Treatment of pulmonary hypertension

Abstract

The present disclosure provides for the treatment of pulmonary hypertension by administering to a subject suffering from pulmonary hypertension a first therapeutically effective amount of a parenteral therapeutic agent for treating pulmonary hypertension, followed by administration of an oral dosage form of a therapeutic agent for treating pulmonary hypertension, wherein the amount of the parenteral therapeutic agent is sufficient to allow for an increased amount of a subsequently administered orally administered therapeutic agent compared to a subject not previously treated with the parenteral therapeutic agent.

Description

[Technical Field]

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

[0002] The present invention relates to a method of treating pulmonary hypertension by first administering to a subject in need thereof a parenteral form of a therapeutic agent for treating pulmonary hypertension, followed by an oral form of a therapeutic agent for treating pulmonary hypertension. [Background technology]

[0003] background All blood passes through the lungs via the pulmonary circulation, primarily to replenish oxygen, which is then distributed to surrounding blood channels in other parts of the body via the systemic circulation. Flow through both circulations is equal under normal circumstances, but the resistance to flow in the pulmonary circulation is generally much less than that in the systemic circulation. As resistance to pulmonary blood flow increases, the pressure in that circulation increases for any particular flow. This condition is called pulmonary hypertension (PH). Pulmonary hypertension is generally defined by the observation of pressures above the normal range appropriate for the majority of people residing at the same altitude and engaging in similar activities.

[0004] Pulmonary hypertension can occur for a variety of reasons, and the various components of pulmonary hypertension have been classified into five categories based on clinical and pathological grounds in accordance with the most recent WHO conventions (see, e.g., Simonneau et al., "Clinical Classification of Pulmonary Hypertension," J. American College of Cardiology, 2004; 43(12 Suppl S):5S-12S). Pulmonary hypertension can be a manifestation of obvious or explainable increased resistance, such as impaired blood flow due to pulmonary emboli, impaired function of the cardiac valves or myocardium in handling blood after passage through the lungs, reduced pulmonary vessel diameter as a reflex response to alveolar hypoxia due to lung disease or high altitude, or a mismatch between vascular volume and required blood flow, such as bypass of blood in congenital anomalies or surgical removal of lung tissue. In addition, certain infections, such as HIV, and liver disease associated with portal hypertension can also cause pulmonary hypertension. Autoimmune diseases, such as collagen vascular disease, also frequently cause pulmonary vascular narrowing and contribute to a significant number of patients with pulmonary hypertension. The remaining cases of pulmonary hypertension in which the cause of increased resistance remains unexplained are defined as idiopathic (primary) pulmonary hypertension (iPAH), which is diagnosed after excluding secondary causes of pulmonary hypertension. The majority of cases are associated with genetic mutations in the bone morphogenetic protein receptor-2 gene. Cases of idiopathic pulmonary arterial hypertension (PAH) tend to comprise a recognizable proportion, approximately 40%, of patients treated at large centers specializing in pulmonary hypertension. Approximately 65% ​​of patients are women and young adults, but the disease has also occurred in children and patients over the age of 50. Life expectancy from the time of diagnosis is short, approximately 3 to 5 years without specific treatment, although spontaneous remission and extended life expectancy can occasionally be reported, depending on the nature of the diagnostic process. However, disease progression through syncope and right heart failure is generally inevitable, and death is very often sudden.

[0005] Pulmonary hypertension refers to a condition associated with an elevation of pulmonary arterial pressure (PAP) above normal levels. In humans, normal mean PAP is approximately 12–15 mmHg. Pulmonary hypertension, on the other hand, can be defined as a mean PAP exceeding 25 mmHg as assessed by right heart catheterization. Pulmonary arterial pressure can approach or even exceed systemic pressure levels in severe forms of pulmonary hypertension. When PAP increases significantly due to pulmonary venous congestion, i.e., in left-sided heart failure or left-sided valvular dysfunction, plasma can escape from capillaries into the pulmonary interstitium and alveoli. This results in fluid accumulation in the lungs (pulmonary edema) and an associated decline in pulmonary function, which can be fatal in some cases. However, pulmonary edema is not a hallmark of severe pulmonary hypertension, even if it is due to pulmonary vascular changes, among all other components of this disease.

