Method for treating pulmonary arterial hypertension

Abstract

To provide an agent for the treatment of a patient suffering from pulmonary arterial hypertension (PAH).SOLUTION: An agent for initial triple combination therapy with macitentan, tadalafil, and selexipag for treating a patient having PAH, the agent containing macitentan, tadalafil, and selexipag, wherein the patient has, at initiation of the initial triple combination therapy, a resting mean pulmonary arterial pressure (mPAP) of about 25 mmHg or more, a mean pulmonary arterial wedge pressure (PAWP) of about 15 mmHg or less, and a pulmonary vascular resistance (PVR) of about 240 dyne sec / cm5 or more, and wherein the macitentan and the tadalafil are administered on day 1, and the selexipag is administered within 4 weeks.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 076,149, filed September 9, 2020, U.S. Provisional Patent Application No. 63 / 023,452, filed May 12, 2020, and U.S. Provisional Patent Application No. 62 / 941,910, filed November 29, 2019, the disclosures of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THE INVENTION The present disclosure relates to methods of treating pulmonary arterial hypertension (PAH), including methods of reducing the risk of disease progression in patients with PAH, comprising administering to a patient in need thereof an initial triple therapy regimen of an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 (PDE-5) inhibitor, and a prostacyclin receptor agonist (IP receptor agonist). [Background technology]

[0003] Pulmonary arterial hypertension (PAH) is a serious chronic disease of the pulmonary circulation with diverse etiologies and pathogenetic mechanisms. It is characterized by a progressive increase in pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP), as well as a decrease in cardiac output (CO), ultimately leading to right heart failure and death. The complex pathogenesis of PAH involves dysfunction of three major pathways: the prostacyclin pathway, the endothelin pathway, and the nitric oxide pathway.

[0004] PAH is characterized by a hemodynamically normal pulmonary artery occlusion pressure (or left ventricular end-diastolic pressure) of 15 mmHg or less and a PVR of 240 dyne seconds / cm 5(or 3 Wood units) and a resting mean pulmonary artery pressure of 25 mmHg or greater. PAH is further classified clinically into four subclasses based on clinical findings, pathology, pathophysiology, prognosis, and treatment approach: 1) without a demonstrable cause (idiopathic), 2) due to familial background (genetic), 3) as a result of the use of certain drugs and toxins, and 4) as a result of connective tissue disease, HIV infection, portal hypertension, congenital heart disease, or schistosomiasis.

[0005] Current ESC / ERS guidelines for treating PAH recommend initial dual or sequential combination therapy in patients with an inadequate clinical response to initial monotherapy. In high-risk patients, initial combination therapy including intravenous epoprostenol is recommended. More recently, the "Proceedings from the 6th World Symposium on Pulmonary Hypertension" suggested initial oral combination therapy with an endothelin receptor antagonist (ERA) and a type 5 phosphodiesterase inhibitor (PDE-5i) in patients with a low or moderate risk of death within 1 year, and initial combination therapy including intravenous prostacyclin in high-risk patients. Summary of the Invention [Means for solving the problem]

[0006] In some embodiments, the present invention relates to methods for reducing the risk of disease progression in patients with pulmonary arterial hypertension (PAH), comprising administering to a patient in need thereof an initial triple therapy regimen of an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 (PDE-5) inhibitor, and a prostacyclin receptor agonist (IP receptor agonist). [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 is a subject-level schematic diagram of study duration. [Figure 2] FIG. 1 is a schematic diagram showing planned durations at test levels. [Figure 3] Scatter plot of change (relative to baseline) in PVR from baseline to week 26 (analysis set: full analysis set). [Figure 4] Forest plot of ANCOVA. PVR ratio at week 26 relative to baseline by subgroup (analysis set: full analysis set). In the figure, the solid vertical line indicates the overall treatment effect. The size of the subgroup markers is based on the number of subjects per group. P values ​​reflect a treatment-by-subgroup interaction test for the expanded main model, which includes stratification factors and baseline as covariates, adding the effect of the subgroup variable and its interaction with treatment. * = p-value for interaction; Sel = selexipag; Plc = placebo. [Figure 5] FIG. 1 is a scatter plot of change (relative to baseline) in 6MWD from baseline to week 26. [Figure 6] Line graph showing time to first disease progression event from randomization to EOMOP+7 days (analysis set: full analysis set). In the figure, subjects are censored at EOMOP+7 days or end of study, whichever comes first. Graph is truncated when less than 10% of subjects are at risk in both treatment groups. p-values ​​are based on stratified log-rank test. Hazard ratio estimates obtained from stratified Cox regression with Wald confidence limits. Analyses are stratified by WHO functional class at baseline and geographic region. [Figure 7] 1 is a line graph showing the time to first disease progression event until first treatment discontinuation of any of the three study drugs in the treatment analysis. In this figure, subjects were censored at EOMOP + 7 days, or at the time of first treatment discontinuation of any of the three study drugs + 7 days, or EOS, whichever came first. [Figure 8] Line graph showing time to death or hospitalization due to PAH up to EOMOP (full analysis set). [Figure 8A]Line graphs showing time to death due to PAH or hospitalization due to worsening PAH up to EOMOP+7 days (full analysis set). In the figure, subjects were censored at least at EOMOP+7 days or EOS, whichever came first. Graphs are truncated when less than 10% of subjects are at risk in both treatment groups. p-values ​​are based on stratified log-rank tests. Hazard ratio estimates obtained from Cox regression with Wald confidence limits. Analyses are stratified by WHO functional class at baseline and geographic region. [Figure 9] Line graph showing time to death or first hospitalization (all causes) until EOMOP (full analysis set). [Figure 9A] Line graph showing time to death or first hospitalization (all causes) by EOMOP+7 days (full analysis set). In the figure, subjects were censored at least at EOMOP+7 days or EOS, whichever came first. Graphs are truncated when less than 10% of subjects are at risk in both treatment groups. p-values ​​are based on stratified log-rank tests. Hazard ratio estimates obtained from Cox regression with Wald confidence limits. Analyses are stratified by WHO functional class at baseline and geographic region. [Figure 10] 1 is a line graph showing time to death (all causes) from randomization to EOMOP+7 days for the full analysis set. [Figure 11] Line graph of time to disease progression by median PVR at baseline up to EOMOP+7 days for patients with a PVR <888 dynes·sec / cm5. [Figure 12] Line graph of time to disease progression by median PVR at baseline up to EOMOP+7 days for patients with a PVR ≥ 888 dynes·sec / cm5. [Figure 13] 1 is a line graph of time to disease progression by mPAP at baseline up to EOMOP+7 days for patients with mPAP<52 mmHg. [Figure 14]1 is a line graph of time to disease progression by mPAP at baseline up to EOMOP+7 days for patients with mPAP≧52 mmHg. [Figure 15] 1 is a line graph of time to disease progression by median mRAP at baseline up to EOMOP+7 days for patients with mRAP<8 mmHg. [Figure 16] 1 is a line graph of time to disease progression by median RPAP up to EOMOP+7 days for patients with mRAP≧8 mmHg. [Figure 17] FIG. 10 is a line graph of time to disease progression by CI at baseline up to EOMOP+7 days for patients with a CI≧2.1 L / min / m2. [Figure 18] FIG. 10 is a line graph of time to disease progression by CI at baseline up to EOMOP+7 days for patients with a CI<2.1 L / min / m2. [Figure 19] 1 is a line graph of time to disease progression by median NT-proBNP at baseline up to EOMOP+7 days for patients with NT-proBNP<1360 ng / L. [Figure 20] 1 is a line graph of time to disease progression by median NT-proBNP at baseline up to EOMOP+7 days for patients with NT-proBNP≧1360 ng / L. [Figure 21] Schematic diagram of the study design showing patient disposition to EOS. *Four patients did not initiate selexipag and were assigned to the initial dual therapy arm for safety analysis. **One patient did not receive either treatment and was therefore excluded from the safety analysis population. †120 patients received placebo. [Figure 22]Line graph showing time to disease progression by EOS. In the figure, th = therapy. Subjects were censored at EOS. Graphs are truncated when <10% of subjects were at risk in both treatment arms. p-values ​​are based on a stratified log-rank test. Hazard ratio estimates obtained from Cox regression stratified by WHO functional class at baseline and geographic region. Triplet therapy (N=123), doublet therapy (N=124). [Figure 23] Line graph showing time to death by EOMOP. In the figure, th = therapy. Subjects were censored at EOMOP or end of study, whichever came first. Graphs are truncated when less than 10% of subjects were at risk in both treatment arms. p-values ​​are based on a stratified log-rank test. Hazard ratio estimates obtained from stratified Cox regression with Wald confidence limit analysis stratified by WHO functional class at baseline and geographic region. Triplet therapy (N=123), doublet therapy (N=124). [Figure 24] Line graph showing time to death by EOS. In the figure, th = therapy. Subjects were censored at EOS. Graphs are truncated when <10% of subjects were at risk in both treatment arms. p-values ​​are based on a stratified log-rank test. Hazard ratio estimates obtained from stratified Cox regression with Wald confidence limit analysis stratified by WHO functional class at baseline and geographic region. Triplet therapy (N=123), doublet therapy (N=124). [Figure 25] 1 is a bar graph showing disease progression events (ALL, primary and subsequent) up to EOMOP+7 days. [Figure 26] 1 is a bar graph showing disease progression events (ALL, first and subsequent) until EOS. DETAILED DESCRIPTION OF THE INVENTION

[0008] 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.

[0009] When values ​​are expressed as approximations, by use of the descriptors "about" or "substantially," it is understood that the particular value forms another embodiment. Generally, 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 and should be interpreted in the specific context in which it is used based on its function. Those skilled in the art may interpret this as merely formal. In some cases, the number of significant figures used for a particular value may be one non-limiting method 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. Where present, all ranges are inclusive and combinable; that is, reference to values ​​stated in ranges includes all values ​​within that range.

[0010] When lists are presented, it is to be understood that each individual element 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."

[0011] It is understood that certain features of the invention, which 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 individual embodiment is deemed combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, different features of the invention that are described in the context of a single embodiment for simplicity of description may also be provided separately or in any subcombination. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this description is intended to serve as a basis for prior limitation on the use of exclusive terminology, such as "only," "only," and the like, or the use of a "negative" limitation in connection with the recitation of claim elements. 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 an independent embodiment in itself.

[0012] 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.

[0013] The terms "subject" and "patient" are used interchangeably herein to refer to a human who has been the object of treatment, observation, or experiment. Preferably, a patient is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented.

[0014] The term "amount," as used herein, means the amount of an active compound or pharmaceutical ingredient that elicits the biological or pharmaceutical response in humans that is desired by an examiner, physician, or other clinician, including the alleviation of one or more symptoms of the disease or disorder being treated.

[0015] The term "disease progression," as used herein, is classified by many factors as will be understood by those of skill in the art. In some embodiments, disease is progressing when death occurs. In other embodiments, disease is progressing when a patient is hospitalized due to worsening PAH. In further embodiments, disease is progressing when a patient's PAH worsens and they need to begin administering a medication to reduce the worsening of PAH, such as prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist. In yet other embodiments, disease is considered to be progressing when a patient has clinical deterioration.

[0016] The term "clinical deterioration," as used herein, refers to a post-baseline decline in 6MWD of greater than 15% from the best 6MWD obtained at or after baseline, accompanied by WHO functional class III or IV (either condition confirmed on two consecutive post-baseline assessments separated by 1 to 21 days).

[0017] Initial triple therapy The methods described herein relate to reducing the risk of disease progression in patients with pulmonary arterial hypertension (PAH), comprising administering to a patient in need thereof an initial triple therapy regimen of an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 (PDE-5) inhibitor, and a prostacyclin receptor agonist (IP receptor agonist).

