Combination of macitentan and tadalafil for treatment of pulmonary arterial hypertension

Abstract

The present disclosure relates to methods for treating pulmonary arterial hypertension (PAH) comprising administering to a human patient in need thereof a fixed dose combination (FDC) comprising macitentan and tadalafil. The present disclosure also provides a method of reducing pulmonary vascular resistance (PVR) and / or increasing six minute walking distance (6MWD) in a patient suffering from PAH, the method comprising transitioning the patient to FDC of macitentan and tadalafil. In some embodiments, the patient is not subjected to PAH-specific treatment, is treated with an endothelin receptor antagonist (ERA) monotherapy, or is treated with a phosphodiesterase type 5 inhibitor (PDE-5) monotherapy prior to administration of the FDC.

Description

Technical Field

[0001] The present disclosure relates to methods for treating pulmonary arterial hypertension (PAH). Background Art

[0002] Pulmonary arterial hypertension (PAH) is a serious chronic pulmonary circulatory disorder with diverse etiologies and pathogeneses. PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), potentially leading to right heart failure and death. The complex pathogenesis of PAH involves dysfunction of three key pathways: the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway. The hemodynamic characteristics of PAH are a resting mean pulmonary arterial pressure (mPAP) of at least 25 mmHg (in the latest guidelines, >20 mmHg), where the normal pulmonary artery wedge pressure (PAWP; or left ventricular end-diastolic pressure [LVEDP]) is 15 mmHg or less, and PVR is greater than 3 Wood units (WU) (in the latest guidelines, >2 WU).

[0003] The 2013 clinical classification of pulmonary hypertension grouped many conditions known to cause or be associated with the development of PAH into four groups, based on their similar clinical manifestations, pathology, pathophysiology, prognosis, and most importantly, similar treatment methods. PAH can occur in the absence of an obvious cause / associated etiology (idiopathic), in a familial setting (hereditary), or due to the use of certain drugs or toxins, or it can be associated with connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, or schistosomiasis.

[0004] Currently available PAH-specific treatment options include treatments that target the above three pathways (the endothelin, nitric oxide, and prostacyclin pathways). According to current treatment guidelines, many patients are treated with combination therapies to target multiple pathways at once. Such combination therapies typically require the daily administration of multiple tablets. Summary of the Invention

[0005] The present disclosure provides a method for treating pulmonary arterial hypertension (PAH), the method comprising administering to a human patient in need thereof a fixed-dose combination (FDC) comprising macitentan and tadalafil. Prior to administration of the FDC, the patient has not been treated with PAH-specific treatment, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy. In some embodiments, one or both of B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) are reduced in the patient, such as a reduction in BNP, or such as a reduction in NT-proBNP.

[0006] The present disclosure also provides a method for reducing pulmonary vascular resistance (PVR) and / or increasing six-minute walk distance (6MWD) in a patient with PAH, the method comprising transitioning the patient to a fixed-dose combination (FDC) of macitentan and tadalafil. In a specific embodiment, the patient has not been treated with PAH-specific therapy, treated with ERA monotherapy, or treated with PDE-5 inhibitor monotherapy prior to the transition.

[0007] The present disclosure further provides a method for reducing the level of one or both of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a patient with pulmonary arterial hypertension (PAH), the method comprising transitioning the patient to a fixed-dose combination (FDC) of macitentan and tadalafil. In a specific embodiment, prior to administration of the FDC, the patient has not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy.

[0008] The present disclosure also provides a method for treating pulmonary arterial hypertension, the method comprising: initiating administration to a human patient in need thereof of a fixed-dose combination (FDC) of macitentan and tadalafil; and continuing to administer to a human patient in need thereof a fixed-dose combination (FDC) of macitentan and tadalafil in the event that the patient is identified as biomarker signature positive. A patient is biomarker signature positive if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) that is lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) that is lower than the reference level of NT-proBNP; or (iii) both (i) and (ii). In a specific embodiment, prior to administration of the FDC, the patient has not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy.

[0009] The present disclosure further provides a method for treating pulmonary arterial hypertension, the method comprising administering to a human patient in need thereof a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient is identified as positive for a biomarker profile. A patient is positive for a biomarker profile if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) that is lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) that is lower than the reference level of NT-proBNP; or (iii) both (i) and (ii). In a specific embodiment, prior to administering the FDC, the patient has not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy.

[0010] A method of identifying a patient with pulmonary arterial hypertension who will respond to treatment with a fixed-dose combination (FDC) of macitentan and tadalafil, the method comprising: administering the FDC to a patient in need thereof; and identifying the patient as responsive to treatment with the FDC if the patient is identified as positive for a biomarker profile. In a specific embodiment, prior to administering the FDC, the patient has not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy.

[0011] The present disclosure further provides a fixed-dose combination (FDC) of macitentan and tadalafil for treating pulmonary arterial hypertension (PAH). Prior to administering the FDC to a patient in need thereof, the patient has not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy. In some embodiments, one or both of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) are reduced in the patient, such as a reduction in BNP, or such as a reduction in NT-proBNP.

[0012] The present disclosure also provides a fixed-dose combination (FDC) of macitentan and tadalafil for reducing pulmonary vascular resistance (PVR) and / or increasing six-minute walk distance (6MWD) in a patient with pulmonary arterial hypertension (PAH). The patient has not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy. In some embodiments, one or both of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) are reduced in the patient, such as a reduction in BNP, or such as a reduction in NT-proBNP.

[0013] The present disclosure further provides a fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of reducing the level of one or both of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a patient suffering from pulmonary arterial hypertension (PAH). The patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy.

[0014] The present disclosure also provides a fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of treating pulmonary arterial hypertension. The method comprises: initiating administration of a fixed-dose combination (FDC) of macitentan and tadalafil to a human patient in need thereof, wherein the patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy; and continuing to administer a fixed-dose combination (FDC) of macitentan and tadalafil to a human patient in need thereof if the patient is identified as biomarker signature positive. In some embodiments, the patient is biomarker signature positive if a biological sample obtained from the patient is identified as having a sample level of: (i) B-type natriuretic peptide (BNP) lower than the reference level of BNP; (ii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

[0015] The present disclosure further provides a fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of treating pulmonary arterial hypertension, the method comprising administering a fixed-dose combination (FDC) of macitentan and tadalafil to a human patient in need thereof, wherein the patient is identified as biomarker signature positive. In some embodiments, the patient is biomarker signature positive if a biological sample obtained from the patient is identified as having a sample level of: (i) B-type natriuretic peptide (BNP) lower than the reference level of BNP; (ii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

[0016] The present disclosure also provides a fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of identifying a patient with pulmonary arterial hypertension who will respond to treatment with the FDC of macitentan and tadalafil, the method comprising: administering the FDC to a patient in need thereof; and identifying the patient as responsive to treatment with the FDC if the patient is identified as biomarker signature positive. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the study design of Example 1. In this figure, BL is baseline; EDBT is the end of double-blind treatment, EOLT is the end of open-label treatment; EOS is the end of the study; ERA is endothelin receptor antagonist, FDC is fixed-dose combination, PDE-5i is phosphodiesterase type 5 inhibitor, and V is visit.

[0018] Figure 2 is a schematic diagram of the participant randomization in Example 1.

[0019] Figure 3 is a schematic diagram showing the comparisons made in Example 1.

[0020] Figure 4 is a schematic diagram of the results summary in Example 1.

[0021] Figure 5 is a forest plot of the results of the primary analysis and sensitivity analysis, (full analysis set) M / T FDC compared with macitentan, showing the EDBT / W16 vs. baseline PVR ratio.

[0022] Figure 6 is a forest plot of the results of the primary analysis and sensitivity analysis, (full analysis set) M / T FDC compared with tadalafil, showing the EDBT / W16 vs. baseline PVR ratio.

[0023] Figure 7 is a forest plot of the EDBT vs. baseline PVR ratio (ANCOVA) for subgroups, (full analysis set) M / T FDC compared with macitentan.

[0024] Figure 8 is a forest plot of the EDBT vs. baseline PVR ratio (ANCOVA) for subgroups, (full analysis set) M / T FDC compared with tadalafil.

[0025] Figure 9 is a graph showing the change over time in the mean (±SE) of 6MWD relative to baseline during the combined double-blind and open-label period of the long-term M / T FDC set. In this figure, the number of subjects for which measurements were taken is the number of subjects with no missing values at both baseline and post-baseline time points.

[0026] Figure 10 It is a graph showing the change in the mean (±SE) of 6MWD over time relative to baseline during the combined double-blind and open-label periods of the full analysis set. In this graph, the number of subjects with measurements is the number of subjects with no missing values at both baseline and post-baseline time points.

[0027] Figure 11 It is a graph of the baseline percentage (geometric mean and 95% CL) of NT-proBNP through the analysis visits up to week 94 for the long-term M / T FDC set. In this graph, baseline and on-treatment measurements (from the first study treatment administration until EOT + 7 days) are included. The N (number) of measurements is the number of subjects with no missing values for laboratory tests at the specified time points and at baseline.

[0028] Figure 12 It is a graph of the baseline percentage (geometric mean and 95% CL) of NT-proBNP for the full analysis set (DB-OL combination) through the analysis visits. In this graph, the N (number) of measurements is the number of subjects with no missing values for laboratory tests at the specified time points and at baseline.

[0029] Figure 13A and Figure 13B It is a sensitivity analysis of the post hoc analysis of the primary endpoint, showing the EDBT vs. baseline PVR ratio (ANCOVA) - critical point analysis of the full analysis set. In these graphs, all patients with imputed data for the primary analysis (due to concurrent events or missing data) are considered for this analysis, and missing is considered as the starting point. For each comparison of interest and each stage, multiple imputations with an increment (Δ) of deterioration are applied. For each group, the mean effect (EDBT / baseline PVR ratio) after withdrawal will deteriorate by an amount of 0.15 starting from Δ = 0. The inverse normal combination method (INC) is used to calculate the final p-value.

[0030] Figure 14 It is a forest plot of the EDBT vs. baseline PVR ratio for the full analysis set. n(fdc) = the number of subjects in M / T FDC; n(mon) = the number of subjects in the monotherapy group. In this graph, the PVR values are derived from the assessments provided by the sponsor using a central reader (WCC). The EDBT values correspond to the assessments conducted at the 8th visit / week 16 or at the premature EDBT visit (in the case where the subject prematurely discontinues the DB study treatment), and the marker sizes for the subgroups are based on the number of subjects in each group (if feasible).

[0031] Figure 15A and Figure 15B It is a sensitivity analysis of the primary endpoint - critical point analysis. Figure 15Ais a comparison of M / TFDC with macitentan monotherapy, and Figure 15B is a comparison of M / T FDC with tadalafil monotherapy. In these figures, for each comparison of interest and each stage, multiple imputations with incremental (Δ) worsening were applied. For each group, the mean effect (EDBT / baseline PVR ratio) after dropout will worsen by an amount of 0.15 starting from Δ = 0. The inverse normal combination method (INC) was used to calculate the final p-value.

[0032] Figure 16 is a forest plot of the change in 6MWD from baseline to EDBT, subgroup: full analysis set. In this figure, the interaction p-value was obtained from the following model, which used two-way analysis of covariance (ANCOVA) (once for each pairwise comparison) to analyze the change in 6MWD from baseline to EDBT, utilizing the factors of randomized treatment group, stratification factors (never treated, previously used ERA, or previously used PDE-5i), subgroup, subgroup*treatment interaction, and the continuous covariate of baseline 6MWD. The EDBT value corresponds to the assessment conducted at the 8th visit / 16th week or at an early EDBT visit (in the case where the subject prematurely discontinues DB study treatment). The marker size for the subgroup is based on the number of subjects in each group (if feasible). Detailed implementation mode

[0033] In the present disclosure, unless the context clearly indicates otherwise, the singular forms "a", "an", "the", and "said" include plural meanings, and references to specific numerical values include at least that specific value. Thus, for example, a reference to "a material" refers to at least one of such materials, as well as equivalents of such materials known to those skilled in the art, and the like.

[0034] When a value is expressed as an approximation using the descriptors "about" or "substantially", it should be understood that that specific value constitutes another embodiment. Generally speaking, the use of the terms "about" or "substantially" indicates approximations that may vary depending on the desired characteristics sought for the disclosed subject matter and will be interpreted based on their function in the particular context in which the approximation is used. Those skilled in the art will be able to interpret these approximations routinely. In some cases, the number of significant digits used for a particular value can be a non-limiting method for determining the range of the words "about" or "substantially". In other cases, the gradients used in a series of values can be used to determine the expected range applicable to the terms "about" or "substantially" for each value. Where ranges are present, all ranges include the end values and are combinable. That is, a reference to a value specified within a range includes each value within that range.