[0006] Pulmonary hypertension can be acute or chronic. Acute pulmonary hypertension is often a potentially reversible phenomenon generally caused by constriction of pulmonary vascular smooth muscle, which can be triggered by conditions such as hypoxia (as in high altitude sickness), acidosis, inflammation, or pulmonary embolism. Chronic pulmonary hypertension is characterized by major structural changes in the pulmonary vasculature that result in a reduction in the cross-sectional area of ​​pulmonary vessels. This can be caused, for example, by chronic hypoxia, thromboembolism, collagen vascular disease, excessive pulmonary circulation due to left-to-right shunting, HIV infection, portal hypertension, or a combination of genetic mutations and unknown causes, as seen in idiopathic pulmonary arterial hypertension.

[0007] Several drugs can treat 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 in intravenous and subcutaneous forms as Remodulin® and in oral form as Orenitram®. One such prostacyclin receptor agonist is ralinepag.

[0008] Pulmonary hypertension patients who received higher total daily doses of oral treprostinil had better outcomes, including increased 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 had better outcomes, including pulmonary vascular resistance and 6-minute walk distance, compared with 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 randomized, parallel group, placebo-controlled trial,” European Respiratory Journal, 2019; 54: 1901030. Summary of the Invention

[0010] One embodiment is a method of treating pulmonary hypertension, comprising administering to a subject suffering from pulmonary hypertension a therapeutically effective amount of a parenteral form of a therapeutic agent for treating pulmonary hypertension, followed by an oral form of a therapeutic agent for treating pulmonary hypertension, wherein the therapeutically effective amount of the parenteral form of the therapeutic agent is sufficient to allow for an increased dose of the subsequent orally administered therapeutic agent compared to a subject not previously treated with the parenteral therapeutic agent. In addition to achieving a higher total daily dose of the oral therapeutic agent, subjects treated according to this embodiment also experience an improvement in at least one side effect selected from the group consisting of headache, nausea, and vomiting. In some embodiments, the parenteral therapeutic agent is an inhaled therapeutic agent or a parenteral agent. In some embodiments, the subject is human. [Brief explanation of the drawings]

[0011] [Figures 1A-1D] Figures 1A–1D show clinical parameters at baseline and week 16. Figure 1A) WHO functional class (FC) is expressed as the percentage of patients in each class at baseline and week 16; p-values ​​for functional class improvement correspond to the median net change from baseline and are obtained using McNemar's test. Percentages are truncated so that the total percentages at week 16 add up to 99%. Figure 1B) NT-proBNP, Figure 1C) 6MWD, and Figure 1D) RA area are shown as medians with boxes representing the interquartile range. P-values ​​in Figures 1B–1D correspond to the median net change from baseline and are obtained using the Wilcoxon signed-rank test. WHO FC: World Health Organization functional class; NT-proBNP: N-terminal fragment of brain natriuretic peptide precursor; 6MWD: 6-minute walk distance; RA: right atrium.

[0012] [Figures 2A-2D]Figures 2A-2D show risk stratification at baseline and week 16. Risk stratification is based on the 2015 ESC / ERS guidelines. Each graph represents the percentage of patients in each risk strata at baseline and week 16 for Figure 2A) WHO FC, Figure 2B) NT-proBNP, Figure 2C) 6MWD, and Figure 2D) RA area. Of the 29 patients in the protocol-compliant population, only those with baseline and week 16 assessments are shown here. WHO FC: World Health Organization functional class; NT-proBNP: N-terminal fragment of precursor brain natriuretic peptide; 6MWD: 6-minute walk distance; RA: right atrium. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description of the Invention Unless otherwise specified, "a" or "an" means "one or more." In one aspect, provided herein are methods of treating a subject suffering from a condition associated with hypertension.