[0018] As described herein, initial triple therapy reduces a patient's risk of disease progression, including, for example, the risk of hospitalization. In certain embodiments, the risk is reduced relative to a patient population with PAH, e.g., a population with approximately the same level of disease progression as patients receiving initial dual therapy of an ERA and a PDE-5 inhibitor (i.e., without an IP receptor agonist). Such a relative analysis is disclosed in Example 1. In some embodiments, the method reduces the risk of disease progression by at least about 20% relative to a patient population receiving initial dual therapy. In other embodiments, the method reduces the risk of disease progression by about 20% to about 50%, more preferably about 30% to about 40%, compared to initial dual therapy. In further embodiments, the method reduces the risk of disease progression by about 25% to about 45%, about 30% to about 45%, about 35% to about 50%, or about 40% to about 50%, compared to initial dual therapy. In yet other embodiments, the method reduces the risk of disease progression by at least about 30% (including about 30%) relative to initial dual therapy. In yet other embodiments, the method reduces the risk of disease progression by at least about 40% (including about 40%) relative to initial dual therapy. In yet other embodiments, the method reduces the risk of disease progression by at least about 50% (including about 50%) relative to initial dual therapy.

[0019] The term "triple therapy" as used herein refers to the treatment protocol disclosed herein that uses ERA, PDE-5 inhibitor and IP receptor agonist.The ERA, PDE-5 inhibitor and IP receptor agonist can be administered simultaneously or at different times (for example, sequentially) in the treatment method.Similarly, the term "double therapy" refers to the treatment protocol and method in the art that uses ERA and PDE-5 inhibitor without IP receptor agonist.

[0020] The term "initial" when referring to "triple therapy" refers to prior combination treatment with an ERA, a PDE-5 inhibitor, and an IP receptor agonist. In "initial" triple therapy (or "initial" dual therapy), each component is initiated within a short time period from each other, and then each is administered according to the prescription of a doctor or other medical professional. For example, in the initial triple therapy, each of the ERA, the PDE-5 inhibitor, and the IP receptor agonist can be initiated on the same day. In other embodiments, treatment with each component can be initiated within a short time period from each other, for example, within 1 week, 2 weeks, 3 weeks, or 4 weeks from each other. The order and timing of the initiation of each component (in the case of initial triple therapy or initial dual therapy) can be changed, for example, based on the instructions of a doctor or other medical professional. In some embodiments, one or two of the IP receptor agonist, ERA, or PDE-5 inhibitor are administered on day 1 of initiation of combination therapy, and one or two of the IP receptor agonist, ERA, or PDE-5 inhibitor are administered within about one week to about three weeks after day 1. For example, as in the Examples section herein, the ERA and PDE-5 inhibitor are initiated on day 1, and the IP receptor agonist is initiated on day 15 ± 3 days.

[0021] The term "initial" when referring to "triple therapy" is in contrast to sequential therapy, in which one or two of the components are added based on the patient's clinical response to previous treatment, such as monotherapy or double therapy. For example, initial triple therapy with an ERA, PDE-5, and IP receptor agonist includes a prior treatment regimen containing all three components, as opposed to sequential triple therapy, in which an IP receptor agonist is added to the initial double therapy with an ERA and a PDE-5 inhibitor after the patient is assessed as having an inadequate clinical response to the initial double therapy with an ERA and a PDE-5 inhibitor. Initial triple therapy can also be administered independently of the patient's clinical response to monotherapy with one of the components, such as an ERA or a PDE-5 inhibitor. Similarly, initial double therapy includes prior treatment with two of the components, usually an ERA and a PDE-5 inhibitor, as opposed to sequential therapy, in which one component is added based on the patient's clinical response to previous initial monotherapy with one of the other components.

[0022] As used herein and in the art, the terms "pulmonary arterial hypertension" and "PAH" are used interchangeably to define a condition in which a patient experiences high blood pressure in the lungs. PAH develops when the diameter of the very small arteries throughout the lungs narrows, thereby increasing resistance to blood flow through the lungs. In some embodiments, the underlying cause of this narrowing is unknown (i.e., idiopathic pulmonary hypertension). 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, liver hypertension, HIV, infections (schistosomiasis), and sickle cell anemia; (iv) PAH caused by rare blood conditions (e.g., pulmonary capillary hemangiomatosis); or (v) infantile PAH (persistent pulmonary hypertension of the newborn). The severity of a patient's PAH is commonly assessed by a classification system, namely the World Health Organization (WHO) class system. See Table A.

[0023] [Table 1]

[0024] Generally, a higher PAH class indicates a more severe disease state and / or a greater urgency to accurately diagnose the patient and initiate PAH therapy. Thus, the method reduces the risk of a patient progressing from a lower WHO PAH class to a higher WHO PAH class. In some embodiments, the method reduces the risk of a PAH patient progressing from WHO class I to WHO class II, from WHO class I to WHO class III, from WHO class II to WHO class IV, from WHO class II to WHO class III, from WHO class II to WHO class IV, or from WHO class III to WHO class IV.

[0025] The methods may also reduce or further slow PAH disease progression by preventing or limiting PAH-related hospitalization, clinical worsening of PAH, initiation of medications that reduce PAH worsening, or death. In some embodiments, the methods reduce the patient's risk of hospitalization, e.g., due to worsening PAH. In other embodiments, the methods reduce the risk of clinical worsening of PAH. In further embodiments, the methods reduce the risk of patient death. In other embodiments, the methods avoid the need to initiate medications to reduce PAH worsening, such as prostacyclin, prostacyclin analogs, or prostacyclin receptor agonists. For example, Table 13 in the Examples section herein includes assessments of specific disease progression events.

[0026] In certain embodiments, the patient is treatment-naive for PAH, although patients who have previously undergone or are currently undergoing a treatment regimen for PAH may also benefit from the methods disclosed herein. The term "treatment-naive," as used herein, refers to a patient who has not been treated for PAH prior to initiating treatment in accordance with the methods described herein. In some embodiments, the patient has not taken an endothelin receptor antagonist (ERA) prior to initiating treatment in accordance with the methods described herein. In some embodiments, the patient has not taken a type 5 phosphodiesterase (PDE-5) inhibitor prior to initiating treatment in accordance with the methods described herein. In further embodiments, the patient has not taken a prostacyclin receptor agonist (IP receptor agonist) prior to initiating treatment in accordance with the methods described herein. In yet other embodiments, the patient has not taken an endothelin receptor antagonist (ERA), a type 5 phosphodiesterase (PDE-5) inhibitor, or a prostacyclin receptor agonist (IP receptor agonist) prior to initiating treatment in accordance with the methods described herein.

[0027] In other embodiments, the patient is also, or in addition to being treatment-naive, newly diagnosed with PAH. For example, the patient's initial PAH diagnosis occurs within about 6 months of initiating initial triple therapy. In some embodiments, the initial PAH diagnosis occurs within about 6, about 5, about 4, about 3, about 2, or about 1 month of initiating initial triple therapy.

[0028] The methods described herein are also effective in normalizing and / or improving one or more of mean pulmonary arterial hypertension (mPAP), pulmonary artery wedge pressure (PAWP), and pulmonary vascular resistance (PVR). In some embodiments, the methods are effective in reducing abnormally elevated levels of one or more of mPAP or PVR. Thus, mPAP and / or PVR may be elevated at the time of initiation therapy and are reduced using the initial triple therapy methods disclosed herein.

[0029] At the start of these initial triple therapy regimens, patients may have an mPAP of about 25 mmHg or greater at rest. Generally, initial triple therapy regimens can reduce a patient's mPAP levels. In some embodiments, the method reduces mPAP levels by about 5 mmHg, about 10 mmHg, about 15 mmHg, or about 20 mmHg.

[0030] The patient may also have a mean PAWP of about 15 mmHg or less at the start of initial triple therapy, hi some embodiments, the patient may have a mean pulmonary artery wedge pressure of less than about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 mmHg at the start of initial triple therapy.

[0031] Additionally, patients had a plasma count of approximately 240 dynes·sec / cm at the start of initial triple therapy. 5 In other embodiments, patients may have a PVR of about 480 dyne·sec / cm at the start of initial triple therapy. 5 The method reduces the patient's PVR.

[0032] It is also contemplated that the patient will have a 6-minute walk distance (6MWD) of about 50 meters or greater at the start of initial triple therapy. For example, the 6MWD of a newly diagnosed patient typically ranges from about 150 to 500 meters. However, in other embodiments, the patient will have a 6MWD of less than 50 meters at the start of initial therapy. The initial triple therapy disclosed herein is effective in increasing 6MWD levels.

[0033] Endothelin receptor antagonists The methods described herein include administering a predetermined amount of an ERA. The "endothelin receptor antagonist" or "ERA" can be selected by a physician or other healthcare professional. In some embodiments, the ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof. In other embodiments, the ERA is macitentan. In a further embodiment, the ERA is bosentan. In yet another embodiment, the ERA is ambrisentan.

[0034] In some embodiments, the amount of ERA is less than about 15 mg. In further embodiments, the amount of ERA 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 amount of ERA 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 amount of ERA is about 5 to about 15 mg. In yet further embodiments, the amount of ERA is about 10 mg. The amount of ERA may remain the same or may vary throughout the treatment method. In some embodiments, the amount of ERA is increased. In other embodiments, the amount of ERA is decreased. Desirably, the ERA is taken by the patient at the same time during the day. Therefore, in some embodiments, the ERA is taken in the morning. In other embodiments, the ERA is taken at night. The amount of the ERA can be taken as a single dose or divided into two or more doses as determined by a doctor or other medical professional. Preferably, the ERA is taken as a single dose.

[0035] As used herein, unless otherwise specified, the term "macitentan" refers to N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl sulfide of formula (I).

[0036] [ka]

[0037] In other embodiments, macitentan refers to stereoisomers of macitentan, such as enantiomers and diastereomers, in pure or substantially pure form. Macitentan also refers to racemic mixtures thereof. As used herein, "macitentan" also refers to amorphous or crystalline forms of macitentan. In some embodiments, macitentan is in a crystalline form. In other embodiments, macitentan is in an amorphous form. Crystallinity can be determined by one of ordinary 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. As used herein, "macitentan" includes anhydrous forms or hydrates thereof. In certain embodiments, macitentan is in anhydrous form. In other embodiments, macitentan is a hydrate thereof. As used herein, "macitentan" also refers to solvates thereof. Such solvates include molecules of solvent attached to one or more positions of the macitentan molecule via intermolecular forces or chemical bonds. As used herein, "macitentan" may refer to its polymorphs. Such macitentan polymorphs include crystalline forms of the molecule with variations in the crystal lattice of the respective polymorphs. The term "macitentan" also includes pharmaceutically acceptable salts thereof, which can be readily selected by one skilled in the art. The term "pharmaceutically 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, etc., or, if the compound of Formula I is acidic in nature, inorganic bases, such as alkali or alkaline earth bases, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. Macitentan is commercially available, as will be appreciated by those skilled in the art. For example, macitentan is available as OPSUMIT®. Macitentan is an endothelin receptor antagonist and can be prepared according to the process as disclosed in US Pat. No. 7,094,781, which is incorporated herein by reference.

[0038] The present invention also contemplates the administration of macitentan metabolites or pharmaceutically acceptable salts thereof. Desirably, macitentan metabolites are metabolically active compounds. Thus, in certain embodiments, macitentan metabolites are of formulas I-M1 through I-M7. In some embodiments, macitentan metabolites are of formula I-M6, which is also known by the code name ACT-132577 and the International Nonproprietary Drug Name (IND) aprocitentan.

[0039] [ka]

[0040] [ka]

[0041] Prostacyclin receptor agonists The methods described herein also include the administration of a prostacyclin receptor agonist (IP receptor agonist). One skilled in the art can select a particular IP receptor agonist. In some embodiments, the IP receptor agonist is selexipag, 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), or lalinepag, or a pharmaceutically acceptable salt thereof. Furthermore, prostacyclin analogs (or prostanoids) can be substituted for IP receptor agonists in connection with the methods disclosed herein. Examples of prostacyclin analogs (or prostanoids) include epoprostenol, treprostinil, beraprost, or iloprost, or a pharmaceutically acceptable salt thereof. The disclosures herein regarding IP receptor agonists also apply to prostacyclin analogs (or prostanoids).