[0035] When a list is provided, unless otherwise indicated, each individual element of the list and each combination thereof are understood to be separate embodiments. For example, a list of embodiments presented as "A, B, or C" will be understood to include the embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0036] It should be understood that, for clarity, certain features of the present disclosure are presented in the context of separate embodiments but may also be provided in combination in a single embodiment. That is, each individual embodiment is considered combinable with any other embodiment, unless clearly incompatible or excluded, and such combination is considered another embodiment. Conversely, for brevity, the various features of the present disclosure are presented in the context of a single embodiment and may also be provided individually or in any sub-combination. It should also be noted that the claims may be drafted to exclude any optional elements. Similarly, this statement is intended to serve as a precedent basis when using such special terms in connection with the recitation of claim elements such as "alone", "solely", etc. or when using "negative" limitations. Finally, although an embodiment may be described as part of a series of steps or a more general structure, each such step itself may also be considered an independent embodiment.

[0037] As used herein, unless otherwise specified, the term "treatment" and the like shall include the management and care of a patient for combating a disease, disorder, or condition. The term "treatment" also includes administering a compound or pharmaceutical composition as described herein to (a) alleviate one or more symptoms or complications of a disease, disorder, or condition; (b) prevent the onset of one or more symptoms or complications of a disease, disorder, or condition; and / or (c) eliminate one or more symptoms or complications of a disease, disorder, or condition.

[0038] The terms "subject" and "patient" are used interchangeably herein and refer to a human being who has become the object of treatment, observation, or experiment. Preferably, the patient has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient has East Asian ancestry. In other embodiments, the patient is Chinese.

[0039] It should be understood that references herein to a method of treatment using one or more compounds or their formulations (e.g., a fixed-dose combination of macitentan and tadalafil) should also be construed as references to:

[0040] - one or more compounds or their formulations (e.g., a fixed-dose combination of macitentan and tadalafil) used in the method of treatment; and / or

[0041] - Use of one or more compounds or their formulations (e.g., a fixed-dose combination of macitentan and tadalafil) in the preparation of a medicament for treating a pathological condition.

[0042] Therapeutic method / use

[0043] The methods and uses described herein relate to the treatment of pulmonary arterial hypertension (PAH). The method comprises administering to a human patient in need thereof a fixed-dose combination (FDC) comprising macitentan and tadalafil.

[0044] The methods and uses herein relate to treating patients in a patient population suffering from PAH. Prior to administration of the FDC, the patients have not been treated with PAH-specific therapy, treated with endothelin receptor antagonist (ERA) monotherapy, or treated with type 5 phosphodiesterase inhibitor (PDE-5) inhibitor monotherapy. In some embodiments, the patients have not been treated with PAH-specific therapy prior to administration of the FDC. In other embodiments, the patients have been treated with ERA monotherapy prior to administration of the FDC. In further embodiments, the patients have been treated with PDE-5 inhibitor monotherapy prior to administration of the FDC.

[0045] For ERA or PDE-5 inhibitor monotherapy, the patients may have been treated with the monotherapy for at least about 3 months prior to administration of the FDC. In some embodiments, the patients have been receiving monotherapy for at least about 6 months, about 9 months, about 12, about 18 months, about 24 months, about 30 months, about 36 months or longer prior to administration of the FDC.

[0046] As used herein, the term "ERA monotherapy" refers to the administration of one ERA in the absence of another ERA as defined herein that is useful for treating PAH. Similarly, as used herein, the term "PDE-5 inhibitor monotherapy" refers to the administration of one PDE-5 inhibitor in the absence of another PDE-5 inhibitor as defined herein that is useful for treating PAH.

[0047] The method and use comprise administering a therapeutically effective amount of macitentan. As used herein, the term "therapeutically effective amount" means an amount of an active compound or agent that will elicit the biological or pharmaceutical response sought by a researcher, veterinarian, medical doctor, or other clinician (including alleviation of the symptoms of the disease or disorder being treated) in a tissue system, animal, or human. In some embodiments, the therapeutically effective amount corresponds to the free base or free base morphological form of macitentan. In other embodiments, the therapeutically effective amount corresponds to a salt, solvate, or hydrate of macitentan. Unless otherwise stated, the amounts disclosed herein correspond to the free form of macitentan, excluding, for example, solvents (such as in solvates or hydrates) or counterions (such as in pharmaceutically acceptable salts).

[0048] The ERA monotherapy can be once or twice daily. In some aspects, the ERA monotherapy is once daily. In other aspects, the ERA monotherapy is twice daily. In certain embodiments, the ERA monotherapy comprises administering less than about 15 mg of ERA per day. In additional embodiments, the ERA monotherapy comprises administering 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 of ERA per day. In other embodiments, the ERA monotherapy comprises administering about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, or about 10 mg to about 15 mg of ERA per day. In yet additional embodiments, the ERA monotherapy comprises administering about 5 mg to about 15 mg of ERA per day. In yet additional embodiments, the ERA monotherapy comprises administering about 10 mg of ERA per day. In certain embodiments, the ERA is administered in two or more separate doses to achieve the daily dose. For example, two 20 mg tablets containing ERA are administered to provide 40 mg of ERA. In some embodiments, the ERA monotherapy comprises 10 mg of macitentan. In other embodiments, the ERA monotherapy comprises about 5 mg to about 10 mg of ambrisentan per day. In additional embodiments, the ERA monotherapy comprises about 5 mg of ambrisentan per day. In still other embodiments, the ERA monotherapy comprises about 10 mg of ambrisentan per day.

[0049] In some aspects, the ERA monotherapy involves administering bosentan once or twice daily. In some aspects, the bosentan monotherapy is once daily. In other aspects, the bosentan monotherapy is twice daily. In some embodiments, the bosentan monotherapy involves administering from about 50 mg to about 150 mg of bosentan twice daily. In additional embodiments, the bosentan monotherapy involves administering about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of bosentan twice daily. In other embodiments, the bosentan monotherapy involves administering from about 50 mg to about 150 mg, from about 50 mg to about 140 mg, from about 50 mg to about 130 mg, from about 50 mg to about 120 mg, from about 50 mg to about 110 mg, from about 50 mg to about 100 mg, from about 50 mg to about 90 mg, from about 50 mg to about 80 mg, from about 50 mg to about 70 mg, from about 50 mg to about 60 mg, from 60 mg to about 150 mg, from about 60 mg to about 140 mg, from about 60 mg to about 130 mg, from about 60 mg to about 120 mg, from about 60 mg to about 110 mg, from about 60 mg to about 100 mg, from about 60 mg to about 90 mg, from about 60 mg to about 80 mg, from 70 mg to about 150 mg, from about 70 mg to about 140 mg, from about 70 mg to about 130 mg, from about 70 mg to about 120 mg, from about 70 mg to about 110 mg, from about 70 mg to about 100 mg, from about 70 mg to about 90 mg, from about 70 mg to about 80 mg, from 80 mg to about 150 mg, from about 80 mg to about 140 mg, from about 80 mg to about 130 mg, from about 80 mg to about 120 mg, from about 80 mg to about 110 mg, from about 80 mg to about 100 mg, from about 80 mg to about 90 mg, from 90 mg to about 150 mg, from about 90 mg to about 140 mg, from about 90 mg to about 130 mg, from about 90 mg to about 120 mg, from about 90 mg to about 110 mg, from about 90 mg to about 100 mg, from 100 mg to about 150 mg, from about 100 mg to about 140 mg, from about 100 mg to about 130 mg, from about 100 mg to about 120 mg, from about 100 mg to about 110 mg, from 110 mg to about 150 mg, from about 110 mg to about 140 mg, from about 110 mg to about 130 mg, from about 110 mg to about 120 mg, from about 120 mg to about 150 mg, from about 120 mg to about 140 mg, from about 120 mg to about 130 mg, from about 130 mg to about 150 mg, from about 130 mg to about 140 mg, or from about 140 mg to about 150 mg of bosentan. In additional embodiments, the bosentan monotherapy involves administering 62.5 mg of bosentan twice daily.In still other embodiments, bosentan monotherapy comprises administering about 125 mg of bosentan twice daily. The PDE-5 inhibitor in the monotherapy may be administered once daily, twice daily, or three times daily. In some embodiments, the PDE-5 monotherapy is once daily. In other embodiments, the PDE-5 monotherapy is twice daily. In additional embodiments, the PDE-5 monotherapy is three times daily.

[0050] The amount of PDE-5 inhibitor for PDE-5 inhibitor monotherapy can be selected by a physician or other healthcare provider based on factors such as the severity of the disease, the physical characteristics of the patient, etc. In some embodiments, PDE-5 inhibitor monotherapy comprises administering about 5 mg of the PDE-5 inhibitor once daily. In some embodiments, PDE-5 inhibitor monotherapy comprises administering from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 100 mg, from about 40 mg to about 90 mg, from about 40 mg to about 80 mg, from about 40 mg to about 70 mg, from about 40 mg to about 60 mg, from about 40 mg to about 50 mg, from about 50 mg to about 100 mg, from about 50 mg to about 90 mg, from about 50 mg to about 80 mg, from about 50 mg to about 70 mg, from about 50 mg to about 60 mg, from about 60 mg to about 100 mg, from about 60 mg to about 90 mg, from about 60 mg to about 80 mg, from about 60 mg to about 70 mg, from about 70 mg to about 100 mg, from about 70 mg to about 90 mg, from about 70 mg to about 80 mg, from about 80 mg to about 100 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg of the PDE-5 inhibitor once daily. In additional embodiments, PDE-5 inhibitor monotherapy comprises administering from about 20 mg to about 40 mg of the PDE-5 inhibitor once daily. In still other embodiments, PDE-5 inhibitor monotherapy comprises administering about 20 mg of the PDE-5 inhibitor once daily. In additional embodiments, PDE-5 inhibitor monotherapy comprises administering about 40 mg of the PDE-5 inhibitor once daily. In certain embodiments, two doses of the PDE-5 inhibitor are administered to achieve the daily dose. For example, two 20 mg tablets containing the PDE-5 inhibitor are administered to provide 40 mg of the PDE-5 inhibitor. For example, a patient typically administers two 20 mg tadalafil tablets once daily (total daily dose of 40 mg) during tadalafil monotherapy. In certain embodiments, three doses of the PDE-5 inhibitor are administered to achieve the daily dose.In other embodiments, sildenafil is administered at a total daily dose of 60 mg to 120 mg, or in some embodiments, at a total daily dose of 60 mg to 240 mg. In certain embodiments, for example, sildenafil is administered three times a day at a dose of 20 mg (total daily dose of 60 mg). In other embodiments, sildenafil is administered three times a day at up to 80 mg (total daily dose of 240 mg). In additional embodiments, vardenafil is administered at a total daily dose of 10 mg.

[0051] As used herein, the term "fixed dose combination" or "FDC" refers to an oral dosage unit containing a specific amount of macitentan and tadalafil. Such FDCs are also referred to as "dual pathway agents". In some embodiments, the FDC is a solid. Examples of solid FDCs include, for example, lozenges, films, pastes, troches, granules, powders, capsules, pills such as caplets, capsule pills, tablets, and capsules (each including immediate release, timed release, and sustained release pills). Preferably, the FDC is a tablet. If desired, tablets or caplets can be sugar-coated or enteric-coated or otherwise compounded by standard techniques to obtain an FDC that provides long-acting advantages.

[0052] In certain embodiments, the FDC contains less than about 15 mg of macitentan. In additional embodiments, the FDC contains 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 of macitentan. In other embodiments, the FDC contains about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, or about 10 mg to about 15 mg of macitentan. In yet additional embodiments, the FDC contains about 5 mg to about 15 mg of macitentan. In yet additional embodiments, the FDC contains about 10 mg of macitentan.

[0053] The FDC also contains a certain amount of tadalafil. In some embodiments, the FDC contains about 5 mg of tadalafil. In other embodiments, the FDC contains from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 10 mg to about 90 mg, from about 10 mg to about 80 mg, from about 10 mg to about 70 mg, from about 10 mg to about 60 mg, from about 10 mg to about 50 mg, from about 10 mg to about 40 mg, from about 10 mg to about 30 mg, from about 10 mg to about 20 mg, from about 20 mg to about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about 70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg, from about 30 mg to about 40 mg, from about 40 mg to about 100 mg, from about 40 mg to about 90 mg, from about 40 mg to about 80 mg, from about 40 mg to about 70 mg, from about 40 mg to about 60 mg, from about 40 mg to about 50 mg, from about 50 mg to about 100 mg, from about 50 mg to about 90 mg, from about 50 mg to about 80 mg, from about 50 mg to about 70 mg, from about 50 mg to about 60 mg, from about 60 mg to about 100 mg, from about 60 mg to about 90 mg, from about 60 mg to about 80 mg, from about 60 mg to about 70 mg, from about 70 mg to about 100 mg, from about 70 mg to about 90 mg, from about 70 mg to about 80 mg, from about 80 mg to about 100 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg of tadalafil. In further embodiments, the FDC contains from about 20 mg to about 40 mg of tadalafil. In still other embodiments, the FDC contains about 20 mg of tadalafil. In additional embodiments, the FDC contains about 40 mg of tadalafil.

