/L or N-terminal proB-type natriuretic peptide (NT-proBNP) <300 ng/L or RAP <8 mmHg. Art.;

CI >2.5 L/min/m ² or SvO ₂ >65%;

and failure to meet any of the criteria (dsevere).

In accordance with a more detailed assessment, severe RAS is defined as follows: (dsevere): compliance with at least two of the following indicators, including CI or SvO ₂ : WHO FC IV;

- 3 044958

6MWD <165 m;

BNP >300 ng/L or NT-proBNP >1400 ng/L or RAP >14 mmHg. Art.;

CI <2.0 l/min/m ² or SvO ₂ <60%.

According to a more detailed assessment, moderate RAS is defined as follows:

(dmoderate): the above assessments of criteria (dmild) and criteria (dsevere) in none of the cases allow us to classify the patient's wound as mild PAH, and also do not allow us to classify the patient's wound as severe PAH.

Preferably, the NT-proBNP concentration is determined rather than the BNP concentration and used to decide whether the patient has mild, moderate or severe PAH according to the more detailed assessment definitions above.

BNP is measured as follows: a plasma sample is collected and transported frozen (-20°C or below) in an EDTA polymer tube and analyzed using an immunochemiluminescence assay (ICMA). The ICMA analysis is based on the following principles.

Use a commercially available kit (Triage® BNP test) with the following three working solutions/suspensions:

S1a: paramagnetic particles coated with mouse omniclonal antibodies to human BNP suspended in TRIS buffered saline (150 mM NaCl, 50 mM Tris-HCl, pH 7.6 aq), with bovine serum albumin (BSA), 0.1 % ProClin™ 300 (0.60-1.00% 2-methyl-4-isothiazolin-3-one and 2.10-2.80% 5-chloro-2-methyl-4-isothiazolin-3-one, aq. . solution) and <0.1% sodium azide;

S1b: Purified mouse and goat IgG in TRIS buffered saline (150 mM NaCl, 50 mM Tris-HCl, pH 7.6 aq), with bovine serum albumin (BSA), 0.1% ProClin™ 300 (0. 60-1.00% 2-methyl-4-isothiazolin-3-one and 2.10-2.80% 5-chloro-2-methyl-4-isothiazolin-3-one, aq. solution) and <0, 1% sodium azide; And

S1c: conjugate of mouse monoclonal antibody against human BNP with bovine alkaline phosphatase in physiological PBS buffer solution (pH 7.4; 137 mmol/L NaCl, 2.7 mmol/L KCl, 10 mmol/L Na ₂ HPO ₄ and 1.8 mmol/L KH2PO4), with bovine serum albumin (BSA), 0.1% ProClin™ 300 (0.60-1.00% 2-methyl-4-isothiazolin-3-one and 2.10-2.80% 5-chloro-2-methyl-4isothiazolin-3-one, aq. solution) and <0.1% sodium azide.

A blood sample (500 μl) is collected from the patient and placed in a polymer blood collection tube containing K ₂ EDTA as an anticoagulant. The blood sample must be mixed by carefully inverting the tube several times.

The S1a suspension and S1c solution are placed in a reaction vessel and 55 μl of blood sample is added.

After incubation in the reaction vessel, a magnetic field is used to retain substances bound to the solid phase, and free substances are washed away using solution S1b.

Lumi-Phos® 530 chemiluminescent substrate (Chemical Abstracts Substance No. 146239-76-1) is then added to the reaction vessel and the light emitted by the reaction is detected by a luminometer. The measured light intensity is proportional to the BNP concentration, allowing the concentration of BNP in the sample to be determined.

To ensure the accuracy of ICMA assay results, the luminometer should be periodically calibrated using commercially available standard solutions.

NT-proBNP is determined as follows: a serum or plasma sample is collected and transported at ambient temperature if such transport continues within 3 days of collection, or frozen in a red cap tube after centrifugation and analyzed using an electrochemiluminescent immunoassay (ECLIA). The ECLIA analysis is based on the following principles.

Use a commercially available kit with the following 3 working solutions/suspensions:

S1: suspension (6.5 ml) of microparticles coated with streptavidin (0.72 mg/ml) containing a preservative;

S2: solution (9 ml) anti-NT-proBNP-Ab-biotin containing biotinylated monoclonal anti-NT-proBNP antibody (mouse) (1.1 μg/ml), phosphate buffer 40 mmol/l, pH 5.8, and preservative; And

S3: solution (9 ml) anti-NT-proBNP-Ab-Ru(bpy) containing a monoclonal NT-proBNP-specific antibody labeled with tris-(2,2'-bipyridyl)ruthenium(R) complex (Ru(bpy)) ( 1.1 µg/ml), phosphate buffer 40 mmol/l, pH 5.8, and preservative.

The sample (15 μl) is first incubated with solutions S2 and S3; a biotinylated monoclonal NT-proBNP-specific antibody and a monoclonal NT-proBNP-specific antibody labeled with a ruthenium complex form a sandwich complex.

Then a second incubation is carried out, during which, after adding the S1 suspension, the complex binds to the solid phase due to the interaction of biotin and streptavidin.

The reaction mixture is sucked into the measuring cell, where under the influence of a magnetic field

- 4 044958 microparticles are retained on the surface of the electrode. Free substances are then removed. After this, applying a voltage to the electrode causes the emission of chemiluminescence, the intensity of which is measured by a photomultiplier tube.

The results are evaluated against a calibration curve using commercially available standard solutions.

CI is measured as follows. CI measures the blood flow (L/min) through the heart, called cardiac output (CO), standardized to the patient's body surface area (BSA); therefore CI is expressed in l/min/ ^m2 . The standard procedure for diagnosing PAH is right cardiac catheterization (RHC). This is an invasive procedure in which a catheter is inserted through a large vein and advanced to the right side of the heart and then into the pulmonary artery. There are various methods for measuring CI, but the most common methods are the Fick cardiac index method or the thermodilution cardiac index method. They are standardized and well-studied methods. The most acceptable method is the thermodilution method. In accordance with the present invention, thermodilution (TD) will be the method of choice for measuring CI. TD determines CO based on how quickly a given amount of fluid (typically at room temperature, i.e. 25°C) moves from the right atrium [inserted into the proximal port of a pulmonary artery (PA) catheter] to the PA (detected by a temperature sensor near tip of the distal part of the RA catheter). The area under the curve (AUC) of temperature change is determined. The procedure should be repeated at least 3 times and then the average value should be calculated, but for the reliability of the measurements taken, the values should be within (±) 10-15% of each other. Curves should also be evaluated to ensure smooth flow without sudden changes in the curve that could indicate input or measurement errors. Based on the resulting average patient AUC and BSA, calculated as follows:

BSA = /[(height in cm x weight in kg) / 3600], calculate CI.