[0042] Treatment with an IP receptor agonist in an initial triple therapy can be initiated simultaneously with an ERA and a PDE-5 inhibitor, but is generally initiated after initial treatment with a PDE-5 inhibitor and an ERA has begun. Typically, the initial dose of the IP receptor agonist is administered to the patient about 10 to about 20 days after Day 1 of the initial triple therapy. In some embodiments, the initial dose of the IP receptor agonist is administered about 12 to about 18, about 13 to about 17, about 14 to about 16, about 13 to about 18, about 13 to about 17, about 13 to about 16, about 13 to about 15, about 14 to about 18, about 14 to about 17, about 14 to about 16, about 15 to about 18, about 15 to about 17, about 15 to about 16, about 16 to about 18, about 16 to about 17, or about 17 to about 18 days after Day 1 of the initial triple therapy. In another embodiment, the starting dose of the IP receptor agonist is administered about 12 days after day 1 of the initial triple combination therapy. In a further embodiment, the starting dose of the IP receptor agonist is administered about 13 days after day 1 of the initial triple combination therapy. In yet another embodiment, the starting dose of the IP receptor agonist is administered about 14 days after day 1 of the initial triple combination therapy. In an even further embodiment, the starting dose of the IP receptor agonist is administered about 15 days after day 1 of the initial triple combination therapy. In another embodiment, the starting dose of the IP receptor agonist is administered about 16 days after day 1 of the initial triple combination therapy. In a further embodiment, the starting dose of the IP receptor agonist is administered about 17 days after day 1 of the initial triple combination therapy. In yet another embodiment, the starting dose of the IP receptor agonist is administered about 18 days after day 1 of the initial triple combination therapy.

[0043] The amount of IP receptor agonist can be selected by a physician or other medical professional based on factors such as the severity of the disease, the physical characteristics of the patient, etc. In some embodiments, the amount of IP receptor agonist is at least about 10 μg. In some embodiments, the amount of IP receptor agonist is at least about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200, about 3300, about 3400, or about 3500 μg.

[0044] The daily dose of the IP receptor agonist can be administered once a day, twice a day, or three times a day, preferably twice a day. In some embodiments, the dose is administered twice a day. In other embodiments, the dose is administered once before noon and once after noon. In further embodiments, the daily dose is administered once a day.

[0045] Desirably, the dose of IP receptor agonist does not exceed about 1600 μg twice daily, ie, 3200 μg per day. In some embodiments, the twice-daily dose of IP receptor agonist is about 100 to about 3500 μg, about 200 to about 3200, about 200 to about 3000, about 200 to about 2800, about 200 to about 2600, about 200 to about 2400, about 200 to about 2200, about 200 to about 2000, about 200 to about 1800, about 200 to about 1600, about 200 to about 1400, about 200 to about 1200, about 200 to about 1000, about 200 to about 800, about 200 to about 600, about 200 to about 400, about 400 to about 3200, about 400 to about 3000, about 400 to about 2 800, about 400 to about 2600, about 400 to about 2400, about 400 to about 2200, about 400 to about 2000, about 400 to about 1800, about 400 to about 1600, about 400 to about 1400, about 400 to about 1200, about 400 to about 1000, about 400 to about 800, about 400 to about 600, about 600 to about 3200, about 600 to about 3000, about 600 to about 2800, about 600 to about 2600, about 600 to about 2400, about 600 to about 2200, about 600 to about 2000, about 600 to about 1800, about 600 to about 1600, about 600 to about 1400, about 60 0 to about 1200, about 600 to about 1000, about 600 to about 800, about 800 to about 3200, about 800 to about 3000, about 800 to about 2800, about 800 to about 2600, about 800 to about 2400, about 800 to about 2200, about 800 to about 2000, about 800 to about 1800, about 800 to about 1600, about 800 to about 1400, about 800 to about 1200, about 800 to about 1000, about 1000 to about 3200, about 1000 to about 3000, about 1000 to about 2800, about 1000 to about 2600, about 1000 to about 2400, about 1000 to about 2200, about 10 00 to about 2000, about 1000 to about 1800, about 1000 to about 1600, about 1000 to about 1400, about 1000 to about 1200, about 1200 to about 3200, about 1200 to about 3000, about 1200 to about 2800, about 1200 to about 2600, about 1200 to about 2400, about 1200 to about 2200, about 1200 to about 2000, about 1200 to about 1800, about 1200 to about 1600, about 1200 to about 1400, about 1400 to about 3200, about 1400 to about 3000, about 1400 to about 2800, about 1400 to about 2600, about 1400 to about 2400,About 1400 to about 2200, about 1400 to about 2000, about 1400 to about 1800, about 1400 to about 1600, about 1600 to about 3200, about 1600 to about 3000, about 1600 to about 2800, about 1600 to about 2600, about 1600 to about 2400, about 1600 to about 2200, about 1600 to about 2000, about 1600 to about 1800, about 1800 to about 3200, about 1800 to about 3000, about 1800 to about 2800, about 1800 to about 2600, about 1800 to about 2400, about 1800 to about 2200, about 1800 to about 2000, about 2000 to about 3200, about 20 about 2000 to about 3000, about 2000 to about 2800, about 2000 to about 2600, about 2000 to about 2400, about 2000 to about 2200, about 2200 to about 3200, about 2200 to about 3000, about 2200 to about 2800, about 2200 to about 2600, about 2200 to about 2400, about 2400 to about 3200, about 2400 to about 3000, about 2400 to about 2800, about 2400 to about 2600, about 2600 to about 3200, about 2600 to about 3000, about 2600 to about 2800, about 2800 to about 3200, about 2800 to about 3000, or about 3000 to about 3200 μg. In a further embodiment, the twice-daily dose of the IP receptor agonist is about 200 to about 1600 μg. In another embodiment, the twice-daily dose of the IP receptor agonist is about 200 μg to about 1600 μg. In yet a further embodiment, the twice-daily dose of the IP receptor agonist is about 1200 μg to about 1600 μg twice-daily.

[0046] Generally, the starting daily dose of IP receptor agonist is about 400 μg. This can be administered to patients in one dose (400 μg) or preferably in two doses (200 μg / dose). When administered to patients in two doses, each dose can be taken simultaneously or at different times. In some embodiments, the first 200 μg dose can be taken in the morning, and the second 200 μg dose is taken in the evening. In other embodiments, the starting dose of 400 μg is taken in the morning. In a further embodiment, the starting dose of 400 μg is taken in the evening.

[0047] Desirably, the amount of IP receptor agonist is adjusted to provide the maximum tolerated dose as determined by a physician or other medical professional. The dose of the IP receptor agonist is increased at regular intervals, depending on the patient's tolerance, from the initial dose to the maximum tolerated dose (MTD) of the IP receptor agonist. Typically, the MTD is 1600 μg twice daily, or until the patient experiences adverse pharmacological effects that cannot be tolerated and / or medically managed. The regular intervals can be daily or weekly, but the dosage is typically increased at weekly intervals.

[0048] In certain embodiments, the IP receptor agonist is selexipag.Unless otherwise specified, as used herein, the term "selexipag" refers to 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide of formula (II).

[0049] [ka]

[0050] As used herein, "selexipag" also refers to amorphous forms of selexipag or crystalline forms, such as polymorphs, of selexipag. In some embodiments, selexipag is in a crystalline form, such as a polymorph. In other embodiments, selexipag is in an amorphous form. In other embodiments, selexipag is Form I, as described in U.S. Pat. Nos. 8,791,122 and 9,284,280, Form II, as described in U.S. Pat. No. 9,340,516, or Form III, as described in U.S. Pat. No. 9,440,931, all of which are incorporated herein by reference. Crystallinity can be determined by one of ordinary 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. As used herein, "selexipag" includes its anhydrate or its hydrate. In certain embodiments, selexipag is in an anhydrate form. In other embodiments, selexipag is its hydrate. As used herein, "selexipag" further refers to solvates thereof, which include molecules of solvent bound to the selexipag molecule at one or more positions through intermolecular forces or chemical bonds.

[0051] The term "selexipag" may also include pharmaceutically acceptable salts thereof, which can be readily selected by one skilled in the art. "Pharmaceutically acceptable salts" refers to salts of selexipag that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See, for example, Berge, "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002, which are incorporated herein by reference. Selexipag can be used in the form of a free base or acid, or can be used after being converted into a pharmaceutically acceptable salt by known methods. When selexipag is basic, examples of "salts" include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, as well as salts with organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. When selexipag is acidic, examples of "salts" include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. Geometric isomers (Z-form and E-form) of selexipag or mixtures thereof are also contemplated. Selexipag is commercially available, as will be understood by those skilled in the art. See, for example, U.S. Patent No. 7,205,302, incorporated herein by reference. For example, selexipag is available as Uptravi® and is also known as ACT-293987 or NS-304. Selexipag is a prostacyclin receptor agonist and can be prepared according to the process disclosed in US Pat. No. 7,205,302.

[0052] The present disclosure also contemplates the administration of selexipag metabolites. Desirably, the selexipag metabolite is a metabolically active compound. Thus, in certain embodiments, the selexipag metabolite is 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid of formula II-M1. II-M1 is also known by the code names ACT-333679 or MRE-269. The preparation of selexipag is described in WO 2002 / 088084 (incorporated herein by reference). The preparation of polymorphic forms, i.e., crystalline Forms I, II, and III of the free base, is disclosed in WO 2010 / 150865 (incorporated herein by reference), and polymorphic forms of pharmaceutically acceptable salts are disclosed in WO 2011 / 024874 (incorporated herein by reference).

[0053] [ka]

[0054] Type 5 phosphodiesterase inhibitors The methods described herein also include administering a type 5 phosphodiesterase (PDE-5) inhibitor. A physician or other healthcare professional can select an appropriate PDE-5 inhibitor. In some embodiments, the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharmaceutically acceptable salt thereof. In other embodiments, the PDE-5 inhibitor is tadalafil. In other embodiments, the PDE-5 inhibitor is sildenafil. In a further embodiment, the PDE-5 inhibitor is vardenafil. In yet another embodiment, the PDE-5 inhibitor is udenafil.

[0055] The daily dose of the PDE-5 inhibitor can be administered once a day, twice a day, or three times a day, preferably twice a day. In some embodiments, the dose is administered twice a day. The amount of the PDE-5 inhibitor can be selected by a doctor or other medical professional based on factors such as the severity of the disease and the physical characteristics of the patient. In some embodiments, the amount of the PDE-5 inhibitor is at least about 5 mg. In some embodiments, the amount of PDE-5 inhibitor is about 5 to about 100 mg, about 10 to about 100 mg, about 10 to about 90 mg, about 10 to about 80 mg, about 10 to about 70 mg, about 10 to about 60 mg, about 10 to about 50 mg, about 10 to about 40 mg, about 10 to about 30 mg, about 10 to about 20 mg, about 20 to about 100 mg, about 20 to about 90 mg, about 20 to about 80 mg, about 20 to about 70 mg, about 20 to about 60 mg, about 20 to about 50 mg, about 20 to about 40 mg, about 20 to about 30 mg, about 30 to about 100 mg, about 30 to about 90 mg, about 30 to about 80 mg, about 30 to about 70 mg, about In a further embodiment, the dose of the PDE-5 inhibitor is about 20 to about 40 mg. In yet another embodiment, the dose of the PDE-5 inhibitor is about 20 mg. In a further embodiment, the dose of the PDE-5 inhibitor is about 40 mg.

[0056] It is desirable to reach the maximum tolerated dose (MTD) of the PDE-5 inhibitor during the initial triple therapy. Therefore, the amount of the PDE-5 inhibitor may remain the same or may vary throughout the treatment method. In some embodiments, the amount of the PDE-5 inhibitor is increased from the initial dose. In other embodiments, the amount of the PDE-5 inhibitor is decreased from the initial dose. The dose of the PDE-5 inhibitor can be adjusted depending on many factors, including, but not limited to, renal and hepatic impairment. Thus, in some embodiments, the initial dose of the PDE-5 inhibitor is increased by about 20 mg during the initial triple therapy. For example, the initial dose of the PDE-5 inhibitor is about 20 mg and is later increased to about 40 mg depending on the patient's tolerance. The dose of the PDE-5 inhibitor is adjusted one day after the initial triple therapy. In some embodiments, the dose of the PDE-5 inhibitor is adjusted at least about five days after the first day of the initial triple therapy. In other embodiments, the dose of the PDE-5 inhibitor is adjusted at least about eight days after the first day of the initial triple therapy. In further embodiments, the dose of the PDE-5 inhibitor is adjusted at least about 11 days after Day 1 of initial triple therapy. In some embodiments, the dose of the PDE-5 inhibitor agonist is adjusted about 5 to about 15 days, about 5 to about 11 days, about 5 to about 8 days, about 6 to about 15 days, about 6 to about 11 days, about 6 to about 8 days, about 7 to about 15 days, about 7 to about 11 days, about 7 to about 8 days, about 8 to about 15 days, or about 8 to about 11 days after Day 1 of initial triple therapy. Preferably, the initial dose of the PDE-5 inhibitor is about 20 mg, and the dose is subsequently increased to a dose of about 40 mg over about 5 to about 11 days.

