Method for treating pulmonary hypertension in patients implanted with left ventricular assist devices - Patent Application 20070123333

Abstract

The present disclosure provides methods of treating pulmonary hypertension in left ventricular assist device (LVAD) implanted patients and methods of improving heart transplant eligibility in LVAD implanted patients, comprising administering a therapeutically effective amount of macitentan or aprocitentan to a patient in need thereof.

Description

[Technical field]

[0001] The present invention relates to a method for treating pulmonary hypertension in patients implanted with a left ventricular assist device. [Background technology]

[0002] End-stage heart failure (HF) is a debilitating condition for which heart transplantation offers the best therapeutic option, but the need for donor hearts greatly exceeds the supply. Since their initial approval, left ventricular assist devices (LVADs) have become an increasingly frequent treatment option for patients with end-stage HF. Although LVADs improve left-sided hemodynamic variables, right ventricular failure (RVF) that occurs after implantation of an LVAD is a major cause of morbidity and mortality. Persistently elevated pulmonary vascular resistance (PVR) is associated with RVF after LVAD implantation.

[0003] Management of PH after LVAD implantation begins with measures to prevent RVF in the preoperative period. After surgery, management of PH complicated by RVF in these patients includes the use of pulmonary vasodilators, modification of pump speed under echocardiographic guidance, and consideration of right ventricular assist device (RVAD) implantation in cases of refractory RVF. To date, targeted PAH therapy has not demonstrated efficacy and safety from randomized controlled trials in this patient population. Summary of the Invention [Problem to be solved by the invention]

[0004] There is a need for therapies to manage PH in patients with PH after LVAD implantation. [Means for solving the problem]

[0005] In certain embodiments, the present disclosure provides a method of treating pulmonary hypertension in a left ventricular assist device (LVAD) implanted patient, comprising administering a therapeutically effective amount of macitentan to a patient in need thereof.

[0006] In some embodiments, the present disclosure provides a method of treating pulmonary hypertension in an LVAD-implanted patient, comprising administering a therapeutically effective amount of aprocitentan to a patient in need thereof.

[0007] In a further embodiment, the present disclosure provides a method of improving heart transplant eligibility in an LVAD implanted patient, comprising administering a therapeutically effective amount of macitentan to a patient in need thereof.

[0008] In other embodiments, the present disclosure provides a method of improving heart transplant eligibility in an LVAD-implanted patient, comprising administering a therapeutically effective amount of aprocitentan to a patient in need thereof.

[0009] In a further embodiment, the present disclosure provides a method for treating pulmonary hypertension in a left ventricular assist device (LVAD) implanted patient, comprising administering an amount of macitentan, where the LVAD implantation is within about 90 days prior to administering macitentan.

[0010] In another embodiment, the present disclosure provides aprocitentan for treating pulmonary hypertension in a left ventricular assist device (LVAD) implanted patient, comprising administering an amount of aprocitentan, where the LVAD implantation is within about 90 days prior to administering aprocitentan.

[0011] In a further embodiment, the present disclosure provides an amount of macitentan for improving heart transplant eligibility in a left ventricular assist device (LVAD) implanted patient, comprising administering an amount of macitentan, where the LVAD implantation is within 90 days prior to administering macitentan.

[0012] In yet another embodiment, the present disclosure provides an amount of aprocitentan for improving heart transplant eligibility in a left ventricular assist device (LVAD) implanted patient, comprising administering an amount of aprocitentan, where the LVAD implantation occurs within 90 days prior to administering aprocitentan. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram of the treatment described in Example 1. In the figure, aLVAD implantation must occur within 90 days (inclusive) prior to the date of randomization, which must occur within 14 days after RHC certification. b Patients with documented severe obstructive pulmonary disease, moderate to severe restrictive pulmonary disease, or pulmonary veno-occlusive disease are excluded. c All secondary and exploratory endpoints are calculated as change from baseline to week 12. [Diagram 2] 1 is a flowchart showing patient positioning in Example 1. [Diagram 3] FIG. 1 is a scatter plot showing the proportion of patients achieving a PVR of less than 3 WU. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In this disclosure, unless expressly stated otherwise, the singular forms "a," "an," and "the" include plural references and a reference to a particular numerical value includes at least that particular value. Thus, for example, a reference to "a material" is a reference to at least one such material and equivalents and similar known to those skilled in the art.

[0015] When values ​​are expressed as approximations by use of the descriptors "about" or "substantially," it is understood that the particular value forms another embodiment. In general, the use of the terms "about" or "substantially" indicates approximations that may vary depending on the desired properties sought to be obtained by the disclosed subject matter, but should be interpreted in the particular context in which it is used based on its function. Those skilled in the art can interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting way of determining the extent of the term "about" or "substantially." In other cases, the gradations used in a series of values ​​may be used to determine the intended range available for the term "about" or "substantially" for each value. When present, all ranges are inclusive and combinable. That is, reference to values ​​stated in a range includes all values ​​within that range.

[0016] When lists are presented, it is to be understood that each individual member of that list and every combination of that list is to be construed as a separate embodiment unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be construed to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0017] It is understood that certain features of the invention that are described herein for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless expressly incompatible or excluded, each separate embodiment is deemed to be compatible with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, features of the invention that are described for brevity in the context of a single embodiment may also be provided in combination in a single embodiment. Different features may be provided separately or in any subcombination. It is further noted that the claims may be drafted to exclude any optional element. Thus, this description is intended to serve as a predicate to the use of exclusive terminology such as "only," "only," and the like in connection with the recitation of claim elements, or the use of a "negative" limitation. Finally, while an embodiment may be described as part of a series of steps or as part of a more general structure, each step may be considered to be an independent embodiment in itself.

[0018] method The methods described herein relate to treating pulmonary hypertension (PH) in patients implanted with a left ventricular assist device (LVAD). Such patients are not candidates for heart transplantation due to the increased risk of right heart failure and death after transplantation. In most post-LVAD patients who continue to have PH, medications are often prescribed as standard treatment. However, not all post-LVAD patients require additional PH treatment and may be unnecessarily treated with additional drugs or with drugs that have not demonstrated consistent efficacy. Thus, in certain embodiments, the methods described herein aim to prevent the administration of unnecessary PH drugs to patients and instead treat only those patients who require post-LVAD PH drugs, e.g., post-LVAD patients with persistent PH.

[0019] The methods described herein also improve cardiac transplant eligibility in LVAD transplant patients, especially in patients who are contraindicated for cardiac transplantation due to, for example, elevated PVR. The methods described herein can transition patients from not being considered candidates for orthotopic cardiac transplantation to being listed as candidates for cardiac transplantation after treatment with macitentan or aprocitentan. For patients with advanced heart failure who are already on the cardiac transplant waiting list, the occurrence of a PVR of more than 3WU will result in removal from the transplant list due to the risk of post-transplant RVF and death. These methods could keep PVR in a favorable range (less than 3WU) for transplant eligibility.

[0020] As used herein and in the art, the terms "pulmonary hypertension" and "PH" are interchangeable and define a general condition in which a patient has high blood pressure in the pulmonary arteries. PH develops when the diameter of the very small arteries throughout the lungs narrows, thereby increasing resistance to blood flow through the lungs. PH is classified into subgroups including: (i) pulmonary arterial hypertension (PAH), (ii) PH due to left heart disease, (iii) PH due to pulmonary disease, (iv) PH due to chronic blood clots (CTEPH), or (v) PH due to miscellaneous diseases. In some embodiments, the method desirably treats PAH.

[0021] The terms "pulmonary arterial hypertension" and "PAH" are interchangeable and define chronic pulmonary hypertension in which the walls of the lung arteries become tight and stiff. In some embodiments, the underlying etiology of stenosis, i.e., idiopathic pulmonary hypertension (iPAH), is unknown. PAH is also classified into subgroups, including: (i) familial or hereditary PAH; (ii) PAH caused by drugs or toxins; (iii) PAH associated with other conditions, such as connective tissue disease (scleroderma or lupus), congenital heart disease, hepatic hypertension, HIV, and infections (schistosomiasis); (iv) PAH caused by rare blood conditions (e.g., pulmonary capillary matosis); or (v) infantile PAH (persistent pulmonary hypertension of the newborn). The severity of PAH in patients is generally assessed by a classification system, i.e., the World Health Organization (WHO) class system. See Table 1.

[0022] [Table 1]

[0023] Thus, the method may provide a better quality of life or overall survival for patients after LVAD. Patients eligible for the treatment methods described herein may be selected by one of skill in the art, i.e., the attending physician. In a further embodiment, the patient does not have severe liver damage, e.g., Child-Pugh class C liver disease. As known in the art, the "Child-Pugh score" is determined by scoring five clinical measures of liver disease, and the sum of these scores classifies the patient into either class A, B, or C. See Table 2.

[0024] [Table 2]

[0025] In another embodiment, the patient does not have severe obstructive pulmonary disease, defined as an FEV1 / FVC less than about 0.7 associated with an FEV1 less than about 50% of predicted after bronchodilator administration. In a further embodiment, the patient does not have moderate to severe restrictive pulmonary disease, defined as a total lung capacity less than about 60% of predicted. In yet another embodiment, the patient does not have pulmonary veno-occlusive disease. In a further embodiment, the patient is not undergoing dialysis. In another embodiment, the patient's hemoglobin is greater than about 8.5 g / dL. In a further embodiment, the patient's AST or ALT is less than about 3 times the upper limit of normal. In yet another aspect, the patient's Doppler mean blood pressure is greater than about 65 mmHg. In yet a further embodiment, the patient's GFR is greater than about 30 mL / min.

[0026] An eligible patient may be on a heart transplant waiting list. In some embodiments, the methods described herein move the patient onto the waiting list. In other embodiments, the methods leave the patient on the waiting list. Alternatively, the methods add the patient to the heart transplant waiting list.

[0027] The term "LVAD" as used herein refers to a left ventricular assist device. An LVAD is a battery-powered mechanical pump that helps the left ventricle (the heart's main pumping chamber) pump blood to the rest of the body. As used herein, an LVAD includes several components, including: (i) a surgically implanted pump, (ii) an inflow cannula, (iii) an outflow graft, (iv) a battery with a life of up to 12 hours, (v) a percutaneous driveline, and (vi) a system controller. In some embodiments, the pump pumps blood through the inflow cannula to the left ventricle. The LVAD operates in parallel with the heart via a venous infusion tube and an outflow graft to the ascending aorta. In other embodiments, the LVAD is a continuous flow axial pump, a centrifugal pump, or a mixed design pump, where the pump is axial but the blood exits perpendicular to the inflow as in a centrifugal pump. LVAD devices are known in the art and include, but are not limited to, the HVAD® (Medtronic), HeartMate II™ (Abbott), and HeartMate 3™ (Abbott).

[0028] Desirably, LVAD implantation is within about 90 days prior to initiation of treatment with macitentan or aprocitentan, hi some embodiments, LVAD implantation is within about 90 days, about 80 days, about 75 days, about 70 days, about 65 days, about 60 days, about 55 days, about 50 days, about 45 days, about 40 days, about 35 days, about 30 days, about 25 days, about 20 days, about 15 days, about 10 days, or within about 10 days prior to initiation of treatment with macitentan or aprocitentan. In further embodiments, LVAD implantation is performed about 5 to about 90 days, about 5 to about 80 days, about 5 to about 70 days, about 5 to about 60 days, about 5 to about 50 days, about 5 to about 40 days, about 5 to about 30 days, about 5 to about 20 days, about 5 to about 10 days, about 10 to about 90 days, about 10 to about 80 days, about 10 to about 70 days, about 10 to about 60 days, about 10 to about 50 days, about 10 to about 40 days, about 10 to about 30 days, about 10 to about 20 days, about 20 to about 90 days, about 20 to about 80 days, about 20 to about 70 days, about 20 to about 60 days, about 20 to about 50 days, about 20 to about 40 days, It is within about 20 to about 30 days, about 30 to about 30 to about 90 days, about 30 to about 80 days, about 30 to about 70 days, about 30 to about 60 days, about 30 to about 50 days, about 30 to about 40 days, about 40 to about 90 days, about 40 to about 80 days, about 40 to about 70 days, about 40 to about 60 days, about 40 to about 50 days, about 45 to about 90 days, about 45 to about 80 days, about 45 to about 70 days, about 45 to about 60 days, about 50 to about 90 days, about 50 to about 80 days, about 50 to about 70 days, about 50 to about 60 days, about 60 to about 90 days, about 60 to about 80 days, about 60 to about 70 days, about 70 to about 90 days, about 70 to about 80 days, or about 80 to about 90 days. In other embodiments, LVAD implantation is within about 90 days prior to initiation of treatment with macitentan or aprocitentan, hi further embodiments, LVAD implantation is greater than 45 days to about 90 days prior to initiation of treatment with macitentan or aprocitentan.

[0029] The method includes administering a therapeutically effective amount of macitentan or aprocitentan to a patient in need thereof. After LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient has a resting mean pulmonary artery pressure (mPAP) of about 25 mmHg or greater. As used herein, the term "resting" refers to a period of time during which the patient is inactive, e.g., sitting without movement. In some embodiments, the patient has an mPAP of about 30 mmHg, about 35 mmHg, about 40 mmHg, about 45 mmHg, about 50 mmHg, about 55 mmHg, about 60 mmHg, about 65 mmHg, about 70 mmHg, about 75 mmHg, about 80 mmHg, about 85 mmHg, about 90 mmHg, about 95 mmHg, or about 100 mmHg or greater. In other embodiments, the patient has an mPAP of about 30 mmHg or greater. In a further embodiment, the patient has an mPAP of about 40 mmHg or greater.