RAP is measured as follows: RAP (sometimes referred to as mean RAP (mRAP)) is also measured during the RHC procedure as described above to measure CI. The tip of the catheter contains a pressure sensor that is inserted into a vein leading to the right side of the heart. The sensor measures the pressure when the tip of the catheter is in the right atrium, and this measured pressure is the RAP. This measurement is carried out once.

SvO ₂ is measured as follows: SvO ₂ is also measured during the RHC procedure as described above for the CI measurement. With the tip of the catheter in the central vein or right atrium, blood is drawn and the oxygen concentration/content (partial pressure of oxygen in the blood) in this blood sample is analyzed using standard blood gas analyzers/sensors; The % oxygenation in a given blood sample is SvO ₂ . This measurement is also carried out once.

For a more detailed assessment, mild and moderate forms of PAH can be diagnosed using an algorithm based on the Registry for Early Evaluation and Long-Term Treatment of RAS Diseases (REVEAL Registry). The algorithm can be described by a sequence of the following stages:

(i) defining the subgroup for the patient's WHO group I and assigning the following scores:

+1 point for PAH-CTD (PAH associated with connective tissue disease), +2 points for PAH-PoPH (PAH associated with portopulmonary hypertension), +2 points for FAPH (familial PAH, now called hereditary PAH) , scores for any other PAH subgroups;

(ii) determining demographic indicators and comorbidities and assigning the following scores:

+1 point for renal failure, +2 points for men aged >60 years, points for other patients;

(iii) determining the WHO functional class and assigning the following ratings:

-2 points for WHO FC I, points for WHO FC II, +1 point for WHO FG III, +2 points for WHO FG IV;

(iv) determining the main indicators of the body’s condition and assigning the following ratings:

+1 point for SBP (systolic systemic blood pressure) <110 mmHg. Art., +1 point for HR (heart rate) >92 BPM (beats per minute), points for all other cases;

(v) determining the distance after a 6-minute walk and assigning the following ratings:

-1 point for >440 m,

- 5 044958 +1 point for <165 m, points for all other cases;

(vi) determination of brain natriuretic peptide (BNP) and assignment of the following scores:

-2 points for BNP <50 pg/ml, +1 point for BNP >180 pg/ml, points for BNP from 50 to 180 pg/ml;

(vii) taking an echocardiogram and assigning the following scores:

+1 point for pericardial effusion, points for all other cases;

(viii) examination of lung functions and assignment of the following scores:

-1 point for % predicted DLCO >80% (lung diffusivity of carbon monoxide), +1 point for % predicted DLCO <32%, points for % predicted DLCO between 32 and 80%;

(ix) right-sided cardiac catheterization and assignment of the following scores:

+1 point for RAP (mean right atrial pressure) >20 mmHg. Art. within 1 year, +2 points for PVR (pulmonary vascular resistance) >32 Wood units points for all other cases;

(x) sum up the points scored in stages (i)-(ix) and add the number 6;

(xi) mild PAH is diagnosed with a score of 1 to 7, and moderate PAH is diagnosed with a score of 8 or 9.

In the above algorithm, + means addition, - means subtraction.

The Wood unit is a simplified system measure for assessing pulmonary vascular resistance (PVR) that uses pressure increments. PVR measurements are made by subtracting the pulmonary artery wedge pressure from the mean pulmonary arterial pressure and then dividing by the cardiac output in liters per minute.

Thus, mild PAH is associated with a score of 1–7, and moderate PAH is associated with a score of 8 or 9.

More detailed definitions are detailed in the ESC/ERS Guidelines, European Heart Journal (2016), 37, 67-119.

Inherited transmission of PAH has been reported in approximately 6 to 10% of patients with PAH; 50 to 90% of these subjects had mutations in bone morphogenetic protein receptor type 2 (BMPR2). Mutations in BMPR2 in familial pulmonary arterial hypertension (FPAH) are characterized by genetic anticipation and incomplete penetrance of the mutation. BMPR2 is also called hereditary PAH. PAH. Expression of the phenotype does not occur in all generations, and when expressed, it occurs at an earlier age and is associated with more severe and rapidly progressive disease. Many other genetic mutations have been identified that are associated with familial (hereditary) PAH, but they do occur much less common than the BMPR2 mutation (Morrell et al., Eur. Respir. J. (2018), Dec. 13. pii: 1801899. doi: 10.1183:13993003.01899-2018 [Epub ahead of print]).

In the present invention, PAH-CTD (PAH associated with connective tissue disease) is characterized by PAH in patients also suffering from an autoimmune disease, also called connective tissue disease. The most common connective tissue diseases associated with PAH are scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus/SLE), mixed connective tissue diseases, and Sjögren's disease.

In the present invention, PAH-PoPH (PAH associated with portal pulmonary hypertension) is characterized by PAH associated with portal hypertension. Portal hypertension is defined as increased pressure in the portal vein, as evidenced by an increase in the pressure gradient between the portal vein and the hepatic vein by more than 5 mmHg. Art. (this becomes clinically significant when the pressure gradient is >10 mmHg). The portal vein carries blood from the gastrointestinal system to the liver. Although this situation is more likely to occur in cases of advanced liver disease causing portal hypertension, in the presence of portal hypertension, portopulmonary hypertension can occur in the absence of liver disease.

PAH associated with portal hypertension is commonly referred to as PoPH. This form should not be confused with hepatopulmonary syndrome, which is characterized by abnormal pulmonary vasodilation and hypoxemia. However, there may be common symptoms for both conditions. As the term suggests, PoPH as defined above is associated with the presence of portal hypertension, but not necessarily with the presence of liver disease. However, since cirrhosis appears to be the most common cause of portal hypertension, RoPH is most common in patients with cirrhosis.

- 6 044958

To assess disease severity, hemodynamic profile, and other potential causes of PH, including pulmonary disease, LHD, or chronic thromboembolic disease (ESC/ERS Guidelines,

European Heart Journal (2016), 37, 67-119), a full diagnostic workup, including right cardiac catheterization (RHC), is necessary.

In the present invention, renal failure is characterized by a glomerular filtration rate (GFR) of less than 90 ml/min/1.73 m ² . The GFR is calculated from the patient's standardized blood creatinine concentration (SCr) and using the MDRD equation, which is as follows:

GFR=175 χ SCr ^-1.154 χ age ^-0.203 χ (0.742 for women) χ (1.21 for African Americans).