[0057] Preferably, the PDE-5 inhibitor is taken by the patient at the same time during the day.Therefore, in some embodiments, the PDE-5 inhibitor is taken in the morning.In other embodiments, the PDE-5 inhibitor is taken at night.The amount of the PDE-5 inhibitor can be taken as a single dose or divided into two or more doses, as determined by those skilled in the art.Preferably, the PDE-5 inhibitor is taken as a single dose.

[0058] As used herein, unless otherwise specified, the term "tadalafil" refers to pyrazino[1';,2';:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)2,3,6,7,12,12a-hexahydro-2-methyl-,(6R,12aR)- of formula (III).

[0059] [ka]

[0060] "Tadalafil" may also include pharmaceutically acceptable salts thereof, which can be readily selected by those skilled in the art. "Pharmaceutically acceptable salts" refers to salts of tadalafil that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See, for example, Berge, "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002, which are incorporated herein by reference. Tadalafil can be used in the form of a free base or acid, or can be used after being converted into a pharmaceutically acceptable salt by known methods. When tadalafil is basic, examples of "salts" include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, and salts with organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. When tadalafil is acidic, examples of "salts" include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. Tadalafil is commercially available as Adcirca™.

[0061] Maintenance treatment period The treatment period of the initial triple therapy generally includes a maintenance period. The maintenance period can be determined by a physician or other medical professional. The maintenance period generally begins after a sufficient time has passed to determine the maximum tolerated dose (MTD) of one or more of the ERA, PDE-5 inhibitor, and IP receptor agonist. In certain embodiments, the maintenance period begins after the MTD of the IP receptor agonist has been determined. Thus, the time from the start of the initial triple therapy to the start of the maintenance phase can vary, for example, from about 4 weeks to about 30 weeks. Typically, the treating physician evaluates the patient to assess the need to maintain treatment with all of the ERA, PDE-5 inhibitor, and IP receptor agonist, or to discontinue use of one or more of the ERA, PDE-5 inhibitor, or IP receptor agonist. In some embodiments, the patient continues treatment with the ERA, PDE-5 inhibitor, and IP receptor agonist during the maintenance treatment period. In other embodiments, the patient continues treatment with the ERA and PDE-5 inhibitor during the maintenance treatment period. In a further embodiment, the patient continues treatment with an ERA and an IP receptor agonist during the maintenance treatment period. In yet another embodiment, the patient continues treatment with a PDE-5 inhibitor and an IP receptor agonist during the maintenance treatment period. In an even further embodiment, the patient continues treatment with an ERA during the maintenance treatment period. In another embodiment, the patient continues treatment with a PDE-5 inhibitor during the maintenance treatment period. In a further embodiment, the patient continues treatment with an IP receptor agonist during the maintenance treatment period.

[0062] The dosage and frequency of one or more of the ERA, PDE-5 inhibitor, or IP receptor agonist during the maintenance treatment period are determined by the attending physician. The administration frequency and amount of the ERA, PDE-5 inhibitor, and / or IP receptor agonist during the maintenance treatment period are the minimum frequency and amount necessary to reduce the patient's risk of disease progression. In some embodiments, the maintenance treatment period is at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 1 year, or about 2 years. In some embodiments, the maintenance treatment period is at least 6 months. In other embodiments, the maintenance treatment period is at least 1 year.

[0063] The maintenance treatment period may include longer periods depending on the patient's condition. In some embodiments, these longer periods may be at least about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years, including indefinitely. Patients remain on the maintenance treatment period until they no longer exhibit PAH symptoms, until their PAH symptoms continue to decrease, until their PAH symptoms no longer worsen, and / or until they no longer respond to treatment.

[0064] The amount of ERA, PDE-5 inhibitor, or IP receptor agonist administered to a patient during the maintenance treatment period is an amount that induces a biological or medical response that results in the elimination or reduction of one or more PAH symptoms. In some embodiments, the amount of one or more of the ERA, PDE-5 inhibitor, or IP receptor agonist will be the same as the amount administered prior to the maintenance period. In other embodiments, the amount of one or more of the ERA, PDE-5 inhibitor, or IP receptor agonist can be increased or decreased as needed.

[0065] The patient's response to treatment can be assessed at any stage during the treatment period, i.e., before or during the maintenance treatment period, until the patient is deemed by a physician or other healthcare professional to have achieved an adequate response to the initial triple combination therapy.

[0066] Dosing regimen In the methods described herein, the amount / dosage of PDE-5 inhibitor, ERA, and IP receptor agonist is safe, effective, or safe and effective.As used herein, unless otherwise specified, the term "safe" shall mean the absence of undue harmful side effects (such as toxicity, irritation, or allergic reaction), and when used in the manner of the present invention, is commensurate with a reasonable benefit / risk ratio.Similarly, unless otherwise specified, the term "effective ... means that therapeutic efficacy has been demonstrated for treating patients with pulmonary arterial hypertension 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, therapeutically effective amounts of PDE-5 inhibitors, ERAs, and IP receptor agonists are safe. In even further embodiments, therapeutically effective amounts of PDE-5 inhibitors, ERAs, and IP receptor agonists are effective. In other embodiments, therapeutically effective amounts of PDE-5 inhibitors, ERAs, and IP receptor agonists are safe and effective.

[0067] As used herein, unless otherwise specified, the term "clinically proven" (used independently or to modify the terms "safety" and / or "efficacy") means that the evidence is established by a Phase III or IV clinical trial sufficient to meet the approval standards of the U.S. Food and Drug Administration or a similar trial for market approval by the EMEA. Preferably, an appropriately sized randomized, double-blind, controlled trial is used to clinically demonstrate the efficacy of PDE-5 inhibitors, ERAs, and IP receptor agonists compared to placebo, depending on the patient's condition as assessed by the techniques described herein.

[0068] As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment has been proven to be statistically significant by a Phase III or Phase IV clinical trial, i.e., the clinical trial results are unlikely to be attributable to an alpha level of less than 0.05, or the clinical efficacy results are sufficient to meet the approval standards of the U.S. Food and Drug Administration or similar tests for market approval by the EMEA. For example, selexipag, macitentan, and tadalafil have each been independently clinically proven effective in treating patients with pulmonary arterial hypertension at therapeutically effective doses, as described herein and specifically described in the Examples.

[0069] As used herein, unless otherwise specified, the term "clinically proven safe" means that the safety of the treatment has been demonstrated by a Phase III or Phase IV clinical trial through analysis of the trial data and results, the treatment is free of excessive side effects, and meets the approval criteria of the U.S. Food and Drug Administration or the European, Middle East, and Africa (EMEA) Food and Drug Administration. "This means corresponding to a statistically significant clinical benefit (efficacy) sufficient to satisfy similar trials for market approval by the FDA. For example, selexipag, macitentan, and tadalafil have each been independently proven to be clinically safe for the treatment of patients with pulmonary arterial hypertension when administered at therapeutically effective amounts, as described herein and specifically described in the Examples.

[0070] In certain aspects, methods for selling formulations comprising a PDE-5 inhibitor, an ERA, and an IP receptor agonist are also provided. As used herein, the terms "sale" or "selling" refer to the transfer of a formulation, e.g., a pharmaceutical composition or dosage form, from a distributor to a purchaser. Thus, the methods include selling a formulation comprising a PDE-5 inhibitor, an ERA, and an IP receptor agonist, and the methods include selling the formulation. In some embodiments, the formulation's reference listing drug package insert includes instructions for treating PAH. The methods also include marketing a formulation comprising a PDE-5 inhibitor, an ERA, and an IP receptor agonist. As used herein, the term "marketing" refers to the offering of a formulation, e.g., a pharmaceutical composition or dosage form, for sale by a distributor to a purchaser. These methods include marketing the formulation.

[0071] In some embodiments, the present disclosure provides a pharmaceutical product comprising a PDE-5 inhibitor, an ERA, and an IP receptor agonist in clinically proven safe and clinically proven effective amounts, wherein the pharmaceutical product is packaged, the package including a label identifying the PDE-5 inhibitor, the ERA, and the IP receptor agonist as chemical entities approved by a regulatory agency, and including instructions for treating PAH.

[0072] The term "formulation" refers to a product containing active pharmaceutical ingredients that has been approved for manufacture and sale by a government agency, such as the U.S. Food and Drug Administration or a similar agency in another country. In some embodiments, the formulation includes a PDE-5 inhibitor, an ERA, and an IP receptor agonist.

[0073] Similarly, a "label" or "drug insert" refers to information provided to a patient that provides relevant information about a drug product. Such information may include, but is not limited to, one or more of: drug description, clinical pharmacology, indications (use of the drug product), contraindications (who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use during pregnancy, use in nursing mothers, use in children and elderly patients, drug delivery methods, patient safety information, or any combination thereof. In certain embodiments, the label or drug insert provides instructions for treating PAH. In further embodiments, the label or drug insert identifies PDE-5 inhibitors, ERAs, and IP receptor agonists as regulatory agency-approved chemical components.

[0074] As used herein, the term "Reference Listed Drug" or "R "LD" refers to the drug product to which a new generic product is compared to demonstrate its bioequivalence. It is also a medicinal product that has been granted a marketing authorisation by a Member State of the European Union or by the Commission on the basis of a complete dossier, i.e., by the submission of quality, preclinical and clinical data pursuant to Articles 8(3), 10a, 10b or 10c of Directive 2001 / 83 / EC, and to which an application for marketing authorisation of a generic / hybrid medicinal product refers by demonstrating bioequivalence, usually through the submission of appropriate bioavailability studies.

[0075] In certain embodiments, the formulation is an ANDA formulation, a supplemental drug product application (SDA) formulation, or a 505(b)(2) formulation. In the United States, companies seeking approval to market a generic equivalent must reference an RLD in their Abbreviated New Drug Application (ANDA). For example, ANDA applicants must rely on FDA's findings that the previously approved formulation, i.e., the RLD, is safe and effective and demonstrate in certain ways that their proposed generic formulation is identical to the RLD. Specifically, with limited exceptions, the formulation submitted in an ANDA must have, among other things, the same active ingredient, conditions of use, route of administration, dosage form, strength, and package insert (with certain tolerances) as the RLD. The RLD is a listed drug, to which ANDA applicants must demonstrate that their proposed formulation is identical with respect to the active ingredient, dosage form, route of administration, strength, package insert, and conditions of use, among other characteristics. The electronic Orange Book includes a section for the RLD and a section for the reference standard. In the printed Orange Book, RLDs and reference standards are identified by specific symbols.

[0076] In Europe, applicants identify the reference medicinal product (product name, strength, pharmaceutical form, marketing authorisation holder (MAH, first authorisation, Member State / Community)) in their generic / hybrid medicinal product (ANDA or equivalent to supplemental NDA (sNDA) formulation) application, which is synonymous with the RLD, including: 1. A medicinal product that is authorised or has been authorised in the European Economic Area (EEA) and that serves as the basis for indicating that the data protection period provided for in European medicine legislation has expired. This reference medicinal product is identified for the purposes of calculating the expiry of the data protection period and may be of a different strength, pharmaceutical form, route of administration or labelling than the generic / hybrid medicinal product. 2. The medicinal product to which the dossier (product name, strength, pharmaceutical form, MAH, marketing authorization number) is cross-referenced within the generic / hybrid application. This reference medicinal product may be one that has been authorised under a different name and in a separate procedure, as specified for the purposes of calculating the expiry of the data protection period. The product information of this reference medicinal product will in principle serve as the basis for the product information claimed for the generic / hybrid medicinal product. 3.Medicinal products (product name, strength, pharmaceutical form, MAH, Member State of source) used in bioequivalence studies (if applicable).

