Methods of treating pulmonary hypertension

Abstract

The present disclosure provides for the treatment of pulmonary hypertension by administering to a subject suffering from pulmonary hypertension a therapeutically effective amount of a non-oral therapeutic agent for the treatment of pulmonary hypertension followed by the administration of a therapeutic agent for the treatment of pulmonary hypertension in an oral administration form wherein the therapeutic agent for the treatment of pulmonary hypertension is more effective than a subject not previously treated with the non-oral therapeutic agent. The amount of the non-oral therapeutic agent is sufficient to allow an increase in the amount of orally administered therapeutic agent to be subsequently administered.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 421,111, filed Oct. 31, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to a method for treating pulmonary hypertension by first administering a therapeutic agent for treating pulmonary hypertension in a non-oral form to a subject in need, and then administering a therapeutic agent for treating pulmonary hypertension in an oral form. Background Art

[0003] All blood is driven through the lungs via the pulmonary circulation, one of the purposes of which is to replenish the oxygen released by the blood as it flows through the rest of the body via the systemic circulation. Under normal circumstances, the flow rates of the two circulations are equal, but the resistance experienced in the pulmonary circulation is generally much less than that in the systemic circulation. When the resistance to blood flow in the lungs increases, the pressure of any segment of the blood flow in the circulation will increase. The symptoms described above are known as pulmonary hypertension (PH). Generally speaking, pulmonary hypertension is defined by an observed pressure higher than the normal pressure range of most people living at the same altitude and engaging in similar activities.

[0004] Pulmonary hypertension can be caused by a variety of reasons. According to the World Health Organization (WHO) convention, based on clinical and pathological evidence, different types of pulmonary hypertension are classified into 5 categories. See, for example, Simonneau et al., “Clinical Classification of Pulmonary Hypertension,” J. American College of Cardiology, 2004; 43(12 Suppl S): 5S - 12S. Pulmonary hypertension can manifest as a significant or explicable increase in resistance, such as blood flow obstruction caused by pulmonary embolism, dysfunction of the heart valves or muscles in handling blood after passing through the lungs, narrowing of the pulmonary vascular diameter due to a reflex response to alveolar hypoxia caused by lung diseases or high altitude, or a mismatch between vascular volume and basal blood flow, such as blood shunting caused by congenital malformations or surgical resection of lung tissue. In addition, certain infectious diseases, such as HIV, and liver diseases accompanied by portal hypertension may trigger pulmonary hypertension. Autoimmune diseases, such as collagen vascular diseases, also often lead to pulmonary vascular stenosis, and a large number of pulmonary hypertension patients result from this. Cases of pulmonary hypertension where the cause of the increased resistance cannot be explained are defined as idiopathic (primary) pulmonary hypertension (iPAH), which is diagnosed by excluding the causes of secondary pulmonary hypertension and is, in most cases, associated with hereditary mutations in the bone morphogenetic protein receptor - 2 gene. Among the patients treated in large specialized pulmonary hypertension centers, cases of idiopathic pulmonary arterial hypertension (PAH) often account for approximately 40% of the identifiable entities. Approximately 65% of the most common patients are women and young adults, although it also occurs in children and patients over 50 years old. Without specific treatment, the life expectancy after diagnosis is relatively short, about 3 to 5 years. Although, given the nature of the diagnostic process, occasional reports of spontaneous remission and longer survival are to be expected, generally speaking, the progression of the disease is inevitable, leading to syncope and right heart failure, and death often occurs suddenly.

[0005] Pulmonary hypertension refers to a condition in which the pulmonary arterial pressure (PAP) is elevated above normal levels. The normal average PAP in humans is approximately 12 - 15 mm Hg. On the other hand, pulmonary hypertension can be defined as an average PAP, as evaluated by right heart catheterization, that exceeds 25 mm Hg. In some severe forms of pulmonary hypertension, the pulmonary arterial pressure can reach levels even exceeding the systemic circulation pressure. When the PAP is significantly increased due to pulmonary venous congestion, such as in cases of left heart failure or valvular dysfunction, plasma can escape from the capillaries into the pulmonary interstitium and alveoli. This can lead to the accumulation of fluid in the lungs (pulmonary edema), along with a related decline in lung function, which can be fatal in some cases. However, in all other entities of this disease, even severe pulmonary hypertension, due to changes in the pulmonary blood vessels, is not characterized by pulmonary edema.

[0006] Pulmonary hypertension can be acute or chronic. Acute pulmonary hypertension is usually a potentially reversible phenomenon, generally attributed to the constriction of pulmonary vascular smooth muscle, which may be caused by conditions such as hypoxia (e.g., in altitude sickness), acidosis, inflammation, or pulmonary embolism. Chronic pulmonary hypertension is characterized by significant changes in the structure of the pulmonary blood vessels, resulting in a reduced cross-sectional area of the pulmonary blood vessels. Possible causes include, for example, chronic hypoxia, thromboembolism, collagen vascular diseases, excessive pulmonary circulation due to left-to-right shunts, HIV infection, portal hypertension, or a combination of genetic mutations and unknown causes, as in idiopathic pulmonary hypertension.