The GFR obtained from the above equation is expressed in ml/min per 1.73 m ² body surface area. If the patient's body surface area is different from 1.73 m ² , the value obtained for GFR from the MDRD equation above must be adjusted accordingly.

Pericardial effusion is an accumulation of fluid around the heart. Typically, a very thin layer of fluid, usually invisible to the naked eye, must be placed between the heart and the pericardium (the fibrinous layer that surrounds and protects the heart) as a lubricant. In advanced ROP (as well as many other diseases), this fluid forms and accumulates around the heart, a condition called pericardial effusion. The presence of such an effusion carries a poor prognosis as it indicates progressive ROP and right-sided cardiac dysfunction/failure.

DLCO is determined by the results of a pulmonary function test. Such studies are carried out in accordance with the description in Graham et al., 2017, ERS/ATS standards for single-breath carbon monoxide uptake in the lung, Eur. Respira. J. (2017), 49, 1600016.

RHC is an invasive, typically outpatient procedure that involves inserting a catheter through a central vein and then passing it through the right chambers of the heart to enter the pulmonary artery. During this procedure, various measurements are taken, including pressure and blood flow parameters called cardiac output.

(c) Another aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is from 60 to 90 mg per day. The dose is preferably 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg, 60 to 80 mg, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day. In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(d) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is from 25 to 50 mg per day. The dose is preferably 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 25 to 45 mg per day or 25 to 40 mg per day. Additionally, doses of 30 to 50 mg per day or 30 to 40 mg per day are presented. Additional preferred ranges are 36 to 39 mg per day. In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(e) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is from 110 to 200 mg per day. The dosage is preferably 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. Additionally, doses of 125 to 160 mg per day or 140 to 175 mg per day are provided. Additional preferred ranges are 145 to 155 mg per day. In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(f) A further aspect of the present invention relates to macitentan for use in

- 7 044958 treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is from 60 to 90 mg twice a day. The dosage is preferably 65 to 85 mg twice daily, more preferably 70 to 80 mg twice daily, and most preferably 75 mg twice daily. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg twice daily, 60 to 80 mg twice daily, or 60 to 75 mg twice daily. Additionally, doses of 65 to 90 mg twice daily or 65 to 75 mg twice daily are provided. Additional preferred ranges are 72 to 78 mg twice daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(g) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is from 25 to 50 mg twice daily, preferably from 30 to 45 mg twice daily, more preferably 35 to 40 mg twice daily and most preferably 37.5 mg twice daily. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 25 to 45 mg twice daily or 25 to 40 mg twice daily. Additionally, doses of 30 to 50 mg twice daily or 30 to 40 mg twice daily are provided. Additional preferred ranges are 36 to 39 mg twice daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(h) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is increased from 10 mg per day followed by 25 to 50 mg per day , preferably 37.5 mg per day, optionally followed by 60 to 90 mg per day, preferably 75 mg per day. Here, the expression followed by 25 to 50 mg per day means preferably a dose of 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the given lower limits can be combined with each of the upper limits, i.e. the dose may also be 25 to 45 mg per day or 25 to 40 mg per day. Additionally, doses of 30 to 50 mg per day or 30 to 40 mg per day are presented. Additional preferred ranges are 36 to 39 mg per day. It should be understood that any increase in dose to a higher dose may be followed by a return to a lower dose if the higher dose is not tolerated.

Moreover, the expression optionally followed by 60 to 90 mg per day means preferably a dose of 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day. It should be understood that any increase in dose to a higher dose may be followed by a return to a lower dose if the higher dose is not tolerated.

In a more preferred aspect, such doses are administered once daily.

The current dose of macitentan for use in the treatment of PAH is 10 mg per day. Patients receiving this dose may have their dose increased immediately to 37.5 mg per day, optionally followed by 75 mg per day.

A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH according to aspect (a) or (b), wherein the dosage of macitentan is increased from 10 mg per day followed by 25 to 50 mg per day, preferably 37 .5 mg per day, optionally followed by 60 to 90 mg per day, preferably 75 mg per day, optionally followed by 110 to 200 mg per day, preferably 150 mg per day.

The expression optionally followed by 110 to 200 mg per day preferably means a dose of 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. Additionally, doses of 125 to 160 mg per day or 140 to 175 mg per day are provided. Additional preferred ranges are 145 to 155 mg per day. In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(i) A further aspect of the present invention relates to macitentan for use in

- 8 044958 treatment and/or prevention of PAH according to aspect (a) or (b), wherein the dosage of macitentan is increased from 10 mg per day followed by 60 to 90 mg per day, preferably mg per day or 37.5 mg twice a day.

The expression optionally followed by 60 to 90 mg per day means preferably a dose of 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day. It should be understood that any increase in dose to a higher dose may be followed by a return to a lower dose if the higher dose is not tolerated.

In a more preferred aspect, such doses are administered once daily.

A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH according to aspect (a) or (b), wherein the dosage of macitentan is increased from 10 mg per day followed by 60 to 90 mg per day, preferably 75 mg daily or 37.5 mg twice daily, optionally followed by 110 to 200 mg daily, preferably 150 mg daily.

The expression optionally followed by 110 to 200 mg per day preferably means a dose of 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. Additionally, doses of 125 to 160 mg per day or 140 to 175 mg per day are provided. Additional preferred ranges are 145 to 155 mg per day. In a more preferred aspect, such doses are administered once daily.

The current dose of macitentan for use in the treatment of PAH is 10 mg per day. Patients receiving this dose may have their dose increased immediately to 75 mg per day or to 150 mg per day.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(j) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (h), wherein the dosage of macitentan is increased from 10 mg per day, preferably over 15 to 45 days; followed by 25 to 50 mg per day, preferably 37.5 mg once daily, preferably for 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that any increase in dose to a higher dose may be followed by a return to a lower dose if the higher dose is not tolerated.

Here, the term 15 to 45 days means preferably 20 to 40 days, more preferably 21 to 35 days, and most preferably 28 to 30 days, i.e. approximately one month.

Moreover, the expression followed by 25 to 50 mg per day means preferably a dose of 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the given lower limits can be combined with each of the upper limits, i.e. the dose may also be 25 to 45 mg per day or 25 to 40 mg per day. Additionally, doses of 30 to 50 mg per day or 30 to 40 mg per day are presented. Additional preferred ranges are 36 to 39 mg per day.

Moreover, the expression followed by 60 to 90 mg per day means preferably a dose of 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day or 36 to 39 mg twice daily.

In a more preferred aspect, such doses are administered once daily.