[0077] The different abbreviated approval pathways for drug products under the Food, Drug, and Cosmetic Act (FD&C Act) are the abbreviated approval pathways set forth in sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 355(b)(2), respectively).

[0078] According to the FDA ("Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry," U.S. Department of Health and Human Services, October 2017, pp. 1-14, the contents of which are incorporated herein by reference), NDAs and ANDAs can be classified into the following four categories: (1) A "stand-alone NDA" is an application submitted under section 505(b)(1) of the FD&C Act and approved under section 505(c) that contains a complete report of the safety and effectiveness studies conducted by or on behalf of the applicant, or to which the applicant has a right of reference or use. (2) A chapter 505(b)(2) application is an NDA submitted under chapter 505(b)(1) of the FD&C Act and approved under chapter 505(c) that contains a complete report of a safety and effectiveness study, and at least some of the information required for approval is derived from studies not conducted by or for the applicant, or to which the applicant did not obtain access or rights to use. (3) An ANDA is an application submitted and approved under Chapter 505(j) of the FD&C Act to duplicate a previously approved drug product. An ANDA relies on FDA's finding that the previously approved drug product, i.e., the Reference List Drug (RLD), is safe and effective. An ANDA generally must contain information to demonstrate that the proposed generic product (a) is identical to the RLD in terms of active ingredient, conditions of use, route of administration, dosage form, strength, and package insert (subject to certain tolerances), and (b) is bioequivalent to the RLD. An ANDA cannot be submitted if testing is required to demonstrate the safety and effectiveness of the proposed product. (4) The ANDA is for a type of drug product (for a product with two or more active ingredients) that differs from the RLD in dosage form, route of administration, strength, or active ingredient, and FDA has determined, in response to a petition filed under chapter 505(j)(2) of the FD&C Act (a suitability petition), that the testing is not necessary to demonstrate the safety and effectiveness of the proposed drug product.

[0079] The scientific premise underlying the Hatch-Waxman Act is that a drug product approved in an ANDA under Chapter 505(j) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent are interchangeable, and when administered to patients under the conditions specified in the package insert, the substituted product is reasonably expected to produce the same clinical efficacy and safety profile as the given product. In contrast to ANDAs, Chapter 505(b)(2) applications are more flexible regarding the characteristics of the product submitted. Chapter 505(b)(2) applications do not have to be classified as therapeutically equivalent to the listed drug referenced in the approval.

[0080] The method may also include, consist of, or consist essentially of placing the PDE-5 inhibitor, ERA, and IP receptor agonist into stream-of-commerce. In certain embodiments, the PDE-5 inhibitor, ERA, and IP receptor agonist include a package insert containing instructions for treating PAH.

[0081] In a further aspect, described herein is a method of marketing a pharmaceutical composition containing, independently, a PDE-5 inhibitor, an ERA, and an IP receptor agonist, the method comprising, consisting of, or consisting essentially of placing the pharmaceutical composition in the stream of commerce. In certain embodiments, the pharmaceutical composition includes a package insert containing instructions for treating PAH.

[0082] In yet a further aspect, described herein are methods of marketing a PDE-5 inhibitor, an ERA, and an IP receptor agonist, comprising, consisting of, or consisting essentially of placing the PDE-5 inhibitor, the ERA, and the IP receptor agonist in stream-of-commerce. In certain embodiments, the PDE-5 inhibitor, the ERA, and the IP receptor agonist include a package insert containing instructions for treating PAH.

[0083] Formulation / Composition Pharmaceutical compositions containing one or more of an IP receptor agonist, a PDE-5 inhibitor, or an ERA independently as an active ingredient can be prepared by thoroughly mixing one or more compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. As used herein, the terms "composition" and "formulation" are used interchangeably and include 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 containing specified ingredients in specified amounts. Overviews of pharmaceutical compositions are described, for example, in *Remington: The Science and Practice of Pharmacy, Nineteenth Ed.* (Easton, Pa.: Mack Publishing Company, 1995); *Hoover, John E., *Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; *Liberman, H.A. and *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), the disclosures of which are incorporated herein by reference. For example, formulations containing macitentan are disclosed in U.S. Patent Nos. 8,367,685 and 9,265,762, the disclosures of which are incorporated herein by reference.

[0084] Preferably, the IP receptor agonist, PDE-5 inhibitor, and ERA are formulated independently in the compositions described herein, although one or more of the IP receptor agonist, ERA, and PDE-5 inhibitor may be combined in a single formulation. Such compositions can be administered to patients undiluted or in a mixture with a pharmaceutically acceptable, non-toxic, inert carrier, for example, as a pharmaceutical composition containing the compound at a concentration of 0.1% to 99.5% by weight, preferably 0.5% to 90%, based on the total weight of the composition. One or more formulation adjuvants, such as solid, semi-solid, and liquid diluents, as well as fillers and other adjuvants for drug formulation, can also be used as carriers. The pharmaceutical composition is preferably administered in unit dosage form.

[0085] The IP receptor agonist, PDE-5 inhibitor, and / or ERA can be independently administered by a number of routes as determined by those skilled in the art. Preferably, the IP receptor agonist, PDE-5 inhibitor, and / or ERA are independently administered by a route appropriate for the IP receptor agonist. In some embodiments, the IP receptor agonist, PDE-5 inhibitor, and / or ERA are independently administered orally, parenterally, or any combination thereof. In other embodiments, the IP receptor agonist, PDE-5 inhibitor, or ERA are independently administered orally. In a further embodiment, the IP receptor agonist, PDE-5 inhibitor, or ERA are independently administered orally in the form of one or more tablets. As used herein, the term "independently administered" refers to the IP receptor agonist, PDE-5 inhibitor, and ERA being present in separate formulations, i.e., one unit dose / preparation contains the IP receptor agonist, one unit dose / preparation contains the PDE-5 inhibitor, and one unit dose / preparation contains the ERA.However, such independent preparations can be administered simultaneously, i.e., the unit dose containing the IP receptor, the unit dose / preparation containing the PDE-5 inhibitor, and the unit dose / preparation containing the ERA can be administered at the same time or at different times as described herein.In other embodiments, the ERA and the PDE-5 inhibitor are orally administered together in the form of a single tablet, and the IP receptor agonist is orally administered in the form of one or more separate tablets.

[0086] In some embodiments, the IP receptor agonist, PDE-5 inhibitor, and / or ERA are administered independently as an injection or infusion solution, such as intravenous injection. For intravenous administration, the IP receptor agonist, PDE-5 inhibitor, and / or ERA or pharmaceutical product is a sterile solution. Injectable suspensions or solutions can be prepared using aqueous carriers with appropriate additives. For intravenous administration, the carrier is usually composed of sterile water and other ingredients that enhance solubility or preservation. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin. When intravenous administration is desired, isotonic preparations, which may contain appropriate preservatives, are used. In some embodiments, the carrier used in intravenous preparations comprises sterile water.

[0087] For oral administration, each formulation can be solid or liquid. Preferably, the oral dosage forms of the IP receptor agonist, PDE-5 inhibitor, and ERA described herein are solid. Examples of solid formulations include, for example, troches, thin films, pastes, lozenges, granules, powders, capsules, caplets, gelcaps, tablets, and pills such as capsules (including immediate-release, sustained-release, and extended-release pills, respectively). Preferably, the oral composition is administered as a tablet, i.e., the pharmaceutical product preferably comprises a tablet. If desired, the tablet or caplet can be sugar-coated or enteric-coated by standard techniques, or otherwise compounded to provide a dosage form that provides the advantage of prolonged action. To prepare a solid composition such as a tablet, the main active ingredient (e.g., IP receptor agonist, PDE-5 inhibitor, or ERA) is mixed with a pharmaceutical carrier / additive such as starch, a sweetener such as sugar, a diluent, a colorant, a granulating agent, a preservative, a lubricant, a flavoring agent, a binder, a disintegrating agent, etc. For tablets, 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, ethanol, and glycerol, can be used. 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 and tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Liquid forms into which the compositions of the present disclosure can be incorporated for administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar vehicles. Liquid oral formulations contain, independently, an IP receptor agonist, a PDE-5 inhibitor, and / or an ERA and one or more suitable carriers / additives such as water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.

[0088] To prepare the pharmaceutical composition of the present disclosure, the IP receptor agonist, PDE-5 inhibitor or ERA as active ingredient can be thoroughly mixed with pharmaceutical carrier according to conventional pharmaceutical compounding technology, and such carrier can take a wide variety of forms depending on the preparation form desired for administration (for example, oral or parenteral).Suitable pharmaceutically acceptable carriers are well known in the art.Some descriptions 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, and the disclosures thereof are incorporated herein by reference.

[0089] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al., published by Marcel Dekker, Inc., Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al., and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al., the disclosures of which are incorporated herein by reference.

[0090] Aspects Aspect 1. A method of reducing the risk of disease progression in a patient with pulmonary arterial hypertension (PAH), comprising administering to a patient in need thereof an initial triple therapy of an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 (PDE-5) inhibitor, and a prostacyclin receptor agonist (IP receptor agonist).

[0091] Aspect 2. The method of Aspect 1, wherein the reduced risk of disease progression is for a patient population with PAH receiving initial dual therapy of an ERA and a PDE-5 inhibitor.

[0092] Aspect 3. The method of aspect 1 or 2, wherein the ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof, the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharmaceutically acceptable salt thereof, and the IP receptor agonist is selexipag, 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 4. The method of embodiment 3, wherein the ERA is macitentan, the PDE-5 inhibitor is tadalafil, and the IP receptor agonist is selexipag.

[0094] Embodiment 5. The method of any one of embodiments 1 to 4, wherein the patient is treatment-naive for PAH.

[0095] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the initial PAH diagnosis in the patient is made within six months of initiating initial triple therapy.

[0096] Aspect 7. The patient has a resting mean pulmonary arterial hypertension (mPAP) of about 25 mmHg or greater, a mean pulmonary artery wedge pressure (PAWP) of about 15 mmHg or less, and a mean pulmonary artery occlusion pressure (PAWP) of about 240 dyne·sec / cm at the start of initial triple therapy. 5 7. The method according to any one of aspects 1 to 6, wherein the patient has a pulmonary vascular resistance (PVR) of at least 100 mg / kg.

[0097] Embodiment 8. The method of any one of embodiments 1-7, wherein the patient has a 6-minute walk distance (6MWD) of about 50 meters or greater at the start of initial triple therapy.

[0098] Embodiment 9 The method of any one of embodiments 4 to 8, wherein macitentan is administered in an amount of about 10 mg once daily.

[0099] Aspect 10. The method of any one of Aspects 4 to 9, wherein tadalafil is administered in an amount of about 20 mg to about 40 mg once daily.

[0100] Embodiment 11 The method of any one of embodiments 4 to 10, wherein tadalafil is administered once daily in an amount of about 40 mg.

[0101] Embodiment 12. The method of any one of embodiments 4 to 11, wherein selexipag is administered in an amount of about 200 μg to about 1600 μg twice daily.

[0102] Aspect 13 The method of any one of Aspects 4 to 12, wherein each of macitentan, tadalafil, and selexipag is orally administered in the form of one or more tablets.

[0103] Aspect 14. The method of any one of aspects 4 to 12, wherein macitentan and tadalafil are administered orally in the form of a single tablet, and selexipag is administered orally in the form of one or more separate tablets.

[0104] Embodiment 15. The method of any one of embodiments 2 to 14, wherein the initial triple therapy reduces the risk of disease progression by about 30-40% relative to the initial double therapy.

[0105] Embodiment 16 The method of any one of embodiments 1 to 15, wherein disease progression comprises hospitalization due to worsening PAH, clinical worsening of PAH, or death.

[0106] [Table 2] [Example]

[0107] Example 1 This example is a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group, phase 3b study comparing an initial triple oral combination (macitentan 10 mg, tadalafil 40 mg, and selexipag 200-1600 mg twice daily) with an initial double oral combination (macitentan 10 mg, tadalafil 40 mg, and placebo) in newly diagnosed, treatment-naive subjects with PAH. The study used a group sequential design with one planned interim analysis (failure-only) when approximately 33% of subjects completed the 26-week PVR assessment (primary endpoint) or discontinued the study early.