[0030] The patient may also have a pulmonary artery wedge pressure (PAWP) of about 18 mmHg or less after LVAD implantation and before starting treatment with macitentan or aprocitentan. In some embodiments, the patient's PAWP is about 18 mmHg, about 17 mmHg, about 16 mmHg, about 15 mmHg, about 14 mmHg, about 13 mmHg, about 12 mmHg, about 11 mmHg, about 10 mmHg, about 9 mmHg, about 8 mmHg, about 7 mmHg, about 6 mmHg, or about 5 mmHg or less. In further embodiments, the patient's PAWP is about 17 mmHg or less. In yet other embodiments, the patient's PAWP is about 15 mmHg or less. In further embodiments, the patient's PAWP is about 12 mmHg or less. In other embodiments, the patient's PAWP is about 10 mmHg or less.

[0031] Patients are post-LVAD implantation and begin treatment with macitentan or aprocitentan The patient may further have a pulmonary vascular resistance (PVR) of greater than about 3 WU (Wood units) prior to initiation of treatment with macitentan or aprocitentan. In certain embodiments, the patient has a PVR of about 4 WU, about 5 WU, about 6 WU, about 6.5 WU, about 7 WU, about 8 WU, or about 9 WU after LVAD implantation and prior to initiating treatment with macitentan or aprocitentan. In other embodiments, the patient has a PVR of greater than about 3 to about 7 WU, greater than about 3 to about 6.5 WU, greater than about 3 to about 6 WU, greater than about 3 to about 5 WU, greater than about 3 to about 4 WU, about 4 to about 7 WU, about 4 to about 6 WU, about 4 to about 5 WU, about 5 to about 7 WU, about 5 to about 6 WU, or about 6 to about 7 WU.

[0032] After LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient may also have a resting mPAP of about 25 mmHg or greater and a PAWP of about 18 mmHg or less. In a further embodiment, after LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient has a resting mPAP of about 25 mmHg or greater and a PVR of about 3 WU or greater. In yet another embodiment, after LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient has a resting mPAP of about 18 mmHg or less, a resting mPAP of about 25 mmHg or greater, and a PVR of about 3 WU or greater. In yet another embodiment, after LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient has a resting mPAP of about 25 mmHg or greater, a PAWP of about 18 mmHg or less, and a PVR of about 3 WU or greater.

[0033] After LVAD implantation and prior to initiating macitentan or aprocitentan therapy, the patient may also have a transpulmonary gradient (TPG) of greater than about 12 mmHg. In some embodiments, after LVAD implantation and prior to initiating macitentan or aprocitentan therapy, the patient has a TPG of greater than about 15 mmHg, about 20 mmHg, about 25 mmHg, about 30 mmHg, about 35 mmHg, about 40 mmHg, about 45 mmHg, about 50 mmHg, about 55 mmHg, about 60 mmHg, about 65 mmHg, or about 70 mmHg. In further embodiments, the patient has a blood glucose level of about 12 to about 60 mmHg, about 12 to about 55 mmHg, about 12 to about 50 mmHg, about 12 to about 45 mmHg, about 12 to about 40 mmHg, about 12 to about 35 mmHg, about 12 to about 30 mmHg, about 12 to about 25 mmHg, about 12 to about 20mmHg, about 15 to about 60mmHg, about 15 to about 55mmHg, about 15 to about 50mmHg, about 15 to about 45mmHg, about 15 to about 40mmHg, about 15 to about 35mmHg, about 15 to about 30mmHg, about 15 to about 25mmHg, about 20 to about 60mmHg, about 20 to about 55mmHg, about 20 to about 50mmHg, about 20 to about 45mmHg, about 20 ~ about 40mmHg, about 20 to about 35mmHg, about 20 to about 30mmHg, about 25 to about 60mmHg, about 25 to about 55mmHg, about 25 to about 50mmHg, about 25 to about 45mmHg, about 25 to about 40mmHg, about 25 to about 35mmHg, about 30 to about 60mmHg, about 30 to about 55mmHg, about 30 to about 50mmHg, about 30 to about 45mmHg, The patient has a TPG of about 30 to about 40 mmHg, about 35 to about 60 mmHg, about 35 to about 55 mmHg, about 35 to about 50 mmHg, about 35 to about 45 mmHg, about 40 to about 60 mmHg, about 40 to about 55 mmHg, about 40 to about 50 mmHg, about 45 to about 60 mmHg, about 45 to about 55 mmHg, about 50 to about 60 mmHg, or about 55 to about 60 mmHg. In another embodiment, after LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient has a TPG of about 12 to about 45 mmHg.

[0034] After LVAD implantation and prior to initiating macitentan or aprocitentan therapy, the patient may further have a pulmonary artery wedge pressure (PAWP) of about 18 mmHg or less. In some embodiments, after LVAD implantation and prior to initiating macitentan or aprocitentan therapy, the patient may have a PAWP of about 17 mmHg, about 16 mmHg, about 15 mmHg, about 14 mmHg, about 13 mmHg, about 12 mmHg, about 11 mmHg, about 10 mmHg, about 9 mmHg, about 8 mmHg, about 7 mmHg, about 6 mmHg, about 5 mmHg, about 4 mmHg, about 3 mmHg, about 2 mmHg, or about 1 mmHg or less. In some embodiments, After LVAD implantation and prior to initiating treatment with macitentan or aprocitentan, the patient may have a PAWP of about 1 to about 15 mmHg, about 1 to about 10 mmHg, about 1 to about 5 mmHg, about 5 to about 15, about 5 to about 10 mmHg, or about 10 to about 15 mmHg.

[0035] Desirably, the method is effective to reduce the patient's PVR, for example, to a level within the normal range. For example, the method is effective to reduce the patient's PVR to less than about 3 WU. In other embodiments, the method is effective to reduce the patient's TPG. For example, the method is effective to reduce the patient's TPG to less than about 12 mmHg. In further embodiments, the method is effective to reduce the patient's PVR and TPG. For example, the method is effective to reduce the patient's PVR to less than about 3 WU and the patient's TPG to less than about 12 mmHg.

[0036] Typically, after implantation of the LVAD, the patient meets baseline hemodynamic criteria for PH via right heart catheterization (RHC) during the last measurement before the first administration of the drug. In certain embodiments, after implantation of the LVAD and before starting treatment with macitentan or aprocitentan, the patient has a resting mean pulmonary artery pressure (mPAP) of 25 mmHg or more, a pulmonary artery wedge pressure (PAWP) of 18 mmHg or less, and a pulmonary vascular resistance (PVR) of more than 3 WU (Wood units). More specifically, within about 14 days before starting treatment with macitentan or aprocitentan, the patient has a resting mean pulmonary artery pressure (mPAP) of 25 mmHg or more, a pulmonary artery wedge pressure (PAWP) of 18 mmHg or less, and a pulmonary vascular resistance (PVR) of more than 3 WU (Wood units). Establishing such timing may, for example, avoid administering unnecessary PH medication to the patient and instead treat the patient in need of a post-LVAD PH medication.

[0037] The method may also be effective to reduce the PVR of a patient by at least about 10% compared to a patient with a similar level of disease diagnosis who is not treated with macitentan or aprocitentan. As used herein, the term "patient population" refers to a number of patients that provide a statistically reliable result. In some embodiments, the patient population is two or more patients. For example, the patient population includes the population of patients described in Example 1. In other embodiments, the patient population is about 10 patients, about 50 patients, about 100 patients, about 150 patients, about 200 patients, about 250 patients, about 300 patients, about 350 patients, about 400 patients, about 450 patients, about 500 patients, about 550 patients, about 600 patients, about 650 patients, about 700 patients, about 750 patients, about 800 patients, about 850 patients, about 900 patients, about 950 patients, about 1000 patients, or more. In further embodiments, the patient population is about 50 or more patients. In yet other embodiments, the patient population is about 100 or more patients. In still further embodiments, the patient population is about 150 or more patients. In other embodiments, the patient population is about 200 or more patients. However, one of skill in the art could readily determine the number of patients necessary to obtain statistically relevant results.

[0038] In some embodiments, the method is effective to reduce the PVR of a patient by about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or more, compared to a patient population with the same level of disease diagnosis not treated with macitentan or aprocitentan, hi some embodiments, the method is effective to reduce the PVR of a patient population by about 30%, compared to a patient population with the same level of disease diagnosis not treated with macitentan or aprocitentan.

[0039] The method may further be effective to reduce the patient's TPG by at least about 10% as compared to a patient population with the same disease and at the same disease diagnosis level not treated with macitentan or aprocitentan. In some embodiments, the method may reduce the patient's TPG by at least about 10% as compared to a patient population with the same disease and at the same disease diagnosis level not treated with macitentan or aprocitentan. In comparison, it is effective to reduce a patient's TPG by about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or more.

[0040] The method includes administering a therapeutically effective amount of macitentan or aprocitentan. As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue system, animal or human, including alleviation of symptoms of the disease or disorder being treated, as desired by a researcher, veterinarian, physician or other clinician. In some embodiments, the therapeutically effective amount corresponds to the free base or free base form of macitentan or aprocitentan. In other embodiments, the therapeutically effective amount corresponds to a salt, solvate, or hydrate of macitentan or aprocitentan. Unless otherwise specified, the amounts disclosed herein correspond to the free form of macitentan or aprocitentan, excluding, for example, a solvent (such as a solvate or hydrate) or a counterion (such as a pharma- ceutically acceptable salt).

[0041] In certain embodiments, the therapeutically effective amount of macitentan is less than about 15 mg. In further embodiments, the therapeutically effective amount of macitentan is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg. In other embodiments, the therapeutically effective amount of macitentan is about 1 to about 15 mg, about 1 to about 10 mg, about 1 to about 5 mg, about 5 to about 15 mg, about 5 to about 10 mg, or about 10 to about 15 mg. In yet further embodiments, the therapeutically effective amount is about 5 to about 15 mg. In yet further embodiments, the therapeutically effective amount is about 10 mg.

[0042] Higher amounts of macitentan may also be used in the methods described herein, hi some embodiments, the therapeutically effective amount of macitentan is at least about 15 mg. In further embodiments, the therapeutically effective amount of macitentan is about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 52.5 mg, about 60 mg, about 62.5 mg, about 65 mg, about 67.5 mg, about 70 mg, about 72.5 mg, about 75 mg, about 77.5 mg, about 80 mg, about 82.5 mg, about 85 mg, about 87.5 mg, about 90 mg, about 92.5 mg, about 95 mg, about 97.5 mg, about 100 mg, about 102.5 mg, about 105 mg, about 107.5 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 400 mg, about 410 mg, about 420 mg, about 45 mg, about 4 12.5mg, about 115mg, about 117.5mg, about 120mg, about 122.5mg, about 125mg, about 127.5mg, about 130mg, about 132.5mg, about 1 35mg, about 137.5mg, about 140, about 142.5mg, about 145mg, about 147.5mg, about 150, about 152.5mg, about 155mg, about 157.5mg , about 160 mg, about 162.5 mg, about 165 mg, about 167.5 mg, about 170 mg, about 172.5 mg, about 175 mg, about 177.5 mg, about 180 mg, about 182.5 mg, about 185 mg, about 187.5 mg, about 190 mg, about 192.5 mg, about 195 mg, about 197.5 mg, about 200 mg, or more.In other embodiments, the therapeutically effective amount of macitentan is about 25 to 40 mg, 25 to 45 mg, 25 to 50 mg, 30 to 40 mg, 30 to 45 mg, 30 to 50 mg, 35 to 40 mg, 36 to 39 mg, 50 to about 90 mg, about 50 to about 85 mg, about 50 to about 80 mg, about 50 to about 75 mg, about 50 to about 70 mg, about 50 to about 65 mg, about 50 to about 60 mg, about 60 to about 90 mg, about 60 to about 85 mg, about 60 to about 80 mg, about 60 to about 75 mg, about 60 to about 70 mg, or about 65 to about 90 mg, about 65 to about 85 mg, about 65 to about 80 mg, about 65 to about 75 mg, about 70 to about 90 mg, about 70 to about 85 mg, about 70 to about 80 mg, about 70 to about 75 mg, about 72 to about 78 mg, about 75 to about 90 mg, about 75 to about 85 mg, about 80 to about 90 mg, about 110 to about 200 mg, about 110 to about 150 mg, about 110 to about 160, about 125 to about 160 mg, about 125 to about 175 mg, about 145 to about 155 mg, about 140 to about 160 mg, or about 140 to about 200 mg. In yet a further embodiment, the therapeutically effective amount of macitentan is about 60 to about 90 mg. In a further embodiment, the therapeutically effective amount of macitentan is about 75 mg.

[0043] These amounts may be administered once or twice per day. In some aspects, these amounts are administered once per day. In another embodiment, the therapeutically effective amount of macitentan is about 25 to about 40 mg once per day. In a further embodiment, the therapeutically effective amount of macitentan is about 25 to about 45 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 25 to about 50 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 30 to about 40 mg once per day. In another embodiment, the therapeutically effective amount of macitentan is about 30 to about 45 mg once per day. In a further embodiment, the therapeutically effective amount of macitentan is about 30 to about 50 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 35 to about 40 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 36 to about 39 mg once per day. In another embodiment, the therapeutically effective amount of macitentan is about 37.5 mg once per day. In a further embodiment, the therapeutically effective amount of macitentan is about 60 to about 80 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 60 to about 85 mg once per day. In yet a further embodiment, the therapeutically effective amount of macitentan is about 60 to about 90 mg once per day. In another embodiment, the therapeutically effective amount of macitentan is about 65 to about 75 mg once per day. In a further embodiment, the therapeutically effective amount of macitentan is about 65 to about 85 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 65 to about 90 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 70 to about 80 mg once per day. In another embodiment, the therapeutically effective amount of macitentan is about 72 to about 78 mg once per day. In a further embodiment, the therapeutically effective amount of macitentan is about 75 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 110 to about 200 mg once per day. In yet a further embodiment, the therapeutically effective amount of macitentan is about 110 to about 150 mg once per day. In another embodiment, the therapeutically effective amount of macitentan is about 110 to about 160 mg once per day.In a further embodiment, the therapeutically effective amount of macitentan is about 125 to about 160 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 125 to about 175 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 145 to about 155 mg once per day. In another embodiment, the therapeutically effective amount of macitentan is about 140 to about 160 mg once per day. In a further embodiment, the therapeutically effective amount of macitentan is about 140 to about 175 mg once per day. In yet another embodiment, the therapeutically effective amount of macitentan is about 150 mg once per day.