A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (h), wherein the dosage of macitentan is increased from 10 mg per day, preferably over 15 to 45 days; followed by 25 to 50 mg per day, preferably 37.5 mg once daily, preferably for 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily, preferably for 15 to 45 days; optionally followed by 110 to 200 mg per day, preferably 150 mg per day.

- 9 044958

The expression optionally followed by 110 to 200 mg per day preferably means a dose of 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. In addition, doses of 125 to 160 mg or 140 to 175 mg per day are presented. Additional preferred ranges are 145 to 155 mg per day. In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(k) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (i), wherein the dosage of macitentan is increased from 10 mg per day, preferably over a period of 15 to 45 days; followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily.

Here, the term 15 to 45 days means preferably 20 to 40 days, more preferably 21 to 35 days, and most preferably 28 to 30 days, i.e. approximately one month.

The expression followed by 60 to 90 mg per day means preferably a dose of 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day or 36 to 39 mg twice daily.

A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with (i), wherein the dosage of macitentan is increased from 10 mg per day, preferably over 15 to 45 days; followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily, preferably for 15 to 45 days; optionally followed by 110 to 200 mg per day, preferably 150 mg per day. The expression optionally followed by 110 to 200 mg per day preferably means a dose of 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. In addition, doses of 125 to 160 mg or 140 to 175 mg per day are presented. Additional preferred ranges are 145 to 155 mg per day.

In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(l) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with any of aspects (a)-(d), wherein the dosage of macitentan is increased from 25 to 50 mg per day, preferably 37.5 mg in a day; preferably from 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg per day; provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that any increase in dose to a higher dose may be followed by a return to a lower dose if the higher dose is not tolerated.

Here, the term 15 to 45 days means preferably 20 to 40 days, more preferably 21 to 35 days, and most preferably 28 to 30 days, i.e. approximately one month.

Moreover, the expression followed by 25 to 50 mg per day means preferably a dose of 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that each of the given lower limits can be combined with each of the upper limits, i.e. the dose may also be 25 to 45 mg per day or 25 to 40 mg per day. Additionally, doses of 30 to 50 mg per day or 30 to 40 mg per day are presented. Additional preferred ranges are 36 to 39 mg per day.

Moreover, the expression followed by 60 to 90 mg per day means preferably a dose of 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. In addition, doses of 65 to 90 mg or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day or 36 to 39 mg twice daily.

- 10 044958

It should be understood that optionally the dose of macitentan can be further increased from 110 to

200 mg per day. Thus, the dose is increased as in aspect (i), (j) or (k).

In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(m) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with any of aspects (a) to (c), wherein the dosage of macitentan is from 60 to 90 mg per day, preferably 75 mg per day ; provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan.

The expression 60 to 90 mg per day means preferably a dose of 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. Additional preferred ranges are 72 to 78 mg per day or 36 to 39 mg twice daily.

It should be understood that optionally the dose of macitentan can be further increased from 110 to 200 mg per day. Thus, the dose is increased as in aspect (i), (j) or (k).

In a more preferred aspect, such doses are administered once daily.

In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(n) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with any of aspects (a)-(m), wherein macitentan is combined with a PDE5 inhibitor, and/or a prostacyclin analogue, and/or an agonist prostacyclin receptor, and/or a soluble guanylate cyclase stimulator.

Inhibition of cyclic guanosine monophosphate (cGMP), the cleaving enzyme phosphodiesterase type 5, results in vasodilation through the NO/cGMP pathway at sites expressing this enzyme. Because the pulmonary vasculature contains significant amounts of phosphodiesterase type 5, the potential clinical benefit of phosphodiesterase type 5 inhibitors (PDE5is) has been investigated for RAS. In addition, PDE5is has antiproliferative effects (ESC/ERS Guidelines; European Heart Journal (2016), 37, 67-119).

Prostacyclin is produced predominantly by endothelial cells and has a powerful vasodilator effect on the entire network of blood vessels. This compound is the most effective endogenous inhibitor of platelet aggregation and also appears to have both cytoprotective and antiproliferative activities. Patients with RAS showed dysregulation of prostacyclin metabolic pathways, which was assessed by decreased expression of prostacyclin synthase in the pulmonary arteries and prostacyclin metabolites in the urine. The clinical use of prostacyclin in patients with PAH has expanded through the synthesis of stable analogues with different pharmacokinetic properties but qualitatively similar pharmacodynamic effects (ESC/ER Guidelines; European Heart Journal (2016), 37, 67-119).

To date, no drug interactions have been observed for macitentan and its active metabolite, ACT-132577.

For example, macitentan 10 mg daily had no effect on the pharmacokinetics of 1 mg rosuvastatin, indicating no inhibition of BCRP transporters. BCRP is an efflux pump found in the intestine, liver tubular membrane, and kidney, and is affected by intracellular drug concentrations in the liver and kidney.

Macitentan and ACT-132577 activated human PXR with EC ₅₀ values of 1.1 to 1.2 μM and 7.2 to 8.7 μM, respectively. In human hepatocytes, both compounds caused a concentration-dependent increase in CYP3A4 mRNA and enzyme activity.

Based on the results of an additional PK study and assuming dose linearity, the predicted peak plasma concentrations of macitentan and AST-132577 in patients with PAH at a dose of 75 mg per day were calculated to be approximately 5 and 14 μM, respectively. Given the high degree of protein binding, free plasma concentrations for macitentan and ACT132577 are expected to range from 0.02 to 0.07 μM, respectively. It is unlikely that these levels of free concentrations of macitentan and ACT-132577 result in any inhibition of BCRP in the liver or kidneys or induce the enzyme CYP3A4 in the liver.

Thus, the dose of macitentan in aspect (n) may be from 60 to 90 mg per day. The dose is preferably 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Except

- 11 044958 In addition, doses from 65 to 90 mg per day or from 65 to 75 mg per day are presented. An additional preferred dose range is 72 to 78 mg per day.

In addition, the dose of macitentan can be increased from 10 mg per day, followed by 25 to 50 mg per day, preferably 37.5 mg per day, followed by 60 to 90 mg per day, preferably 75 mg per day, optional followed by 100 to 200 mg per day, preferably 150 mg per day.

In a preferred aspect, such combinations relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(o) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (n), wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil and udenafil; the prostacyclin analogue is selected from epoprostenol, treprostinil, iloprost and beraprost; the prostacyclin receptor agonist is selected from selexipag and ralinepag; and the soluble guanylate cyclase stimulator is selected from riociguat and vericiguat.