[0007] Multiple agents are available for the treatment of pulmonary hypertension, including prostacyclin, prostacyclin analogs, and prostacyclin receptor agonists. See Mandras et al., “Combination Therapy in Pulmonary Arterial Hypertension—Targeting the Nitric Oxide and Prostacyclin Pathways,” J. Cardiovascular Pharmacology Theory, 2021 Sept; 26(5). See also Gomberg-Maitland and Olschewski, “Prostacyclin therapies for the treatment of pulmonary arterial hypertension,” European Respiratory Journal, 2008; 31. One such prostacyclin analog is treprostinil. Treprostinil is approved for the treatment of pulmonary hypertension, and its intravenous and subcutaneous forms are The oral administration form is One such prostacyclin receptor agonist is ralinepag.

[0008] Patients with pulmonary hypertension who receive a higher total daily dose of oral treprostinil have a better prognosis, including an increase in the six-minute walk distance. See Balasubramanian et al., “Dosing characteristics of oral treprostinil in real-world clinical practice,” Pulmonary Circulation, 2018 Apr-Jun; 8(2):2045894018770654. See also Ramani et al., “Novel dose–response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations,” Pulmonary Circulation. 2020;10(3).

[0009] Patients with pulmonary arterial hypertension treated with ralinepag have a better prognosis (including pulmonary vascular resistance and six-minute walk distance) compared to patients treated with placebo. See Torres et al., “Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial,” European Respiratory Journal, 2019;54:1901030. Summary of the Invention

[0010] One embodiment is a method for treating pulmonary hypertension, which comprises administering to a subject suffering from pulmonary hypertension a therapeutically effective amount of a therapeutic agent for treating pulmonary hypertension in a non-oral form, followed by administering a therapeutic agent for treating pulmonary hypertension in an oral form, wherein the therapeutically effective amount of the non-oral form of the therapeutic agent is sufficient to allow an increase in the amount of the orally administered therapeutic agent to be administered subsequently, as compared to a subject who has not been treated with the non-oral therapeutic agent previously. In addition to achieving a higher total daily dose of the oral therapeutic agent, the subject treated according to this embodiment may also experience an improvement in at least one side effect selected from the group consisting of headache, nausea, and vomiting. In some embodiments, the non-oral therapeutic agent is an inhaled therapeutic agent or a parenteral agent. In some embodiments, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figures 1A-1D show clinical parameters at baseline and week 16. Figure 1A) WHO FC is represented as the percentage of patients in each grade at baseline and week 16; the p-value for the improvement in functional class corresponds to the median individual change relative to baseline, obtained using the McNemar test. The total percentage at week 16 adds up to 99% because the percentages are rounded down to the nearest integer. Figure 1B) NT-proBNP, Figure 1C) 6MWD, and Figure 1D) RA area are represented as medians, and the boxes represent the interquartile range. The p-values in Figures 1B-1D correspond to the median individual change relative to baseline, obtained using the Wilcoxon signed-rank test. WHO FC: World Health Organization functional class; NT-proBNP: N-terminal-pro brain natriuretic peptide; 6MWD: 6-minute walk distance; RA: right atrium.

[0012] Figures 2A-2D show risk stratification at baseline and week 16. The risk stratification is based on the 2015 ESC / ERS guidelines. Each figure represents the percentage of patients in each risk stratum at baseline and week 16 for Figure 2A) WHO FC, Figure 2B) NT-proBNP, Figure 2C) 6MWD, and Figure 2D) RA area. Among the 29 patients in the per-protocol population, only the patients evaluated at baseline and week 16 are listed here. WHO FC: World Health Organization functional class; NT-proBNP: N-terminal-pro brain natriuretic peptide; 6MWD: 6-minute walk distance; RA: right atrium. DETAILED DESCRIPTION

[0013] Unless otherwise specified, "a" or "an" means "one or more". In one aspect, provided herein are methods for treating a subject suffering from a condition associated with elevated blood pressure.

[0014] As used herein, the term "subject" refers to a living multi-cellular organism, including a vertebrate organism, and this category includes human and non-human mammals. The methods and compositions disclosed herein have equal application in medical and veterinary settings. Accordingly, the general term "subject" being treated should be understood to include all animals, such as humans, domestic animals, wild animals, and laboratory animals.

[0015] The term "treating" or "treatment" encompasses the treatment of a disease or disorder described herein in a subject (such as a human), and includes: (i) inhibiting the disease or disorder, such as preventing its development; (ii) alleviating the disease or disorder, such as causing the regression of the disorder; (iii) slowing the progression of the disorder; and / or (iv) inhibiting, alleviating, or slowing the progression of one or more symptoms of the disease or disorder. For example, the treatment of a condition associated with elevated blood pressure includes, but is not limited to, preventing or ameliorating an elevation of blood pressure above the normal range in the pulmonary and / or systemic circulation of a subject, and the attendant symptoms and complications.