[0054] The FDC is administered once daily, twice daily, three times daily, etc. However, once-daily administration of the FDC is preferred.

[0055] The present disclosure also provides for increasing the amount of tadalafil in the FDC from a lesser amount to a greater amount over a period of time. In some embodiments, the starting amount of tadalafil is present in the FDC for a first period of time. In some embodiments, the first period of time is about 14 days or less. In other embodiments, the first period of time is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 14 days. In additional embodiments, the first period of time is from 1 day to 14 days, from 1 day to 12 days, from 1 day to 10 days, from 1 day to 8 days, from 1 day to 6 days, from 1 day to 5 days, from 1 day to 4 days, from 2 days to 14 days, from 2 days to 12 days, from 2 days to 10 days, from 2 days to 8 days, from 2 days to 6 days, from 2 days to 4 days, from 3 days to 14 days, from 3 days to 12 days, from 3 days to 10 days, from 3 days to 8 days, from 3 days to 6 days, from 3 days to 5 days, from 4 days to 12 days, from 4 days to 10 days, from 4 days to 8 days, from 4 days to 6 days, from 5 days to 15 days, from 5 days to 12 days, from 5 days to 10 days, from 5 days to 8 days, from 6 days to 14 days, from 6 days to 12 days, from 6 days to 10 days, from 6 days to 8 days, from 8 days to 14 days, from 8 days to 12 days, from 8 days to 10 days, from 10 days to 14 days, from 10 days to 12 days, or from 12 days to 14 days. In still other embodiments, the first period of time is 7 days. Then the starting amount of tadalafil is increased (i.e., up-titrated) to a subsequent amount for a subsequent period of time. For example, a second amount of tadalafil is administered for a second period of time. Generally, up-titration is performed when the patient has not undergone PAH-specific treatment. Up-titration is also performed when the patient is treatment-naïve to any PDE-5 inhibitor therapy or for patients transitioning from ERA monotherapy. For such patients, and in a specific embodiment, the FDC contains 20 mg of tadalafil and is up-titrated by administering a second FDC having a higher amount of tadalafil, such as 40 mg. The FDC allows for the administration of fewer pills and reduces the risk of taking an incorrect amount. In a specific embodiment, prior to administering the FDC having a higher amount of tadalafil (e.g., 40 mg), the FDC having a lower amount of tadalafil (e.g., 20 mg) is administered once daily for seven days.

[0056] In other embodiments, prior to administering the FDC having a higher amount of tadalafil (e.g., 40 mg), up-titration is performed using separate tablets. For example, up-titration includes administering a 10 mg macitentan tablet and a separate 20 mg tadalafil tablet for a first period of time, such as once daily for seven days, and then administering the FDC having a higher amount of tadalafil (e.g., 40 mg of tadalafil) for a second period of time.

[0057] In certain embodiments, prior to administration of the FDC, the monotherapy is sildenafil and the amount of tadalafil in the FDC is not up - titrated over a period of time, e.g., not up - titrated from a smaller amount to a larger amount. For example, in such embodiments, the tadalafil in the FDC is not up - titrated, where the starting amount of tadalafil in the FDC contains a higher amount of tadalafil (such as 40 mg).

[0058] The FDC is administered for a period of time as determined by one of ordinary skill in the art. In some embodiments, the FDC is administered for at least about 12 weeks. In additional embodiments, the FDC is administered for at least about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 or about 52 weeks. In other embodiments, the FDC is administered for about 16 weeks. In yet additional embodiments, the FDC is administered for about 40 weeks.

[0059] To prepare the solid FDC, macitentan and tadalafil are mixed with a pharmaceutical carrier / additive such as starch, a sweetening agent such as sugar, a diluent, a coloring agent, a granulating agent, a preservative, a lubricant, a flavoring agent, a binder, a disintegrant, etc. For tablets, conventional tableting ingredients can be used, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dibasic calcium phosphate, or gums, and other pharmaceutical diluents, such as water, ethanol, glycerol, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or β - lactose), corn sweeteners, natural gums and synthetic gums (such as gum arabic, tragacanth), or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0060] To prepare the FDC, macitentan and tadalafil may be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which may take a variety of forms depending on the dosage form required for administration (e.g., oral or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in “The Handbook of Pharmaceutical Excipients” published by the American Pharmaceutical Association and the British Pharmaceutical Association, the disclosure of which is hereby incorporated by reference. In a specific embodiment, the excipients in the tablet core include one or more of, for example, hydroxypropyl cellulose, lactose monohydrate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polysorbates (such as polysorbate 80), povidones (such as povidone K30), sodium lauryl sulfate, and sodium starch glycolate (such as type A sodium starch glycolate). In the case where the FDC tablet is film-coated, the film-coating material includes one or more of, for example, hydroxypropyl methyl cellulose, lactose monohydrate, talc, titanium dioxide, and triacetin.

[0061] Methods of formulating the FDC are described in a number of publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 - 3, edited by Lieberman et al.; 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.; published by Marcel Dekker, Inc., the disclosures of which are hereby incorporated by reference.

[0062] The methods and uses described herein are also used to reduce pulmonary vascular resistance (PVR) and / or increase six-minute walk distance (6MWD) in a patient population with PAH (such as the patient population disclosed in Example 1) relative to patients in the patient population who have not been treated with PAH-specific therapy, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy. In some embodiments, the method or use reduces PVR. In other embodiments, the method or use increases 6MWD. In additional embodiments, the method or use reduces PVR and increases 6MWD.

[0063] As described above, in certain methods or uses, a patient has not been treated with a PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy, and then transitions to a fixed-dose combination (FDC) of macitentan and tadalafil.

[0064] In certain aspects, the method and use result in a reduction in PVR of about 15% to about 45% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy. In some embodiments, the method and use result in a reduction in PVR of about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy. In other embodiments, the method and use result in a reduction in PVR of about 15% to about 40%, about 15% to about 35%, about 15% to about 30%, about 15% to about 25%, about 15% to about 20%, about 20% to about 45%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 20% to about 25%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 45%, about 35% to about 40%, or about 40% to about 45% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy. In additional embodiments, the method and use result in a reduction in PVR of about 18% to about 39% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy. In still other embodiments, the method and use result in a reduction in PVR of about 20% to about 36% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy. In additional embodiments, the method results in a reduction in PVR of about 28% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy. In still other embodiments, the method and use result in a reduction in PVR of about 29% relative to patients in a patient population who have not been treated with a PAH-specific therapy, have been treated with macitentan monotherapy, or have been treated with tadalafil monotherapy.

[0065] In other respects, the method and use result in a reduction in PVR of about 15% to about 45% relative to patients in the patient population who have not received PAH-specific treatment. In some embodiments, the method and use result in a reduction in PVR of about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% relative to patients in the patient population who have not received PAH-specific treatment. In some embodiments, the method and use result in a reduction in PVR of about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% relative to patients in the patient population who have not received PAH-specific treatment. In other embodiments, the method and use result in a reduction in PVR of about 15% to about 40%, about 15% to about 35%, about 15% to about 30%, about 15% to about 25%, about 15% to about 20%, about 20% to about 45%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 20% to about 25%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 45%, about 35% to about 40%, or about 40% to about 45%. In additional embodiments, the method and use result in a reduction in PVR of about 16% to about 42% relative to patients in the patient population who have not received PAH-specific treatment. In still other embodiments, the method and use result in a reduction in PVR of about 22% to about 44% relative to patients in the patient population who have not received PAH-specific treatment, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy. In additional embodiments, the method and use result in a reduction in PVR of about 30% relative to patients in the patient population who have not received PAH-specific treatment, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy. In still other embodiments, the method results in a reduction in PVR of about 34% relative to patients in the patient population who have not received PAH-specific treatment.

[0066] In still other aspects, the method and use result in a reduction in PVR of from about 10% to about 50% relative to patients in a patient population treated with macitentan monotherapy. In some embodiments, the method and use result in a reduction in PVR of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% relative to patients in a patient population treated with macitentan monotherapy. In other embodiments, the method and use result in a reduction in PVR of from about 10% to about 50%, from about 10% to about 45%, from about 10% to about 40%, from about 10% to about 35%, from about 10% to about 30%, from about 10% to about 25%, from about 10% to about 20%, from about 10% to about 15%, from about 15% to about 50%, from about 15% to about 45%, from about 15% to about 40%, from about 15% to about 35%, from about 15% to about 30%, from about 15% to about 25%, from about 15% to about 20%, from about 20% to about 50%, from about 20% to about 45%, from about 20% to about 40%, from about 20% to about 35%, from about 20% to about 30%, from about 20% to about 25%, from about 25% to about 50%, from about 25% to about 45%, from about 25% to about 40%, from about 25% to about 35%, from about 25% to about 30%, from about 30% to about 50%, from about 30% to about 45%, from about 30% to about 40%, from about 30% to about 35%, from about 35% to about 50%, from about 35% to about 45%, from about 35% to about 40%, from about 50% to about 50%, from about 40% to about 45%, or from about 45% to about 50% relative to patients in a patient population treated with macitentan monotherapy. In additional embodiments, the method and use result in a reduction in PVR of from about 14% to about 47% relative to patients in a patient population treated with macitentan monotherapy. In still other embodiments, the method and use result in a reduction in PVR of about 32% relative to patients in a patient population treated with macitentan monotherapy.

[0067] In still other respects, the method and use result in a PVR of from about 5% to about 30% relative to patients in a patient population who have been treated with tadalafil monotherapy. In some embodiments, the method and use result in a reduction in PVR of about 5%, about 10%, about 15%, about 20%, about 25% or about 30% relative to patients in a patient population who have been treated with tadalafil monotherapy. In other embodiments, the method and use result in a reduction in PVR of from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 5% to about 10%, from about 10% to about 30%, from about 10% to about 25%, from about 10% to about 20%, from about 10% to about 15%, from about 15% to about 30%, from about 15% to about 25%, from about 15% to about 20%, from about 20% to about 30%, from about 20% to about 25, or from about 25% to about 30% relative to patients in a patient population who have been treated with tadalafil monotherapy. In additional embodiments, the method and use result in a reduction in PVR of from about 6% to about 30% relative to patients in a patient population who have been treated with tadalafil monotherapy. In still other embodiments, the method and use result in a reduction in PVR of about 19% relative to patients in a patient population who have been treated with tadalafil monotherapy.

[0068] In some aspects, the method and use result in an increase in 6MWD of from about 0.5 meters to about 55 meters relative to patients in a patient population who have not been treated with PAH-specific therapy, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy. In some embodiments, the method and use result in an increase in 6MWD of about 0.5 meters, about 1 meter, about 5 meters, about 10 meters, about 15 meters, about 20 meters, about 25 meters, about 30 meters, about 35 meters, about 40 meters, about 45 meters, about 50 meters or about 55 meters relative to patients in a patient population who have not been treated with PAH-specific therapy, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy.In other embodiments, the method and use result in an increase in 6MWD of about 0.5 meters to about 55 meters, about 0.5 meters to about 50 meters, about 0.5 meters to about 45 meters, about 0.5 meters to about 40 meters, about 0.5 meters to about 35 meters, about 0.5 meters to about 30 meters, about 0.5 meters to about 25 meters, about 0.5 meters to about 20 meters, about 0.5 meters to about 15 meters, about 0.5 meters to about 10 meters, about 0.5 meters to about 5 meters, about 0.5 meters to about 1 meter, about 1 meter to about 55 meters, about 1 meter to about 50 meters, about 1 meter to about 45 meters, about 1 meter to about 40 meters, about 1 meter to about 35 meters, about 1 meter to about 30 meters, about 1 meter to about 25 meters, about 1 meter to about 20 meters, about 1 meter to about 15 meters, about 1 meter to about 10 meters, about 1 meter to about 5 meters, about 5 meters to about 55 meters, about 5 meters to about 50 meters, about 5 meters to about 45 meters, about 5 meters to about 40 meters, about 5 meters to about 35 meters, about 5 meters to about 30 meters, about 5 meters to about 25 meters, about 5 meters to about 20 meters, about 5 meters to about 15 meters, about 4 meters to about 10 meters, about 10 meters to about 55 meters, about 10 meters to about 50 meters, about 10 meters to about 45 meters, about 10 meters to about 40 meters, about 10 meters to about 35 meters, about 10 meters to about 30 meters, about 10 meters to about 25 meters, about 10 meters to about 20 meters, about 10 meters to about 15 meters, about 15 meters to about 55 meters, about 15 meters to about 50 meters, about 15 meters to about 45 meters, about 15 meters to about 40 meters, about 15 meters to about 35 meters, about 15 meters to about 30 meters, about 15 meters to about 25 meters, about 15 meters to about 20 meters, about 20 meters to about 55 meters, about 15 meters to about 50 meters, about 20 meters to about 45 meters, about 20 meters to about 40 meters, about 20 meters to about 35 meters, about 20 meters to about 30 meters, about 20 meters to about 25 meters, about 25 meters to about 55 meters, about 25 meters to about 50 meters, about 25 meters to about 45 meters, about 25 meters to about 40 meters, about 25 meters to about 35 meters, about 25 meters to about 30 meters, about 30 meters to about 55 meters, about 30 meters to about 50 meters, about 30 meters to about 45 meters, about 30 meters to about 40 meters, about 30 meters to about 35 meters, about 35 meters to about 55 meters, about 35 meters to about 50 meters, about 35 meters to about 45 meters, about 35 meters to about 40 meters, about 40 meters to about 55 meters, about 40 meters to about 50 meters, about 40 meters to about 45 meters, about 45 meters to about 55 meters, about 45 meters to about 50 meters, or about 50 meters to about 55 meters, relative to patients in a patient population who have not received PAH-specific treatment, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy. In additional embodiments, the method and use result in an increase in 6MWD of about 17 meters to about 49 meters, relative to patients in a patient population who have not received PAH-specific treatment, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy.In still other embodiments, the method and use result in an increase in 6MWD of about 16 meters relative to patients in a patient population who have not received PAH-specific treatment, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy. In still further embodiments, the method and use result in an increase in 6MWD of about 25 meters relative to patients in a patient population who have not received PAH-specific treatment, who have been treated with macitentan monotherapy, or who have been treated with tadalafil monotherapy.