In this case, the dose or regimen of macitentan corresponds to one of aspects (a)-(l) and (n). In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH.

In a preferred aspect, such combinations relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(p) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (n) or (o), wherein macitentan is combined with tadalafil and/or selexipag or ralinepag. Macitentan is preferably combined with tadalafil and/or selexipag.

In this case, the dose or regimen of macitentan corresponds to one of aspects (a)-(k) and (n). In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH.

In a preferred aspect, such combinations relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(q) A further aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with aspect (p), wherein tadalafil, when used, is used at a dose of 20 to 40 mg per day, preferably 40 mg per day, Selexipag, when used, is used at a dose of 0.2 to 1.6 mg twice daily, and ralinepag, when used, is used at a dose of 0.05 to 1.45 mg per day.

In this case, the dose or regimen of macitentan corresponds to one of aspects (a)-(k) and (n). In a preferred aspect, such dosages relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH.

In a preferred aspect, such combinations relate to macitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

(r) A further aspect of the present invention relates to a pharmaceutical composition for use in the treatment and/or prevention of PAH, which includes macitentan and at least a pharmaceutically acceptable excipient and contains macitentan in an amount of from more than 20 to 300 mg or less, for example from more 20 to less than 250 mg, preferably 37.5, 75 or 150 mg, more preferably 37.5 or 75 mg, most preferably 75 mg.

It should be understood that macitentan may be administered at a dose in accordance with any of the daily dosages of aspects (a)-(e).

In a preferred aspect, the pharmaceutical composition is for use in the treatment and/or prevention of mild to moderate PAH.

(s) A further aspect of the present invention relates to a pharmaceutical composition in accordance with aspect (r), which includes:

i) macitentan in a total amount of from 10 to 50% by weight based on the total weight of the pharmaceutical composition;

ii) a filler containing lactose monohydrate with microcrystalline cellulose, in a total amount of from 10 to 85% by weight, based on the total weight of the pharmaceutical composition;

iii) a disintegrant containing sodium carboxymethyl starch or a mixture of sodium carboxymethyl starch and polyvinylpyrrolidone, in a total amount of 1 to 10% by weight based on the total weight of the pharmaceutical composition;

iv) a surfactant containing polysorbate in a total amount of from 0.1 to 1% by weight based on the total weight of the pharmaceutical composition; And

v) a lubricant containing magnesium stearate in a total amount of from 0.05 to 5% by weight based on the total weight of the pharmaceutical composition.

(t) A further aspect of the present invention relates to a pharmaceutical composition according to aspect (r) or (s), which is provided in the form of a capsule or tablet (in particular, in the form of a tablet, namely a tablet containing 75 mg of macitentan).

- 12 044958 (u) Another aspect of the present invention relates to macitentan for use in the treatment and/or prevention of PAH in accordance with any of aspects (a)-(q), wherein by treatment and/or prevention is meant a reduction in the risk of disease and/or mortality for the Russian Academy of Sciences. Thus, this aspect of the present invention relates to macitentan for use in reducing the risk of morbidity and/or mortality for RAS, wherein macitentan is used in accordance with any of aspects (a)-(q).

The reduction in morbidity and/or mortality risk for RAS can be assessed by the reduction in the composite morbidity/mortality risk, for example, by the time to first clinical deterioration within up to 7 days after the end of treatment (EOT), defined as the time from the initial point to the registration of the first of the following events (primary outcome):

death (mortality from any cause);

hospitalization associated with pulmonary hypertension (including due to worsening RAS, atrial septostomy, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclins);

worsening of PAH with the need to initiate parenteral prostanoid therapy;

progression of disease associated with pulmonary hypertension, defined as:

for patients of functional classes II and III in relation to the initial level (both criteria must be met):

a decrease in six-minute walking distance (6MWD) of more than 15% from baseline, confirmed by two 6MWD tests performed on separate days within 2 weeks of each other;

initiation of additional therapy for PAH or conclusion of worsening WHO functional class;

for patients in functional class IV relative to baseline (both criteria must be met):

a reduction in distance with 6MWD of more than 15% relative to baseline, confirmed by two 6MWD tests performed on different days within 2 weeks of each other;

initiation of additional therapy for PAH.

In an alternative embodiment, the reduction in risk of morbidity and/or mortality for PAH can be assessed independently.

The above assessment may be carried out, for example, according to the following schedule:

i) a run-in period (eg 4 weeks) with a dosage of macitentan 10 mg per day;

ii) a titration period (eg, 4 weeks) with a dosage of macitentan 37.5 mg per day;

iii) maintenance period with macitentan 75 mg per day.

The above assessment can be carried out, for example, using a double-blind test in which the control group receives a dose of macitentan 10 mg per day during the titration and maintenance period.

To reduce the risk of morbidity and/or mortality for PAH, the dose of macitentan may be 60 to 90 mg per day. The dose is preferably 65 to 85 mg per day, more preferably the dose is 70 to 80 mg per day, and most preferably the dose is 75 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose may also be 60 to 85 mg per day, 60 to 80 mg per day, or 60 to 75 mg per day. Additionally, doses of 65 to 90 mg per day or 65 to 75 mg per day are presented. An additional preferred dose range is 72 to 78 mg per day.

In addition, the dose of macitentan can be increased from 10 mg per day, followed by 25 to 50 mg per day, preferably 37.5 mg per day, followed by 60 to 90 mg per day, preferably 75 mg per day, optional followed by 100 to 200 mg per day, preferably 150 mg per day.

It should be understood that all of the above aspects are to be considered as being disclosed also with respect to the form of macitentan for the manufacture of a medicinal product for use in accordance with any of aspects (a)-(q) and (u).

(a') One aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH) in humans, wherein the dose of macitentan is from more than 20 to 300 mg per day or less, for example from more 20 to less than 250 mg per day. It should be understood that the description of aspect (a) applies in a similar manner.

(b') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH) in accordance with aspect (a'), wherein the PAH is a mild or moderate form of PAH, preferably moderate PAH form. It should be understood that the description of aspect (b) applies in a similar manner.

- 13 044958 (c') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a') or (b'), wherein the dosage of macitentan is from 60 to 90 mg per day, preferably 65 to 85 mg per day, more preferably 70 to 80 mg per day, and most preferably 75 mg per day. It should be understood that the description of aspect (c) applies in a similar manner.

(d') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a') or (b'), wherein the dosage of macitentan is from 25 to 50 mg per day, preferably 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that the description of aspect (d) applies in a similar manner.

(e') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a') or (b'), wherein the dosage of macitentan is from 110 to 200 mg per day, preferably 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that the description of aspect (e) applies in a similar manner.