[0108] Randomization: Subjects were stratified by region (North America vs. rest of the world) and baseline WHO functional class (I / II vs. III / IV) and randomized 1:1 to triple therapy or dual therapy (double-blind Selexig / placebo and open-label macitentan and tadalafil).

[0109] Study / Treatment Period: The treatment period consisted of 2 weeks of open-label macitentan and tadalafil, followed by a double-blind phase (+open-label macitentan and tadalafil) with selexipag / placebo titration through week 12 and a maintenance treatment period continuing until the EOT visit. Once the last subject completed the 26-week visit, all patients still on study returned for the EOMOP visit, which was the individual cutoff date for primary database lock. Subjects, regardless of whether they were receiving any study treatment, will be followed up until EOS, i.e., 30 days after EOT. See Figures 1 and 2 for the study design. See Figure 1 below. 1 Signed written informed consent will be obtained prior to all study-mandated procedures. Right heart catheterization (RHC) data obtained at the investigational site prior to signed informed consent but within 28 days prior to Day 1 will be acceptable. 2 Study treatment initiation scheme. 3For simplicity, most visits between Day 1 and the end of the main observation period (EOMOP) are not shown. 4 If double-blind treatment (selexipag / placebo) is discontinued before week 26, the week 26 assessment must occur at week 26 or before the start of rescue therapy (prostacyclin, prostacyclin analog, or prostacyclin receptor agonist), whichever occurs first. 5 EOMOP is data cleaning and unblinding of treatment group assignment following the data cutoff for the primary efficacy and safety analyses. The EOMOP visit is scheduled 26 ± 1 weeks after the last subject enrolled. An EOMOP visit is not required if it is within ± 2 weeks of a patient's 26-week visit or the 12-month, 18-month, 24-month, 30-month, etc. visits. 6 All three study treatments will be given until the EOT visit, which is scheduled approximately 4 months after the EOMOP visit. If all three study treatments are discontinued early, the EOT visit must occur within 1 week, but subjects should be followed up according to the schedule of evaluations until the end of the study. 7 EOS is defined as the subject's last data collection. The EOS visit for all subjects (regardless of whether the subject is receiving 3, 2, 1, or no study treatments) will be scheduled approximately 5 months after the EOMOP visit. Follow-up for disease progression (including death) will continue until EOS for all randomized patients. For the purposes of this study, baseline refers to the last available assessment / measurement obtained before or on Day 1 (prior to randomization).

[0110] Primary analysis set for efficacy: The FAS includes all randomized subjects. Subjects are assessed according to the treatment to which they were randomized (estimates of treatment policies missing the Week 26 assessment were imputed by LOCF for all types of intercurrent events).

[0111] Primary efficacy variable: Week 26 to baseline PVR ratio (week 26 divided by baseline PVR). (PVR is log-transformed and the change from baseline to week 26 in logPVR is analyzed using an ANCOVA model with factors for the stratification variables domain of treatment and randomization, and WHO functional class and baseline logPVR as covariates. The ratio of geometric means [triplet therapy vs. doublet therapy] is obtained by exponentiation.)

[0112] Key secondary efficacy variables (in order of testing): Change in 6MWD from baseline to week 26 (analyzed using the same model as for the primary endpoint, but without logarithmic transformation), NT-proBNP change from baseline to week 26 (analyzed using the same model as for the primary endpoint), time to first disease progression event by EOMOP+7 days (analyzed using the log-rank test for treatment group differences stratified for the randomization stratification variables domain and WHO functional class); No worsening in WHO functional class from baseline to week 26 (analyzed using a logistic regression model with factors for treatment and randomization stratification variables domain and WHO functional class). Changes in RHC variables other than PVR (mPAP, cardiac index, total pulmonary resistance, mRAP, venous oxygen saturation) from baseline to week 26.

[0113] Study Methodology: The safety analysis population includes all subjects who received at least one dose of any of the three study treatments. The FAS includes all randomized subjects. The modified FAS includes all subjects from the FAS who received at least one dose of each of the three study treatments. The per-protocol set includes all subjects from the FAS who received at least one dose of double-blind study treatment and who have no major protocol deviations.

[0114] Statistical analysis tests were performed at a two-sided significance level of 0.05. Regarding testing multiple endpoints (primary and secondary), multiplicity was adjusted by a fixed-order testing procedure; i.e., the first secondary hypothesis was tested only after the null hypothesis for the primary endpoint was rejected. A planned interim analysis focusing only on infertility was performed (after 33% of subjects completed or discontinued the primary endpoint assessment).

[0115] Inclusion criteria included: 1. Signing informed consent prior to any study-mandated procedures. 2. Men and women aged 18 years or older and 75 years or younger at the time of screening. 3. First PAH diagnosed within 6 months prior to Day 1. 4. RHC performed on Day 28–Day 1 (RHC data obtained at the investigational site within this time frame but pre-study, i.e., prior to signed informed consent, are acceptable), meeting all of the following criteria: Mean pulmonary artery pressure (mPAP) ≥ 25mmHg Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≦15mmHg PVR ≥ 480 dyne sec / cm 5 (≧6 Wood units) · Negative vasoreactivity testing as required for idiopathic, hereditary, and drug / toxin-induced PAH (at this or a previous RHC). 5. Symptomatic PAH belonging to one of the following subgroups: Idiopathic Hereditary Drug or toxin induced Surgical repair more than one year prior, associated with one of the following congenital heart diseases (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with connective tissue disease, HIV infection, or simple systemic-pulmonary shunt. 6.6MWD ≥ 50m at screening 7. Women of childbearing potential must: A negative serum pregnancy test at the screening visit and a negative urine pregnancy test at the Day 1 visit, and Agree to take a pregnancy test every month until EOS, and Agree to use reliable contraception from screening until one month after discontinuation of the last study treatment, · Reliable birth control should be started at least 11 days before Day 1.

[0116] Exclusion criteria included: 1. Any PAH-specific medication (e.g., any ERA, PDE-5i, soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) at any time before Day 1 (vasoreactivity testing is permitted, and previous PAH-specific medications used intermittently to treat digital ulcers or Raynaud's disease are permitted if discontinued less than 6 months before Day 1). 2. An exercise-based cardiopulmonary rehabilitation program (if scheduled or started within 12 weeks prior to Day 1). 3. Body mass index (BMI) > 40 kg / m at screening 2 . 4. Have three or more of the following risk factors for heart failure with preserved ejection fraction at screening: BMI > 30 kg / m 2 Any type of diabetes Essential hypertension Coronary artery disease, i.e., any of the following: - History of stable angina or ->50% stenosis of coronary arteries (by coronary angiography) or - History of myocardial infarction or - History of or planned coronary artery bypass grafting and / or coronary stent placement. 5. Acute myocardial infarction within 12 weeks prior to screening. 6. Cerebrovascular event (e.g., transient ischemic attack, stroke) within 12 weeks prior to screening. 7. Known permanent atrial fibrillation. 8. Systolic blood pressure <-90mmHg at screening or day 1. 9. Ongoing or planned treatment with organic nitrates and / or doxazosin. 10. One or more of the following signs of relevant lung disease at any time leading up to screening: DLCO<40% predicted, except in cases where interstitial lung disease is absent or mild as documented by computed tomography. ·FVC<60% of predicted. FEV1<60% of predicted. Pulmonary function tests can be performed with or without bronchodilator use according to local clinical practice. 11. Known or suspected pulmonary veno-occlusive disease. 12. Severe liver impairment (with or without cirrhosis) documented according to the National Cancer Institute Organ Dysfunction Working Group criteria, defined as total bilirubin >3 × upper limit of ULN >ULN (assessed at screening) with AST, and / or Child-Pugh class C. 13. Serum AST and / or ALT >3 x ULN (assessed at screening). 14. Severe renal impairment assessed at screening (estimated creatinine clearance ≤ 30 mL / min / 1.73 m 2 ). 15. Ongoing or scheduled dialysis. 16. Hemoglobin <100g / L at screening. 17. Known or suspected uncontrolled thyroid disease (hypothyroidism or hyperthyroidism). 18. Loss of vision in one or both eyes due to non-arteritic ischemic optic neuropathy. 19. Treatment with strong inducers of cytochrome P450 3A4 (CYP3A4) (e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentine, phenobarbital, phenytoin, and St. John's wort) within 28 days prior to Day 1. 20. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) and / or strong inhibitors of CYP2C8 (e.g., gemfibrozil) within 28 days prior to Day 1. 21. Treatment with another investigational drug (scheduled or within 12 weeks prior to Day 1). 22. Hypersensitivity to any of the three study treatments or any of the excipients in their formulations (lactose, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, povidone, corn starch, sodium starch glycolate type A, polyvinyl alcohol, polysorbate 80, titanium dioxide, talc, xanthan gum, soy lecithin, croscarmellose sodium, hypromellose, sodium lauryl sulfate, triacetin, yellow iron oxide, red iron oxide, black iron oxide, d-mannitol, propylene glycol, carnauba wax). 23. Pregnant, breastfeeding, or intending to become pregnant during the study. 24. Concomitant life-limiting illness with life expectancy <12 months. 25. Alcohol abuse. 26. Any factors or conditions likely to affect the Protocol.

[0117] Contraindicated concomitant therapies included: 1. Any PAH-specific medication (e.g., ERA, PDE-5i [even when used for erectile dysfunction], soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) other than the three study treatments up to the EOT, except when used as rescue therapy. If another PAH-specific medication is initiated (and the corresponding study treatment is stopped), the subject will remain in the study regardless of whether they are receiving three, two, one, or no study treatments. 2. Organic nitrates (caution must be exercised with the use of other drugs with vasodilatory properties). 3. Doxazosin. 4. Strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentine, phenobarbital, phenytoin, and St. John's wort) during treatment with macitentan and / or tadalafil. 5. Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) during treatment with macitentan and / or tadalafil. 6. Strong inhibitors of CYP2C8 (e.g., gemfibrozil) during treatment with selexipag / placebo. 7. Any investigational drug other than the three study treatments. 8. Exercise-based cardiorespiratory recovery program between screening and the 26-week visit.

[0118] The following safety endpoints will be used: Treatment-emergent AEs. AEs leading to early discontinuation of any of the three study treatments. Treatment-emergent SAEs. Treatment-emergent deaths. - Significant treatment-emergent laboratory abnormalities. Change from baseline in laboratory variables. Changes from baseline in vital signs.

[0119] Safety endpoints will be analyzed over the following time periods: · From Day 1 to EOMOP. From Day 1 to the start of double-blind treatment (selexipag / placebo). From the start of macitentan study treatment until discontinuation (or EOMOP, whichever occurs first) + 30 days of safety follow-up. From the start of tadalafil study treatment until discontinuation (or EOMOP, whichever occurs first) plus 30 days of safety follow-up. From start to discontinuation of double-blind study treatment (or until EOMOP, whichever occurs first) + 30 days of safety follow-up. · EOMOP to EOT + 30 days safety follow-up. 30-day safety follow-up.

[0120] Primary objective: To compare the effects of an initial two-drug oral regimen (macitentan, tadalafil, placebo) with an initial three-drug oral regimen (macitentan, tadalafil, selexipag) on ​​PVR at week 26 in treatment-naive subjects with newly diagnosed PAH. The primary endpoint was the ratio of PVR at week 26 to baseline PVR assessed by right heart catheterization (RHC).

[0121] Secondary Objectives: To compare the effects of initial dual therapy with initial triple therapy on cardiopulmonary hemodynamics other than PVR, exercise capacity, and disease severity (e.g., NYHA functional class and NT-proBNP) at 26 weeks, and on disease progression events, safety, and tolerability until EOMOP, as defined below.

[0122] The comparison group will receive the following: Macitentan oral tablet, 10 mg, once daily. Tadalafil oral tablets, one or two 20 mg tablets once daily. Matching placebo oral tablets for selexipag, 200 μg, 1 to 8 tablets twice daily (morning and evening).