[0016] The term "pulmonary hypertension" includes patients with pulmonary hypertension associated with or secondary to other conditions, including interstitial lung disease or fibrosis.

[0017] As used herein, "agent" or "drug" refers to a compound or other composition that, when appropriately administered to a subject, is capable of inducing a desired therapeutic or prophylactic effect. In some embodiments, the agent or drug may be administered as a prodrug, substrate, or precursor, terms that refer to a compound that is metabolized (i.e., transformed in vivo) into a pharmacologically active agent after administration. For example, a prodrug, substrate, or precursor may be used to improve the absorption, distribution, metabolism, and / or excretion (ADME profile) of the corresponding drug, and thereby improve the pharmacodynamics of the corresponding drug, such as bioavailability.

[0018] As used herein, the term "pharmaceutically acceptable" means that it is safe and sufficiently non-toxic for administration to a subject.

[0019] As used herein, the term "therapeutically effective amount" refers to the amount of a compound sufficient to achieve a desired effect in a subject being treated. For example, a therapeutically effective amount of a therapeutic agent or drug for treating pulmonary hypertension may be the amount necessary to improve or inhibit an elevation of the pulmonary artery pressure in a subject above normal levels, and more specifically, an amount sufficient to maintain one or more of the right atrial pressure, pulmonary capillary wedge pressure, right ventricular systolic and diastolic pressures, pulmonary artery systolic and diastolic pressures, and filling pressures of the subject within the normal range.

[0020] Specifically, the present disclosure contemplates methods and compositions for treating or preventing conditions (such as pulmonary hypertension) associated with elevated blood pressure in the lungs in a subject. In some embodiments, this includes treating subjects with neonatal pulmonary hypertension. In other embodiments, this includes treating subjects with primary and / or secondary pulmonary hypertension. In some embodiments, this includes treating subjects with pulmonary arterial hypertension (PAH). The "pulmonary hypertension" being treated can be one or more of the WHO classifications for pulmonary hypertension: Group 1 (pulmonary arterial hypertension); Group 1' (pulmonary veno-occlusive disease (PVOD) and / or pulmonary capillary hemangiomatosis (PCH)); Group 2 (pulmonary hypertension due to left heart disease); Group 3 (pulmonary hypertension due to lung diseases and / or hypoxia); Group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)); Group 5 (pulmonary hypertension with multifactorial mechanisms of unknown origin). For example, "pulmonary hypertension" can refer to any one of Groups 1-5 pulmonary hypertension or any combination of those groups.

[0021] The present disclosure also contemplates methods and compositions for treating or preventing other conditions associated with elevated blood pressure or reduced blood flow, including vasospasm, stroke, angina, ischemia, revascularization of coronary and other arteries (peripheral vascular disease), transplantation (such as transplantation of the kidney, heart, lung, or liver), treating hypotension (such as hypotension seen in shock or trauma, surgery, and cardiac arrest) to prevent reperfusion injury to vital organs, skin ulcers (such as using topical non-acidified nitrite), Raynaud's phenomenon, treating hemolytic conditions (such as sickle cell, malaria, TTP, and HUS), hemolysis due to pre- and postnatal immunoincompatibility, and other conditions.

[0022] A subject's disease can be treated by administering a suitable agent or drug to the subject having the disease or a disease-related condition or symptom.

[0023] In some embodiments, the therapeutic agent in non-oral form for treating pulmonary hypertension is prostacyclin (e.g., epoprostenol (flolan), treprostinil, beraprost, iloprost), a prostaglandin drug, or a prostacyclin receptor agonist, such as ralinepag. In some embodiments, the non-oral and oral therapeutic agents are the same. In one embodiment, the non-oral therapeutic agent is treprostinil, and the oral therapeutic agent is treprostinil.

[0024] One embodiment of the present invention is a method of administering a first therapeutically effective amount of a non-oral therapeutic agent for treating pulmonary hypertension to a subject (such as a human) suffering from pulmonary hypertension, and subsequently administering a therapeutic agent for treating pulmonary hypertension in an oral administration form, wherein the first therapeutically effective amount of the non-oral therapeutic agent for treating pulmonary hypertension is sufficient to allow an increase in the amount of the orally administered therapeutic agent to be administered subsequently, as compared to a subject who has not been previously treated with a non-oral therapeutic agent for treating pulmonary hypertension.

[0025] In some embodiments, a first therapeutically effective amount of the non-oral therapeutic agent is administered parenterally. In other embodiments, the subject inhales a first therapeutically effective amount of the non-oral therapeutic agent.