(f) Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a') or (b'), wherein the dosage of macitentan is from 60 to 90 mg twice daily , preferably 65 to 85 mg twice daily, more preferably 70 to 80 mg twice daily, and most preferably 75 mg twice daily. It should be understood that the description of aspect (f) applies in a similar manner.

(g') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a') or (b'), wherein the dosage of macitentan is from 25 to 50 mg twice a day day, preferably 30 to 45 mg twice daily, more preferably 35 to 40 mg twice daily, and most preferably 37.5 mg twice daily. It should be understood that the description of aspect (g) applies in a similar manner.

(h') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a') or (b'), wherein the dosage of macitentan is increased from 10 mg per day followed by 25 to 50 mg per day, preferably 37.5 mg per day, optionally followed by 60 to 90 mg per day, preferably 75 mg per day. It should be understood that the description of aspect (h) applies in a similar manner.

(i') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the dosage of macitentan is increased from 10 mg per day, followed by 60 to 90 mg per day, preferably 75 mg per day or 37.5 mg twice daily. It should be understood that the description of aspect (i) applies in a similar manner.

(j') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (h'), wherein the dosage of macitentan is increased from 10 mg per day, preferably over a period of 15 to 45 days; followed by 25 to 50 mg per day, preferably 37.5 mg once daily, preferably for 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the description of aspect (j) applies in a similar manner.

(k') Another aspect of the present invention relates to macitentan for the production of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (i'), wherein the dosage of macitentan is increased from 10 mg per day, preferably over a period of 15 to 45 days; followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the description of aspect (k) applies in a similar manner.

(D) Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with any of aspects (a')-(d'), wherein the dosage of macitentan is increased from 25 to 50 mg per day, preferably 37.5 mg per day, preferably for 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg per day; provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the description of aspect (l) applies in a similar manner.

(m') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with any of aspects (a')-(c'), wherein the dosage of macitentan is from 60 to 90 mg per day, preferably 75 mg

- 14 044958 per day; provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the description of aspect (m) applies in a similar manner.

(n') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with any of aspects (a')-(m'), wherein macitentan is combined with a PDE5 inhibitor, and/or a prostacyclin analogue, and/or a prostacyclin receptor agonist, and/or a soluble guanylate cyclase stimulator. It should be understood that the description of aspect (n) applies in a similar manner.

(o') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (n'), wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil and udenafil; the prostacyclin analogue is selected from epoprostenol, treprostinil, iloprost and beraprost; the prostacyclin receptor agonist is selected from selexipag and ralinepag; and the soluble guanylate cyclase stimulator is selected from riociguat and vericiguat. It should be understood that the description of aspect (o) applies in a similar manner.

(p') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (n') or (o'), wherein macitentan is combined with tadalafil and/or selexipag or ralinepag, preferably with tadalafil and/or selexipag. It should be understood that the description of aspect (p) applies in a similar manner.

(q') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with aspect (p'), wherein tadalafil, when used, is used at a dose of 20 to 40 mg per day, preferably 40 mg per day, selexipag, when used, is used at a dose of 0.2 to 1.6 mg twice daily, and ralinepag, when used, is used at a dose of 0.05 to 1.45 mg per day. It should be understood that the description of aspect (q) applies in a similar manner.

(u') Another aspect of the present invention relates to macitentan for the manufacture of a medicament for use in the treatment and/or prevention of PAH in accordance with any of aspects (a')-(q'), wherein by treatment and/or prevention is meant risk reduction morbidity and/or mortality for RAS. Thus, this aspect of the present invention relates to macitentan for the production of a medicament for reducing the risk of morbidity and/or mortality for wounds, wherein macitentan is administered in accordance with any of aspects (a')-(q'). It should be understood that the description of aspect (u) applies in a similar manner.

It should be understood that the comments and details of aspects (a)-(q) and (u) also apply to aspects (a')-(q') and (u').

Moreover, it should be understood that all of the above aspects (a)-(q) and (u) should be considered as being disclosed in relation to the form of the method of treatment.

(a'') One aspect of the present invention provides a method for treating and/or preventing pulmonary arterial hypertension (PAH) in a human, the method comprising administering to a subject in need thereof macitentan at a dose of greater than 20 to 300 mg per day or less, e.g. more than 20 to less than 250 mg per day. It should be understood that the description of aspect (a) applies in a similar manner.

(b'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a''), wherein RAS is a mild or moderate form of RAS, preferably a moderate form of RAS. It should be understood that the description of aspect (b) applies in a similar manner.

(c'') Another aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a'') or (b''), wherein the dosage of macitentan is from 60 to 90 mg per day , preferably 65 to 85 mg per day, more preferably 70 to 80 mg per day, and most preferably 75 mg per day. It should be understood that the description of aspect (c) applies in a similar manner.

(d'') Another aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a'') or (b''), wherein the dosage of macitentan is from 25 to 50 mg per day , preferably 30 to 45 mg per day, more preferably 35 to 40 mg per day, and most preferably 37.5 mg per day. It should be understood that the description of aspect (d) applies in a similar manner.

(e'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a'') or (b''), wherein the dosage of macitentan is from 110 to 200 mg per day , preferably 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It should be understood that the description of aspect (e) applies in a similar manner.

(D) Another aspect of the present invention relates to a method of treatment and/or prevention

- 15 044958 pulmonary arterial hypertension (PAH) according to aspect (a'') or (b''), wherein the dosage of macitentan is 60 to 90 mg twice daily, preferably 65 to 85 mg twice daily, more preferably 70 to 80 mg twice daily and most preferably 75 mg twice daily.

It should be understood that the description of aspect (f) applies in a similar manner.

(g'') Another aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a'') or (b''), wherein the dosage of macitentan is from 25 to 50 mg twice per day, preferably 30 to 45 mg twice daily, more preferably 35 to 40 mg twice daily, and most preferably 37.5 mg twice daily. It should be understood that the description of aspect (g) applies in a similar manner.

(h'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a'') or (b''), wherein the dosage of macitentan is increased from 10 mg per day followed by taking 25 to 50 mg per day, preferably 37.5 mg per day, optionally followed by 60 to 90 mg per day, preferably 75 mg per day. It should be understood that the description of aspect (h) applies in a similar manner.

(i'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (a'') or (b''), wherein the dosage of macitentan is increased from 10 mg per day, with followed by 60 to 90 mg daily, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the description of aspect (i) applies in a similar manner.