[0014] The term "subject," as used herein, refers to living multicellular organisms, including vertebrates, a category that includes both human and non-human mammals. The methods and compositions disclosed herein have equal application in human and veterinary settings. Thus, the general term "subject" under treatment is understood to include all animals, such as, for example, 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, e.g., a human, and includes: (i) inhibiting the disease or disorder, e.g., halting its progression; (ii) relieving the disease or disorder, e.g., causing regression of the disorder; (iii) slowing the progression of the disorder; and / or (iv) inhibiting, relieving, or slowing the progression of one or more symptoms of the disease or disorder. For example, treatment of conditions associated with elevated blood pressure includes, but is not limited to, preventing or ameliorating an increase in blood pressure in the subject's pulmonary and / or systemic circulation above the normal range, and subsequent symptoms and complications.

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

[0017] "Pharmaceutical agent" or "drug," as used herein, refers to a chemical or other composition capable of producing a desired therapeutic or prophylactic effect when properly administered to a subject. In some embodiments, a pharmaceutical agent or drug may be administered as a prodrug, substrate, or precursor, and the term refers to a compound that is metabolized (i.e., converted within the body) to 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 scheme) of the corresponding drug, thereby improving the pharmacodynamics, e.g., bioavailability, of the corresponding drug.

[0018] The term "pharmaceutically acceptable" as used herein refers to safe and sufficiently non-toxic for administration to a subject.

[0019] The term "therapeutically effective amount," as used herein, refers to an amount of a compound sufficient to achieve a desired effect in a treated subject. For example, a therapeutically effective amount of a therapeutic agent or drug for treating pulmonary hypertension may be the amount necessary to ameliorate or inhibit an increase in pulmonary artery pressure above normal levels in a subject, more particularly, an amount sufficient to maintain one or more of the following within normal ranges in the subject: right atrial pressure, pulmonary capillary wedge pressure, right ventricular systolic and diastolic pressure, pulmonary artery systolic and diastolic pressure, and filling pressure.

[0020] In particular, methods and compositions for treating or preventing a subject's condition associated with elevated pulmonary blood pressure, such as pulmonary hypertension, are contemplated herein. In some embodiments, this includes treating a subject suffering from neonatal pulmonary hypertension. In other embodiments, this includes treating a subject suffering from primary and / or secondary pulmonary hypertension. In some embodiments, this includes treating a subject suffering from pulmonary arterial hypertension (PAH). The "pulmonary hypertension" being treated may be one or more of the following 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 disease and / or anoxemia); Group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)); or Group 5 (pulmonary hypertension due to undefined multiple mechanisms). For example, "pulmonary hypertension" refers to any of pulmonary hypertension groups 1 to 5, or any combination of these groups.

[0021] Also contemplated herein are 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 (e.g., of kidney, heart, lung, or liver), treatment of hypotension to prevent reperfusion injury to vital organs (such as that seen in shock or traumatic injury, surgery, and cardiopulmonary arrest), skin ulcers (e.g., with topical, non-acidifying nitrites), Raynaud's phenomenon, treatment of hemolytic conditions (such as sickle cell, malaria, TTP, and hemolytic uremic syndrome), hemolysis caused by perinatal and postnatal immune incompatibility, and other conditions.

[0022] Treatment of a disease in a subject can be by administration of a suitable pharmaceutical agent(s) or drug to a subject suffering from a disease or condition, or symptoms associated with a disease.

[0023] In some embodiments, the parenteral form of the therapeutic agent for treating pulmonary hypertension is a prostacyclin (e.g., floran, treprostinil, beraprost, iloprost), a prostanoid drug, or a prostacyclin receptor agonist such as larinepag. In some embodiments, the parenteral therapeutic agent and the oral therapeutic agent are the same. In one embodiment, the parenteral therapeutic agent is treprostinil and the oral therapeutic agent is treprostinil.