[0026] Specifically, in some embodiments, the therapeutic agent for treating pulmonary hypertension is treprostinil. In some embodiments, the form of treprostinil used may be a pharmaceutically acceptable salt or ester or prodrug of treprostinil. Suitable salts of treprostinil include sodium salt, potassium salt, and diethanolamine salt. Other suitable esters and salts of treprostinil are disclosed in U.S. Patent Nos. 9,278,901 and 9,701,611. Suitable prodrugs of treprostinil are also disclosed in U.S. Serial Nos. 16 / 434,938 and 17 / 001,123 and U.S. Patent No. 9,371,264.

[0027] In some embodiments, the first therapeutically effective amount of the non-oral therapeutic agent for treating pulmonary hypertension is parenteral treprostinil. More specifically, in some embodiments, parenteral treprostinil is intravenous treprostinil. In other embodiments, parenteral treprostinil is subcutaneous treprostinil.

[0028] One embodiment of the present invention is a method of administering a therapeutically effective amount of a non-oral prostacyclin analogue to a subject (such as a human) suffering from pulmonary hypertension, and subsequently administering a prostacyclin receptor agonist in an oral administration form, wherein the therapeutically effective amount of the non-oral prostacyclin analogue is sufficient to allow an increase in the amount of the orally administered prostacyclin receptor agonist to be administered subsequently, as compared to a subject who has not been previously treated with a prostacyclin analogue.

[0029] Specifically, in some embodiments, the prostacyclin receptor agonist is ralinepag. In some embodiments, the form of ralinepag used may be a pharmaceutically acceptable salt or prodrug of ralinepag. Suitable prodrugs of ralinepag are disclosed in WO 2023 / 177877. Other suitable forms of ralinepag are also disclosed in WO 2023 / 158634.

[0030] In some embodiments, in addition to prostacyclin, prostacyclin analogs, or prostacyclin receptor agonists, multiple oral therapeutic agents are co-administered to a subject for the treatment of pulmonary hypertension. As used herein, the term "co-administer (co-administer or co-administration)" refers to the administration of multiple therapeutic agents, such as phosphodiesterase type 5 (PDE5) inhibitors, endothelin receptor antagonists, soluble guanylate cyclase stimulators, such that the duration of their respective biological activities overlaps in the subject being treated. Co-administration can be carried out by simultaneously or sequentially administering the multiple therapeutic agents, e.g., administering a second therapeutic agent before, during, or after administering a first therapeutic agent.

[0031] The following examples further illustrate, but in no way limit the scope of the foregoing embodiments. Example 1 Rapid titration of parenteral treprostinil and transition to oral treprostinil Overview

[0032] A Phase 4, multicenter, open-label study of 16 weeks in duration was conducted in patients with pulmonary arterial hypertension to optimize oral (intravenous or subcutaneous treprostinil) after induction and (oral treprostinil). During the study, patients may have been receiving other non-prostacyclin pulmonary hypertension therapies. The study enrollment was completed, and a total of 35 patients were enrolled. 32 patients initiated oral treprostinil. 29 patients were in the per-protocol population, including all patients without major protocol deviations. 28 patients from the per-protocol population completed the study. Once enrolled, patients initiated intravenous or subcutaneous and were titrated to a minimum dose of 20 ng / kg / min over 2 to 8 weeks. Then, in an inpatient or outpatient setting, patients transitioned to The primary endpoint was to evaluate the percentage of subjects who achieved a dose of 4 mg three times daily (TID) - or a total daily dose of 12 mg - or higher at week 16.

[0033] ​The secondary endpoints of this study included the measurement of the following: changes in prostaglandin adverse events (AEs), echocardiogram, changes in 6-minute walk distance (6MWD), changes in Borg dyspnea score, changes in World Health Organization (WHO) functional class (FC), changes in serum N-terminal-pro brain natriuretic peptide (NT-proBNP) levels, the impact of pulmonary hypertension on a person's life (health-related quality of life), and treatment satisfaction. Specifically, this study aimed to measure the percentage of subjects in whom each of the following four independent clinical parameters (6MWD, NT-proBNP, WHO FC, right atrial area) improved to a lower risk stratum (as defined by the 2015 ESC / ERS guidelines (Gailè et al., DOI: 10.1183 / 13993003.01032-2015)) at week 16 compared with the baseline measurement. Another endpoint was to determine the percentage of subjects in whom each of the following four independent clinical parameters met the definition of the low-risk category according to the 2015 ESC / ERS guidelines at week 16: 6MWD > 440 m, serum NT-proBNP.