(j'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (h''), wherein the dosage of macitentan is increased from 10 mg once daily, preferably over a period of 15 to 45 days; followed by 25 to 50 mg per day, preferably 37.5 mg once daily, preferably for 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the description of aspect (j) applies in a similar manner.

(k') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (i''), wherein the dosage of macitentan is increased from 10 mg once daily, preferably over 15 to 45 days; followed by 60 to 90 mg per day, preferably 75 mg once daily or 37.5 mg twice daily. It should be understood that the description of aspect (k) applies in a similar manner.

(!”) Another aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with one of aspects (a'')-(d''), wherein the dosage of macitentan is increased from 25 to 50 mg per day, preferably 37.5 mg per day, preferably for 15 to 45 days; optionally followed by 60 to 90 mg per day, preferably 75 mg per day; provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the description of aspect (l) applies in a similar manner.

(m'') Another aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with one of aspects (a'')-(c''), wherein the dosage of macitentan is from 60 to 90 mg per day, preferably 75 mg per day; provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. It should be understood that the description of aspect (m) applies in a similar manner.

(n'') A further aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with any of aspects (a'')-(m''), wherein macitentan is combined with a PDE5 inhibitor, and/ or a prostacyclin analogue, and/or a prostacyclin receptor agonist, and/or a soluble guanylate cyclase stimulator. It should be understood that the description of aspect (n) applies in a similar manner.

(o'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (n''), wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil and udenafil; the prostacyclin analogue is selected from epoprostenol, treprostinil, iloprost and beraprost; the prostacyclin receptor agonist is selected from selexipag and ralinepag; and the soluble guanylate cyclase stimulator is selected from riociguat and vericiguat. It should be understood that the description of aspect (o) applies in a similar manner.

(p'') Another aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (n'') or (o''), wherein macitentan is combined with tadalafil and/or selexipag or ralinepag , preferably with tadalafil and/or selexipag. It should be understood that the description of aspect (p) applies in a similar manner.

(q'') A further aspect of the present invention relates to a method for treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with aspect (p''), wherein

- 16 044958 tadalafil, when used, is used at a dose of 20 to 40 mg per day, preferably 40 mg per day, selexipag, when used, is used at a dose of 0.2 to 1.6 mg twice a day, and ralinepag, when used, it is used in a dose of 0.05 to 1.45 mg per day. It should be understood that the description of aspect (q) applies in a similar manner.

(u'') Another aspect of the present invention relates to a method of treating and/or preventing pulmonary arterial hypertension (PAH) in accordance with any of aspects (a)-(q), wherein by treatment and/or prevention is meant a reduction in the risk of the disease and/ or mortality for RAS. Thus, this aspect of the present invention relates to a method of reducing the risk of morbidity and/or mortality for wounds, wherein macitentan is used in accordance with any of aspects (a'')-(q''). It should be understood that the description of aspect (u) applies in a similar manner.

It should be understood that the comments and details of aspects (a)-(q) also apply to aspects (a'')-(q'') and (u'').

According to a further aspect of the present invention, in each of the above aspects, i.e. in each of aspects (a)-(t) and (u), (a')-(q') and (u'), and (a'')-(q) and (u''), macitentan may be replaced by its active metabolite, known by the code name ACT-132577 and the international nonproprietary name aprocytentan with the chemical formula

in this case, any mass amount of macitentan will be replaced by 5 times the mass amount of aprocitentan.

For example, in the case of aspect (c) of the invention described above, a further aspect of the invention relates to aprocitentan for use in the treatment and/or prevention of PAH in accordance with aspect (a) or (b), wherein the weight amounts of macitentan in the case of aprocitentan will be replaced by 5- multiple mass amounts of aprocytentan, with the dose of aprocytentan ranging from 300 to 450 mg per day. The dose of aprocitentan is preferably 325 to 425 mg per day, the dose of aprocitentan is more preferably 350 to 400 mg per day, and the dose of aprocitentan is most preferably 375 mg per day. It should be understood that each of the above lower limits can be combined with each of the upper limits, i.e. the dose of aciprotentan may also be 300 to 425 mg per day, 300 to 400 mg per day, or 300 to 375 mg per day. In addition, aciprotentan doses of 325 to 450 mg or 325 to 375 mg per day are presented. Additional preferred ranges are 360 to 390 mg of aciprotentan per day. In a more preferred aspect, such doses of aciprotentan are administered once daily. In a preferred aspect, such dosages relate to aprocitentan for use in the treatment and/or prevention of mild to moderate PAH, preferably moderate PAH.

In addition, the following abbreviations are used in this description.

Abbreviations

PAH-CTD - PAH associated with connective tissue disease;

ALAH-RoPH - PAH associated with portopulmonary hypertension;

aq. - water;

BNP - brain natriuretic peptide;

BRM - contractions per minute;

CI - cardiac index;

DLCO - diffusion capacity of the lungs for CO (carbon monoxide);

EDTA - ethylenediaminetetraacetic acid;

ERA - endothelin receptor antagonist;

ET - endothelin;

SLAG - familial PAH;

HR - heart rate;

IgG - immunoglobulin G;

K ₂ EDTA - dipotassium salt of ethylenediaminetetraacetic acid;

mPAP - mean pulmonary artery pressure;

6MWD - distance for a 6-minute walk;

NT-proBNP - N-terminal brain pronatriuretic peptide;

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Claims (22)