[0044] In a further aspect, the therapeutically effective amount is administered twice daily. In another embodiment, the therapeutically effective amount of macitentan is about 25 to about 40 mg twice daily. In a further embodiment, the therapeutically effective amount of macitentan is about 25 to about 45 mg twice daily. In yet another embodiment, the therapeutically effective amount of macitentan is about 25 to about 50 mg twice daily. In yet another embodiment, the therapeutically effective amount of macitentan is about 30 to about 40 mg twice daily. In another embodiment, the therapeutically effective amount of macitentan is about 30 to about 45 mg twice daily. In a further embodiment, the therapeutically effective amount of macitentan is about 30 to about 50 mg twice daily. In yet another embodiment, the therapeutically effective amount of macitentan is about 35 to about 40 mg twice daily. In yet another embodiment, the therapeutically effective amount of macitentan is about 36 to about 39 mg twice daily. In another embodiment, the therapeutically effective amount of macitentan is about 37.5 mg twice daily. In a further embodiment, the therapeutically effective amount of macitentan is about 60 to about 80 mg twice daily. In yet another embodiment, the therapeutically effective amount of macitentan is about 60 to about 85 mg twice daily. In yet a further embodiment, the therapeutically effective amount of macitentan is about 60 to about 90 mg twice daily. In another embodiment, macitentan A therapeutically effective amount of macitentan is about 65 to about 75 mg twice daily. In a further embodiment, a therapeutically effective amount of macitentan is about 65 to about 85 mg twice daily. In yet another embodiment, a therapeutically effective amount of macitentan is about 65 to about 90 mg twice daily. In yet another embodiment, a therapeutically effective amount of macitentan is about 70 to about 80 mg twice daily. In another embodiment, a therapeutically effective amount of macitentan is about 72 to about 78 mg twice daily. In a further embodiment, a therapeutically effective amount of macitentan is about 75 mg twice daily.

[0045] The method also includes administering a therapeutically effective amount of aprocitentan. In certain embodiments, the therapeutically effective amount of aprocitentan is about 100 mg per day to about 1500 mg per day. In other embodiments, the therapeutically effective amount of aprocitentan is about 100 mg per day to about 1500 mg per day. In another embodiment, the therapeutically effective amount of aprocitentan is about 300 to about 450 mg per day. In another embodiment, the therapeutically effective amount of aprocitentan is about 325 to about 425 mg per day. In a further embodiment, the therapeutically effective amount of aprocitentan is about 350 to about 400 mg per day. In yet another embodiment, the therapeutically effective amount of aprocitentan is about 375 mg per day. In some embodiments of the present disclosure, the therapeutically effective amount of aprocitentan is about 300 to about 425 mg. In another embodiment, the therapeutically effective amount of aprocitentan is about 300 to about 400 mg. In a further embodiment, the therapeutically effective amount of aprocitentan is about 300 to about 375 mg per day. In yet another embodiment, the therapeutically effective amount of aprocitentan is about 325 to about 450 mg. In yet a further embodiment, the therapeutically effective amount of aprocitentan is about 325 to about 375 mg per day. In another embodiment, the therapeutically effective amount of aprocitentan is about 360 to about 390 mg per day. In a further embodiment, the therapeutically effective amount of aprocitentan is less than about 75 mg. In a further embodiment, the therapeutically effective amount of aprocitentan is about 1 mg, about 10 mg, about 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg. In other embodiments, the therapeutically effective amount of aprocitentan is about 5 to about 75 mg, about 5 to about 50 mg, about 5 to about 25 mg, about 12.5 to about 75 mg, about 12.5 to about 50 mg, about 25 to about 75 mg, about 25 to about 50 mg, or about 50 to about 75 mg. In yet a further embodiment, the therapeutically effective amount of aprocitentan is about 25 to about 75 mg. In yet a further embodiment, the therapeutically effective amount of aprocitentan is about 50 mg.

[0046] The present disclosure also provides for titrating the amount of macitentan from a smaller amount to a larger amount over a period of time. In some embodiments, a starting amount of macitentan is administered to a patient for a first period of time. The starting amount of macitentan is then titrated, i.e., increased, to a subsequent amount for a subsequent period of time. For example, a second amount of macitentan is administered for a second period of time. The second amount of macitentan is then titrated to a third amount of macitentan for a third period of time.

[0047] The initial amount may be increased to the subsequent amount(s) in increments as determined by the attending physician. In some embodiments, the increments are about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. The initial amount and subsequent amounts of macitentan may be any therapeutically effective amount mentioned in this disclosure. In some embodiments, the initial amount of macitentan is about 10 mg per day. In other embodiments, the subsequent amounts may be about 25 mg to about 50 mg or about 60 mg to about 90 mg of macitentan per day. In further embodiments, the first subsequent amount of macitentan following the initial amount of macitentan is about 25 mg to about 50 mg per day. In other embodiments, the second subsequent amount of macitentan following the first subsequent amount of macitentan is about 60 mg to about 90 mg. For example, the starting dose of macitentan is about 10 mg per day, which may be titrated to about 25 mg to about 50 mg of macitentan per day. , which is then increased to about 60 mg to about 90 mg of macitentan per day.

[0048] In some embodiments, the starting amount of macitentan is about 10 mg for a first period. For example, the first period is about 1 or 2 days, preferably 2 days. The starting amount of macitentan is then titrated to a second amount of macitentan of about 37.5 mg for a second period. For example, the second period is about 2 to 4 days, preferably 3 days. The second amount of macitentan is then titrated to a third amount of macitentan of about 75 mg for a third period. For example, the third period is about 6 to about 10 days, preferably 8 days. In other embodiments, 10 mg is administered to the patient for 2 consecutive days, followed by about 37.5 mg of macitentan for 3 consecutive days, followed by about 75 mg of macitentan for 8 days.

[0049] In some embodiments, about 10 mg / day of macitentan is administered for about 15 to about 45 days. In other embodiments, about 25 mg to about 50 mg of macitentan is administered for about 15 to about 45 days. In further embodiments, the amount of macitentan is titrated from about 10 mg per day, then to about 25 mg to about 50 mg per day, then to about 60 mg to about 90 mg per day.

[0050] The following aspects (a)-(l) and (a')-(l') describe aspects for administering macitentan or aprocitentan. In some embodiments, aspects (a)-(l) and (a')-(l') relate to methods for treating pulmonary hypertension in left ventricular assist device (LVAD) implanted patients by administering macitentan. In other embodiments, aspects (a)-(l) and (a')-(l') relate to methods for treating pulmonary hypertension in left ventricular assist device (LVAD) implanted patients by administering aprocitentan. In further embodiments, aspects (a)-(l) and (a')-(l') relate to methods for improving heart transplant eligibility in left ventricular assist device (LVAD) implanted patients using macitentan. In yet other embodiments, aspects (a)-(l) and (a')-(l') relate to methods for improving heart transplant eligibility in left ventricular assist device (LVAD) implanted patients using aprocitentan.

[0051] (a) In some embodiments, the amount of macitentan is between 20 mg per day and 300 mg per day. The amount can also be between more than 20 mg per day and 300 mg per day. The amount can be between 25 mg per day and 300 mg per day. For example, the amount is between 20 mg per day and 250 mg per day. Preferably, the amount is between 25 mg and 200 mg per day. According to more preferred embodiments, these amounts are applied once a day.

[0052] (b) According to other embodiments, such as embodiment (a), the amount of macitentan is 60-90 mg per day. Preferably, the amount is 65-85 mg per day, more preferably, the amount is 70-80 mg per day, and most preferably, the amount is 75 mg per day. It is understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the amount may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg, or 65-75 mg per day. A further preferred range is 72-78 mg per day. Furthermore, the dosage of macitentan may be titrated from 10 mg per day, followed by 25-50 mg per day, preferably 37.5 mg per day, followed by 60-90 mg per day, preferably 75 mg per day, optionally followed by 100-200 mg per day, preferably 150 mg per day. According to a more preferred embodiment, these amounts are applied once a day.

[0053] (c) According to a further embodiment, such as embodiment (a), the amount of macitentan is between 25 and 50 mg per day. Preferably, the amount is between 30 and 45 mg per day, more preferably between 35 and 40 mg per day, most preferably between 37.5 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be between 25 and 45 mg per day, or between 25 and 40 mg per day. Also disclosed are amounts between 30 and 50 mg per day, or between 30 and 40 mg per day. Further preferred ranges are between 36 and 39 mg per day. According to more preferred embodiments, these amounts are applied once per day.

[0054] (d) According to other embodiments, for example embodiment (a), the amount of macitentan is 110-200 mg per day. Preferably, the amount is 125-175 mg per day, more preferably 140-160 mg per day, most preferably 150 mg per day. It is understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Also disclosed are amounts of 125-160 mg or 140-175 mg per day. Further preferred ranges are 145-155 mg per day. According to more preferred embodiments, these amounts are applied once per day.

[0055] (e) In a further embodiment, for example according to embodiment (a), the amount of macitentan is 60-90 mg twice daily. Preferably, the amount is 65-85 mg twice daily, more preferably 70-80 mg twice daily, and most preferably 75 mg twice daily. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 60-85 mg twice daily, 60-80 mg twice daily, or 60-75 mg twice daily. Also disclosed are amounts of 65-90 mg twice daily, or 65-75 mg twice daily. A further preferred range is 72-78 mg twice daily.

[0056] (f) In other embodiments, for example according to embodiment (a), the amount of macitentan is 25-50 mg twice daily, preferably 30-45 mg twice daily, more preferably 35-40 mg twice daily, most preferably 37.5 mg twice daily. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 25-45 mg twice daily, or 25-40 mg twice daily. Also disclosed are amounts of 30-50 mg twice daily, or 30-40 mg twice daily. A further preferred range is 36-39 mg twice daily.

[0057] (g) In a further embodiment, for example according to embodiment (a), the amount of macitentan may be titrated from 10 mg per day, followed by 25-50 mg per day, preferably 37.5 mg per day, optionally followed by 60-90 mg per day, preferably 75 mg per day. "Followed by 25-50 mg per day" preferably means that the amount is 30-45 mg per day, more preferably 35-40 mg per day, and most preferably 37.5 mg per day. It is to be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e. the amount may also be 25-45 mg per day, or 25-40 mg per day. Also disclosed are amounts of 30-50 mg per day, or 30-40 mg per day. A further preferred range is 36-39 mg per day. It is understood that any titration to a higher amount can be backed off to a lower amount if the higher amount is not tolerated. The phrase "optionally followed by 60-90 mg per day" preferably means that the amount is 65-85 mg per day, more preferably that the amount is 70-80 mg per day, and most preferably that the amount is 75 mg per day. Each of the lower limits disclosed above is mutually exclusive with each of the upper limits. It is to be understood that combinations may also be used, i.e. the amounts may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg, or 65-75 mg per day. A more preferred range is 72-78 mg per day. It is to be understood that any titration to a higher amount can be backed off to a lower amount if the higher amount is not tolerated. According to a more preferred embodiment, these amounts are applied once per day.

[0058] In yet a further embodiment, the amount of macitentan is 10 mg per day. Patients obtaining this amount may undergo immediate dose escalation to 37.5 mg per day, optionally followed by 75 mg per day.

[0059] Furthermore, the amount of macitentan may be titrated from 10 mg per day, followed by 25-50 mg per day, preferably 37.5 mg per day, optionally followed by 60-90 mg per day, preferably 75 mg per day, optionally followed by 110-200 mg per day, preferably 150 mg per day. The phrase "optionally followed by 110-200 mg per day" preferably means that the amount is 125-175 mg per day, more preferably 140-160 mg per day, and most preferably 150 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Also disclosed are amounts of 125-160 mg or 140-175 mg per day. More preferred ranges are 145-155 mg per day. According to more preferred embodiments, these amounts are applied once per day.

[0060] (h) In a further embodiment, for example according to embodiment (a), the amount of macitentan is titrated from 10 mg per day, followed by 60-90 mg per day, preferably 75 mg once per day or 37.5 mg twice per day. The phrase "optionally followed by 60-90 mg per day" preferably means that the amount is 65-85 mg per day, more preferably 70-80 mg per day, and most preferably 75 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg, or 65-75 mg per day. A further preferred range is 72-78 mg per day. It is understood that any titration to a higher amount can be backed off to a lower amount if the higher amount is not tolerated. According to a more preferred embodiment, these amounts are applied once a day.

[0061] In another embodiment, according to embodiment (a), the amount of macitentan is titrated from 10 mg per day, followed by 60-90 mg per day, preferably 75 mg once per day, 37.5 mg twice per day, optionally followed by 110-200 mg per day, preferably 150 mg per day. The phrase "optionally followed by 110-200 mg per day" preferably means that the amount is 125-175 mg per day, more preferably 140-160 mg per day, and most preferably 150 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Also disclosed are amounts of 125-160 mg or 140-175 mg per day. A more preferred range is 145-155 mg per day. According to a more preferred embodiment, these amounts are applied once a day.

[0062] In yet another embodiment, the amount of macitentan is 10 mg per day. Patients receiving this amount may receive immediate dose escalation to 75 mg per day or 150 mg per day.