[0024] One embodiment of the present invention is a method of administering to a subject, such as a human, suffering from pulmonary hypertension a first therapeutically effective amount of a parenteral therapeutic agent for treating pulmonary hypertension, followed by an oral dosage form of the therapeutic agent for treating pulmonary hypertension, wherein the first therapeutically effective amount of the parenteral therapeutic agent for treating pulmonary hypertension is sufficient to allow for an increased amount of the subsequently administered orally administered therapeutic agent compared to a subject not previously treated with the parenteral therapeutic agent for treating pulmonary hypertension.

[0025] In some embodiments, the first therapeutically effective amount of the parenteral therapeutic agent is administered parenterally, hi other embodiments, the first therapeutically effective amount of the parenteral therapeutic agent is inhaled by the subject.

[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 of treprostinil, or a prodrug. Suitable salts of treprostinil include sodium, potassium, and diethanolamine salts. 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 disclosed in U.S. Patent Application 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 a parenteral therapeutic agent for treating pulmonary hypertension is parenteral treprostinil. More particularly, in some embodiments, the parenteral treprostinil is intravenous treprostinil. In other embodiments, the parenteral treprostinil is subcutaneous treprostinil.

[0028] One embodiment of the present invention is a method of administering a therapeutically effective amount of a parenteral prostacyclin analog to a subject, such as a human, suffering from pulmonary hypertension, followed by administration of an oral dosage form of a prostacyclin receptor agonist, wherein the therapeutically effective amount of the parenteral prostacyclin analog is sufficient to allow for a subsequent increased dosage of the orally administered prostacyclin receptor agonist compared to a subject not previously treated with a prostacyclin analog.

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

[0030] In some embodiments, in addition to prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist, multiple oral therapeutic agents are simultaneously administered to a subject to treat pulmonary hypertension. The term "simultaneous administration" or "co-administration," as used herein, means that multiple therapeutic agents, such as, for example, phosphodiesterase type 5 (PDE5) inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators, are administered so that their respective effective periods of biological activity overlap in the treated subject. Co-administration can be achieved by simultaneous or sequential administration of multiple therapeutic agents, for example, by administering a second therapeutic agent before, during, or after the administration of a first therapeutic agent.

[0031] The following examples further illustrate, without limiting in any way, the scope of the above-described embodiments. [Example]

[0032] Example 1 Rapid parenteral treprostinil titration and transition to oral treprostinil overview A phase 4, multicenter, open-label, 16-week study was conducted to evaluate Remodulin® (intravenous or subcutaneous treprostinil) induction and subsequent optimization with oral Orenitram® (oral treprostinil) in patients with pulmonary arterial hypertension. Patients could be receiving other non-prostacyclin-class pulmonary arterial hypertension treatments during the study period. Enrollment in the study was completed with a total of 35 patients enrolled. Thirty-two patients initiated oral treprostinil. Twenty-nine patients were in the per-protocol population, which included all patients without major protocol deviations. Twenty-eight patients from the per-protocol population completed the study. Upon enrollment, patients were initiated on intravenous or subcutaneous Remodulin® in an inpatient or outpatient setting and titrated to a minimum dose of 20 ng / kg / min over 2 to 8 weeks. Patients were then transitioned to Orenitram® over a period of 1 to 21 days in an inpatient or outpatient setting. The primary endpoint was to assess the percentage of subjects achieving 4 mg three times daily (TID)—or a total daily dose of 12 mg—or a higher Orenitram® dosage at 16 weeks.