[0123] The three study treatments will be administered as follows: Day 1: Initiation of open-label macitentan 10 mg once daily and open-label tadalafil 20 mg once daily. Days 8 ± 3: Increase the tadalafil dose to 40 mg once daily (creatinine clearance > 30 and ≤ 80 mL / min / 1.73 m 2 In subjects with mild or moderate renal impairment, defined as ≥ 25 years, dose increases of tadalafil to 40 mg once daily should be based on individual tolerability. Day 15 ± 3: Initiation of double-blind selexipag or placebo. See details below. Double-blind treatment must also be initiated in subjects who previously had to discontinue one or both of the other study treatments.

[0124] The starting dose of double-blind selexipag or placebo on Day 15 ± 3 is 200 μg twice daily (morning and evening). The dose is increased in 200 μg increments twice daily, usually at weekly intervals, until a maximum dose of 1600 μg twice daily is reached or until intolerable or medically unmanageable adverse pharmacological effects occur (whichever occurs first) (see Table 1). If adverse effects common to prostanoid therapy occur, it is recommended not to discontinue double-blind treatment, as these effects are usually transient or manageable with symptomatic treatment. If an intolerable dose is reached, the dose should be reduced to the previous dose level.

[0125] [Table 3]

[0126] For all three study treatments, tablets will be taken orally with or without food. Tolerability may be improved if taken with food. Tablets should not be broken, crushed, or chewed; they should be swallowed with some water. If a dose is missed, subjects will take that dose as soon as possible (unless the next dose is within the next 6 hours), and then take the next dose at the next scheduled time.

[0127] Exploratory Efficacy Endpoints 1. Change from baseline in NT-proBNP, 6MWD, and WHO functional class to all routine collection time points up to EOMOP. 2. Inadequate clinical response, defined as the proportion of subjects meeting at least one of the following three criteria analyzed at each scheduled visit from Week 26 through EOMOP: a.WHO functional class III or IV. b. 6MWD ≤ 440m and NT-proBNP ≥ 3 × ULN. c. Clinical worsening events as defined by the secondary efficacy endpoint 5 at any time up to each visit. 3. Number of treatment goals achieved at week 26 (for each goal, score 0 = no or 1 = yes, i.e., total score 0-5, with 5 representing the best treatment outcome): a.WHO functional class I or II. b. Cardiac index > 3 L / min / m 2 . c. mRAP<8mmHg. d.6MWD>440m. e. NT-proBNP < 3 × ULN. 4. Defined by Exploratory Efficacy Endpoint 3, but with an alternative cardiac index cutoff of 2.5 L / min / m 2 Number of treatment goals using. 5. Number of treatment goals defined by Exploratory Efficacy Endpoint 3, but using <1800 pg / mL as an alternative cutoff for NT-proBNP.

[0128] Laboratory tests Below is a summary of "general" laboratory tests: hematology, liver and hemoglobin tests, coagulation tests, and clinical chemistry tests, including NT-proBNP.

[0129] Hematological tests: hemoglobin, hematocrit, red blood cell count (reticulocyte count), differential white blood cell count, and platelet count

[0130] Clinical Chemistry: The Cockcroft-Gault formula is used to estimate creatinine clearance: Estimated creatine clearance rate = (140 - age) x (weight in kg) x (1.23 for men, 1.04 for women) divided by serum creatinine (µmol / L).

[0131] Aminotransferase (AST / ALT), alkaline phosphatase, total and direct bilirubin, lactate dehydrogenase Creatinine, urea Uric acid (serum urate) ·glucose Sodium, potassium, chloride, calcium Protein, albumin

[0132] Coagulation tests: international normalized ratio, prothrombin time, and activated partial thromboplastin time

[0133] Biomarkers of myocardial stress and right ventricular function and structure: NT-proBNP and circulating biomarkers involved in right ventricular function and structure.

[0134] Visit Schedule Monthly (± 1 week) central laboratory testing of liver aminotransferases, total and direct bilirubin, and hemoglobin will be mandatory throughout the study. For monthly testing, blood draws will be performed at the investigational site, at a satellite laboratory near the subject's residence, or by a phlebotomy service in the subject's home.

[0135] During the screening period, the following will be recorded: eligibility (inclusion and exclusion criteria), demographics, medical history, RHC, physical examination, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general, serum pregnancy test, and biomarkers), (subject eligibility at screening can alternatively be determined using local laboratory tests as long as central laboratory kits are used in parallel), contraceptive methods used, previous therapies, and confirmation of AEs and SAEs.

[0136] At the Day 1 (randomization) visit, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general), urine pregnancy test, contraceptive methods used, concomitant medications, and AEs and SAEs will be recorded. At the end of this visit, subjects will be randomized to one of two treatment groups. Macitentan and tadalafil study treatment will be distributed to subjects. Treatment will begin.

[0137] The visit on Day 8 (± 3 days) involves recording AEs and SAEs. At the end of this visit, the tadalafil dose will be increased.

[0138] The Day 15 (± 3 days) visit will involve a physical examination, vital signs (BP, HR), contraception used, concomitant medications, and recording of AEs and SAEs. At the end of this visit, subjects will be dispensed double-blind selexipag / placebo. Subjects will begin treatment and dose escalation (in addition to ongoing study treatment with macitentan and tadalafil).

[0139] At the visit at week 12 (± 1 week), physical examination, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general, serum pregnancy test), contraceptive methods used, concomitant medications, and AEs and SAEs will be recorded.

[0140] At the 26th week (± 1 week) visit, RHC, physical examination, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general, serum pregnancy test, and biomarkers), contraceptive methods used, concomitant medications, and AEs and SAEs will be recorded.

[0141] At visits at 12, 18, 24, and 30 months (± 2 weeks), physical examination, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general, serum pregnancy test), contraceptive methods used, concomitant medications, and AEs and SAEs will be recorded.

[0142] The EOMOP visit will involve a physical examination, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general, serum pregnancy test), contraceptive methods used, concomitant medications, and recording of AEs.

[0143] At the EOT visit, physical examination, vital signs (BP, HR), WHO functional class, 6MWD, Borg dyspnea index, central laboratory tests (general, serum pregnancy test), contraceptive methods used, concomitant medications, and AEs will be recorded.

[0144] All subjects underwent 30 days of safety follow-up prior to EOS.

[0145] The EOS visit will be conducted at the end of safety follow-up, i.e., 30-35 days after EOT. At the EOS visit, pregnancy tests (serum or urine), contraceptive methods used, and AEs and SAEs will be recorded.

[0146] Subject and Treatment Information A total of 291 subjects were screened across 67 clinical trial sites in 16 countries. Of these, 247 subjects were randomized 1:1: 1, with 123 receiving triple therapy (double-blind selexipag vs. open-label macitentan and tadalafil) and 124 receiving dual therapy (double-blind placebo vs. open-label macitentan and tadalafil). The majority of subjects were white (85.0%), and 75.7% were female (see Table 5). The mean age was 51.9 years, ranging from 21 to 75 years.

[0147] [Table 4]

[0148] Subjects were primarily in WHO functional class III / IV at randomization (79.8%). See Table 6. Each treatment group was generally well balanced in terms of demographics and baseline disease characteristics.

[0149] [Table 5-1]

[0150] [Table 5-2]

[0151] Of the 247 randomized subjects (FAS), one subject in the dual therapy group did not receive either study drug and was therefore not included in the safety analysis set. Four subjects randomized to the triple therapy group and included in the safety analysis set did not receive selexipag therapy and were therefore included in the dual therapy group for safety analysis (N=119 in the triple therapy group and N=127 in the dual therapy group).

[0152] Early cancellation Overall, 24% of subjects discontinued double-blind treatment prematurely (i.e., selexipag / placebo) before EOMOP. See Tables 3 and 4. The most frequent reasons for discontinuation of double-blind treatment were physician discretion due to adverse events (15 [12.6%] subjects in the triple therapy group and 12 [9.4%] subjects in the dual therapy group), lack of efficacy / treatment failure (3 [2.5%] subjects in the triple therapy group and 10 [7.9%] subjects in the dual therapy group), and death (0 subjects in the triple therapy group and 7 [5.5%] subjects in the dual therapy group).

[0153] [Table 6]

[0154] [Table 7]

[0155] Exposure until EOMOP Table 2 shows a summary of patient disposition up to EOMOP.

[0156] [Table 8]

[0157] The median duration of exposure to double-blind treatment until EOMOP was 477 days for triple therapy and 399 days for double therapy. See Table 7.

[0158] [Table 9]

[0159] The median individual maintenance dose of selexipag was 1200 μg b.id for triple therapy. See Table 8.

[0160] [Table 10]

[0161] Primary efficacy endpoint: The primary endpoint was not met. Triple therapy reduced PVR at week 26 similarly to dual therapy. The ANCOVA-adjusted geometric mean of the baseline to week 26 ratio was 0.46 (54% PVR reduction) for triple therapy and 0.48 (52% PVR reduction) for dual therapy, yielding a geometric mean ratio (triple vs. dual) of 0.96 (95% CL: 0.86, 1.07, p=0.4239). See Table 9. Missing assessments at week 26 were imputed using LOCF for 11 (8.9%) subjects in the triple therapy group and for 7 (5.6%) subjects in the dual therapy group. The median baseline PVR [Q1, Q3] was 880.0 [673.7, 1131.0] in the triplet group and 932.7 [712.6, 1220.5] in the dual therapy group. At week 26, the median PVR [Q1, Q3] was 378.2 [272.7, 581.8] in the triplet group and 443.7 [306.9, 585.5] in the dual therapy group. To interpret these data, a PVR >240 dyne·sec / cm was required. 5 It is important to consider that this indicates pulmonary hypertension.

[0162] [Table 11]

[0163] The ANCOVA-adjusted change from baseline to week 26 (sensitivity analysis) was −472.1 dyne·sec / cm for triple therapy. 5 , and −480.0 dyne·sec / cm for dual therapy. 5 is 8 dyne·sec / cm 5 The treatment difference (3-drug minus 2-drug) was 0.8041 (95% CL: -55.1, 71.0, p=0.8041). See Table 10 and Figures 3 and 4.

[0164] [Table 12]

[0165] All sensitivity / supportive analyses were consistent with the primary analysis: treatment effects were consistent across subgroups (there were no significant treatment-by-subgroup interactions).

[0166] Key secondary efficacy endpoint The change in 6MWD from baseline to week 26 was similar in both groups (ANCOVA-adjusted mean = +56.4 m for dual therapy vs. +55.0 m for triple therapy; mean difference (triplet-drug): -1.4 m [95% CL: -19.4, 16.5]; p = 0.8758). See Table 11 and Figure 5. The median baseline 6MWD [Q1, Q3] was 354 [267, 415] in the initial triple therapy group and 366 [255, 432] in the initial dual therapy group. At week 26, the median [Q1, Q3] was 405 [334, 470] in the initial triple therapy group and 421 [338, 482] in the initial dual therapy group. The 6MWD is used in multiparameter risk assessment of patients with PAH, and values ​​at 26 weeks should be interpreted relative to the established "low risk" threshold of 440 m.

[0167] [Table 13]

[0168] Changes in NT-proBNP from baseline to week 26 were similar in both groups (ANCOVA-adjusted geometric mean of the ratio of baseline to week 26 = 0.25 (75% reduction) for dual therapy vs. 0.26 (74% reduction) for triple therapy. Geometric mean ratio (double vs. triple therapy): 1.03 [95% CL: 0.77, 1.37], p=0.8529). See Table 12.

[0169] [Table 14]

[0170] Triple therapy reduced the risk of developing a disease progression event (centrally adjudicated) by 7 days after EOMOP by 41% compared with dual therapy (hazard ratio for triple therapy vs. dual therapy 0.59, 95% CL 0.32, 1.09, p = 0.0867 by two-sided log-rank). A total of 16 (13.0%) subjects in triple therapy and 27 (21.8%) subjects in dual therapy experienced at least one event. See Table 13 and Figure 6. The most frequently reported first event was "hospitalization due to worsening PAH." Among patients with an event, the proportion of "hospitalization due to worsening PAH" was 62.5% in the triple therapy group compared with 70.4% in the dual therapy group. There were no deaths as the first event in patients in the triple therapy group compared with 14.8% in the dual therapy group.