[0063] (i) In a further embodiment, for example according to embodiment (g), the amount of macitentan is preferably titrated from 10 mg once a day for 15-45 days, followed by 25-50 mg, preferably 37.5 mg once a day, preferably for 15-45 days, and optionally followed by 60-90 mg, preferably 75 mg once a day, or 37.5 mg twice a day. It should be understood that any titration to a higher amount can be reverted back to a lower amount if the higher amount is not tolerated. In this regard, the term "15-45 days" preferably means 20-40 days, more preferably 21-35 days, most preferably 28-30 days, i.e. about one month. Furthermore, the phrase "followed by 25-50 mg per day" preferably means that the amount is 30-45 mg per day, more preferably 35-40 mg per day, and most preferably 37.5 mg per day. It is to be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e. the amount may also be 25-45 mg per day, or 25-40 mg per day. Also disclosed are amounts of 30-50 mg or 30-40 mg per day. A more preferred range is 36-39 mg per day. Furthermore, the phrase "then 60-90 mg per day" preferably means that the amount is 65-85 mg per day, more preferably that the amount is 70-80 mg per day, and most preferably that the amount is 75 mg per day. It is to be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e. the amount may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg or 65-75 mg per day. More preferred ranges are 72-78 mg per day, or 36-39 mg twice a day. According to more preferred embodiments, these amounts are applied once a day.

[0064] In other embodiments, for example according to embodiment (g), the amount of macitentan is increased from 10 mg once daily, preferably for 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. The phrase "optionally followed by 110 to 200 mg per day" preferably means that the amount is 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 110-175 mg per day, 110-160 mg per day, or 110-150 mg per day. Also disclosed are amounts of 125-160 mg per day or 140-175 mg per day. A further preferred range is 145-155 mg per day. According to a more preferred embodiment, these amounts are applied once a day.

[0065] (j) In a further embodiment, for example according to embodiment (h), the amount of macitentan is increased from 10 mg once a day, preferably for 15 to 45 days, followed by 60 to 90 mg per day, preferably 75 mg once a day, or 37.5 mg twice a day. In this regard, the term "15 to 45 days" preferably means 20 to 40 days, more preferably 21 to 35 days, most preferably 28 to 30 days, i.e. about one month. The phrase "followed by 60 to 90 mg per day" preferably means that the amount is 65 to 85 mg per day, more preferably that the amount is 70 to 80 mg per day, and most preferably that the amount is 75 mg per day. Each of the lower limits disclosed above is inclusive with each of the upper limits. It is understood that combinations may also be used, i.e. amounts may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg, or 65-75 mg per day. More preferred ranges are 72-78 mg per day, or 36-39 mg twice daily.

[0066] In other embodiments, for example according to embodiment (h), the amount of macitentan is increased from 10 mg once a day, preferably for 15 to 45 days, followed by 60 to 90 mg per day, preferably 75 mg once a day, or 37.5 mg twice a day, preferably for 15 to 45 days, optionally followed by 110 to 200 mg per day, preferably 150 mg per day. The phrase "optionally followed by 110 to 200 mg per day" preferably means that the amount is 125 to 175 mg per day, more preferably 140 to 160 mg per day, and most preferably 150 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 110 to 175 mg per day, 110 to 160 mg per day, or 110 to 150 mg per day. Also disclosed are amounts of 125-160 mg or 140-175 mg per day. More preferred ranges are 145-155 mg per day. According to more preferred embodiments, these amounts are applied once per day.

[0067] (k) In a further embodiment, for example according to any one of the embodiments (a) to (c), the amount of macitentan is titrated to 25-50 mg per day, preferably 37.5 mg per day, preferably for 15-45 days, optionally followed by 60-90 mg per day, preferably 75 mg per day, it being understood that any titration to a higher amount can be back to a lower amount if the higher amount is not tolerated. In this regard, the term "15-45 days" preferably means 20-40 days, more preferably 21-35 days, most preferably 28-30 days, i.e. about one month. Furthermore, the phrase "followed by 25-50 mg per day" preferably means that the amount is 30-45 mg per day, more preferably 35-40 mg per day, and most preferably 37.5 mg per day. It is to be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e. the amount may also be 25-45 mg per day, or 25-40 mg per day. Also disclosed are amounts of 30-50 mg or 30-40 mg per day. A more preferred range is 36-39 mg per day. Furthermore, the phrase "then 60-90 mg per day" preferably means that the amount is 65-85 mg per day, more preferably that the amount is 70-80 mg per day, and most preferably that the amount is 75 mg per day. It is to be understood that each of the disclosed lower limits may be combined with each of the upper limits, i.e. the amount may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg or 65-75 mg per day. More preferred ranges are 72-78 mg per day, or 36-39 mg twice per day. It is understood that, optionally, the amount of macitentan can be further increased to reach 110-200 mg per day, whereby the amount is titrated as in embodiments (h)-(k). According to more preferred embodiments, these amounts are applied once per day.

[0068] (l) In another embodiment, for example according to embodiment (a) or (b), the amount of macitentan is 60-90 mg per day, preferably 75 mg per day. The phrase "60-90 mg per day" preferably means that the amount is 65-85 mg per day, more preferably that the amount is 70-80 mg per day, and most preferably that the amount is 75 mg per day. It is to be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e. the amount may also be 60-85 mg, 60-80 mg, or 60-75 mg per day. Also disclosed are amounts of 65-90 mg, or 65-75 mg per day. Further preferred ranges are 72-85 mg per day, 75-85 mg per day, 75-85 mg per day, 75-80 ... 78 mg, or 36-39 mg twice a day. Optionally, it is understood that the amount of macitentan can be further increased to reach 110-200 mg per day, whereby the amount is titrated as in embodiments (h)-(k). According to a more preferred embodiment, these amounts are applied once a day.

[0069] (a') In certain embodiments, the amount of macitentan is between 20 mg per day and 300 mg per day. It is understood that the disclosure of embodiment (a) applies equally.

[0070] (b') In another embodiment, for example according to embodiment (a'), the amount of macitentan is 60-90 mg per day, preferably 65-85 mg per day, more preferably 70-80 mg per day, most preferably 75 mg per day, it being understood that the disclosure of embodiment (b) applies analogously.

[0071] (c') In a further embodiment, for example according to embodiment (a'), the amount of macitentan is 25-50 mg per day, preferably 30-45 mg per day, more preferably 35-40 mg per day, most preferably 37.5 mg / day, it being understood that the disclosure of embodiment (c) applies analogously.

[0072] (d') In another embodiment, for example according to embodiment (a'), the amount of macitentan is 110-200 mg per day, preferably 125-175 mg per day, more preferably 140-160 mg per day, most preferably 150 mg per day, it being understood that the disclosure of embodiment (d) applies analogously.

[0073] (e') In a further embodiment, for example according to embodiment (a'), the amount of macitentan is 60-90 mg twice a day, preferably 65-85 mg twice a day, more preferably 70-80 mg twice a day, most preferably 75 mg twice a day. It is to be understood that the disclosure of embodiment (e) applies analogously.

[0074] (f') In another embodiment, for example according to embodiment (a'), the amount of macitentan is 25-50 mg twice a day, preferably 30-45 mg twice a day, more preferably 35-40 mg twice a day, most preferably 37.5 mg twice a day. It is to be understood that the disclosure of embodiment (f) applies analogously.

[0075] (g') In another embodiment, for example according to embodiment (a'), the amount of macitentan is titrated from 10 mg per day, followed by 25-50 mg per day, preferably 37.5 mg per day, optionally followed by 60-90 mg per day, preferably 75 mg per day, it being understood that the disclosure of embodiment (g) applies as well.

[0076] (h') In a further embodiment, such as according to embodiment (a'), the amount of macitentan is titrated from 10 mg per day to 60-90 mg per day, preferably 75 mg once per day or 37.5 mg twice per day. It is understood that the disclosure of embodiment (h) applies analogously.

[0077] (i') In another embodiment, for example according to embodiment (g'), the amount of macitentan is titrated 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 per day, preferably for 15 to 45 days, and optionally followed by 60 to 90 mg per day, preferably 75 mg once per day or 37.5 mg twice per day, according to claim 9. It is understood that the disclosure of embodiment (i) applies analogously.

[0078] (j') In a further embodiment, for example according to embodiment (h'), the amount of macitentan is titrated from 10 mg once a day, preferably for 15 to 45 days, followed by 60 to 90 mg per day, preferably 75 mg once a day, or 37.5 mg twice a day. It is understood that the disclosure of embodiment (j) applies analogously.

[0079] (k') In another embodiment, for example according to any one of embodiments (a')-(c'), the amount of macitentan is preferably increased to 25-50 mg per day, preferably 37.5 mg per day, for 15-45 days, optionally subsequently to 60-90 mg per day, preferably 75 mg per day. It is understood that the disclosure of embodiment (k) applies analogously.

[0080] (l') In a further embodiment, for example according to embodiment (a') or (b'), the amount of macitentan is 60-90 mg per day, preferably 75 mg per day. It is understood that the disclosure of embodiment (l) applies analogously.

[0081] It is to be understood that the comments and details of embodiments (a)-(l) also apply to embodiments (a')-(l').

[0082] According to a further aspect of the present invention, in each of the above-mentioned aspects, i.e. in each of the aspects (a) to (l) and (a') to (l'), macitentan can be replaced by aprocitentan, and the weight of macitentan is replaced by 5 times the weight of aprocitentan, and the amount of aprocitentan is 300 to 450 mg per day. Preferably, the amount of aprocitentan is 325 to 425 mg per day, more preferably, the amount of aprocitentan is 350 to 400 mg per day, and most preferably, the amount of aprocitentan is 375 mg per day. It should be understood that each of the lower limits disclosed above may be combined with each of the upper limits, i.e., the amount of aprocitentan may also be 300 to 425 mg, 300 to 400 mg, or 300 to 375 mg per day. Also disclosed are amounts of aprocitentan of 325-450 mg or 325-375 mg per day. A more preferred range is 360-390 mg of aprocitentan per day. According to more preferred embodiments, these amounts of aprocitentan are applied once per day.

[0083] The methods described herein may also include discontinuing administration of another pharmaceutical agent useful for treating pulmonary hypertension. In some embodiments, the methods include discontinuing treatment with an endothelin receptor antagonist (ERA) that is not macitentan or aprocitentan prior to administration of macitentan or aprocitentan. For example, the ERA is bosentan, ambrisentan, or a pharma- ceutically acceptable salt thereof. In some aspects, the ERA is bosentan. In other embodiments, the ERA is ambrisentan.

[0084] In other embodiments, the method includes discontinuing treatment with a phosphodiesterase type 5 (PDE-5) inhibitor before administration of macitentan or aprocitentan. For example, the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharma- ceutically acceptable salt thereof. In some embodiments, the PDE-5 inhibitor is sildenafil. In further embodiments, the PDE-5 inhibitor is vardenafil. In other embodiments, the PDE-5 inhibitor is udenafil. In yet further embodiments, the PDE-5 inhibitor is tadalafil. Tadalafil is commercially available as Adcirca™ and has the following structure:

[0085] [ka]

[0086] In further embodiments, the method includes discontinuing treatment with other PAH-specific therapies prior to administration of macitentan or aprocitentan. For example, other PAH-specific therapies include inhaled nitric oxide (iNO), soluble guanylate cyclase (sGC) stimulators, or oral prostanoids (e.g., intravenous or subcutaneous), among others. In some embodiments, the PAH-specific therapy is iNO. In other aspects, the PAH-specific therapy is an sGC stimulator. One example of an sGC stimulator is riociguat. Riociguat is commercially available as Adempas™ and has the following structure:

[0087] [ka]

[0088] In patients who have been receiving other PAH therapies, the methods may also include a washout period before administering macitentan or aprocitentan. As used herein, the term "washout period" refers to a period during which the other PAH therapy is not continued. In some embodiments, the washout period is at least one day, or preferably at least one week.

[0089] The methods described herein are effective in reducing PVR. In some embodiments, PVR is reduced by at least about 10% relative to patients with the same disease diagnosis not treated with macitentan (placebo group). In other embodiments, the methods result in a reduction in PVR levels to less than about 4 WU. In further embodiments, the methods result in a reduction in PVR levels to less than about 3 WU. In yet other embodiments, the methods result in a reduction in PVR levels to less than about 2 WU, or to about 1 WU.

[0090] As used herein, unless otherwise indicated, macitentan refers to propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide,

[0091] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or morphological form thereof. In some embodiments, the disclosure relates to macitentan free base. In other embodiments, the disclosure relates to macitentan salts. In further embodiments, the disclosure relates to macitentan solvates. In yet other embodiments, the disclosure relates to macitentan hydrates. In further embodiments, the disclosure relates to morphological forms of macitentan.

[0092] Macitentan is an endothelin receptor antagonist (ERA) that acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB (Kholdani et al., 2013). et al,Macitentan for the treatment of pulmonary arterial hypertension. Vasc. Health Risk Manag.(2014),10,665-673). Currently, macitentan is taken as an oral dose of 10 mg once daily. The half-life in humans is about 16 hours, and steady state is reached by 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 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, i.e. aprocitentan, which reaches peak plasma concentrations about 30 hours after the first dose is administered and has a half-life of about 48 hours. ACT-132577 has a lower affinity for ET receptors than 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), and it maintains higher plasma concentrations than macitentan. Both compounds can be excreted from the body through urine or feces.