[0033] Secondary endpoints of this study included changes in prostanoid adverse events (AEs), echocardiograms, 6-minute walk distance (6MWD), Borg dyspnea score, World Health Organization (WHO) functional class (FC), serum N-terminal fragment of precursor brain natriuretic peptide (NT-proBNP) levels, the impact of pulmonary hypertension on human lifespan (health-related quality of life), and treatment satisfaction. Specifically, this study sought to measure the percentage of subjects who achieved improvement in each of the following four clinical parameters (6MWD, NT-proBNP, WHO FC, and right atrial area) at 16 weeks compared to baseline measurements, leading to a lower risk stratification as defined by the 2015 ESC / ERS (Gaile et al., DOI: 10.1183 / 13993003.01032-2015). Additional endpoints measured the percentage of subjects meeting each of the following four individual clinical parameters at week 16 in the low-risk category as defined by the 2015 ESC / ERS guidelines: 6MWD >440 meters, serum NT-proBNP.

[0034] In this clinical trial, patients enrolled in the study achieved a mean total daily dose of 16.4 mg of Orenitram® at 16 weeks, with 79% of study subjects reaching the study's primary endpoint of a total daily dose of 12 mg. Treatment with Orenitram® three times daily was well tolerated, and the safety profile was consistent with prior Orenitram® studies in pulmonary arterial hypertension. In the study, some well-known treprostinil adverse events, such as headache, nausea, and vomiting, tended to improve after transitioning from Remodulin® (parenteral treprostinil) to Orenitram® (oral treprostinil). method Inclusion criteria

[0035] Based on the 2015 ESC / ERS guidelines, specific hemodynamic inclusion criteria included the absence of untreated congenital heart disease, mean pulmonary artery blood pressure ≥ 25 mmHg, pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg, and pulmonary vascular resistance > 3 Wood units. 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 be receiving up to two oral PAH background therapies, provided they were taking stable doses for ≥ 30 days prior to baseline. Because this study focused on the addition of a new therapy rather than the replacement of one with another, participants were eligible regardless of the number of prior pulmonary arterial hypertension therapies they were receiving at baseline (0, 1, or 2). Patients were excluded if they had received any prostacyclin-class therapy (i.e., treprostinil, epoprostenol, iloprost, or selexipag) within 28 days of baseline, or if they had a diagnosis of uncontrolled sleep apnea, renal insufficiency, Child-Pugh B or C liver disease, or ischemic heart disease with a pulmonary artery wedge pressure (PAWP) >15 mmHg or a left ventricular ejection fraction (LVEF) <50%. Baseline assessments were collected up to 14 days before initiation of parenteral treprostinil and included hemodynamics via echocardiogram and RHC, FC, N-terminal fragment of precursor brain natriuretic peptide (NT-proBNP), 6MWD, and medication history. Of note, historical RHC data may be used for baseline assessment if performed ≥180 days prior to initiating parenteral treprostinil. Echocardiograms were uploaded and stored in a central repository and 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 selected baseline characteristics for patients in the protocol-compliant population.

[0036] [Table 1-1] [Table 1-2] treatment

[0037] Patients were initiated on subcutaneous (SC) or intravenous (IV) treprostinil at 2 ng / kg / min in an inpatient or outpatient setting at the clinician's discretion. Parenteral treprostinil was titrated over 2 to 8 weeks, if tolerated, to a dose that improved PAH symptoms. Investigators selected frequency and dosage increases to facilitate titration and instructed participants to use parenteral therapy to achieve the optimal treprostinil dose; titration was individualized and optimized for each participant to achieve a dose that improved PAH symptoms. There was no maximum parenteral treprostinil dose.

[0038] Once patients reached at least 20 ng / kg / min and were deemed suitable for transition based on physician assessment, they were transitioned to oral treprostinil by cross-titration over 1 to 21 days in an inpatient or outpatient setting at weeks 2, 4, or 8. All participants still receiving parenteral treprostinil at week 8 began transitioning to oral treprostinil regardless of their parenteral treprostinil dosage unless deemed unsuitable for transition by their clinician. Before transition, 6MWD, WHO FC, NT-proBNP, and echocardiogram parameters were assessed.