[0034] In this clinical trial, the mean daily total dose reached 16.4 mg at week 16 in the enrolled patients, and 79% of the study subjects achieved the primary endpoint of the study, which was a total daily dose of 12 mg. The treatment was well tolerated three times daily, and the safety profile was consistent with that of previous studies in pulmonary arterial hypertension. In this study, several well-known adverse events of treprostinil, such as headache, nausea, and vomiting, tended to improve after the transition from (parenteral treprostinil) to (oral treprostinil). Method Inclusion criteria

[0035] According to the 2015 ESC / ERS guidelines, the specific hemodynamic inclusion criteria included mean pulmonary artery pressure ≥25 mmHg, pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤15 mmHg, pulmonary vascular resistance >3 Wood units, and no unrepaired congenital heart disease. Other key inclusion criteria were World Health Organization functional class (FC) II or III, 6-minute walk distance (6MWD) >250 m, and REVEAL 2.0 risk score ≤9 (Benza et al. 2021, DOI: https: / / doi.org / 10.1016 / j.chest.2020.08.2069). Patients could receive at most two oral PAH background therapies if they had been on a stable dose for ≥30 days before baseline. Since the focus of this study was to add a new therapy rather than replace one therapy with another, participants were eligible regardless of the number of pulmonary hypertension background therapies (0, 1, or 2) they received at baseline. Patients were excluded if they had received any prostanoid therapy (i.e., treprostinil, epoprostenol, iloprost, or selexipag) within 28 days of baseline, or were diagnosed with uncontrolled sleep apnea, renal insufficiency, Child-Pugh B or C liver disease, or ischemic heart disease with pulmonary artery wedge pressure (PAWP) >15 mmHg or left ventricular ejection fraction (LVEF) <50%. Baseline assessments were collected up to 14 days before the start of parenteral treprostinil and included hemodynamics, FC, N-terminal pro-brain natriuretic peptide (NT-proBNP), 6MWD, and medication history by echocardiography and RHC. Notably, historical RHC data were used for baseline assessment if performed up to 180 days before the start of parenteral treprostinil. Echocardiograms were uploaded and stored in a central repository and were evaluated by an independent central reader according to the American Society of Echocardiography Guidelines (Bossone et al., DOI: 10.1016 / j.echo.2012.10.009). Table 1 shows the selected baseline characteristics of the patients in the per-protocol population. Table 1. Selected characteristics of 29 patients who received oral treprostinil in the per-protocol population. Treatment

[0036] Based on the decision of the clinician, in an inpatient or outpatient setting, the patient initiated subcutaneous (SC) or intravenous (IV) treprostinil at 2 ng / kg / min. Parenteral treprostinil was dose-adjusted over 2 - 8 weeks to the dose tolerated to improve PAH symptoms. The investigator selected the frequency of up-titration and the dose increment and was instructed to use parenteral therapy to achieve the optimal treprostinil dose; the dose adjustment for each participant was individualized and optimized until the dose to improve PAH symptoms was reached. There was no maximum parenteral dose of treprostinil.

[0037] Once the patient reached at least 20 ng / kg / min and was considered suitable for transition according to the doctor's assessment, at week 2, 4, or 8, in an inpatient or outpatient setting, the patient was transitioned to oral treprostinil within 1 - 21 days through cross-dose adjustment. All participants who were still receiving parenteral treprostinil at week 8, regardless of their parenteral treprostinil dose, initiated the transition to oral treprostinil, unless their clinician considered them unsuitable for transition. Before the transition, 6MWD, WHOFC, NT-proBNP, and echocardiogram parameters were evaluated.

[0038] The daily dose of oral treprostinil was calculated according to Formula I. The dose conversion steps and representative cross-dose adjustments for outpatient and inpatient transitions are shown in Tables 2 - 3. A post-transition visit was conducted 7 - 14 days after initiating oral treprostinil. The oral treprostinil dose was adjusted to the maximum tolerated dose up to week 16. Clinicians were encouraged to continue the oral treprostinil dose adjustment in an outpatient setting by increasing the dose by 0.125 mg TID every 3 - 4 days if the patient tolerated it. The target dose of oral treprostinil at the end of the transition was determined using the following weight-based equation: (0.0072) x (patient weight, kg) x (parenteral dose, ng / kg / min). Table 2 . Representative outpatient transition dosing schedule. Table 3 . Representative inpatient transition dosing schedule. Endpoint measurement

[0039] The primary endpoint was the percentage of patients who achieved at least 12 mg of oral treprostinil TDD (0.171 mg / kg for patients <70 kg) at week 16. Secondary endpoints included changes in risk stratification and clinical parameters from baseline to week 16, where the baseline values were collected within 14 days before the start of parenteral treprostinil. The 2015 ESC / ERS guidelines were used to assess changes in risk stratification of FC, NT-proBNP, 6MWD, and right atrial (RA) area, which classified the risk of each determinant as low, medium, and high (Galiè et al., 2016). The clinical parameters of interest included FC, NT-proBNP, 6MWD, echocardiographic parameters, REVEAL Lite 2 score (Benza et al., 2021), and Borg Dyspnea Score (Borg, 1982, DOI: https: / / doi.org / 10.1249 / 00005768-198205000-00012). The REVEAL Lite 2 score included clinical parameters used to determine the risk status (low, medium, high) of pulmonary hypertension. The Borg Dyspnea Score ranged from 0 to 10, where 0 indicated no dyspnea and 10 indicated very, very severe (almost maximal) dyspnea. Patient-reported outcomes were assessed using the emPHasis-10 quality of life questionnaire (Yorke et al., 2014, DOI: 10.1183 / 09031936.00127113) and the Pulmonary Arterial Hypertension Symptom Scale (PAHSS) (Matura et al., 2015, DOI: https: / / doi.org / 10.1016 / j.apnr.2014.04.001). The Treatment Satisfaction Questionnaire for Medication (TSQM) (Atkinson et al., 2004, DOI: https: / / doi.org / 10.1186 / 1477-7525-2-12) was used to measure patients' satisfaction with their medications in the past two to three weeks; higher scores indicated higher satisfaction. The emPHasis-10 score could range from 0 to 50, with lower scores indicating better quality of life.