[0093] According to a further aspect of the present disclosure, macitentan may be replaced by its active metabolite, known by the code name ACT-132577 and the international non-proprietary name aprocitentan,

[0094] [ka] This allows any weight of macitentan to be replaced by 5 times the weight of aprocitentan. In some embodiments, the disclosure relates to aprocitentan free base. In other embodiments, the disclosure relates to aprocitentan salts. In further embodiments, the disclosure relates to aprocitentan solvates. In yet other embodiments, the disclosure relates to aprocitentan hydrates. In further embodiments, the disclosure relates to morphological forms of aprocitentan.

[0095] As used herein, "morphological form" refers to an amorphous or crystalline form of macitentan or aprocitentan. In some embodiments, macitentan or aprocitentan is in a crystalline form. In other embodiments, macitentan or aprocitentan is in an amorphous form. Crystallinity can be determined by one of skill in the art using one or more techniques, such as, for example, single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, melting point, among others.

[0096] As used herein, "hydrate" includes forms of macitentan or aprocitentan whereby one or more water molecules are bound to one or more positions of macitentan or aprocitentan via intermolecular forces or chemical bonds.

[0097] As used herein, "solvate" refers to a form of macitentan or aprocitentan in which one or more solvents are bound to one or more positions on macitentan or aprocitentan via intermolecular forces or chemical bonds.

[0098] Pharmaceutically acceptable salts of macitentan or aprocitentan can be readily selected by one skilled in the art. The term pharma- ceutically acceptable salts includes either inorganic or organic acid addition salts, such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-toluenesulfonic acid, and the like, or, if macitentan or aprocitentan is acidic in nature, inorganic bases, such as alkali or alkaline earth bases, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like.

[0099] As used herein, unless otherwise indicated, the terms "treating," "treatment," and the like, are intended to include the management and care of a patient for the purpose of combating a disease, condition, or disorder. The terms "treating" and "treatment" also include the administration of a compound or pharmaceutical composition described herein to (a) alleviate one or more symptoms or complications of a disease, condition, or disorder, (b) prevent the onset of one or more symptoms or complications of a disease, condition, or disorder, and / or (c) eliminate one or more symptoms or complications of a disease, condition, or disorder.

[0100] The terms "subject" and "patient", as used herein, refer to an animal, preferably a mammal, and most preferably a human, who is the object of treatment.

[0101] This method also allows for the administration of a concomitant standard of care or background therapy. The term "standard of care" typically refers to a physician-prescribed treatment for the condition in question. In some embodiments, the standard of care includes, consists of, or consists essentially of administering an additional medication effective to treat PH. The standard of care may be administered to the patient before, after, or simultaneously with macitentan or aprocitentan. In some embodiments, the standard of care is administered before macitentan or aprocitentan. In other embodiments, the standard of care is administered after macitentan or aprocitentan. In further embodiments, the standard of care is administered simultaneously with macitentan or aprocitentan. In yet other embodiments, the standard of care is present at a stable dose for at least three months prior to administration of macitentan or aprocitentan.

[0102] In some embodiments, the standard of care is a PDE5 inhibitor. Examples of PDE5 inhibitors include, but are not limited to, sildenafil, tadalafil, vardenafil, and udenafil, preferably tadalafil. In certain embodiments that include the PDE5 inhibitor standard of care, sildenafil is not used. In other embodiments, the standard of care is a prostacyclin analog. Examples of prostacyclin analogs include, but are not limited to, epoprostenol, treprostinil, iloprost, and beraprost. In further embodiments, the standard of care is a prostacyclin receptor antagonist. Examples of useful prostacyclin receptor antagonists include, but are not limited to, selexipag and ralinepag, preferably selexipag. In yet other embodiments, the standard of care is a soluble guanylate cyclase stimulator. Examples of soluble guanylate cyclase stimulators include, but are not limited to, riociguat and vericiguat.

[0103] In the methods described herein, the therapeutically effective amount of macitentan or aprocitentan is safe, effective, or safe and effective. As used herein, unless otherwise specified, the term "safe" shall mean free from undue adverse side effects (such as toxicity, irritation, or allergic reaction), and is commensurate with a reasonable benefit / risk ratio when used in the manner of the present invention. Similarly, unless otherwise specified, the term "effective" means that the therapeutic efficacy has been demonstrated for treating PH patients when administered in a therapeutically effective amount. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In further embodiments, the methods described herein are safe and effective. In yet other embodiments, the therapeutically effective amount of macitentan or aprocitentan is safe. In yet further embodiments, the therapeutically effective amount of macitentan or aprocitentan is effective. In other embodiments, the therapeutically effective amount of macitentan or aprocitentan is safe and effective.

[0104] Formulation / Composition Pharmaceutical compositions containing macitentan or aprocitentan as an active ingredient can be prepared by intimately mixing macitentan or aprocitentan with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. As used herein, the terms "composition" and "formulation" are used interchangeably and encompass any product, such as a pharmaceutical product, that results directly or indirectly from the combination of specified ingredients in specified amounts, in addition to a product that contains specified ingredients in specified amounts. A summary of pharmaceutical compositions is provided, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mac Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HAand Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0105] The pharmaceutical composition or pharmaceutical formulation may be administered by a number of routes as determined by the skilled artisan. Preferably, the pharmaceutical composition or formulation is administered by a route suitable for macitentan or aprocitentan. In some embodiments, the pharmaceutical composition or formulation is administered orally, rectally, parenterally, for example, by intravenous, intramuscular, subcutaneous, intrathecal, or transdermal administration, or sublingually, or as an intraocular formulation, or as an aerosol, preferably orally. Preferably, the pharmaceutical composition or drug product is administered orally. Examples of applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye drops, ointments, or aerosols / nebulizers.

[0106] The preferred application is oral administration. The doses used vary depending on the type of specific active ingredient, the age and requirements of the patient, and the type of application. In general, a dose of 0.001 to 0.25 mg / kg body weight per day is considered for an average body weight of about 70 kg. The preparations can contain inert or similarly pharmacodynamically active excipients. Tablets or granules can contain, for example, many binders, filler excipients, carrier substances, or diluents.

[0107] The compositions may be administered, for example, in enteral or oral form, such as tablets, dragees, gelatin capsules, emulsions, solutions or suspensions, in nasal form, such as sprays, or rectally in the form of suppositories. The compositions may also be administered intramuscularly, parenterally or intravenously, for example in the form of injections.

[0108] These pharmaceutical compositions may contain macitentan or aprocitentan in combination with inorganic and / or organic excipients that are usual in the pharmaceutical industry, such as lactose, corn or derivatives thereof, talcum, talc, stearic acid, or salts of these materials.

[0109] Gelatin capsules may use vegetable oils, waxes, fats, liquid or semi-liquid polyols. For the preparation of liquids and syrups, for example, water, polyols, saccharose, glucose may be used. Injections may be prepared, for example, by using water, polyols, alcohols, glycerin, vegetable oils, lecithin or liposomes. Suppositories may be prepared by using natural or hardened oils, waxes, fatty acids (fats), liquid or semi-liquid polyols.

[0110] The compositions may additionally contain preservatives, stability enhancing substances, viscosity enhancing or adjusting substances, solubility enhancing substances, sweeteners, dyes, taste enhancing compounds, salts for altering osmotic pressure, buffers, or antioxidants.

[0111] To prepare such pharmaceutical compositions, macitentan or aprocitentan as the active ingredient is thoroughly mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which may take a variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral, e.g., intramuscular. When preparing the composition in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for example, for oral liquid preparations such as suspensions, elixirs and solutions, suitable Carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For oral solid formulations such as powders, capsules, caplets, gelcaps, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Because of ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case it is obvious that solid pharmaceutical carriers are used. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier usually comprises sterile water, but may contain other ingredients, for example, for purposes such as aiding solubility or for preservation. Injectable suspensions may be prepared, in which case suitable liquid carriers, suspending agents, and the like may be used. The pharmaceutical compositions herein will contain the amount of active ingredient required to deliver the above-mentioned effective dose per dosage unit, for example, tablet, capsule, powder, injection, teaspoon, and the like. The pharmaceutical compositions herein contain a therapeutically effective amount of macitentan or aprocitentan as disclosed herein per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoon, etc. Dosage amounts, however, may vary depending on the requirements of the patient, the severity of the condition being treated, and the macitentan or aprocitentan used. Either daily or intermittent dosing may be used.

[0112] Preferably, the pharmaceutical composition is in unit dosage form, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories, for oral parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation. For the preparation of solid compositions such as tablets, the main active ingredient (e.g., macitentan or aprocitentan) is mixed with pharmaceutical carriers, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing an intimate mixture of macitentan or aprocitentan. In certain embodiments, the two active ingredients can be blended together, such as, for example, a biphasic tablet formulation. When these preformulated compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition such that the composition can be readily subdivided into equally effective dosage forms such as tablets, pills, and capsules. This preformulated composition is then subdivided into unit dosage forms of the type described above containing a therapeutically effective amount of either macitentan or aprocitentan. The tablets or pills of the composition may be coated or otherwise compounded to provide a dosage form that confers the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of encapsulating the former.

[0113] Liquid dosage forms into which the compositions of the present disclosure may be administered orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions in edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, or gelatin.

[0114] The methods described herein may also be practiced using a pharmaceutical composition comprising macitentan or aprocitentan and a pharma- ceutically acceptable carrier. Carriers include necessary inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid dosage forms, such as pills, tablets, caplets, capsules (including immediate release, timed release, and sustained release formulations, respectively), granules, and powders, as well as liquid dosage forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Parenteral Administration Forms that may be useful include sterile solutions, emulsions and suspensions.

[0115] Advantageously, macitentan or aprocitentan may be administered in a single daily dose, or the total daily dose may be divided and administered two, three or four times a day. In some embodiments, macitentan or aprocitentan is orally administered once a day in tablet form. Preferably, macitentan or aprocitentan is administered in a single dose, or more preferably in a tablet once a day.

[0116] For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient (e.g., macitentan or aprocitentan) can be combined with an oral, non-toxic, pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Furthermore, where desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0117] The liquids take the form of suitably flavored suspending or dispersing agents such as, for example, tragacanth, acacia, methylcellulose, etc. For parenteral administration, sterile suspensions and solutions are desired. If intravenous administration is desired, isotonic preparations are used, generally containing suitable preservatives.

[0118] To prepare the pharmaceutical composition of the present disclosure, the active ingredient macitentan or aprocitentan is thoroughly mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which can take a wide variety of forms depending on the form of preparation desired for administration (e.g., oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the British Pharmaceutical Association, the disclosures of which are incorporated herein by reference.

[0119] Methods for formulating pharmaceutical compositions are described in Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al., published by Marcel Dekker, Inc.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al., the disclosures of which are incorporated herein by reference.

[0120] The following examples are provided to illustrate some of the concepts described in this disclosure. The examples are considered to provide embodiments, but should not be considered to limit the more general embodiments described herein. Furthermore, in the following examples, efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0121] [Table 3-1]

[0122] [Table 3-2]

[0123] EXAMPLES

[0124] This is a double-blind, placebo-controlled, multicenter, parallel-group Phase 2 study evaluating the efficacy and safety of macitentan in PH after LVAD implantation. Approximately 57 adult patients with PH after LVAD implantation were randomized (1:1) to receive either macitentan 10 mg or matching placebo orally once daily.

[0125] After LVAD implantation, patients will meet baseline hemodynamic criteria for RHC-mediated PH during the last measurement prior to the first administration of drug, defined as a resting mPAP of 25 mmHg or greater, a PAWP of 18 mmHg or less, and a PVR of >3 WU. Patients will be randomized within 90 days of LVAD surgical implantation and within 14 days of baseline RHC.

[0126] Patients are considered stable 48 hours prior to baseline RHC, defined as no change in LVAD pump speed / flow, stable dose of oral diuretics, no intravenous inotropes or vasopressors, and ambulatory 48 hours prior to baseline RHC.

[0127] These advantages include: See Table 3:

[0128] Screening Period (Visit 1) All screening assessments will occur within the 90-day screening period beginning with LVAD implantation and prior to randomization. Screening and randomization can occur on the same day if all procedures at Visit 1 are completed before procedures at Visit 2 begin. Visit 1 will include the following: · Obtain patient number. · Recording demographics, baseline characteristics, and medical history. Records of past and concomitant medications. Physical examination. -Measurement of vital signs, height, and weight. Complete laboratory testing, including pregnancy testing for women of childbearing potential. · Recording of contraceptive method (for women of childbearing potential only) and initiation of protocol-compliant contraception, if applicable. · RHC (unless the procedure has already been performed and is within 90 days of randomization). · AE and SAE records.

[0129] Randomization (Visit 2) Visit 2 corresponds to the start of the treatment period (Day 1) for patients who are eligible after all screening evaluations have been performed. It is within 90 days after LVAD implantation and within 14 days of baseline RHC. Visit 2 includes the following: -Record changes in concomitant medications. -Measurement of vital signs and weight. Complete laboratory testing, including serum pregnancy testing for women of childbearing potential. · Contraceptive evaluation (women of childbearing potential only). Blood samples for serum NT-proBNP. Blood samples for additional circulating biomarkers such as IL-6, TNF-α, hsCRP, ET-1, Galectin-3, GDF-15, Interleukin 1 receptor ST2, NGAL, Copeptin, hs-cTnT, Cystatin-C, and Osteopontin. ·WHO FC. Echoes (i.e. 3D, 2D, M-mode and Doppler echocardiography) will be performed. These include: TAPSE, S', RVFAC, E', A', global RVLS, RV area and RVSI. In addition, right and left ventricular echo variables may be analyzed in an exploratory fashion (post-hoc) based on available scientific evidence. Baseline ECHO will occur on the day of randomization. ·AE / SAE records.

[0130] Treatment Period: Treatment is defined as the patient's administration (taking) of double-blind medication (macitentan or placebo). The double-blind treatment period begins immediately after randomization, at the end of Visit 2 (Day 1). The treatment period began with the first dose of drug and ended at the EOT of the last dose of drug (designated as Day 84, Week 12) or earlier in case of early discontinuation of treatment.