[0069] In other respects, the method and use result in an increase in 6MWD of about 15 meters to about 35 meters relative to patients in a patient population who have not received PAH-specific treatment. In some embodiments, the method and use result in an increase in 6MWD of about 15 meters, about 20 meters, about 25 meters, about 30 meters, or about 35 meters relative to patients in a patient population who have not received PAH-specific treatment. In other embodiments, the method and use result in an increase in 6MWD of about 15 meters to about 30 meters, about 15 meters to about 25 meters, about 15 meters to about 20 meters, about 20 meters to about 35 meters, about 20 meters to about 30 meters, about 20 meters to about 25 meters, about 25 meters to about 35 meters, about 25 meters to about 30 meters, or about 30 meters to about 35 meters relative to patients in a patient population who have not received PAH-specific treatment. In further embodiments, the method and use result in an increase in 6MWD of about 20 meters relative to patients in a patient population who have not received PAH-specific treatment. In still further embodiments, the method and use result in an increase in 6MWD of about 33 meters relative to patients in a patient population who have not received PAH-specific treatment.

[0070] In additional aspects, the method and use result in an increase in 6MWD of about 1 meter to about 15 meters relative to patients in a patient population who have been treated with macitentan monotherapy. In some embodiments, the method and use result in an increase in 6MWD of about 1 meter, about 5 meters, about 10 meters, or about 15 meters relative to patients in a patient population who have been treated with macitentan monotherapy. In other embodiments, the method and use result in an increase in 6MWD of about 1 meter to about 15 meters, about 1 meter to about 10 meters, about 1 meter to about 5 meters, about 5 meters to about 15 meters, about 1 meter to about 10 meters, about 1 meter to about 5 meters, about 5 meters to about 15 meters, about 5 meters to about 10, or about 10 meters to about 15 meters relative to patients in a patient population who have been treated with macitentan monotherapy. In further embodiments, the method and use result in an increase in 6MWD of about 8 meters relative to patients in a patient population who have been treated with macitentan monotherapy. In other embodiments, the method and use result in an increase in 6MWD of about 9 meters relative to patients in a patient population who have been treated with macitentan monotherapy. In still further embodiments, the method and use result in an increase in 6MWD of about 8.5 meters relative to patients in a patient population who have been treated with macitentan monotherapy.

[0071] In still other aspects, the method and use result in an increase in 6MWD of from about 20 meters to about 35 meters relative to patients in a patient population treated with tadalafil monotherapy. In some embodiments, the method and use result in an increase in 6MWD of about 20 meters, about 25 meters, about 30 meters, or about 35 meters relative to patients in a patient population treated with tadalafil monotherapy. In other embodiments, the method and use result in an increase in 6MWD of from about 20 meters to about 30 meters, from about 20 meters to about 25 meters, from about 25 meters to about 35 meters, from about 25 meters to about 30 meters, or from about 30 meters to about 35 meters relative to patients in a patient population treated with tadalafil monotherapy. In additional embodiments, the method and use result in an increase in 6MWD of about 25 meters relative to patients in a patient population treated with tadalafil monotherapy. In still other embodiments, the method and use result in an increase in 6MWD of about 26 meters relative to patients in a patient population treated with tadalafil monotherapy.

[0072] The methods and uses described herein also result in a decrease in one or both of B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) in a patient population with PAH (such as the patient population disclosed in Example 1) relative to patients in a patient population who have not been treated with PAH-specific therapy, treated with macitentan monotherapy, or treated with tadalafil monotherapy.

[0073] As used herein, the term "BNP" refers to B-type natriuretic peptide, and "NT-proBNP" refers to the N-terminal (NT)-hormone proBNP. BNP and NT-proBNP are peptides that are released in response to changes in pressure within the heart. In certain embodiments, the level of one or both of BNP and / or NT-proBNP increases when heart failure occurs or worsens.

[0074] Methods for identifying and analyzing the levels of BNP and NT-proBNP are known to those of skill in the art. Screening methods can include, but are not limited to, standard methods such as immunohistochemistry of tumor samples, solid-phase immunoassays using microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for detecting specific proteins. Detection methods include the use of site-specific antibodies. Those skilled in the art will recognize that all such well-known techniques for detecting the levels of BNP and NT-proBNP are applicable to this situation.

[0075] Accordingly, in certain embodiments, the present disclosure provides a method of reducing the level of one or both of BNP and NT-proBNP in a patient with pulmonary arterial hypertension (PAH), where the patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy, the method comprising transitioning the patient to a fixed-dose combination (FDC) of macitentan and tadalafil. In some embodiments, the method reduces the level of BNP. In other embodiments, the method reduces the level of NT-proBNP. In additional embodiments, the method reduces the levels of BNP and NT-proBNP. In particular, by measuring BNP and / or NT-proBNP, the disease progression of the patient can be tracked, thereby achieving an improved prognosis.

[0076] As used herein, the term "level of BNP" or "level of NT-proBNP" refers to the concentration of BNP or NT-proBNP present in a sample (e.g., blood) collected from a patient. In some embodiments, the level after administration of the FDC is lower than the level before administration of the FDC.

[0077] In some aspects, prior to administration of the FDC, the patient is a "moderate-risk patient". For example, prior to administration of the FDC, the patient has a BNP of 50 ng / L to 800 ng / L and / or an NT-proBNP of 300 ng / L to 1100 ng / L. In some embodiments, prior to administration of the FDC, the patient has a BNP of 50 ng / L to 800 ng / L. In other embodiments, prior to administration of the FDC, the patient has an NT-proBNP of 300 ng / L to 1100 ng / L. In additional embodiments, the patient has a BNP of 500 ng / L to 800 ng / L and an NT-proBNP of 300 ng / L to 1100 ng / L. In still other embodiments, prior to administration of the FDC, the patient has a BNP of 50 ng / L, about 100 ng / L, about 150 ng / L, about 200 ng / L, about 250 ng / L, about 300 ng / L, about 350 ng / L, about 400 ng / L, about 450 ng / L, about 500 ng / L, about 550 ng / L, about 600 ng / L, about 650 ng / L, about 700 ng / L, about 750 ng / L or 800 ng / L. In still additional embodiments, prior to administration of the FDC, the patient has a BNP of about 100 ng / L to about 800 ng / L, about 100 ng / L to about 600 ng / L, about 100 ng / L to about 400 ng / L, about 100 ng / L to about 300 ng / L, about 200 ng / L to about 800 ng / L, about 200 ng / L to about 600 ng / L, about 200 ng / L to about 400 ng / L, about 300 ng / L to about 800 ng / L, about 300 ng / L to about 600 ng / L, about 400 ng / L to about 800 ng / L, about 400 ng / L to about 600 ng / L, about 500 ng / L to about 800 ng / L, about 600 ng / L to about 800 ng / L, or about 700 ng / L to about 800 ng / L. In other embodiments, prior to administration of the FDC, the patient has an NT-proBNP of 300 ng / L, about 400 ng / L, about 500 ng / L, about 600 ng / L, about 700 ng / L, about 800 ng / L, about 900 ng / L, about 1000 ng / L or about 1100 ng / L.In additional embodiments, prior to administration of the FDC, the patient has an NT-proBNP of from 300 ng / L to about 1000 ng / L, from 300 ng / L to about 800 ng / L, from 300 ng / L to about 600 ng / L, from about 400 ng / L to about 1100 ng / L, from about 400 ng / L to about 1000 ng / L, from about 400 ng / L to about 800 ng / L, from about 400 ng / L to about 600 ng / L, from about 500 ng / L to about 1100 ng / L, from about 500 ng / L to about 1000 ng / L, from about 500 ng / L to about 800 ng / L, from about 600 ng / L to about 1100 ng / L, from about 600 ng / L to about 1000 ng / L, from about 600 ng / L to about 800 ng / L, from about 700 ng / L to about 1100 ng / L, from about 700 ng / L to about 1000 ng / L, from about 800 ng / L to about 1100 ng / L, or from about 800 ng / L to about 1000 ng / L.

[0078] In other respects, the patient is a "high-risk patient" prior to administration of the FDC. For example, prior to administration of the FDC, the patient has a BNP greater than 800 ng / L and / or an NT-proBNP greater than 1100 ng / L. In some embodiments, prior to administration of the FDC, the patient has a BNP greater than 800 ng / L. In other embodiments, prior to administration of the FDC, the patient has an NT-proBNP greater than 1100 ng / L. In additional embodiments, prior to administration of the FDC, the patient has a BNP greater than 800 ng / L and an NT-proBNP greater than 1100 ng / L. In still other embodiments, prior to administration of the FDC, the patient has a BNP of 801 ng / L to about 4800 ng / L. In still additional embodiments, prior to administration of the FDC, the patient has a BNP of about 1000 ng / L, about 2000 ng / L, about 3000 ng / L, about 4000 ng / L, or about 4500 ng / L. In other embodiments, prior to administration of the FDC, the patient has a BNP of about 801 ng / L to about 4500 ng / L, about 801 ng / L to about 4000 ng / L, about 801 ng / L to about 3000 ng / L, about 801 ng / L to about 2000 ng / L, about 801 ng / L to about 1000 ng / L, about 1000 ng / L to about 4500 ng / L, about 1000 ng / L to about 4000 ng / L, about 1000 ng / L to about 3000 ng / L, about 1000 ng / L to about 2000 ng / L, about 2000 ng / L to about 4500 ng / L, about 2000 ng / L to about 4000 ng / L, about 2000 ng / L to about 3000 ng / L, about 3000 ng / L to about 4500 ng / L, about 3000 ng / L to about 4000 ng / L, or about 4000 ng / L to about 4500 ng / L. In additional embodiments, prior to administration of the FDC, the patient has an NT-proBNP of 1101 ng / L to about 4800 ng / L. In still other embodiments, prior to administration of the FDC, the patient has an NT-proBNP of 1101 ng / L, about 1500 ng / L, about 2000 ng / L, about 3000 ng / L, about 4000 ng / L, or about 4500 ng / L.In yet another embodiment, prior to administration of the FDC, the patient has an NT-proBNP of from 1101 ng / L to about 4500 ng / L, from about 1101 ng / L to about 4000 ng / L, from about 1101 ng / L to about 3000 ng / L, from about 1101 ng / L to about 2000 ng / L, from about 2000 ng / L to about 4500 ng / L, from about 2000 ng / L to about 4000 ng / L, from about 2000 ng / L to about 3000 ng / L, from about 3000 ng / L to about 4500 ng / L, from about 3000 ng / L to about 4000 ng / L, or from about 4000 ng / L to about 4500 ng / L.