[0040] During the entire study period, safety and tolerability were evaluated at each scheduled visit and between visits as needed. Tolerability measures of interest included the incidence of all adverse events (AEs) and prostaglandin-related AEs, including headache, diarrhea, nausea, vomiting, flushing, jaw pain, and limb pain. A survey measured the severity and duration of AEs commonly associated with prostaglandin therapy: headache, diarrhea, nausea, vomiting, flushing, jaw pain, and limb pain; scores ranged from 0 (not bothersome at all, zero days) to 14 (very bothersome, every day). An event was recorded only if the prostaglandin-related event captured by the survey was unusual in intensity, frequency, or duration compared to symptoms in the patient's treatment history. Patient compliance with oral treprostinil was evaluated by conducting a study drug accountability at each scheduled study visit. Statistics

[0041] Unless otherwise specified, the primary endpoint and all efficacy endpoints were analyzed using the per-protocol population, which included all patients without major protocol deviations. The exact (Clopper-Pearson) 95% confidence interval for the primary endpoint was calculated. Safety and tolerability were analyzed using the safety population, which included all patients who initiated parenteral treprostinil. For continuous variables, descriptive statistics were reported as the median (interquartile range, IQR or range) or mean (± standard deviation, SD). For categorical variables, descriptive statistics included the frequency and percentage of patients in each category. The change from baseline to week 16 for continuous variables was analyzed using the Wilcoxon signed-rank test. The change in FC from baseline to week 16 was analyzed using the McNemar test. The p-values for these tests were derived for descriptive purposes and were not part of a formal hypothesis testing framework.

[0042] The institutional review board for human research approved the protocol, and written consent was obtained from the subject or their representative, if required by the institutional review board. Results Primary endpoint

[0043] Thirty-five patients initiated the study. Twenty-nine patients received an initial dose of oral treprostinil, and 28 patients completed the study and received oral treprostinil at week 16. The mean duration of parenteral treprostinil use was 55 days (±13), and at the time of transition to oral treprostinil, the mean parenteral dose reached 27.0 ng / kg / min (±9.6). The median (range) dose immediately prior to transition was 24 (6 - 40) ng / kg / min. In this study, participants who initiated transition to oral treprostinil at week 4 reached similar maximum parenteral doses during initiation and up-titration as those who initiated transition at week 8, suggesting that 4 weeks or less may be sufficient time to up-titrate patients to a therapeutic SC or IV dose.

[0044] During the transition visit (week 2, 4, or 8), if the participant reached a minimum parenteral treprostinil dose of 20 ng / kg / min and was considered suitable for transition by physician assessment, the transition was performed. During the transition visit (week 2, 4, or 8), if the participant reached a minimum parenteral treprostinil dose of 20 ng / kg / min, the transition was performed.

[0045] In an inpatient or outpatient setting, the transition from parenteral to oral treprostinil could occur within 1 - 21 days. More than half of the patients (55%) transitioned to oral treprostinil in an outpatient setting, with a mean duration of 5.6 days (±2.3 days). The remaining 45% of patients transitioned in an inpatient setting, with a mean duration of 1.7 days (±0.5). The post-transition visit occurred one to two weeks after the start of the transition. The mean (SD) TDD at the post-transition visit was 16.6 (8.1) mg. At the end of the study, 79.3% of the participants reached an oral treprostinil dose of at least 12 mg TDD at week 16; at week 16, the mean (SD) TDD was 16.4 (7.5) mg, and the median dose was 15.0 mg (IQR 12.0, 22.9). Over the course of the study, the mean (SD) exposure time to oral treprostinil was 64 (16) days.

[0046] From the post-transition visit to week 16, many participants (13 out of 28) continued to up-titrate their oral treprostacyclin dose after the post-transition visit, while 9 participants maintained their oral treprostacyclin dose and 6 participants decreased their oral treprostacyclin dose. None of the participants switched back to parenteral treprostinil after receiving oral treprostinil.