[0131] Week 4 (Visit 3) Visit 3 is scheduled 4 weeks (± 7 days) after randomization. Visit 3 will include the following: -Record changes in concomitant medications. · Complete laboratory testing including serum pregnancy test. · Evaluate contraceptive methods. · AE and SAE records.

[0132] Week 8 (Visit 4) Visit 4 is scheduled 8 weeks (± 7 days) after randomization. Visit 4 will include the following: -Record changes in concomitant medications. Complete laboratory testing, including serum pregnancy testing for women of childbearing potential. · Contraceptive evaluation (women of childbearing potential only). · AE and SAE records.

[0133] End of treatment (visit 5) EOT is planned for 12 weeks (± 7 days) after randomization, or earlier in case of early discontinuation of treatment. EOT includes: -Record changes in concomitant medications. Physical examination. -Measurement of vital signs and weight. Complete laboratory testing, including serum pregnancy testing for women of childbearing potential. · Evaluate contraceptive methods. ·R.H.C. Blood samples for serum NT-proBNP. Blood samples for additional circulating biomarkers such as IL-6, TNF-α, hsCRP, ET-1, Galectin-3, GDF-15, Interleukin 1 receptor ST2, NGAL, Copeptin, hs-cTnT, Cystatin-C, and Osteopontin. ·WHO FC. Echoes (i.e. 3D, 2D, M-mode and Doppler echocardiography) are performed, including: TAPSE, S', RVFAC, E', A', global RVLS, RV area and RVSI. Additionally, right and left ventricular echo variables may be analyzed. · AE and SAE records.

[0134] End of study (visit 6) Patients who completed treatment as planned, i.e., the entire 12-week period, and those who discontinued treatment early, will enter a 30-day safety follow-up period that will end with an EOS visit at least 30 days (+7 days) after permanent cessation of treatment (last dose of drug). EOS includes: -Record changes in concomitant medications. Complete laboratory testing, including serum pregnancy testing for women of childbearing potential. · Evaluate contraceptive methods. · AE and SAE records.

[0135] [Table 4]

[0136] For individual patients, once EOT was performed and 30-day safety follow-up was completed (E OS) and completed treatment. Patients were enrolled for 90 days (screening period) + 12 weeks (double-blind treatment period) + 30 days (safety follow-up period). The overall design is shown in Figure 1.

[0137] 1. Purpose Primary objective: To evaluate the effect of macitentan 10 mg compared with placebo on PVR in patients with PH after LVAD implantation.

[0138] Secondary Objectives To assess the effect of macitentan 10 mg compared with placebo on cardiopulmonary hemodynamics and severity in patients with PH after LVAD implantation. To evaluate the safety and tolerability of macitentan 10 mg in patients with PH after LVAD implantation.

[0139] exploratory purpose To investigate the potential effect of macitentan 10 mg compared with placebo on right ventricular function in patients with PH after LVAD implantation. To investigate the potential effects of macitentan 10 mg compared with placebo on selected clinical events in patients with PH after LVAD implantation. To investigate the potential effect of macitentan 10 mg compared with placebo on renal function as measured by GFR in patients with PH after LVAD implantation.

[0140] 2. Patient population Patients were male or female, aged 18 years or older, and met hemodynamic criteria for PH after LVAD implantation. Patients were considered clinically stable. Patient demographics and baseline characteristics are detailed in Tables 4 and 5.

[0141] [Table 5]

[0142] [Table 6-1]

[0143] [Table 6-2]

[0144] The primary objective was to demonstrate a reduction in PVR vs. baseline with macitentan treatment compared to placebo. Thus, patients who presented with elevated PVR (>3WU) and PAWP ≤18mmHg would exclude that their elevated PVR and mPAP were due to left-sided dysfunction. The lack of restrictions on WHO FC and 6MWD allowed for the enrollment of patients with severe symptomatic PH.

[0145] Patients with hemoglobin <8.5 g / dL or AST and / or ALT >3×ULN who do not recover during the screening period will be excluded.

[0146] A. Inclusion Criteria Regarding inclusion, the inclusion criteria are as follows:

[0147] [Table 7]

[0148] B. Exclusion criteria Patients do not meet any of the following exclusion criteria:

[0149] [Table 8]

[0150] C. Criteria for women of childbearing age A woman is considered to be of childbearing potential unless she meets at least one of the following criteria: Previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy. -Premature ovarian failure confirmed by a medical specialist. · Prepubertal, XY genotype, Turner syndrome, uterine agenesis. Menopause (ICH M3 definition) defined as 12 consecutive months without menses without another medical cause.

[0151] 3. Treatment Protocol Treatment is double-blind and involves the active drug macitentan or a matching placebo administered orally once daily. No dose escalation or reduction will be permitted. The matching placebo will be administered orally and also once daily.

[0152] The first dose of drug will be administered during randomization (Visit 2). Thereafter, one tablet (10 mg macitentan or matching placebo) will be taken orally every morning, regardless of food intake. If a morning dose is missed, the next dose will be administered at the next scheduled morning time point (i.e., one tablet will not be taken in the evening, and one tablet will be taken the following morning). Two tablets will not be taken on the same day.

[0153] At all subsequent visits, the drug will be taken before any procedures are performed. If the dose is not taken the morning before the visit arrives, the next dose can be administered at the visit and before any evaluations.

[0154] A. Treatment Allocation Eligible patients were randomized in a 1:1 ratio to either macitentan 10 mg or matching placebo. See Table 6 for patient exposure to treatment.

[0155] [Table 9]

[0156] At Visit 1 (screening), all screened patients are assigned a number. At Visit 2 (randomization), patients are randomized. This is done in a double-blind fashion and unblinding is performed for the final analysis. If a SUSAR occurs for a participating patient, the unblinding of treatment assignment is unblinded. SUSARs are considered in a blinded fashion. See Figure 2 for patient treatment.

[0157] Criteria for interrupting / prematurely discontinuing treatment included: (i) Pregnancy: If a female patient becomes pregnant during treatment, treatment will be discontinued immediately. (ii) Hepatic aminotransferase abnormalities: For abnormal test results (e.g., elevated ALT or AST) early in the screening period, patients may be monitored, provided appropriate treatment, and re-evaluated for eligibility throughout the screening period (90 days from LVAD implantation).

[0158] Treatment interruption Treatment is discontinued if: aminotransferases (i.e., ALT and / or AST) greater than or equal to 3 and less than or equal to 8×ULN;

[0159] In such cases, retesting of aminotransferases (ALT and AST), total and direct bilirubin, and alkaline phosphatase is performed within one week. If elevated AST and / or ALT are identified, aminotransferase, total and direct bilirubin, and alkaline phosphatase levels are monitored weekly until values ​​return to pretreatment levels or within the normal range. If aminotransferase values ​​return to pretreatment levels or within the normal range, reintroduction of treatment can be considered. Discontinuation is for less than two consecutive weeks. Longer discontinuation will lead to permanent discontinuation of treatment.

[0160] Reintroduction of treatment after treatment interruption should only be considered if the potential benefits of treatment with macitentan outweigh the potential risks and if hepatic aminotransferase values ​​are within pretreatment levels or within the normal range.

[0161] Liver aminotransferase levels are then checked within 3 days of reintroduction, and again after a further 2 weeks, and thereafter as recommended above (ie, at monthly intervals).

[0162] Permanent interruption of treatment: Treatment will be stopped and its reintroduction will not be considered in the following cases: Aminotransferase above 8×ULN. Aminotransferases above 3×ULN and associated clinical signs of liver damage, e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever). · Increases in aminotransferases above 3 x ULN and associated total bilirubin above 2 x ULN.

[0163] (iii) Hemoglobin abnormalities Patients may be monitored for abnormal results (e.g., low hemoglobin) early in the screening period, provided with appropriate treatment, and reevaluated for eligibility throughout the screening period (90 days from LVAD implantation). If there is a hemoglobin decrease from baseline of >2.0 g / dL, retesting will occur within 10 days and additional laboratory evaluations will be performed, which may include, but are not limited to, red blood cell indices (mean corpuscular volume, mean corpuscular hemoglobin content, mean corpuscular hemoglobin concentration), peripheral blood smear, reticulocyte count, iron status (iron level, serum ferritin, total iron binding capacity, transferrin saturation), lactate dehydrogenase, and indirect bilirubin.

[0164] Treatment may be temporarily interrupted in any of the following circumstances: A decrease in hemoglobin to less than 6.5 g / dL. A decrease in hemoglobin from baseline of more than 5.0 g / dL (baseline hemoglobin: last value obtained before the first dose of treatment). The need for blood transfusions.

[0165] (iv) Initiation of a prohibited concomitant medication: If a prohibited concomitant medication is initiated, treatment will be permanently discontinued.

[0166] (v) Clinical evidence of worsening PH or HF: Treatment may be discontinued if the patient exhibits signs and symptoms of progressive HF reflective of worsening PH and RVF. Examples include, but are not limited to, the need for RV support either pharmacologically with inotropes or mechanically with implantation of a RVAD, development of diuretic resistance, objective evidence of declining RV function on echocardiography, evidence of increasing PVR and / or decreasing CO on RHC, and the need for titration of PH therapy.

[0167] (vi) Heart Transplant: If a patient becomes a heart transplant recipient, treatment is permanently discontinued. The RHC obtained prior to heart transplant to define patient candidacy is captured as the EOT RHC. In case of early treatment discontinuation, all EOT assessments, especially the RHC, may be performed as detailed at each EOT visit.

[0168] B. Previous and Concomitant Therapies Prior therapy is any treatment whose end date is prior to the signing of informed consent. Concomitant therapy is any treatment whose start date is at or after the signing of informed consent or up to 30 days after treatment is discontinued. Concomitant therapy is any treatment whose start date is at or after the first dose of treatment up to 12 weeks thereafter, or earlier in case of early discontinuation of treatment.

[0169] Acceptable Combination Therapies Oral or intravenous diuretics are permitted and may be adjusted during treatment. Treatment with oral diuretics is permitted if continued at a stable dose for at least 48 hours prior to the baseline RHC.

[0170] Prohibited Concomitant Therapies PAH-specific therapies (ERAs, intravenous, subcutaneous, inhaled, or oral prostanoids, PDE5 inhibitors, guanylate cyclase stimulators). · iNO. Strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, saquinavir, boceprevir, telaprevir, iopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, and indinavir, as well as strong inducers of CYP3A4 (such as carbamazepine, rifampicin, rifabutin, phenytoin, and St. John's wort). Any investigational drug.

[0171] Allowable LVAD flow rate The LVAD pump speed / flow may be adjusted during the treatment period and during the baseline RHC. The LVAD pump speed / flow is stable for at least 48 hours prior to the baseline RHC.

[0172] 4.Endpoints Baseline is defined as the last value obtained before the first administration of treatment.

[0173] A. Efficacy endpoints (i) Primary Efficacy Endpoint: The primary efficacy endpoint is the PVR ratio at week 12 relative to baseline. PVR is obtained by thermodilution. See Table 7 for FAS, Table 8 for ES, and Table 9 for PPS.

[0174] [Table 10]

[0175] [Table 11]

[0176] [Table 12]

[0177] These results suggest that macitentan significantly reduced PVR in the early post-LVAD population. The results show that treatment with macitentan 10 mg once daily resulted in a statistically significant greater reduction in PVR at week 12 compared to the placebo group, with a placebo-adjusted geometric mean ratio (GMR) of 0.74 (95% CI: 0.58, 0.94, p=0.0158). The treatment effect (GMR-1 x 100%) corresponds to a statistically significant 26% reduction in PVR for macitentan vs. placebo. The scatter plot in Figure 3 shows the change in thermodilution PVR from baseline to week 12 by RHC for evaluable patients receiving either macitentan or placebo. A statistically significant greater reduction in PVR was observed in the macitentan treatment group at week 12 compared to the placebo group.

[0178] Overall, 16 (66.7%) patients in the macitentan group and 10 (40.0%) patients in the placebo group had a post-baseline PVR of less than 3 WU that was statistically significant (based on the Cochran-Mantel-Haenszel statistic adjusted for baseline PVR, p=0.0383), i.e., more patients receiving macitentan versus placebo achieved a PVR of less than 3 WU in the post-hoc analysis (p=0.0383). At baseline, the mean PVR was similar in both treatment groups.

[0179] Among patients with a baseline PVR ≤4 WU, the proportion of postbaseline PVR <3 WU was 90.0% in the macitentan group (n = 10) and 63.6% in the placebo group (n = 11). Among patients with a baseline PVR >4 WU, the proportion of postbaseline PVR <3 WU was 50.0% in the macitentan group (n = 14) and 21.4% in the placebo group (n = 14).

[0180] (ii) Secondary efficacy endpoints Changes from baseline to week 12 in mRAP, mPAP, PAWP, CI, TPR, and mixed SvO2 were all measured at rest.

[0181] Change from baseline to week 12 in NT-proBNP.

[0182] Change from baseline to week 12 in WHO FC. See Table 10.

[0183] [Table 13]

[0184] (iii) Exploratory efficacy endpoints Changes from baseline to week 12 in echocardiographic variables including 2D global RVLS, RVSI, RV end systolic area, RV end diastolic area, TAPSE, S', RVFAC, and E', A'. Time from enrollment to first occurrence of a clinical event through week 12. These clinical events included hospitalization for HF, resumption of intravenous diuretics for ≥48 hours, resumption of intravenous inotropes for ≥48 hours, initiation of a PDE5 inhibitor, need for RVAD / TAH, need for RRT, or death. Number of days since hospitalization for HF. - Change in GFR from baseline to week 12.