[0079] After administration of the FDC, BNP and / or NT-proBNP levels are reduced. Ideally, the BNP or NT-proBNP levels are reduced to values that are safe and / or are only considered to be at “low risk”. For example, after administration of the FDC, BNP is reduced to less than 50 ng / L and / or NT-proBNP is reduced to less than 300 ng / L. In some embodiments, after administration of the FDC, BNP is reduced to less than 50 ng / L. In other embodiments, after administration of the FDC, NT-proBNP is reduced to less than 300 ng / L. In further embodiments, after administration of the FDC, BNP is reduced to less than 50 ng / L and NT-proBNP is reduced to less than 300 ng / L. In still other embodiments, after administration of the FDC, BNP is reduced to less than about 5 ng / L, about 10 ng / L, about 20 ng / L, about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, or about 45 ng / L. In still further embodiments, after administration of the FDC, BNP is reduced to about 10 ng / L to about 40 ng / L, about 10 ng / L to about 30 ng / L, about 10 ng / L to about 20 ng / L, about 20 ng / L to about 40 ng / L, about 20 ng / L to about 30 ng / L, or about 30 ng / L to about 40 ng / L. In other embodiments, after administration of the FDC, NT-proBNP is reduced to less than 300 ng / L. In further embodiments, after administration of the FDC, NT-proBNP is reduced to less than about 250 ng / L, about 200 ng / L, about 150 ng / L, about 100 ng / L, about 75 ng / L, about 50 ng / L, about 25 ng / L, about 10 ng / L, or about 5 ng / L. In still other embodiments, after administration of the FDC, NT-proBNP is reduced to about 10 ng / L to about 250 ng / L, about 10 ng / L to about 200 ng / L, about 10 ng / L to about 150 ng / L, about 10 ng / L to about 100 ng / L, about 10 ng / L to about 50 ng / L, about 25 ng / L to about 250 ng / L, about 25 ng / L to about 200 ng / L, about 25 ng / L to about 150 ng / L, about 25 ng / L to about 100 ng / L, about 25 ng / L to about 50 ng / L, about 50 ng / L to about 250 ng / L, about 50 ng / L to about 200 ng / L, about 50 ng / L to about 150 ng / L, about 50 ng / L to about 100 ng / L, about 100 ng / L to about 250 ng / L, about 100 ng / L to about 200 ng / L, about 100 ng / L to about 150 ng / L, about 150 ng / L to about 250 ng / L, about 150 ng / L to about 200 ng / L, or about 200 ng / L to about 250 ng / L.

[0080] The present disclosure also provides a method for treating pulmonary arterial hypertension, the method comprising: initiating administration to a human patient in need thereof of a fixed dose combination (FDC) of macitentan and tadalafil, wherein the patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy. The method further comprises: continuing to administer to a human patient in need thereof a fixed dose combination (FDC) of macitentan and tadalafil in the event that the patient is identified as biomarker signature positive.

[0081] In some aspects, a patient is biomarker signature positive if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) that is lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) that is lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

[0082] As described above, in certain methods or uses, the patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with type 5 phosphodiesterase inhibitor (PDE-5) inhibitor monotherapy and then transitions to a fixed dose combination (FDC) of macitentan and tadalafil. As used herein, a "biological sample" is obtained from a patient. In some aspects, the biological sample is a serum or blood sample.

[0083] The "reference level" of BNP or NT-proBNP is from a biological sample obtained from the patient prior to initiating administration of the FDC. One or more reference levels of the patient may be measured during the course of treatment and determined by one of ordinary skill in the art. In other embodiments, the reference level of BNP or NT-proBNP is from a biological sample obtained after initiating administration of the FDC. If interim BNP and / or NT-proBNP levels are to be analyzed and compared to each other or to sample levels, the reference level may be obtained after initiating administration of the FDC. In some embodiments, the reference level is determined in vitro. In other embodiments, the reference level is determined ex vivo.

[0084] The "sample level" of BNP or NT-proBNP is from a biological sample obtained from the patient after initiating administration of the FDC. One or more sample levels of the patient may be measured during the course of treatment and determined by one of ordinary skill in the art. In some aspects, any sample level obtained during treatment may be compared to any reference level. In some embodiments, the sample level is determined in vitro. In other embodiments, the sample level is determined ex vivo.

[0085] In some aspects, a biological sample is obtained at any time during FDC treatment. In some aspects, a biological sample is obtained at least about 3 months to about 6 months after initiation of FDC administration. In other aspects, a biological sample is obtained about 16 weeks after initiation of FDC administration. Additional biological samples may be collected after the initial sampling to monitor treatment. In some embodiments, additional biological samples are obtained every about 3 months to about 6 months after obtaining a previous biological sample.

[0086] The present disclosure also provides a method of treating pulmonary arterial hypertension, the method comprising administering to a human patient in need thereof a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient is identified as positive for a biomarker signature. Optionally, the FDC is administered continuously in the case where the patient is identified as positive for a biomarker signature. In some aspects, a patient is positive for a biomarker signature in the case where a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) that is lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) that is lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

[0087] The present disclosure also provides a method of identifying that a patient suffering from pulmonary arterial hypertension will respond to treatment with a fixed-dose combination (FDC) of macitentan and tadalafil. In some embodiments, the identification is performed in vitro. In other embodiments, the identification is performed ex vivo. The method comprises: administering the FDC to a patient in need thereof; and identifying the patient as responsive to treatment with the FDC in the case where the patient is identified as positive for a biomarker signature.

[0088] As used herein and in the art, the terms "pulmonary arterial hypertension" and "PAH" are interchangeable and define a condition in which a patient has high blood pressure in the lungs. PAH occurs when the diameter of very small arteries throughout the lungs narrows, which increases the resistance to blood flow through the lungs. In some embodiments, the underlying cause of the 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 diseases (scleroderma or lupus), congenital heart problems, high blood pressure in the liver, HIV, infections (schistosomiasis), and sickle cell anemia, (iv) PAH caused by rare blood disorders (e.g., pulmonary capillary hemangiomatosis), or (v) PAH in infants (persistent pulmonary hypertension of the newborn). The severity of a patient's PAH is typically assessed by the following classification system, i.e., the World Health Organization (WHO) grading system:

[0089]

[0090] Typically, a higher PAH class indicates a more severe disease state and / or a greater urgency for the patient to be accurately diagnosed and initiate PAH therapy. Accordingly, the methods and uses reduce the risk of a patient progressing from a lower WHO PAH class to a higher WHO PAH class. In some embodiments, the methods and uses reduce 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 I 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. In some embodiments, the patient is a WHO class II patient. In further embodiments, the patient is a WHO class III patient.

[0091] In certain embodiments, the patient has not been treated for PAH. However, as described herein, patients who have previously or are currently receiving a treatment regimen for PAH may also benefit from the methods and uses disclosed herein. As used herein, the term "not previously PAH-specifically treated" refers to a patient who has not been treated for PAH prior to initiation of treatment according to the methods and uses described herein (i.e., prior to administration of the FDC). In some embodiments, the patient has not taken an endothelin receptor antagonist (ERA) prior to initiation of treatment according to the methods and uses described herein. In other embodiments, the patient has not taken a phosphodiesterase type 5 (PDE-5) inhibitor prior to initiation of treatment according to the methods and uses described herein. In still other embodiments, the patient has not taken an endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 (PDE-5) inhibitor prior to initiation of treatment according to the methods and uses described herein.

[0092] In other embodiments, in addition to or instead of not having been treated, the patient is newly diagnosed with PAH. For example, the patient's initial PAH diagnosis is made within about six months of the start of FDC administration. In some embodiments, the initial PAH diagnosis is made within about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month of the start of FDC administration.

[0093] Endothelin receptor antagonist

[0094] As described herein, a patient can be treated with an ERA monotherapy. The ERA can be selected by a physician or other healthcare provider. In some embodiments, the ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof. In other embodiments, the ERA is macitentan. In additional embodiments, the ERA is bosentan. In still other embodiments, the ERA is ambrisentan.

[0095] 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'-propylsulfonamide of formula (I).

[0096]

[0097] In other embodiments, the methods and uses can employ stereoisomers of macitentan, such as enantiomers and diastereomers in pure or substantially pure form. The methods and uses can also utilize racemic mixtures of macitentan in amorphous or crystalline form. In some embodiments, macitentan is in crystalline form, such as the crystalline forms disclosed in Bolli, J. Med. Chem., 2012, 55, 7849-7861 and the corresponding "Supporting Information"). In other embodiments, macitentan is in amorphous form. Crystallinity can be determined by one or more techniques known to those of skill in the art, such as, for example, single crystal x-ray diffraction, powder x-ray diffraction, differential scanning calorimetry, melting point, etc. The present disclosure also contemplates the administration of anhydrous forms or hydrates of macitentan. In certain embodiments, macitentan is in anhydrous form. In other embodiments, macitentan is in its hydrate form. The present disclosure also contemplates the administration of solvates of macitentan. Such solvates include molecules of a solvent that are bound to one or more positions of the macitentan molecule through intermolecular forces or chemical bonds. The present disclosure also contemplates the administration of polymorphs of macitentan. Such polymorphs of macitentan include crystalline forms of the molecule, each having a varying crystal lattice.

[0098] The term "macitentan" also includes its pharmaceutically acceptable salts, which can be readily selected by those of skill in the art. The expression pharmaceutically acceptable salts encompasses salts containing inorganic acids or organic acids (hydrohalic acids, such as hydrochloric acid or hydrobromic acid); sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc., or, in the case where the compound of formula I is inherently acidic, salts containing inorganic bases (such as alkali or alkaline earth bases, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). As understood by those of skill in the art, macitentan is commercially available. For example, macitentan is available under the trade name Obtained. Macitentan is an endothelin receptor antagonist and can be prepared according to the method disclosed in U.S. Patent No. 7,094,781, which is incorporated herein by reference.

[0099] The present disclosure also contemplates administering a macitentan metabolite or a pharmaceutically acceptable salt thereof. Advantageously, the macitentan metabolite is a metabolically active compound. Thus, in certain embodiments, the macitentan metabolite has Formulas I-M1 to I-M7. In some embodiments, the macitentan metabolite has Formula I-M6; I-M6 is also known by the code name ACT-132577 and the international nonproprietary name aprocitentan.

[0100]

[0101]

[0102] Type 5 phosphodiesterase inhibitor

[0103] The methods and uses described herein also include PDE-5 inhibitor monotherapy. A physician or other healthcare provider will be able to select a suitable (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 additional embodiments, the PDE-5 inhibitor is vardenafil. In other embodiments, the PDE-5 inhibitor is udenafil.

[0104] 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).

[0105]

[0106] The term "tadalafil" also includes its pharmaceutically acceptable salts, which can be readily selected by those skilled in the art. "Pharmaceutically acceptable salts" are intended to denote salts of tadalafil that are non-toxic, biologically tolerable or, in other words, biologically suitable for administration to a subject. See, for example, Berge, "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 and Pharmaceutical Salts, Properties, Selection, and Use, edited by Stahl and Wermuth, Wiley-VCH and VHCA, Zurich, 2002, which are incorporated herein by reference. Tadalafil can be used in the free base or acid form, but can also be used after formation of pharmaceutically acceptable salts by known methods. When tadalafil is basic, examples of "salts" include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, and salts of 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 salts and potassium salts, and alkaline earth metal salts such as calcium salts. Tadalafil is available as Adcirca TM commercially.

[0107] The following abbreviations are used herein:

[0108]

[0109]

[0110] The following examples are provided to illustrate some of the concepts described in the present disclosure. While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein. Additionally, in the following examples, efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered.

[0111] Example 1

[0112] A. Study design

[0113] This is a prospective, multicenter, double-blind, randomized, active-controlled, parallel-group, group-sequential, adaptive Phase III study. The study includes interim analyses (IAs) for efficacy, futility, and non-blind sample size adaptation. The study was designed to compare the efficacy and safety of the macitentan / tadalafil fixed-dose combination (M / TFDC) with each monotherapy, macitentan 10 mg or tadalafil 40 mg, in participants with PAH. SeeFigure 1 。

[0114] Participants were randomized according to Figure 2 the protocol, which stratified previous PAH therapies (untreated, ERA therapy, PDE-5i therapy). Untreated participants randomized to the M / T FDC will contribute to each comparison of interest. See Figure 3 and Table A. At randomization, 53.3% of participants in the M / T FDC group, 25.7% of participants in the macitentan group, and 38.6% of participants in the tadalafil group were receiving PAH-specific treatment. Previous PAH-specific medications mainly included ERAs (macitentan, ambrisentan, and bosentan) and PDE-5 inhibitors (tadalafil and sildenafil), with the majority (84%) using sildenafil.

[0115]

[0116] The 16-week double-blind treatment period was followed by a 24-month single-group open-label extension period, during which all participants received M / T FDC. This document focuses on the 16-week double-blind treatment period.

[0117] The full analysis set (FAS) included all randomized subjects who received at least one dose of study treatment. Subjects were evaluated according to the treatment to which they were randomly assigned.

[0118] The ratio of the end of double-blind treatment (EDBT) of pulmonary vascular resistance (PVR) to baseline. The final inference was based on the inverse normal combination method with pre-specified weights to combine the first-stage p-values and second-stage p-values from the ANCOVA model.

[0119] The global significance level α = 0.05 two-sided.

[0120] The study had two co-primary objectives, where PVR was measured by right heart catheterization:

[0121] · In participants with symptomatic WHO Group 1 PAH, evaluate the effect of M / T FDC versus monotherapy with 10 mg macitentan on PVR at the end of double-blind treatment in participants who have not received PAH-specific treatment or are being treated with ERA as monotherapy.

[0122] · In participants with symptomatic WHO Group 1 PAH, evaluate the effect of M / T FDC versus monotherapy with 40 mg tadalafil on PVR at the end of double-blind treatment in participants who have not received PAH-specific treatment or are being treated with PDE-5i as monotherapy.

[0123] Secondary efficacy variables (in the test sequence):

[0124] · Change in six-minute walk distance (6MWD) from baseline to EDBT.