[0047] When participants used parenteral treprostinil, 69%, 55%, and 34% of the participants in the per-protocol population (n = 29) received ondansetron, acetaminophen, and loperamide, respectively, for prostacyclin-related nausea / vomiting, headache, and diarrhea. When using oral treprostinil, 48%, 38%, and 38% of the participants used ondansetron, acetaminophen, and loperamide, respectively. Overall, the use of all concomitant medications decreased after transitioning from parenteral treprostinil to oral treprostinil. Secondary outcome measures Adverse events

[0048] All patients who initiated parenteral treprostinil reported at least one treatment-emergent AE. Table 4 shows the AEs experienced by patients during the parenteral prostacyclin phase, transition phase, and oral prostacyclin phase. Adverse reactions that were not included in Table 4 but occurred in at least 10% of patients included decreased appetite, joint pain, dyspepsia, abdominal pain, infusion site irritation, back pain, dyspnea, muscle spasm, peripheral edema, and dizziness. During parenteral treprostinil induction, the most bothersome AEs were limb pain, followed by jaw pain, headache, and diarrhea; after transitioning to oral treprostinil, all except diarrhea improved to "not bothersome at all", where 1 equals "very bothersome to me" and 4 equals "not bothersome at all" on the current adverse reaction scale. After switching to oral treprostinil, diarrhea and nausea became the most bothersome AEs. During the parenteral and oral treprostinil phases, the number of patients experiencing prostaglandin-related AEs was similar, but flushing increased and headache decreased after the transition. Table 4 . Prostaglandin-related adverse events. The number of patients experiencing specific AEs and the associated percentages during each phase of the study are shown. Clinical parameters and risk assessment

[0049] At the transition visit, the median (IQR) 6MWD, NT-proBNP, tricuspid annular plane systolic excursion (TAPSE), and right atrial area in the per-protocol population were 377 (318, 453) m, 186 (110, 724) ng / L, 18.1 (14.8, 20.9) mm, and 19.3 (16.0, 26.7) cm2, respectively. Among 29 patients, 76% had an improvement in WHO FC at the transition visit, 21% remained unchanged, and 3% deteriorated. Overall, the above clinical variables improved from baseline to the transition period (Table 1).

[0050] In the 16th week, multiple clinical measurements improved compared to the baseline measurements (Tables 1 and 5, Figures 1 and 2). The patients showed clinical improvement in echocardiographic parameters. From baseline to the 16th week, the median change in RA area was -2.9 cm 2 (IQR -6.6, 1.5; p = 0.0102), reaching a median RA area of 17.5 cm 2 (IQR 13.8, 20.5) at the 16th week (Figure 1D). The RA area was determined using the end-diastolic area. In addition to the RA area, several other echocardiographic parameters also showed favorable numerical changes. Table 5 shows the changes in echocardiographic parameters of the patients in the study. From baseline to the 16th week, the median change in cardiac output was +0.5 L / min (IQR -0.4, 1.4), the median change in tricuspid annular plane systolic excursion (TAPSE) was +1.2 mm (IQR -1.6, 4.2), and the median change in left ventricular diameter was +3.5 mm (IQR -0.7, 6.4). Table 5 . Changes in echocardiographic parameters. The values shown are median (IQR). TAPSE: tricuspid annular plane systolic excursion; RA: right atrium; RV: right ventricle; MPI: myocardial performance index; LV: left ventricle; LVOT: left ventricular outflow tract; PVAT: pulmonary valve acceleration time.

[0051] The WHO-FC system has functional classifications I-IV, where a lower FC (e.g., I) indicates a lower severity of the disease. From baseline to the 16th week, the FC symptoms generally shifted towards a lower severity, with 68% of the patients showing improvement in FC and only 1 patient deteriorating (p < 0.0001). From baseline to the 16th week, the percentage of patients classified as FC I increased from 0% to 46% (Figure 1A).

[0052] The patients showed clinical improvement in 6MWD. The median increased from 363 m (IQR 288, 426) at baseline to 395 m (IQR 315, 469) at week 16 (Table 1, Figure 1C). At week 16, the median Borg dyspnea score improved from 4 (IQR 3, 6) to 3 (IQR 1, 4), with a median change from baseline of -1 (IQR -3, 0; p = 0.0009). Most domains of the PAHSS improved from baseline to week 16, including fatigue, dyspnea, edema, orthopnea, and dizziness; chest pain and syncope showed little change. Quality of life improved significantly, as measured by a median change in the emPHasis-10 score of -3 (p = 0.0001) relative to baseline. The median NT-proBNP at week 16 was 212 ng / L (IQR 132, 551), with a median change from baseline of -134 ng / L (IQR -360, 1.5; p = 0.0041) (Figure 1B).

[0053] From baseline to week 16, the median REVEAL Lite 2 score improved from 6 (IQR 4, 7) to 3.5 (IQR 2, 5.5), with a median change from baseline of -1 (IQR -3, 0; p = 0.0006).