PAH - pulmonary arterial hypertension; PAOP is pulmonary artery occlusion pressure, which is synonymous with PAWP; PAWP is pulmonary artery wedge pressure, which is synonymous with PAOP; PAP - pulmonary artery pressure; PBS - phosphate buffered saline; PD - pharmacodynamics; PDE5 - cyclic guanosine 3',5'-monophosphate (cGMP)-specific phosphodiesterase type 5; PDE5is - PDE5 inhibitors; PH - pulmonary hypertension; PK - pharmacokinetics; PVR - pulmonary vascular resistance; RAP - right atrium pressure (sometimes also called mRAP); RHC - right-sided cardiac catheterization; SBP - systolic systemic blood pressure; SvO2 - oxygen saturation of mixed venous blood; Tris - tris-(hydroxymethyl)aminomethane; WHO/WHO - World Health Organization; WHO FC - World Health Organization functional class. experimental part The present invention is illustrated by the following non-limiting examples. Examples Effect of macitentan on reducing hemoglobin concentration. Hemoglobin measurements were pooled from three phase I clinical studies in healthy volunteers. Study AC-055-102: Study of the PK, PD, safety, and tolerability of macitentan in male subjects (study protocol described in the following publication: Sidharta et al., Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J. Clin. Pharmacol. (2013), 53(11),1131-1138). Study AC-055-116: Study of the PK, PD, safety, and tolerability of macitentan in Japanese male subjects (study protocol described in the following publication: Yokoyama et al., Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects. Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics (2016), 47, 143-150). Study AC-055-117: a study of the PK, PD, safety and tolerability of macitentan in male subjects from Korea (the study protocol is described in the following publication: Ahn et al., Pharmacokinetic-pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects, Am J Cardiovasc Drugs (2014), 14(5), 377-385. Hemoglobin concentrations measured in the morning of day 11 of macitentan administration and at baseline on day -1 were used to analyze the results. Changes in hemoglobin concentrations from baseline were regressed against different dose levels of macitentan, including placebo. The Emax curve was approximated with the initial level and the following parameters were assessed based on the results of nonlinear regression: E0: change in hemoglobin level without macitentan, Emax: maximum theoretical change in hemoglobin level that can be caused by macitentan, ED50: dose resulting in a 50% reduction in hemoglobin levels. The following formula was used: Change in hemoglobin level = E0 + ((macitentan dose x Emax)/(macitentan dose + ED50)). The resulting dose-response curve is shown in the figure. According to the results of the analysis, the maximum effect of macitentan on reducing hemoglobin levels could be approximately 1.23 g/dL, and the effect of macitentan on plateauing hemoglobin reduction was observed at a dose of 10 mg (see figure). Therefore, in humans, no clinically significant decrease in hemoglobin is expected at doses of macitentan above 10 mg. CLAIM 1. A method of treating and/or preventing pulmonary arterial hypertension (PAH) in humans, comprising administering macitentan, the dose of macitentan being from 60 to 90 mg per day. 2. A method for treating and/or preventing pulmonary arterial hypertension (PAH) according to claim 1, wherein - 18 044958 the dose of macitentan is 70 to 80 mg per day. 3. A method for treating and/or preventing pulmonary arterial hypertension (PAH) according to claim 1 or 2, wherein the dose of macitentan is 75 mg per day. 4. A method for treating and/or preventing pulmonary arterial hypertension (PAH) according to any one of claims 1 to 3, wherein PAH is mild or moderate PAH. 5. A method for treating and/or preventing PAH according to any one of claims 1-4, wherein the dose of macitentan is from 30 to 45 mg twice a day. 6. A method for treating and/or preventing PAH according to claim 5, wherein the dose of macitentan is 37.5 mg twice a day. 7. A method for the treatment and/or prevention of pulmonary arterial hypertension (PAH) in humans, including the administration of macitentan, wherein the dose of macitentan is from 60 to 90 mg per day, in which before taking from 60 to 90 mg per day, the dosage of macitentan is increased from 10 mg in a day. 8. The method of treatment and/or prevention of PAH according to claim 7, and before taking from 60 to 90 mg per day, the dosage of macitentan is increased from 10 mg per day, followed by taking from 25 to 50 mg per day. 9. The method of treatment and/or prevention of PAH according to claim 7 or 8, and before taking 75 mg per day, the dosage of macitentan is increased from 10 mg per day, followed by 37.5 mg per day. 10. The method of treatment and/or prevention of PAH according to claim 7, and before taking 75 mg per day or 37.5 mg twice a day, the dosage of macitentan is increased from 10 mg per day. 11. The method of treatment and/or prevention of PAH according to claim 7 or 8, and before taking from 60 to 90 mg per day, the dose of macitentan is increased from 10 mg once a day for 15 to 45 days; followed by 25 to 50 mg per day for 15 to 45 days. 12. The method of treatment and/or prevention of PAH according to claim 11, and before taking 75 mg once a day or 37.5 mg twice a day, the dose of macitentan is increased from 10 mg once a day for 15 to 45 days; followed by 37.5 mg once daily for 15 to 45 days. 13. A method for treating and/or preventing PAH according to any one of claims 1 to 4, provided that the patient is already receiving treatment with an endothelin receptor antagonist, preferably selected from bosentan and ambrisentan. 14. A method for treating and/or preventing PAH according to any one of claims 1 to 13, wherein macitentan is combined with a PDE5 inhibitor, and/or a prostacyclin analogue, and/or a prostacyclin receptor agonist, and/or a soluble guanylate cyclase stimulator. 15. A method for treating and/or preventing PAH according to claim 14, wherein the PDE5 inhibitor is selected from sildenafil, tadalafil, vardenafil and udenafil; the prostacyclin analogue is selected from epoprostenol, treprostinil, iloprost and beraprost; the prostacyclin receptor agonist is selected from selexipag and ralinepag and the soluble guanylate cyclase stimulator is selected from riociguat and vericiguat. 16. A method for treating and/or preventing PAH according to claim 14 or 15, wherein macitentan is combined with tadalafil and/or selexipag or ralinepag, preferably with tadalafil and/or selexipag. 17. A method for treating and/or preventing PAH according to claim 16, wherein tadalafil, when used, is used in a dose of 20 to 40 mg per day, preferably 40 mg per day, selexipag, when used, is used in a dose of 0.2 to 1.6 mg twice daily, and ralinepag, when used, is administered at a dose of 0.05 to 1.45 mg per day. 18. A method for treating and/or preventing PAH according to any one of claims 1 to 17, whereby treatment and/or prevention means reducing the risk of morbidity and/or mortality in PAH. 19. A pharmaceutical composition for the treatment of PAH, which includes macitentan and at least a pharmaceutically acceptable excipient containing macitentan in an amount of 37.5 to 50 mg or 60 to 90 mg. 20. Pharmaceutical composition according to claim 19, which contains macitentan in an amount of 37.5 or 75 mg. 21. Pharmaceutical composition according to claim 19 or 20, which includes: (i) macitentan in a total amount of from 10 to 50% by weight based on the total weight of the pharmaceutical composition; (ii) a filler containing lactose monohydrate with microcrystalline cellulose, in a total amount of from 10 to 85% by weight, based on the total weight of the pharmaceutical composition; (iii) a disintegrant containing sodium carboxymethyl starch or a combination of sodium carboxymethyl starch and polyvinylpyrrolidone, in a total amount of from 1 to 10% by weight, based on the total weight of the pharmaceutical composition; (iv) a surfactant containing polysorbate in a total amount of from 0.1 to 1% by weight based on the total weight of the pharmaceutical composition; and (v) a lubricant containing magnesium stearate in a total amount of from 0.05 to 5% by weight, based on the total weight of the pharmaceutical composition. 22. Pharmaceutical composition according to any one of claims 19 to 21, which is in the form of a capsule or tablet. -