[0125] · Change in PAH SYMPACT cardiopulmonary domain score from baseline to EDBT.

[0126] · Change in PAH SYMPACT cardiovascular domain score from baseline to EDBT.

[0127] · WHO FC level at EDBT did not deteriorate compared with baseline.

[0128] The secondary efficacy endpoints were analyzed in the above predefined test sequence at the same significance level as the primary efficacy endpoints, and for each of them, the final inference was based on the inverse normal combination method with pre-specified weights to combine the stage 1 p-values and stage 2 p-values.

[0129] The target sample size of 170 was calculated based on the following assumptions:

[0130] Assume that the effect of M / T FDC is similar to that of each single therapy and is consistent across the naïve stratum, the stratum previously treated with ERA, and the stratum previously treated with PDE-5i, i.e., for M / T FDC compared with the most effective single therapy among the two single therapies, the geometric mean ratio (GMR) of the EDBT / baseline PVR value is equal to 0.75

[0131] · The coefficient of variation of this ratio is 0.45

[0132] · Use the α-spending function from the Hwang, Shih, and DeCani class to plan an IA,

[0133] where (γ) = -2

[0134] · Normal distribution of the log-transformed ratio of EDBT to baseline PVR value

[0135] The overall power of the test of the global null hypothesis is expected to be between 79% and 87%.

[0136] Interim analysis (IA): Based on the primary efficacy endpoint, pre-planned IAs were conducted for futility, efficacy, or non-blind sample size adaptation (increase or decrease).

[0137] The IA was conducted when 100 participants had completed their 16-week assessment or had withdrawn from the study prior to their 16-week assessment (this corresponds to an information fraction of the primary efficacy endpoint of approximately 59% of the pre-planned sample size of 170 participants). Data from 99 participants were used because the most recent protocol amendment for one participant had not received full approval at the time the IA was conducted. The data for that participant were then used in the final analysis as part of Phase 2 of the study.

[0138] A total of 187 patients were randomly assigned.

[0139] Based on the alpha spending function from Hwang, Shih, and DeCani, the remaining alpha for the final comparison was 4.2%. The repeated confidence bounds and combined p-values presented in this document were adjusted for this final level.

[0140] The confidence bounds and p-values by phase were not adjusted.

[0141] B. Study treatment

[0142] The FDC is a film-coated tablet containing 10 mg of macitentan and 40 mg of tadalafil, administered orally once daily (o.d.). In addition to macitentan and tadalafil, the tablet core contains hydroxypropylcellulose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone K30, sodium lauryl sulfate, and sodium starch glycolate type A. The film coating contains hydroxypropylmethylcellulose, lactose monohydrate, talc, titanium dioxide, and triacetin.

[0143] The monotherapy group consisted of macitentan 10 mg and tadalafil 40 mg (2 x 20 mg tablets).

[0144] C. Inclusion criteria

[0145] To be included in the study, all of the following inclusion criteria had to be met. No criteria were waived for any participant.

[0146]

[0147]

[0148] D. Exclusion criteria

[0149] Patients must not meet any of the following exclusion criteria. PAH treatment :

[0150]

[0151] Other therapies :

[0152]

[0153] Medical history / current medical condition :

[0154]

[0155] Criteria related to macitentan / tadalafil use :

[0156]

[0157] General restrictions :

[0158]

[0159] E. Treatment

[0160] Participants were randomized and stratified according to their previous PAH treatment status (treatment-naïve n = 98, ERA therapy n = 32, PDE-5i therapy n = 56):

[0161] · Participants receiving ERA therapy at baseline were randomized 2:1 to M / T FDC or macitentan 10 mg, respectively.

[0162] · Participants receiving PDE-5i therapy at baseline were randomized 2:1 to M / T FDC or tadalafil 40 mg, respectively.

[0163] · Participants treatment-naïve at baseline were randomized 2:1:1 to M / T FDC, macitentan 10 mg, or tadalafil 40 mg, respectively.

[0164] F. Summary of results

[0165] 187 participants were randomized, 108 were randomized to M / T FDC, 35 were randomized to macitentan, and 44 were randomized to tadalafil. One participant assigned to M / T FDC had never been treated and was excluded from the full analysis set.

[0166] The treatment groups were balanced with respect to demographics and baseline disease characteristics, except for WHO FC, which was less severe in the M / T FDC group [for the comparison of M / T FDC with macitentan, participants with WHO FC = III at baseline were 24 / 35 (68.6%) in macitentan and 28 / 70 (40.0%) in M / T FDC, and for the comparison of M / T FDC with tadalafil, they were 25 / 44 (56.8%) in tadalafil and 35 / 86 (40.7%) in M / T FDC] (Tables 5A and 5B). SeeFigure 4 。

[0167] G. Results

[0168] (i) Subject and treatment information

[0169] A total of 294 patients were screened. Of these, 187 subjects were randomized (108 subjects were randomly assigned to M / T FDC, 35 subjects were randomly assigned to macitentan, and 44 subjects were randomly assigned to tadalafil). All randomized participants received at least one dose of study treatment except for one. Tables 4A and 4B summarize the study disposition of the participants, and Tables 5A and 5B show the reasons for premature discontinuation of study treatment. In M / T FDC, the incidence of study treatment discontinuation was 16 / 107 (15.0%), there were no treatment discontinuations in macitentan, and in tadalafil it was 1 / 44 (2.3%). The main reason for treatment discontinuation was adverse events.

[0170] Study completion / withdrawal information

[0171]

[0172]

[0173]

[0174]

[0175]

[0176] Compared with the two monotherapies, M / T FDC has a trend of positive clinical significance: · M / T FDC vs tadalafil (25.4 m, p = 0.059)

[0177] · M / T FDC vs macitentan (16.0 m, p = 0.380) (Table 6).

[0178] This numerical trend was more pronounced in the subgroup of patients who had not received prior treatment. See Table 6A.

[0179]

[0180]

[0181] Compared with the two monotherapies, the 6MWD values of M / T FDC had a trend of greater improvement. Except for WHO FC in the comparison with macitentan, the treatment effect on 6MWD was consistent across predefined subgroups. See Figure 16. Generally, except for WHO FC III in the comparison of M / TFDC with macitentan, the p-values for interactions between subgroups were > 0.10.

[0182] In treatment-naïve and previously treated ERA / PDE5i patients, the effects of M / T FDC and the two monotherapies on PVR and 6MWD were consistent with those observed in the overall population. See Table 6B.

[0183]

[0184] (ii) Demographic and baseline characteristics

[0185] Except for WHO FC in the M / T FDC group with a less severe population, the treatment groups were balanced with respect to demographic and baseline disease characteristics. For the comparison of M / T FDC with macitentan, 24 / 35 (68.6%) of the participants with WHO FC ≥ III at baseline were in the macitentan group and 28 / 70 (40.0%) were in the M / T FDC group, and for the comparison of M / T FDC with tadalafil, 25 / 44 (56.8%) were in the tadalafil group and 35 / 86 (40.7%) were in the M / T FDC group (Tables 7A and 7B).

[0186]

[0187]

[0188]

[0189]

[0190]

[0191] (iii) Exposure level

[0192] The mean total treatment duration was slightly shorter in the M / T FDC treatment group: for the comparison of M / T FDC with macitentan, 14.4 weeks for macitentan vs. 16.9 weeks, and for the comparison of M / T FDC with tadalafil, 14.9 weeks for tadalafil vs. 16.0 weeks.

[0193] This is consistent with a higher number of patients with premature treatment discontinuation in the M / T FDC group.

[0194]

[0195]

[0196]

[0197] (iv) Primary endpoint analysis

[0198] Due to the adaptive nature of the study and as planned in the protocol, the primary analysis of the primary efficacy endpoint for the FAS was performed using the inverse normal combination method with pre-specified weights to combine the stage 1 p-values and the stage 2 p-values. The pre-specified weights were proportional to the pre-planned sample size of 170 subjects (i.e., for stage 1, and for stage 2, ).

[0199] An ANCOVA model for the log e transformation ratio of EDBT versus baseline PVR was applied to derive the stage 1 p-value (i.e., at the interim analysis time point) and the stage 2 p-value (i.e., after the interim analysis) for the final inference. The predefined model covariates included the randomized treatment group, the stratification factors, and the log e transformed baseline PVR. The final inference was based on the final adjusted and combined two-sided p-value, and the median unbiased estimator of the overall treatment effect with the corresponding adjusted repeated confidence interval (RCI).

[0200] The primary objective of the study was met, and M / T FDC was consistently favored relative to the corresponding macitentan and tadalafil monotherapies and all subgroups. Based on the ANCOVA models run at each stage, with treatment group, stratification, and baseline values as covariates, the median unbiased estimate (adjusted repeated confidence interval) of the geometric mean ratio was:

[0201] · 0.71 (0.61, 0.82) (29% difference) between M / T FDC and macitentan

[0202] · 0.72 (0.64, 0.80) (28% difference) between M / T FDC and tadalafil

[0203] The treatment effects for both comparisons were highly statistically significant (two-sided adjusted p-values both < 0.0001). See Tables 10A and 10B.

[0204] The treatment effects were consistent across sensitivity / supplemental analyses, predefined subgroups, stratifications, and stages ( Figures 5 to 8 , Tables 9A and Figure 9 B). The data suggest that improvement in PVR predicts clinical benefit for exercise capacity and clinical outcomes, and that treatment-induced changes in PVR can explain treatment-induced changes in exercise capacity.

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214] Table 10C describes a post hoc sensitivity analysis to exclude patients with a major protocol deviation (MPD) that could be considered potentially influential on the primary endpoint (PVR).

[0215]

[0216]

[0217]

[0218] Based on the results of these sensitivity analyses, it was concluded that the incidence of MPD had no impact on the conclusions of the study. Protocol deviations did not alter the robustness of the primary endpoint or the interpretability of the study results.

[0219] (v) Secondary endpoint analysis (in the test sequence)

[0220] The 6MWD differences between M / T FDC and macitentan and between M / T FDC and tadalafil were not statistically significant. Based on the ANCOVA models run at each stage, with treatment group, stratification, and baseline values as covariates, the median unbiased estimate (adjusted repeated confidence intervals) and combined p-values for the change from baseline to EDBT were:

[0221] Between M / T FDC and macitentan, 16.04 m (-17.0, 49.08), p = 0.3802

[0222] Between M / T FDC and tadalafil, 25.37 m (-0.93, 51.59), p = 0.0591

[0223] See Tables 11A and 11B.

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235] There was no difference between treatment groups in the change in the PAH SYMPACT cardiopulmonary and cardiovascular domain scores from baseline to EDBT:

[0236] Cardiopulmonary domain score: for M / T FDC vs macitentan, -0.03 (-0.21, 0.15), and for M / T FDC vs tadalafil, -0.04 (-0.21, 0.13)

[0237] Cardiovascular domain score: for M / T FDC vs macitentan, 0.01 (-0.17, 0.19), and for M / T FDC vs tadalafil, 0.02 (-0.15, 0.19)

[0238] Since the count of worsening outcomes in the macitentan group was zero, the treatment effect on WHO-FC could not be estimated. The results at each stage showed that M / T FDC did not improve compared with macitentan and tadalafil (Tables 13A and 13B).

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246] Figure 9 It was shown that among the participants who were randomly assigned to M / T FDC during the study's double-blind (DB) period and continued to receive M / T FDC during the open-label (OL) period, the largest and most sustained improvement in 6MWD was observed among those who had not received treatment at DB baseline. Figure 10 The improvement trend of 6MWD data during the combined 12-month DB + OL period is shown.

[0247] (v) Safety

[0248] During the 16-week DB period, AEs of particular interest were predefined as anemia, edema, hypotension, and liver events. The only SOC with a significant imbalance was cardiac disorders (15.0% in M / T FDC (all strata), compared with 9.1% for tadalafil and 5.7% for macitentan). However, there was no clear event pattern for the preferred terms, and many of the reported AEs were known PAH comorbidities.

[0249] Compared with the monotherapy groups, there was a higher frequency of SAEs and discontinuation of study treatment due to AEs in the M / T FDC group, but there was no clear event pattern for the preferred terms.

[0250] For M / T FDC, macitentan, and tadalafil, the proportions of patients who experienced at least one treatment-emergent adverse event (TEAE) were 82.2%, 79.5%, and 71.4%, respectively. See Tables 15A and 15B. The most common treatment-emergent adverse events (TAEs) were headache (16.8%, 17.1%, and 13.6% for M / T FDC (all strata), macitentan, and tadalafil, respectively), diarrhea (4.7%, 0, and 13.6% for M / T FDC (all strata), macitentan, and tadalafil, respectively), and peripheral edema (13.1%, 11.4%, and 11.4% for M / T FDC (all strata), macitentan, and tadalafil, respectively).