[0054] Improvements in FC, 6MWD, NT-proBNP, and RA area were also observed in the 2015 ESC / ERS risk stratification (Figure 2A - 2D). The percentage of patients in the low-risk stratum increased for all four variables at week 16, most notably for NT-proBNP and RA area, where the percentage of patients in the low-risk stratum almost doubled. Thus, at week 16, the percentage of patients in the medium- and high-risk strata decreased. The percentages of patients with FC, NT-proBNP, 6MWD, and RA area shifting to a lower risk stratum from baseline to week 16 were 39%, 39%, 15%, and 35%, respectively. The risk stratification deteriorated for each variable in only one patient. Equivalent scheme

[0055] The technology is not limited to the specific embodiments described in this application, which are intended as single illustrations of various aspects of the technology. Many modifications and variations can be made to the technology without departing from the spirit and scope of the technology, which will be apparent to those skilled in the art. Functional equivalent methods and devices within the scope of the technology, other than those enumerated herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the technology. It should be understood that the technology is not limited to a particular method, reagent, compound composition, or biological system, which can of course vary. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0056] In addition, where the features or aspects of the present disclosure are described in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0057] As will be understood by those skilled in the art, for any and all purposes, particularly in the context of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be readily understood as fully describing and enabling that range to be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be readily broken down into lower third, middle third, and upper third, etc. As will also be understood by those skilled in the art, all such phrases as "at most," "at least," "greater than," "less than," etc. include the recited numbers and the ranges they refer to can subsequently be broken down into sub-ranges as described above.

[0058] All numerical identities, such as pH, temperature, time, concentration, amount, and molecular weight, including ranges, are approximate values that vary by (+) or (-) 10%, 1%, or 0.1% as appropriate. It should be understood that although not always explicitly stated, all numerical identities can be preceded by the term "about." It should also be understood that although not always explicitly stated, the reagents described herein are merely exemplary reagents and their equivalents are known in the art.

[0059] All patents, patent applications, provisional applications, and publications mentioned or cited herein, including all figures and tables, are hereby incorporated by reference in their entirety as long as they are not inconsistent with the explicit teachings of this specification.

Claims

1. A method for treating pulmonary hypertension, which comprises administering to a subject suffering from pulmonary hypertension a first therapeutically effective amount of a non-oral therapeutic agent for treating pulmonary hypertension, followed by administering an orally administered therapeutic agent for treating pulmonary hypertension, wherein, The first therapeutically effective amount of the parenteral therapeutic agent is sufficient to permit an increase in the amount of the orally administered therapeutic agent to be subsequently administered, as compared to a subject who has not been previously treated with the parenteral therapeutic agent.

2. The method according to claim 1, wherein the first therapeutically effective amount of the non-oral therapeutic agent is parenteral prostacyclin.

3. The method according to claim 2, wherein the parenteral prostacyclin is parenteral treprostinil, its salt, ester or prodrug.

4. The method according to claim 3, wherein the parenteral treprostinil is intravenous treprostinil.

5. The method according to claim 3, wherein the parenteral treprostinil is subcutaneous treprostinil.

6. The method according to claim 3, wherein the parenteral treprostinil starts at a dose of 2 ng / kg / min.

7. The method according to claim 3, wherein the parenteral treprostinil is dose-adjusted to a minimum dose of 20 ng / kg / min within at least two weeks.

8. The method according to claim 3, wherein the parenteral treprostinil is dose-adjusted to a minimum dose of 20 ng / kg / min within a time period of about two weeks to about eight weeks.

9. The method according to claim 1, wherein the orally administered therapeutic agent is treprostinil, its salt, ester or prodrug in an orally administered form.

10. The method according to claim 9, wherein the treprostinil in the orally administered form is administered twice a day.

11. The method according to claim 9, wherein the treprostinil in the orally administered form is administered three times a day.

12. The method according to claim 9, wherein the treprostinil in the orally administered form is gradually increased from an initial oral administration dose of 1 mg per day to at least 12 mg per day within a time period of at most 21 days.

13. The method according to claim 9, wherein the treprostinil in the orally administered form is gradually increased from an initial oral administration dose of 0.5 mg per day to at least 12 mg per day within a time period of at most 21 days.

14. The method according to claim 1, wherein at least one side effect selected from the group consisting of headache, nausea and vomiting is improved after transitioning to the orally administered therapeutic agent.

15. The method according to claim 1, wherein the area of the right atrium of the subject is reduced.

16. The method according to claim 1, wherein the six-minute walking distance of the subject is increased.

17. The method according to claim 1, wherein the pulmonary hypertension is pulmonary arterial hypertension.

18. The method according to claim 1, wherein the method comprises treating the subject with an additional therapeutic agent.

19. The method according to claim 18, wherein the additional therapeutic agent treats pulmonary hypertension.

20. The method according to claim 18, wherein the additional therapeutic agent comprises an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, and a soluble guanylate cyclase stimulator.

21. The method according to claim 1, wherein the orally administered therapeutic agent is selected from the group consisting of treprostinil, beraprost, selexipag, and ralinepag.

22. The method according to claim 1, wherein the therapeutically effective amount of the non-oral therapeutic agent is inhaled prostacyclin.

23. The method according to claim 22, wherein the inhaled prostacyclin is inhaled treprostinil.

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