[0171] [Table 15]

[0172] 99.2% of subjects on triple therapy and 97.5% of subjects on dual therapy did not worsen in WHO functional class from baseline to week 26. See Table 14. The odds of no deterioration at week 26 were similar for triple therapy compared with dual therapy (odds ratio: 3.18, 95% CL: 0.32, 31.82, two-sided p=0.3260). Of note, 53.7% of subjects on triple therapy and 52.4% of subjects on dual therapy experienced improvement in WHO functional class at week 26.

[0173] [Table 16]

[0174] safety Overall, 119 (100%) subjects in the triplet group and 123 (96.9%) subjects in the dual therapy group experienced at least one treatment-emergent adverse event (TEAE) by EOMOP. See Table 15. The most common TEAEs in the triplet group were headache (68.9%), diarrhea (53.8%), nausea (47.9%), peripheral edema (37.0%), pain in extremity (30.3%), and jaw pain (29.4%), and in the dual therapy group were headache (60.6%), peripheral edema (36.2%), diarrhea (31.5%), and nausea (25.2%). See Table 15. There were no differences in peripheral edema, a common adverse drug reaction and symptom of ERAs, between treatment groups. However, the incidence of peripheral edema in both treatment groups (approximately 36%) was higher than expected. This observation may reflect the difficulty of titrating diuretics in newly diagnosed (and generally diuretic-naive) patients while starting two or three PAH medications within a short period of time.

[0175] Fifty-one [42.9%] subjects on triple therapy and 40 [31.5%] subjects on dual therapy experienced at least one serious TEA by EOMOP.

[0176] [Table 17-1]

[0177] [Table 17-2]

[0178] [Table 18-1]

[0179] [Table 18-2]

[0180] TEAEs leading to premature discontinuation of double-blind treatment were reported in 19 (16.0%) subjects in the triplet group and 17 (14.2%) subjects in the doublet group. See Table 17.

[0181] [Table 19]

[0182] Eleven subjects died on study by EOMOP (2 in the triplet and 9 in the doublet). See Table 18.

[0183] [Table 20]

[0184] Fifteen [12.8%] subjects in the triple therapy group and 11 [9.1%] subjects in the dual therapy group experienced at least one treatment-emergent liver test abnormality (AST or ALT ≥ 3 ULN) by EOMOP. See Table 19. Two cases with increased AST / ALT ≥ 3 x ULN associated with total bilirubin > 2 x ULN were observed in the initial triple therapy group. MACE was reported in one patient in the triple therapy group and five patients in the initial dual therapy group.

[0185] [Table 21]

[0186] summary In a post hoc exploratory analysis of time to death, initial triple therapy reduced the risk of death by 77% (95% CL: -4.95) compared with initial doublet therapy. Based on available data, selexipag as part of an initial triplet regimen was well tolerated, and the safety profile was consistent with previous studies.

[0187] (i) Short-term effectiveness In summary, the changes in hemodynamic and functional parameters from baseline to week 26 were significant and similar in the two treatment groups. These results support the efficacy of macitentan in combination with tadalafil in patients with newly diagnosed PAH.

[0188] (ii) Long-term efficacy The long-term efficacy of initial triple therapy versus initial dual therapy was assessed by time to first disease progression event by EOMOP + 7 days. Initial triple therapy reduced the risk of disease progression by 41% compared with dual therapy (Figure 6). A total of 16 patients (13.0%) in the triple therapy group and 27 patients (21.8%) in the dual therapy group experienced a disease progression event. These results in favor of the initial triple therapy were supported by fewer hospitalizations for worsening PAH and fewer deaths from any cause.

[0189] Further postmortem analysis A further post-hoc analysis of the study of Example 1 was performed.

[0190] A. Time to first disease progression event Patients' time to first disease progression event was assessed. For example, time to first disease progression event until first treatment discontinuation of any of the three study drugs was analyzed. See Figure 7. Time to death due to PAH or hospitalization due to worsening PAH until EOMOP (and EOMOP + 7 days) is shown in Figures 8 and 8A. Time to death or first hospitalization (all cause) until EOMOP (and EOMOP + 7 days) is shown in Figures 9 and 9A, and time to death (all cause) from randomization until EOMOP is shown in Figure 10.

[0191] B. Time to any disease progression event The cumulative number of disease progression events by EOMOP+7 days was also analyzed. See Table 20 and Figure 25.

[0192] [Table 22]

[0193] In general, these results indicate that triple therapy reduces the recurrence of disease progression events.

[0194] An analysis of the cumulative number of deaths due to PAH or hospitalizations due to worsening PAH up to EOMOP+7 days was also performed. See Table 21.

[0195] [Table 23]

[0196] In general, these results indicate that triple therapy reduces recurrent PAH hospitalizations.

[0197] C. Disease progression based on hemodynamic parameters Further analysis of disease progression based on patients' hemodynamic parameters was performed (up to EOMOP+7 days). See Figure 11: Median PVR at baseline (patients with PVR < 888 dyne sec / cm) 5) and Figure 12: Median PVR at baseline (patients with PVR ≥ 888 dyne·sec / cm 5 ) and Figure 14: Time to disease progression by baseline mPAP (patient mPAP < 52mmHg); Figure 15: Time to disease progression by median mRAP at baseline (patient mRAP < 8mmHg) and Figure 16: Time to disease progression by median mRAP (patient mRAP ≥ 8mmHg); Figure 17: CI at baseline (patient CI ≥ 2.1L / min / m 2 ) and Figure 18: Time to disease progression by CI at baseline (patients with CI < 2.1 L / min / m 2 ) ; Figure 19: Time to disease progression by median NT-proBNP at baseline (patients NT-proBNP<1360ng / L) and Figure 20: Time to disease progression by median NT-proBNP at baseline (patients NT-proBNP>=1360ng / L).

[0198] In general, these results indicate that a reduced risk of disease progression is observed with triple versus doublet combinations, regardless of baseline cardiopulmonary hemodynamic severity.

[0199] Example 2 Further post-hoc analyses of the studies in Example 1 were performed up to and including EOS. See, e.g., Figures 21-26.

[0200] [Table 24]

[0201] [Table 25]

[0202] [Table 26]

[0203] [Table 27]

[0204] [Table 28]

[0205] [Table 29]

[0206] [Table 30]

[0207] Summary of the analysis Exploratory analyses of time to disease progression suggested improved long-term outcomes with initial triplet therapy compared with initial doublet therapy (observed in EOMOP (primary analysis) and EOS (supportive analysis)). Post-hoc analyses including assessment of all disease progression events are consistent with this trial (observed in EOMOP (primary analysis) and EOS (supportive analysis)).

[0208] These results show that initial triple therapy reduced the risk of death by 68% by the end of the study compared with initial doublet therapy. See Figure 24. These results also show that initial triple therapy reduced the time to disease progression by 36% by the end of the study compared with initial doublet therapy. See Figure 22.

[0209] The safety observations from the EOS analysis are consistent with the findings from EOMOP.

Claims

1. A method for reducing the risk of disease progression in patients with pulmonary arterial hypertension (PAH), comprising administering to a patient in need thereof an initial triple therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 (PDE-5) inhibitor, and a prostacyclin receptor agonist (IP receptor agonist).

2. 2. The method of claim 1, wherein the reduced risk of disease progression is for a patient population with PAH receiving initial dual combination therapy of the ERA and the PDE-5 inhibitor.

3. 3. The method of claim 1 or 2, wherein the ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof, the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharmaceutically acceptable salt thereof, and the IP receptor agonist is selexipag, 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), or a pharmaceutically acceptable salt thereof.

4. 4. The method of claim 3, wherein the ERA is macitentan, the PDE-5 inhibitor is tadalafil, and the IP receptor agonist is selexipag.

5. The method of any one of claims 1 to 4, wherein the patient is treatment-naive for PAH.

6. 6. The method of any one of claims 1 to 5, wherein the patient's initial diagnosis of PAH is made within six months of initiating the initial triple therapy.

7. 7. The method of any one of claims 1-6, wherein the patient has a resting mean pulmonary arterial hypertension (mPAP) of about 25 mmHg or greater, a mean pulmonary artery wedge pressure (PAWP) of about 15 mmHg or less, and a pulmonary vascular resistance (PVR) of about 240 dyne-sec / cm or greater at the start of the initial triple therapy.

8. 8. The method of any one of claims 1-7, wherein the patient has a 6-minute walk distance (6MWD) of about 50 meters or greater at the start of the initial triple therapy.

9. 9. The method of any one of claims 4 to 8, wherein the macitentan is administered in an amount of about 10 mg once daily.

10. 10. The method of any one of claims 4 to 9, wherein the tadalafil is administered in an amount of about 20 mg to about 40 mg once daily.

11. 11. The method of any one of claims 4 to 10, wherein the tadalafil is administered in an amount of about 40 mg once daily.

12. 12. The method of any one of claims 4 to 11, wherein the selexipag is administered in an amount of about 200 μg to about 1600 μg twice daily.

13. 13. The method of any one of claims 4 to 12, wherein each of the macitentan, the tadalafil, and the selexipag is orally administered in the form of one or more tablets.

14. 13. The method of any one of claims 4 to 12, wherein the macitentan and the tadalafil are administered orally in the form of a single tablet, and the selexipag is administered orally in the form of one or more separate tablets.

15. 15. The method of any one of claims 2-14, wherein the initial triple therapy reduces the risk of disease progression by about 30-40% relative to the initial dual therapy.

16. 16. The method of any one of claims 1 to 15, wherein the disease progression comprises hospitalization due to worsening PAH, clinical worsening of PAH, or death.

17. Initial triple therapy with an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 (PDE-5) inhibitor, and a prostacyclin receptor agonist (IP receptor agonist) to reduce the risk of disease progression in patients with pulmonary arterial hypertension (PAH).

18. 18. The initial triple therapy of claim 17, wherein the reduced risk of disease progression is for a patient population with PAH receiving initial dual therapy of the ERA and the PDE-5 inhibitor.

19. 19. The initial triple combination therapy of claim 17 or 18, wherein the ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof, the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharmaceutically acceptable salt thereof, and the IP receptor agonist is selexipag, 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), or a pharmaceutically acceptable salt thereof.

20. 20. The initial triple therapy of claim 19, wherein the ERA is macitentan, the PDE-5 inhibitor is tadalafil, and the IP receptor agonist is selexipag.

21. The initial triple therapy of any one of claims 17 to 20, wherein the patient is treatment-naive for PAH.

22. 22. The initial triple therapy of any one of claims 17 to 21, wherein the patient's initial diagnosis of PAH is made within six months of initiation of the initial triple therapy.

23. 23. The initial triple therapy of any one of claims 17-22, wherein the patient has a resting mean pulmonary arterial hypertension (mPAP) of about 25 mmHg or greater, a mean pulmonary artery wedge pressure (PAWP) of about 15 mmHg or less, and a pulmonary vascular resistance (PVR) of about 240 dyne-sec / cm or greater at the start of the initial triple therapy.

24. 24. The initial triple therapy of any one of claims 17-23, wherein the patient has a 6-minute walk distance (6MWD) of about 50 meters or greater at the start of the initial triple therapy.

25. 25. The initial triple therapy of any one of claims 20-24, wherein the macitentan is formulated to be administered in an amount of about 10 mg once daily.

26. 26. The initial triple therapy of any one of claims 20-25, wherein the tadalafil is formulated to be administered in an amount of about 20 mg to about 40 mg once daily.

27. 27. The initial triple therapy of any one of claims 20 to 26, wherein the tadalafil is formulated to be administered in an amount of about 40 mg once daily.

28. 28. The initial triple therapy of any one of claims 20-27, wherein the selexipag is formulated to be administered in an amount of about 200 μg to about 1600 μg twice daily.

29. 29. The initial triple therapy of any one of claims 20-28, wherein each of the macitentan, the tadalafil, and the selexipag is formulated for oral administration in the form of one or more tablets.

30. 29. The initial triple therapy of any one of claims 20-28, wherein the macitentan and the tadalafil are formulated for oral administration in the form of a single tablet, and the selexipag is formulated for oral administration in the form of one or more separate tablets.

31. 31. The initial triple therapy of any one of claims 18 to 30, wherein the initial triple therapy reduces the risk of disease progression by about 30-40% relative to the initial dual therapy.

32. 32. The method of any one of claims 17 to 31, wherein the disease progression comprises hospitalization due to worsening PAH, clinical worsening of PAH, or death.

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