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] The most common TEAEs (AEs reported in at least 10% of patients in any treatment group) were headache (16.8%, 17.1%, and 13.6% for M / T FDC (all strata), macitentan, and tadalafil, respectively), diarrhea (4.7%, 0, and 13.6% for M / T FDC (all strata), macitentan, and tadalafil, respectively), and peripheral edema (13.1%, 11.4%, and 11.4% for M / T FDC (all strata), macitentan, and tadalafil, respectively). There were 3 deaths (all unrelated) in the M / T FDC group (heart failure, COVID-19 pneumonia, Clostridium gastroenteritis), and no deaths in the macitentan and tadalafil groups.

[0259] SAEs were reported more frequently in the M / T FDC group compared to the macitentan and tadalafil groups (14%, 8.6%, and 9.1% for M / T FDC, macitentan, and tadalafil, respectively). The only SOC with a significant imbalance was SOC Heart Disorders (6.5%, 2.9%, and 2.3%).

[0260] AEs leading to discontinuation were reported more frequently in the M / T FDC group compared to the macitentan and tadalafil groups (8.4%, 0, and 4.5% for M / T FDC, macitentan, and tadalafil, respectively). There was no trend based on individual SOC / PT. Among AESIs, hypotension, anemia, and edema were reported more frequently in the M / T FDC group compared to macitentan and tadalafil:

[0261] · Hypotension: Reported in 7.5%, 0, and 0 of patients in the M / T FDC (all strata), macitentan, and tadalafil groups, respectively.

[0262] · Anemia: Reported in 18.7%, 2.9%, and 2.3% of patients in the M / T FDC (all strata), macitentan, and tadalafil groups, respectively.

[0263] · Edema: Reported in 20.6%, 14.3%, and 15.9% in the M / T FDC (all strata), macitentan, and tadalafil groups, respectively. Hepatic events: The incidence of hepatic events was highest in the tadalafil group (0.9%, 2.9%, and 9.1% for M / T FDC (all strata), macitentan, and tadalafil, respectively). No events met the biochemical criteria for Hy's Law.

[0264] The proportion of participants experiencing a hemoglobin decrease ≥20 g / L was higher in the M / T FDC group compared to macitentan (22.9%) and tadalafil (0%) (42.0%).

[0265]

[0266]

[0267] Other of interest AE

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] Other safety observations

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289] A post - hoc analysis of the change in NT - proBNP from baseline to EDBT was performed using the primary endpoint (PVR) estimation strategy to assess the impact of missing data. For the M / T FDC versus macitentan, the treatment effect (adjusted geometric mean ratio) was 0.70 (0.50, 0.98) p = 0.0353, and for the M / T FDC versus tadalafil, the treatment effect (adjusted geometric mean ratio) was 0.64 (0.47, 0.86) p = 0.0029. See Tables 22C and 22D. This post - hoc analysis of the EDBT - to - baseline ratio confirmed that during the 16 - week DB period, NT - proBNP was reduced more with M / T 10 / 40mg FDC compared to each monotherapy.

[0290] Figure 12 A reduction in NT - proBNP from DB baseline was observed in all treatment groups and was slightly more significant in the M / T FDC group during the combined DB + OL period. Figure 11 It was shown that in the long - term M / T FDC group, the greatest reduction in NT - proBNP occurred in the cohort of participants who had not been treated previously. This continued through the 12th month of OL treatment.

[0291] (vi) Critical point analysis

[0292] Pre - planned critical points were performed for two comparisons (i.e., FDC versus either monotherapy). In this comparison, the extreme values in the ratio scale had to be skewed to restore significance, thus confirming the robustness of the primary efficacy outcome. The range was determined by how much the mean effect in the FDC group would need to deteriorate after missing data until the analysis result changed from significant to non - significant. Figure 15A and Figure 15B It shows the critical point grid (p - values of critical values) for each comparison of FDC with each monotherapy.

[0293] Post - hoc critical points were performed to handle missing data and concurrent events. The principle of the analysis was the same as for the pre - planned critical point analysis, but it included more data to deteriorate. Figure 13A and Figure 13B It shows the critical point grid (p - values of critical values) for each comparison of FDC with each monotherapy.

[0294] Example 2: Sub - analysis

[0295] In Example 1, 187 participants were randomly distributed across 16 countries / regions, including 23 participants from China (13 assigned to M / T FDC, 5 assigned to macitentan, and 5 assigned to tadalafil). The demographic and baseline disease characteristics of Chinese participants were generally consistent with those of the overall population. Consistent results for the primary endpoint were observed in Chinese participants compared to the overall population, with a 50% reduction in PVR for M / T FDC compared to macitentan (50%) and a 41% reduction in PVR for M / T FDC compared to tadalafil (41%) (in Chinese participants, for M / T FDC vs macitentan, the adjusted geometric mean ratio relative to monotherapy was 0.5 [95% CL: 0.35, 0.72, p = 0.0017], and for M / T FDC vs tadalafil, it was 0.59 [95% CL: 0.43, 0.80, p = 0.0040]). No clinically important differences were observed between the overall population and Chinese participants in terms of the incidence of AEs, SAEs, and AEs leading to premature discontinuation. There were no deaths among Chinese participants. Adverse events (AEs) leading to discontinuation, serious AEs, and those of particular interest (anemia, hypotension, edema) were more frequent in the M / T FDC group.

[0296] The results indicate that the efficacy results and safety profile of M / T FDC observed in Chinese participants were generally consistent with those of the overall population. See Figure 14 , which shows consistency for the co-primary endpoint observed in both Chinese and East Asian participants compared to the overall population.

Claims

1. A method for treating pulmonary arterial hypertension (PAH), the method comprising administering to a human patient in need thereof a fixed dose combination (FDC) of macitentan and tadalafil, wherein, Prior to administration of the FDC, the patient has not been treated with PAH-specific therapy, with endothelin receptor antagonist (ERA) monotherapy, or with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy.

2. The method according to claim 1, wherein the patient has not been treated with PAH-specific therapy prior to administration of the FDC.

3. The method according to claim 1, wherein the patient has been treated with ERA monotherapy prior to administration of the FDC, and the ERA monotherapy is macitentan.

4. The method according to claim 3, wherein the macitentan monotherapy comprises administering 10 mg of macitentan daily.

5. The method according to claim 1, wherein the patient has been treated with PDE-5 inhibitor monotherapy prior to administration of the FDC, and the PDE-5 inhibitor monotherapy is tadalafil.

6. The method according to claim 5, wherein the tadalafil monotherapy comprises administering 40 mg of tadalafil daily.

7. The method according to any one of the preceding claims, wherein the FDC is administered once daily.

8. The method according to any one of the preceding claims, wherein the dose of macitentan in the FDC is 10 mg.

9. The method according to any one of the preceding claims, wherein the dose of tadalafil in the FDC is 40 mg.

10. The method according to any one of claims 1 to 4 or 7 to 9, wherein the dose of tadalafil in the FDC is upregulated from 20 mg to 40 mg.

11. The method according to claim 10, wherein the dose of tadalafil in the FDC is upregulated 7 days after daily administration of the FDC having 20 mg of tadalafil.

12. The method according to claim 1 or 7 to 9, wherein the patient has been treated with PDE-5 inhibitor monotherapy prior to administration of the FDC, and the PDE-5 inhibitor monotherapy is sildenafil.

13. The method according to claim 12, wherein the sildenafil monotherapy comprises administering 60 mg to 120 mg of sildenafil daily.

14. The method according to claim 12 or 13, wherein the dose of tadalafil in the FDC is not upregulated.

15. A method for reducing pulmonary vascular resistance (PVR) and / or increasing six-minute walk distance (6MWD) in a patient with pulmonary arterial hypertension (PAH), wherein the patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy, the method comprising transitioning the patient to a fixed-dose combination (FDC) of macitentan and tadalafil.

16. The method according to claim 15, wherein the method reduces PVR.

17. The method according to claim 15, wherein the method increases 6MWD.

18. The method according to any one of claims 15 to 17, wherein the patient has not been treated with PAH-specific therapy.

19. The method according to any one of claims 15 to 17, wherein the patient has been treated with ERA monotherapy before administration of the FDC, and the ERA monotherapy is macitentan.

20. The method according to claim 19, wherein macitentan monotherapy comprises administering 10 mg of macitentan daily.

21. The method according to any one of claims 15 to 17, wherein the patient has been treated with PDE-5 inhibitor monotherapy before administration of the FDC, and the PDE-5 monotherapy inhibitor is tadalafil.

22. The method according to claim 21, wherein tadalafil monotherapy comprises administering 40 mg of tadalafil daily.

23. The method according to any one of claims 15 to 22, wherein the FDC is administered once daily.

24. The method according to any one of claims 15 to 23, wherein the dose of macitentan in the FDC is 10 mg.

25. The method according to any one of claims 15 to 24, wherein the dose of tadalafil in the FDC is 40 mg.

26. The method according to any one of claims 15 to 20 or 23 to 25, wherein the dose of tadalafil in the FDC is upregulated from 20 mg to 40 mg.

27. The method according to claim 26, wherein the dose of tadalafil in the FDC is upregulated 7 days after daily administration of the FDC with 20 mg of tadalafil.

28. The method according to any one of claims 15 to 20 or 23 to 27, wherein the patient has been treated with monotherapy of a PDE-5 inhibitor before administration of the FDC, and the monotherapy of the PDE-5 inhibitor is sildenafil.

29. The method according to claim 28, wherein the sildenafil monotherapy comprises administering 60 mg to 120 mg of sildenafil per day.

30. The method according to claim 28 or 29, wherein the dose of tadalafil in the FDC is not up-regulated.

31. The method according to any one of the preceding claims, wherein the macitentan is the free base of macitentan.

32. The method according to any one of the preceding claims, wherein one or both of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) are reduced in the patient, such as a reduction in BNP, or such as a reduction in NT-proBNP.

33. The method according to claim 32, wherein the patient has a BNP of 50 ng / L to 800 ng / L before administration of the FDC.

34. The method according to claim 32 or 33, wherein the patient has an NT-proBNP of 300 ng / L to 1100 ng / L before administration of the FDC.

35. The method according to claim 32, wherein the patient has a BNP greater than 800 ng / L before administration of the FDC.

36. The method according to claim 32 or 35, wherein the patient has an NT-proBNP greater than 1100 ng / L before administration of the FDC.

37. The method according to any one of claims 32 to 36, wherein after administration of the FDC, the BNP is reduced to less than 50 ng / L.

38. The method according to any one of claims 32 to 37, wherein after administration of the FDC, the patient has an NT-proBNP of less than 300 ng / L.

39. A method for reducing the level of one or both of B-type natriuretic peptide (BNP) and N-terminal B-type natriuretic peptide precursor (NT-proBNP) in a patient suffering from pulmonary arterial hypertension (PAH), wherein the patient has not been treated with PAH-specific treatment, treated with monotherapy of an endothelin receptor antagonist (ERA), or treated with monotherapy of a type 5 phosphodiesterase (PDE-5) inhibitor, the method comprising transitioning the patient to a fixed-dose combination (FDC) of macitentan and tadalafil.

40. A method for treating pulmonary arterial hypertension, the method comprising: · Initiate administration to a human patient in need of a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient has not been treated with PAH-specific therapy, with endothelin receptor antagonist (ERA) monotherapy, or with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy; and · In the case where the patient is identified as biomarker signature positive, continue administration to a human patient in need of a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient is biomarker signature positive if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

41. A method for treating pulmonary arterial hypertension, the method comprising administering to a human patient in need thereof a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient is identified as positive for a biomarker profile; wherein the patient is positive for a biomarker profile if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

42. A method for identifying a patient with pulmonary arterial hypertension who will respond to treatment with a fixed-dose combination (FDC) of macitentan and tadalafil, the method comprising: Administer the FDC to a patient in need; and In the case where the patient is identified as biomarker signature positive, identify the patient as responsive to treatment with the FDC.

43. The method according to claim 40 or 41, wherein the reference level for one or both of BNP and NT-proBNP is from a biological sample obtained from the patient before initiating administration of the FDC.

44. The method according to any one of claims 40, 41 or 43, wherein the sample level for one or both of BNP and NT-proBNP is from a biological sample obtained after initiating administration of the FDC.

45. The method according to any one of claims 40, 41 or 43, wherein the biological sample is obtained about 3 months to about 6 months such as 16 weeks after initiating administration of the FDC.

46. The method according to any one of claims 40, 41, 44 or 45, wherein another biological sample is obtained every about 3 months to about 6 months after obtaining the previous biological sample.

47. The method according to any one of claims 40 to 46, wherein the patient is identified as positive for a biomarker profile.

48. The method according to any one of claims 40 to 47, wherein before administering the FDC, the patient has a BNP of 50 ng / L to 800 ng / L.

49. The method according to any one of claims 40 to 48, wherein before administering the FDC, the patient has an NT-proBNP of 300 ng / L to 1100 ng / L.

50. The method according to any one of claims 40 to 47, wherein before administering the FDC, the patient has a BNP greater than 800 ng / L.