[0185] B. Safety endpoints Treatment-emergent AEs up to 30 days after treatment discontinuation. -AEs leading to early discontinuation of treatment. Death up to 30 days after treatment discontinuation. Treatment-emergent SAEs up to 30 days after treatment discontinuation. Change in vital signs from baseline to EOT. Occurrence of abnormal liver function tests (ALT and / or AST) by EOT (≥3×ULN; ≥3×ULN and <5×ULN; ≥5×ULN and <8×ULN; ≥8×ULN). · Occurrence of abnormalities in ALT and / or AST ≥3×ULN with bilirubin ≥2×ULN by EOT. Proportion of patients with treatment-emergent hemoglobin abnormalities (<10.0 g / dL and <8.0 g / dL) compared to baseline by EOT. Significant laboratory abnormalities occurring during treatment up to EOT.

[0186] C. Biomarker endpoints Changes in NT-proBNP will be assessed from baseline to week 12 (EOT) as part of the secondary efficacy endpoint analyses.

[0187] 5. Evaluation Optionally, the evaluation may be performed in the following order: Blood sampling. Physical examination. ·WHO FC. ·RHC at rest. · Echo (i.e. 3D, 2D, M-mode and Doppler echocardiography).

[0188] A. Screening / Baseline Assessment The date of informed consent, baseline demographics (sex, age, race, ethnicity, weight, height), and reasons why the woman is not considered of childbearing potential (if applicable) will be recorded at Visit 1 / Screening only after informed consent has been signed.

[0189] Complete clinically relevant medical history and disease characteristics (past and ongoing at time of randomization), vital signs, BMI, and past / ongoing medications will be recorded at Visit 1 / Screening. Non-baseline historical data pre-LVAD RHC and post-LVAD RHC may be entered.

[0190] At Visit 1 / Screening and Visit 2 / Randomization, a patient physical examination may be performed.

[0191] Serum and pregnancy tests will be performed at Visit 1 / Screening and may be repeated at Visit 2 / Randomization, but blood sampling for baseline NT-proBNP should only be performed at Visit 2 / Randomization.

[0192] At Visit 2 / randomization, WHO FC, vital signs, and weight will be assessed.

[0193] B. Effectiveness Evaluation Eligibility was determined by clinical or hemodynamic evidence of PH (e.g., PVR >3WU) prior to LVAD RHC or immediately following LVAD hemodynamics. Patients without clinical or hemodynamic evidence of PH should not be screened. Patients are stable for 48 hours prior to the baseline RHC. Stabilization is defined as: No change in LVAD pump speed / flow, Stable doses of oral diuretics, No intravenous inotropes or vasopressors, and Ambulatory patients.

[0194] Baseline RHC is defined as the last hemodynamic measurement after LVAD implantation and before the first administration of therapy. Hemodynamic evidence of PH relative to baseline RHC is one of the inclusion criteria. PH is defined as: mPAP ≥ 25mmHg, PAWP ≤ 18mmHg, and PVR > 3WU.

[0195] RHC performed before signing informed consent may be accepted as baseline RHC. Baseline RHC is performed by thermodilution after LVAD implantation and before the first administration of treatment (which must occur within 90 days after surgical implantation of the LVAD). Randomization (Visit 2) is within 14 days of baseline RHC. Patients are excluded if they have been treated with ERAs, PDE5 inhibitors, intravenous, subcutaneous, or oral prostanoids, or guanylate cyclase stimulators within 7 days prior to baseline RHC or treatment initiation. Patients are excluded if they have been treated with inhaled prostanoids (e.g., iloprost, epoprostenol), nitric oxide, or intravenous inotropes or vasopressors within 24 hours prior to baseline RHC or treatment initiation. LVAD pump speed / flow may be adjusted during the treatment period and during baseline RHC.

[0196] RHC will be repeated at week 12 or within 7 days of permanent cessation of treatment if prior to week 12. RHC at week 12 will be performed by thermodilution but not within 24 hours of intravenous inotropic or vasopressor treatment.

[0197] The following variables will also be measured: pulse rate, PAWP, mRAP, systolic / diastolic / mean PAP, CO, and SVO2, as well as non-invasive mean, SBP, and DBP if available. PVR will be calculated. CO measurements and PVR calculations during both baseline and week 12 RHC will be obtained by thermodilution. All primary endpoint calculations will be based on PVR calculated by thermodilution.

[0198] The following hemodynamic variables are calculated: PVR, TPR, and CI.

[0199] See Table 11 for baseline changes in RHC parameters (mPAP, mRAP, PAWP, CO, CI, mPAP, TPR, SvO2, DPG, and TPG).

[0200] [Table 14-1]

[0201] [Table 14-2]

[0202] These results suggest that the use of macitentan improved LV filling in patients after LVAD implantation. See, for example, especially the PAWP and CO data. RHC analysis demonstrated that TPG was statistically significantly reduced with macitentan vs. placebo, with a least squares mean difference of -2.7 and a p-value of 0.0499.

[0203] Blood samples will be collected at randomization (Visit 2) and EOT (Visit 5) for analysis of serum NT-proBNP. See Table 12 for serum NT-proBNP at Week 12 compared to baseline in the FAS.

[0204] [Table 15]

[0205] Echoes (i.e., 3D, 2D, M-mode, and Doppler echocardiography) will be performed at Visit 2 / randomization, which represents a baseline measurement and will be repeated at the Week 12 visit. Baseline ECHO will occur on the day of randomization. The following variables will be evaluated: 2D RVLS, RVSI, RV end systolic area, RV end diastolic area, TAPSE, S'RVFAC, E', and A'.

[0206] B. Clinical Events Time from enrollment to the first occurrence of a clinical event through week 12 will be recorded. These clinical events include hospitalization for HF, resumption of intravenous diuretics for ≥48 hours, resumption of intravenous inotropes for ≥48 hours, initiation of a PDE5 inhibitor, need for RVAD / TAH, need for RRT, and death.

[0207] C. Laboratory Testing Blood Work: Blood work will be performed at every visit (Visits 1-6) and will include hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and platelet count.

[0208] Clinical Chemistry: Clinical chemistry tests will be performed at every visit (Visits 1-6) and include AST / ALT, alkaline phosphatase, total and direct bilirubin, LDH; creatinine, BUN; uric acid; glucose; cholesterol, triglycerides; sodium, potassium, chloride, calcium; and protein and albumin.

[0209] GFR: GFR is estimated based on serum creatinine level.

[0210] Pregnancy Testing: A serum pregnancy test for females of childbearing potential will be performed if pregnancy is suspected during Visits 1-6.

[0211] D. Biomarkers and Genetic Evaluation In addition to NT-proBNP, additional circulating biomarkers may be analyzed, such as IL-6, TNF-α, hsCRP, ET-1, galectin-3, GDF-15, interleukin-1 receptor ST2, NGAL, copeptin, high-sensitivity cardiac troponin Ths-cTnT, cystatin-C, and osteopontin.

[0212] 6. Definition of Safety A. Adverse Events An AE is any adverse change, i.e., any untoward and unintended manifestation, including abnormal laboratory findings, symptoms, or disease, that occurs in a patient. AEs include the following: -Aggravation of existing diseases. · An increase in the frequency or intensity of an existing episodic illness or medical condition. · Any disease or condition that is detected or diagnosed, which may have been present before treatment began. · Persistent disease or symptoms that are present at the time treatment is started and worsen after initiation. Abnormal evaluations, e.g., changes in physical exam, ECG findings, if they represent clinically significant findings that were not present at the start of treatment or that worsened over the course of treatment. Laboratory abnormalities if they represent clinically significant findings, symptomatic or non-syndromic, that were not present at the initiation of treatment or that worsened during the course of treatment or that led to dose reduction, interruption, or permanent discontinuation.

[0213] A treatment-emergent AE is any AE that is temporally related to the use of a treatment (from the start of treatment up to 30 days after treatment is discontinued). Overdosage, misuse, and abuse of a treatment may be considered an AE.

[0214] The intensity of clinical AEs will be graded on a 3-point scale—mild, moderate, or severe. The three categories of intensity are defined as follows: Mild: The event may be noticeable to the patient. The event does not affect daily activities and usually does not require intervention. Moderate: The event may cause discomfort to the patient. Performance of daily activities may be affected and intervention may be required. Severe: The event can cause significant discomfort and usually interferes with daily activities. The patient may be unable to continue and treatment or intervention is usually required.

[0215] Each AE will be evaluated for whether there is a reasonable possibility of a causal relationship to the treatment. An AE will be defined as related to the dosing design or protocol-defined procedures if it appears to have a reasonable possibility of a causal relationship to either the design or protocol-defined procedures. An example would be discontinuing a patient's previous treatment during a washout period, resulting in progression of the underlying disease.

[0216] Tables 13-15 provide an overall overview of adverse events (Table 11), AEs leading to treatment discontinuation for SS (Table 12), and AEs frequently reported for SS in ≥10% of treatment groups.

[0217] [Table 16]

[0218] [Table 17]

[0219] [Table 18]

[0220] These results indicate that macitentan has a favorable safety profile in these post-LVAD implant patients. These results indicate that macitentan was well tolerated in the early post-LVAD population. Notably, the AEs reported were either primarily related to the underlying disease of the study population or were consistent with those observed in other studies of macitentan-treated subjects with PAH.

[0221] B. Serious Adverse Events An SAE is defined by the ICH guidelines as any AE that meets at least one of the following criteria: ·Lethal. Life-threatening: Refers to an event in which the patient was at risk of death at the time of the event. Life-threatening does not refer to an event that, if more severe, could have resulted in death. -Hospitalisation or an extension of an existing hospital stay is required. Leading to permanent or significant impairment / incapacity. · Congenital or birth defects. Medically significant: Refers to a significant medical event that is not immediately fatal, life-threatening, or requiring hospitalization, but may be considered an SAE if it endangers the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition above.

[0222] However, a complication that occurs during hospitalization is an AE or SAE (eg, if the complication prolongs hospitalization).

[0223] Table 16 shows serious AEs in two or more patients in any treatment group.

[0224] [Table 19]

[0225] Overall, similar percentages of patients in each treatment group experienced serious adverse events. See Table 15.

[0226] 7.Statistical methods The statistical analysis plan provides complete details of the analyses, data presentation, and algorithms used to derive the data.

[0227] A. Analysis Set Screened Analysis Set: This analysis set includes all patients who were screened and received a screening number.

[0228] Safety Set (SS): The SS includes all patients who receive at least one dose of drug during the treatment period.

[0229] Full Analysis Set (FAS): The FAS includes all randomized patients.

[0230] Modified Full Analysis Set (FAS): The modified FAS includes all patients in the FAS who received at least one treatment dose during the treatment period and who have a baseline and at least one post-baseline PVR measurement.

[0231] Per Protocol Set (PPS): The PPS includes all patients in the FAS without major deviations from the protocol that could affect the primary analysis of the primary efficacy variable.

[0232] The primary efficacy analysis will be performed on the FAS based on randomized treatment. Secondary and exploratory efficacy analyses will also be performed on the FAS. Sensitivity analyses will be performed on the modified FAS for the primary and selected secondary efficacy endpoints. Safety analyses related to the double-blind treatment period will be performed on the SS based on treatment received. Patient listings will be based on the SS unless otherwise stated. Patient disposition will be described for the screened analysis set. See Table 17.

[0233] [Table 20]

[0234] B. Variables The primary efficacy variable was the PVR ratio at week 12 to baseline. PVR [WU] was calculated as (mPAP-PAWP) / CO.

[0235] Secondary efficacy variables were the change from baseline to week 12 in the following: mRAP (mmHg) mPAP (mmHg) PAWP (mmHg) Cl(L / min / m 2 ), BSA(m 2 ) = 0.007184 x weight 0.425 (kg) x height 0.725 Calculated as (cm). Calculated as TPR(WU), mPAP / CO. SVO2(%) NT-proBNP (pmol / L) ·WHO FC(I-IV).

[0236] Exploratory efficacy variables included: Echocardiographic variables including 2D global RVLS, RVSI, RV end systolic area, RV end diastolic area, TAPSE, S', RVFAC, and E', A'. Clinical events, including hospitalization for HF, resumption of intravenous diuretics for ≥48 hours, resumption of intravenous inotropes for ≥48 hours, initiation of PDE5 inhibitors, need for RVAD / TAH, need for RRT, and death. Length of stay after index hospitalization for heart failure. - Change in GFR from baseline to week 12.

[0237] Safety variables include: Treatment-emergent AEs up to 30 days after treatment discontinuation. -AEs leading to early discontinuation of treatment. Death up to 30 days after treatment discontinuation. Treatment-emergent SAEs up to 30 days after treatment discontinuation. Change in vital signs from baseline to EOT. Proportion of patients with treatment-emergent ALT and / or AST abnormalities from baseline to EOT, categorized as follows: - 3 × ULN or higher; - ≥3×ULN and <5×ULN; - ≥ 5 × ULN and < 8 × ULN; -8×ULN or better. Proportion of patients with ALT and / or AST abnormalities ≥3×ULN in combination with total bilirubin ≥2×ULN from baseline to EOT. Proportion of patients with treatment-emergent hemoglobin abnormalities compared to baseline by EOT, categorized as follows: -Below 8.0 g / dL Less than -10.0 g / dL. Significant laboratory abnormalities occurring during treatment up to EOT.

[0238] The overall type I error was α = 0.025 (one-sided). The type II error was set at 0.20 and the power was set at 80%.

[0239] C. Analysis of Primary Efficacy Variables The null hypothesis is that the mean PVR ratio is the same in the macitentan and placebo groups. An alternative hypothesis is that the mean PVR ratio is lower in the macitentan group compared to the placebo group.