51. The method according to any one of claims 40 to 47 or 50, wherein before administering the FDC, the patient has an NT-proBNP greater than 1100 ng / L.

52. The method according to any one of claims 40 to 51, wherein after administering the FDC, the BNP is reduced to less than 50 ng / L.

53. The method according to any one of claims 40 to 52, wherein after administering the FDC, the patient has an NT-proBNP less than 300 ng / L.

54. The method according to any one of claims 40 to 53, wherein the patient has not undergone PAH-specific treatment.

55. The method according to any one of claims 40 to 53, wherein the patient was treated with an ERA monotherapy before administering the FDC, and the ERA monotherapy is macitentan.

56. The method according to claim 55, wherein the macitentan monotherapy comprises administering 10 mg of macitentan daily.

57. The method according to any one of claims 40 to 53, wherein the patient was treated with a PDE-5 inhibitor monotherapy before administering the FDC, and the PDE-5 inhibitor monotherapy is tadalafil.

58. The method according to claim 57, wherein the tadalafil monotherapy comprises administering 40 mg of tadalafil daily.

59. The method according to any one of claims 40 to 58, wherein the FDC is administered once daily.

60. The method according to any one of claims 40 to 59, wherein the dose of macitentan in the FDC is 10 mg.

61. The method according to any one of claims 40 to 60, wherein the dose of tadalafil in the FDC is 40 mg.

62. The method according to claims 54 and 59 to 61, wherein the dose of tadalafil in the FDC is upregulated from 20 mg to 40 mg.

63. The method according to claim 62, wherein the dose of tadalafil in the FDC is up - regulated after 7 days of once - daily administration of the FDC having 20 mg of tadalafil.

64. The method according to any one of claims 39 to 56 or 59 to 62, wherein the patient has been treated with a PDE - 5 inhibitor monotherapy before administration of the FDC, and the PDE - 5 inhibitor monotherapy is sildenafil.

65. The method according to claim 64, wherein the sildenafil monotherapy comprises administering 60 mg to 120 mg of sildenafil per day.

66. The method according to claim 64 or 65, wherein the dose of tadalafil in the FDC is not up - regulated.

67. The method according to any one of claims 41 to 66, wherein the macitentan is the free base of macitentan.

68. The method according to any one of claims 1 to 67, wherein the patient has East Asian ancestry.

69. The method according to claim 68, wherein the patient is Chinese.

70. A fixed - dose combination (FDC) of macitentan and tadalafil for the treatment of pulmonary arterial hypertension (PAH), wherein, Prior to administration of the FDC to a patient in need, the patient has not been treated with PAH-specific therapy, with endothelin receptor antagonist (ERA) monotherapy, or with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy.

71. The FDC according to claim 70, wherein the patient has not been treated with PAH - specific treatment before administration of the FDC.

72. The FDC according to claim 70, wherein the patient has been treated with an ERA monotherapy before administration of the FDC, and the ERA monotherapy is macitentan.

73. The FDC according to claim 72, wherein the macitentan monotherapy comprises administering 10 mg of macitentan per day.

74. The FDC according to claim 70, wherein the patient has been treated with a PDE - 5 inhibitor monotherapy before administration of the FDC, and the PDE - 5 inhibitor monotherapy is tadalafil.

75. The FDC according to claim 74, wherein the tadalafil monotherapy comprises administering 40 mg of tadalafil per day.

76. The FDC according to any one of claims 70 to 75, wherein the FDC is administered once daily.

77. The FDC according to any one of claims 70 to 76, wherein the dose of macitentan in the FDC is 10 mg.

78. The FDC according to any one of claims 70 to 77, wherein the dose of tadalafil in the FDC is 40 mg.

79. The FDC according to claim 70 and any one of claims 76 to 78, wherein the dose of tadalafil in the FDC is up - regulated from 20 mg to 40 mg.

80. The FDC according to claim 79, wherein the dose of tadalafil in the FDC is up - regulated 7 days after administration of the FDC with 20 mg of tadalafil once daily.

81. The FDC according to any one of claims 70 to 73 or 76 to 80, wherein the patient has been treated with PDE - 5 inhibitor monotherapy before administration of the FDC, and the PDE - 5 inhibitor monotherapy is sildenafil.

82. The FDC according to claim 81, wherein the sildenafil monotherapy comprises administering 60 mg to 120 mg of sildenafil per day.

83. The method according to claim 81 or 82, wherein the dose of tadalafil in the FDC is not up - regulated.

84. A fixed - dose combination (FDC) of macitentan and tadalafil for reducing pulmonary vascular resistance (PVR) and / or increasing six - minute walk distance (6MWD) in a patient with pulmonary arterial hypertension (PAH), wherein the patient has not been treated with PAH - specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with type 5 phosphodiesterase (PDE - 5) inhibitor monotherapy, comprising transitioning the patient to a fixed - dose combination (FDC) of macitentan and tadalafil.

85. The FDC according to claim 84, wherein the method reduces PVR.

86. The FDC according to claim 84, wherein the method increases 6MWD.

87. The FDC according to any one of claims 84 to 86, wherein the patient has not been treated with PAH - specific therapy.

88. The FDC according to any one of claims 84 to 86, wherein the patient has been treated with ERA monotherapy before administration of the FDC, and the ERA monotherapy is macitentan.

89. The FDC according to claim 88, wherein the macitentan monotherapy comprises administering 10 mg of macitentan per day.

90. The FDC according to any one of claims 84 to 86, wherein the patient has been treated with PDE - 5 inhibitor monotherapy before administration of the FDC, and the PDE - 5 inhibitor monotherapy is tadalafil.

91. The FDC according to claim 90, wherein the tadalafil monotherapy comprises administering 40 mg of tadalafil daily.

92. The FDC according to any one of claims 84 to 91, wherein the FDC is administered once daily.

93. The FDC according to any one of claims 84 to 92, wherein the dose of macitentan in the FDC is 10 mg.

94. The FDC according to any one of claims 84 to 93, wherein the dose of tadalafil in the FDC is 40 mg.

95. The FDC according to claim 87 and any one of claims 92 to 94, wherein the dose of tadalafil in the FDC is up - regulated from 20 mg to 40 mg.

96. The FDC according to claim 95, wherein the dose of tadalafil in the FDC is up - regulated 7 days after administering the FDC with 20 mg of tadalafil once daily.

97. The FDC according to any one of claims 84 to 89 or 92 to 96, wherein the patient has been treated with a PDE - 5 inhibitor monotherapy before administering the FDC, and the PDE - 5 inhibitor monotherapy is sildenafil.

98. The FDC according to claim 97, wherein the sildenafil monotherapy comprises administering 60 mg to 120 mg of sildenafil daily.

99. The method according to claim 97 or 98, wherein the dose of tadalafil in the FDC is not up - regulated.

100. The FDC according to any one of claims 93 to 99, wherein the macitentan is the free base of macitentan.

101. The FDC according to any one of claims 70 to 100, wherein one or both of B - type natriuretic peptide (BNP) or N - terminal pro - BNP (NT - proBNP) are reduced in the patient, such as a reduction in BNP, or such as a reduction in NT - proBNP.

102. The FDC according to claim 101, wherein before administering the FDC, the patient has a BNP level of 50 ng / L to 800 ng / L.

103. The FDC according to claim 101 or 102, wherein before administering the FDC, the patient has an NT - proBNP level of 300 ng / L to 1100 ng / L.

104. The FDC according to claim 101, wherein before administering the FDC, the patient has a BNP level greater than 800 ng / L.

105. The FDC according to claim 101 or 102, wherein before administering the FDC, the patient has an NT-proBNP greater than 1100 ng / L.

106. The FDC according to any one of claims 101 to 105, wherein after administering the FDC, the BNP is reduced to less than 50 ng / L.

107. The FDC according to any one of claims 101 to 106, wherein after administering the FDC, the patient has an NT-proBNP less than 300 ng / L.

108. A fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of reducing the level of one or both of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a patient with pulmonary arterial hypertension (PAH), wherein the patient has not been treated with PAH-specific therapy, has been treated with endothelin receptor antagonist (ERA) monotherapy, or has been treated with type 5 phosphodiesterase (PDE-5) inhibitor monotherapy.

109. A fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of treating pulmonary arterial hypertension, the method comprising: · Initiate administration to a human patient in need of a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient has not been treated with PAH-specific therapy, with endothelin receptor antagonist (ERA) monotherapy, or with phosphodiesterase type 5 (PDE-5) inhibitor monotherapy; and · In the case where the patient is identified as biomarker signature positive, continue administration to a human patient in need of a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient is biomarker signature positive if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

110. A fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of treating pulmonary arterial hypertension, the method comprising administering to a human patient in need thereof a fixed-dose combination (FDC) of macitentan and tadalafil, wherein the patient is identified as positive for biomarker signature; wherein the patient is positive for biomarker signature if a biological sample obtained from the patient is identified as having the following sample levels: (i) a sample level of B-type natriuretic peptide (BNP) lower than the reference level of BNP; (ii) a sample level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) lower than the reference level of NT-proBNP; or (iii) both (i) and (ii).

111. A fixed-dose combination (FDC) of macitentan and tadalafil for use in a method of identifying a patient with pulmonary arterial hypertension who will respond to treatment with a fixed-dose combination (FDC) of macitentan and tadalafil, the method comprising: Administer the FDC to a patient in need; and In the case where the patient is identified as biomarker signature positive, identify the patient as responsive to treatment with the FDC.

112. The FDC according to claim 109 or 110, wherein the reference level of one or both of BNP and NT-proBNP is from a biological sample obtained from the patient before initiation of administration of the FDC.

113. The FDC according to any one of claims 109, 110 or 112, wherein the sample level of one or both of BNP and NT-proBNP is from a biological sample obtained after initiation of administration of the FDC.

114. The FDC according to any one of claims 109, 110 or 112, wherein the biological sample is obtained about 3 months to about 6 months, such as 16 weeks, after initiation of administration of the FDC.

115. The FDC according to any one of claims 109, 110, 113 or 114, wherein another biological sample is obtained every about 3 months to about 6 months after obtaining the previous biological sample.

116. The FDC according to any one of claims 109 to 115, wherein the patient is identified as positive for a biomarker profile.

117. The FDC according to any one of claims 108 to 116, wherein before administration of the FDC, the patient has a BNP of 50 ng / L to 800 ng / L.

118. The FDC according to any one of claims 108 to 117, wherein before administration of the FDC, the patient has an NT-proBNP of 300 ng / L to 1100 ng / L.

119. The FDC according to any one of claims 108 to 116, wherein before administration of the FDC, the patient has a BNP greater than 800 ng / L.

120. The FDC according to any one of claims 108 to 116 or 119, wherein before administration of the FDC, the patient has an NT-proBNP greater than 1100 ng / L.

121. The FDC according to any one of claims 108 to 120, wherein after administration of the FDC, the BNP is reduced to less than 50 ng / L.

122. The FDC according to any one of claims 108 to 121, wherein after administration of the FDC, the patient has an NT-proBNP of less than 300 ng / L.

123. The FDC according to any one of claims 108 to 122, wherein the patient has not undergone PAH-specific treatment.

124. The FDC according to any one of claims 108 to 122, wherein the patient has been treated with an ERA monotherapy before administering the FDC, and the ERA monotherapy is macitentan.

125. The FDC according to claim 124, wherein the macitentan monotherapy comprises administering 10 mg of macitentan daily.

126. The FDC according to any one of claims 108 to 122, wherein the patient has been treated with a PDE-5 inhibitor monotherapy before administering the FDC, and the PDE-5 inhibitor is tadalafil.

127. The FDC according to claim 126, wherein the tadalafil monotherapy comprises administering 40 mg of tadalafil daily.

128. The FDC according to any one of claims 108 to 127, wherein the FDC is administered once daily.

129. The FDC according to any one of claims 108 to 128, wherein the dose of macitentan in the FDC is 10 mg.

130. The FDC according to any one of claims 108 to 129, wherein the dose of tadalafil in the FDC is 40 mg.

131. The FDC according to any one of claims 108 to 125 or 128 to 130, wherein the patient has been treated with a PDE-5 inhibitor monotherapy before administering the FDC, and the PDE-5 inhibitor monotherapy is sildenafil.

132. The FDC according to claim 131, wherein the sildenafil monotherapy comprises administering 60 mg to 120 mg of sildenafil daily.

133. The method according to claim 131 or 132, wherein the dose of tadalafil in the FDC is not upregulated.

134. The FDC according to claim 123 and any one of claims 131 to 133, wherein the dose of tadalafil in the FDC is upregulated from 20 mg to 40 mg.

135. The FDC according to claim 134, wherein the dose of tadalafil in the FDC is upregulated 7 days after administering the FDC having 20 mg of tadalafil once daily.

136. The FDC according to any one of claims 108 to 135, wherein the macitentan is the free base of macitentan.

137. The FDC according to any one of claims 70 to 136, wherein the patient has East Asian ancestry.

138. The FDC according to claim 137, wherein the patient is Chinese.

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