[0240] If PVR cannot be calculated due to missing PAWP, but mPAP and CO are available for the same visit, one of the following applies: 1. If PAWP is missing at both baseline and post-baseline, the treatment group median will be imputed (based on the FAS). 2. If PAWP is missing at either baseline or post-baseline, the patient's available PAWP will be imputed.

[0241] This assignment is based on the clinical assumption that macitentan has no effect on PAWP.

[0242] Baseline: Patients without a baseline PVR measurement are excluded from the analysis.

[0243] Post-Baseline: For patients with a post-baseline PVR measurement obtained before Week 12, the last post-baseline PVR measurement will be carried forward.

[0244] If a patient does not have a post-baseline PVR measurement, the week 12 ratio to baseline PVR will be imputed using the treatment arm median based on the FAS.

[0245] Alternative imputation methods for PVR values ​​will be considered as sensitivity analyses (eg, multiple imputation).

[0246] (i) Main analysis The primary efficacy analysis will be performed on the FAS. PVR will be summarized by time point and treatment group using descriptive statistics and geometric means and CVs. The ratio of week 12 to baseline PVR will also be summarized.

[0247] Ratios at week 12 to baseline PVR are log-transformed (base e) and analyzed using analysis of covariance (ANCOVA) with factors for treatment group and covariates for baseline log PVR (macitentan vs. placebo). Treatment group differences (log scale) and their 95% confidence intervals (two-sided) are estimated based on the model. Geometric mean ratios (GMR; macitentan vs. placebo) and their 95% confidence intervals are obtained by exponentiation. If all 95% confidence intervals are less than 1, the null hypothesis is rejected.

[0248] The treatment effect is expressed as (GMR-1) x 100%, with negative values ​​indicating a decrease in PVR in the macitentan group compared to the placebo group.

[0249] The log transformation of PVR is justified by the fact that the ratio to baseline follows a normal distribution more closely after log transformation. In addition, the mean absolute change from baseline on the log scale can be converted to a (geometric) mean ratio by exponentiation.

[0250] (ii) Support / sensitivity analysis The primary efficacy endpoint and selected secondary efficacy endpoints will be analyzed against the modified FAS as a sensitivity analysis.

[0251] (iii) Analysis of other efficacy variables Secondary efficacy analyses will be performed on the FAS with 95% CL at α=0.025 (one-sided). No correction for multiple testing will be applied to these analyses.

[0252] Changes in pressure-volume variables (e.g., mRAP, mPAP, PAWP, CI TPR) and SVO2 from baseline to week 12 will be summarized and analyzed but not log-transformed.

[0253] NT-proBNP will be summarized by time point and treatment group using descriptive statistics and geometric means and CVs. Week 12 ratios to baseline NT-proBNP will be summarized as well. NT-proBNP ratios to baseline will be log-transformed and analyzed using ANCOVA with covariates for treatment group and baseline log NT-proBNP.

[0254] WHO FC will be summarized by time point and treatment group using frequency tables. Changes from baseline in WHO FC will be dichotomized as worsening (i.e., change >0) versus no change or improvement (i.e., change ≤0). Worsening will be analyzed using a logistic regression model with covariates for treatment group and WHO FC.

[0255] (iv) Analysis of exploratory efficacy variables Exploratory efficacy analyses will be performed on the FAS with α=0.025 (one-sided) using 95% CL.

[0256] Echocardiographic variables including TAPSE, S', RVFAC, E', A', RVLS, RV area and RVSI are summarized by treatment and time point (baseline, Week 12 / EOT) using descriptive statistics (n, mean, SD, median, Q1, Q3, and range). Changes in these variables from baseline to Week 12 / EOT are similarly summarized and analyzed using ANCOVA with factors for treatment and the covariates baseline log PVR and baseline TAPSE, S', RVFAC, E', A', RVLS, RV area and RVSI, respectively. Adjusted treatment effects and their 95% CIs are shown.

[0257] Clinical events, including hospitalization for HF, resumption of intravenous diuretics for ≥48 hours, resumption of intravenous inotropes for ≥48 hours, need for RVAD / TAH, need for RRT, and death, will be summarized by treatment group and time-to-event treatment differences will be analyzed using the log-rank test.

[0258] Length of hospital stay, excluding rehabilitation stays, will be pooled by treatment group and analyzed using analysis of covariance with treatment and baseline PVR in the model.

[0259] GFR will be summarized by treatment and time point (baseline, week 12 / EOT) using descriptive statistics (n, mean, SD, median, Q1, Q3, and range). Changes from baseline to week 12 are similarly summarized. Changes from baseline in GFR are analyzed using ANCOVA with factors for treatment and the covariates baseline log PVR and baseline GFR. Adjusted treatment effects and their 95% confidence intervals are shown.

[0260] (vi) Analysis of safety variables The safety analysis described below is performed on SS.

[0261] (vii) Adverse events A treatment-emergent AE is any AE that is temporally related to the use of a therapy. The numbers and percentages of patients who experienced at least one treatment-emergent AE and SAE are tabulated by treatment group and by: MedDRA SOCs and individual preferred terms within each SOC, in order of decreasing incidence. · Frequency of patients having events coded with the same preferred term, in descending order of incidence.

[0262] In addition, treatment-emergent AEs and SAEs are tabulated by severity and relationship to treatment as described above. AEs leading to premature discontinuation of treatment and death are also summarized as above.

[0263] A list will be provided for all reported AEs, including SAEs. In addition, separate lists will be provided for SAEs, AEs leading to premature discontinuation of treatment, and AEs leading to death.

[0264] D. Laboratory Variables Descriptive summary statistics by visit will be provided for observed values ​​and absolute changes from baseline for both hematology and clinical chemistry laboratory tests. To minimize missing data and allow for unscheduled visits, all recorded assessments up to EOT+30 days will be assigned to the most appropriate visit time point according to the best fitting time window for that assessment.

[0265] The laboratory variables were as follows: Haematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, platelet count. ·Blood Chemistry: AST, ALT, Alkaline Phosphatase, Total & Direct Bilirubin, LDH, Creatinine, BUN, Uric Acid, Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride, Calcium, Protein, Albumin.

[0266] The number and percentage of patients with liver function test abnormalities will be tabulated by treatment group. The number and percentage of patients with hemoglobin abnormalities will be tabulated by treatment group.

[0267] Blood pressure (i.e., DBP and SBP), pulse rate, and weight (in kg) will be summarized at each visit using the usual locations and summary statistics by treatment group for both absolute values ​​and change from baseline. Patients with no post-baseline values ​​available will be excluded from the analysis of change from baseline in SS.

[0268] Example 2: Administration of high doses of macitentan This was a single-sequence, open-label, single-center, phase 1 study in healthy male subjects. The study evaluated the effect of macitentan 75 mg qd. The study included a screening phase 21 days prior to the first macitentan dose, followed by an open-label treatment phase. No randomization was used, and subjects received the same treatment.

[0269] A. Target Population Twenty-nine subjects were enrolled: 11 subjects were enrolled under the initial protocol, which did not include an escalation of the dose of macitentan treatment; 18 subjects were enrolled under a modified protocol, which included an escalation of the dose of macitentan treatment.

[0270] B. Study Treatment B.1. Study treatment not including dose escalation of macitentan Dosing of 75 mg qd macitentan was initiated on day 1. Macitentan was administered daily between 8 am and 11 am in 240 ml of non-carbonated water. Thus, one 75 mg macitentan film-coated tablet was administered as multiple qd oral doses under fed conditions.

[0271] Subjects received a standardized meal on dosing days when macitentan was administered in the fed state at the following time points: -Dinner up to 10 hours before the next day's macitentan dose. - Breakfast within 30 minutes before macitentan administration (Days 1-9 and 11-12). Lunch approximately 4 hours after macitentan administration. A light meal approximately 7 hours after administering macitentan. -Dinner approximately 10 hours after macitentan administration.

[0272] Subjects were scheduled to receive 75 mg of macitentan for 15 days, however, the study was stopped on the morning of day 8, when subjects had received seven doses of 75 mg of macitentan.

[0273] B.2. Study treatment involving dose escalation of macitentan Macitentan was administered in a dose-escalating regimen with 240 mL of noncarbonated water between 8:00 and 11:00 AM. One macitentan film-coated tablet (10 mg, 37.5 mg, or 75 mg) was administered as multiple qd oral doses under fed conditions on days 1-9 and 11-12, and under fasted conditions on days 10 and 13. The dose-escalating regimen consisted of 2 qd doses of 10 mg macitentan and 3 qd doses of 37.5 mg macitentan, followed by 8 qd doses of 75 mg macitentan. On days 4, 3, 10, and 13 (i.e., days when administration occurred under fasting conditions), no fluid intake, other than water, was permitted from 1 hour before to 1 hour after macitentan dosing.

[0274] Subjects received a standardized meal on dosing days when macitentan was administered in the fed state at the following time points: -Dinner up to 10 hours before the next day's macitentan dose. - Breakfast within 30 minutes before macitentan administration (Days 1-9 and 11-12). Lunch approximately 4 hours after macitentan administration. A light meal approximately 7 hours after administering macitentan. -Dinner approximately 10 hours after macitentan administration.

[0275] C. Safety measurements Tables 18-20 summarize the frequency and timing of safety measurements.

[0276] [Table 21]

[0277] [Table 22]

[0278] [Table 23]

[0279] The tests in Table 21 were carried out.

[0280] [Table 24]

[0281] D. Safety analysis All reported AEs occurring during the treatment phase were included in the analysis. Effects on cardiovascular variables were evaluated and the following variables were collected: PR (ms), QRS (ms), QT (ms), QTcB (ms), QTcF (ms), heart rate (bpm), and RR. Normal ranges for vital signs were defined as follows: Systolic blood pressure: 100~140mmHg Diastolic blood pressure: 60~90mmHg Pulse rate: 45~90bpm Breathing rate: 8-20 per minute Body temperature: 35.0℃~37.5℃

[0282] An AE is any medical occurrence, i.e., any unintended sign (including abnormal findings), symptom, or disease that is temporally associated with the use of macitentan. A treatment-emergent AE is any event that is new onset or worsening in severity from the baseline condition. All AEs will be assessed using the following: Related: There is a plausible causal relationship between macitentan administration and the AE. -Relevant areas: There is no plausible causal relationship between macitentan administration and the AE.

[0283] AE severity grading was performed using the following general categorical descriptors: Mild: Perceived symptoms that are easily tolerated, cause minimal discomfort, and do not interfere with daily activities. Moderate: There is enough discomfort to cause interference with usual activities. Severe: Extreme distress causing significant impairment or inability to function. Normal daily activities are interfered with.

[0284] E. Results AEs for subjects in the first cohort with and without dose escalation were then analyzed. See Table 22.

[0285] [Table 25]

[0286] AEs were reported from day 2 onwards and were mainly mild. Most of the AEs resolved 4 days after discontinuation of macitentan. No clinically significant changes were reported in vital signs, ECG and laboratory parameters. Furthermore, a decrease in hemoglobin was observed within the expected range (no decrease of >2 g / dL).

[0287] In summary, the data indicate that the introduction of the dose-escalation regimen improved the tolerability of 75 mg macitentan. All subjects completed treatment with macitentan in the dose-escalation regimen cohort.

Claims

1. 1. Macitentan for use in the treatment of pulmonary hypertension in a left ventricular assist device (LVAD) implanted patient comprising administering an amount of macitentan, wherein said LVAD implantation is within about 90 days prior to administering said macitentan.

2. 2. Macitentan for use according to claim 1, wherein after implantation of the LVAD and prior to initiating treatment with macitentan, the patient has a resting mean pulmonary artery pressure (mPAP) of 25 mmHg or more, a pulmonary artery wedge pressure (PAWP) of 18 mmHg or less, and a pulmonary vascular resistance (PVR) of more than 3 WU (Wood's units).

3. 3. Macitentan for use according to claim 1 or 2, wherein within about 14 days prior to the start of treatment with macitentan, the patient has a mean pulmonary artery pressure (mPAP) at rest of 25 mmHg or more, a pulmonary artery wedge pressure (PAWP) of 18 mmHg or less, and a pulmonary vascular resistance (PVR) of more than 3 WU (Wood's units).

4. Macitentan for use according to any one of claims 1 to 3, wherein said LVAD implantation is more than 45 days to about 90 days prior to initiating treatment with macitentan.

5. Macitentan for use according to any one of claims 1 to 4, wherein the patient does not have Child-Pugh class C liver disease.

6. Macitentan for use according to any one of claims 1 to 5, wherein the method reduces PVR.

7. 7. The method of claim 6, wherein the PVR is reduced by at least about 10% compared to a patient with a comparable level of disease diagnosis not receiving treatment with macitentan.

8. Macitentan for use according to any one of claims 1 to 7, wherein after LVAD implantation and prior to initiating treatment with macitentan, the patient has a transpulmonary gradient (TPG) of greater than about 12 mmHg to about 45 mmHg.

9. Macitentan for use according to any one of claims 1 to 8, wherein said macitentan is administered orally once daily in the form of a tablet.

10. Macitentan for use according to any one of claims 1 to 9, wherein the amount of macitentan is from about 60 mg to about 90 mg.

11. 11. The method of claim 10, wherein the amount of macitentan is titrated from 10 mg per day, subsequently to an amount of about 25 mg to about 50 mg per day, subsequently to an amount of about 60 mg to about 90 mg per day.

12. 12. The method of claim 11, wherein said 10 mg of macitentan per day is administered for about 15 to about 45 days.

13. 12. The method of claim 11, wherein said 25 mg to about 50 mg of macitentan per day is administered for about 15 to about 45 days.

14. Macitentan for use according to any one of claims 10 to 13, wherein the amount of macitentan is about 75 mg.

15. Macitentan for use according to any one of claims 10 to 14, wherein said macitentan is administered orally once daily in the form of a tablet.

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