[0039] The oral treprostinil daily dose was calculated according to formula (I). The dose conversion steps and representative cross-titration for outpatient and inpatient transitions are shown in Tables 2-3. Post-transition visits occurred 7-14 days after initiation of oral treprostinil. Oral treprostinil was titrated to the maximum tolerated dose by week 16. Clinicians encouraged patients to continue oral treprostinil titration in the outpatient setting by increasing the dosage by 0.125 mg TID every 3-4 days, if tolerated by the patient. The target oral treprostinil dosage at the end of transition was determined using the following weight-based equation: (0.0072) × (patient weight in kg) × (parenteral dose in ng / kg / min).

[0040] [Table 2]

[0041] [Table 3] Endpoint Measurements

[0042] The primary endpoint was the percentage of patients achieving oral treprostinil TDD of at least 12 mg (0.171 mg / kg for patients <70 kg) at week 16. Secondary endpoints included change in risk stratification and clinical parameters from baseline to week 16, where baseline values ​​were collected within 14 days before starting parenteral treprostinil. Changes in risk stratification for FC, NT-proBNP, 6MWD, and right atrial (RA) area were assessed using the 2015 ESC / ERS guidelines, which classify risk for each determinant as low, intermediate, and high (Galie et al., 2016). Clinical parameters of interest include FC, NT-proBNP, 6MWD, echocardiographic parameters, the REVEAL Lite2 score (Benza et al., 2021), and the Borg dyspnea score (Borg, 1982, DOI: https: / / doi.org / 10.1249 / 00005768-198205000-00012). The REVEAL Lite2 score includes clinical parameters for determining risk status (low, moderate, and high) for pulmonary arterial hypertension. The Borg dyspnea score ranges from 0 to 10, with 0 indicating no dyspnea and 10 indicating extremely 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 patient satisfaction with their medication over the past 2-3 weeks; higher scores indicate greater satisfaction. EmPHasis-10 scores can range from 0 to 50, with lower scores indicating better quality of life.

[0043] Safety and tolerability were assessed at each scheduled visit and between visits as needed throughout the study. Tolerability measures of interest included the occurrence of all adverse events (AEs) and prostanoid-related AEs, including headache, diarrhea, nausea, vomiting, flushing, jaw pain, and acromioclavicular pain. The survey measured the severity and duration of AEs commonly associated with prostanoid therapy: headache, diarrhea, nausea, vomiting, flushing, jaw pain, and acromioclavicular pain; scores ranged from 0 (not at all bothersome, 0 days) to 14 (very bothersome, daily). Prostanoid-related events captured by the survey were recorded only if the event was unusual in intensity, frequency, or duration compared with symptoms in the patient's medical history. Patient compliance with receiving oral treprostinil was assessed by administering an investigational drug accountability questionnaire at each scheduled study visit. statistics

[0044] The primary endpoint and all efficacy endpoints were analyzed using the per-protocol population, which included all patients without major protocol deviations unless otherwise specified. Tight (Clopper-Pearson) 95% confidence intervals were calculated for the primary endpoint. Safety and tolerability were analyzed using the safety population, which included all patients who initiated parenteral treprostinil. For continuous variables, descriptive statistics are reported as median (interquartile range, IQR, or range) or mean (±standard deviation, SD). For categorical variables, descriptive statistics include the frequency and percentage of patients in each category. Changes from baseline to week 16 in continuous variables were analyzed using the Wilcoxon signed-rank test. Changes in FC from baseline to week 16 were analyzed using the McNemar test. p-values ​​from these tests were obtained for descriptive purposes and not as part of a formal hypothesis-testing framework.

[0045] The Institutional Review Board for Human Research approved the protocol, and consent was obtained from subjects or their representatives when required by the Institutional Review Board. result Primary endpoint

[0046] Thirty-five patients began the study. Twenty-nine of these patients received the initial dose of oral treprostinil, and 28 patients completed the study and received oral treprostinil at week 16. Patients remained on parenteral treprostinil for a mean duration of 55 days (±13 days) and achieved a mean parenteral dose of 27.0 ng / kg / min (±9.6) at the time of transition to oral treprostinil. The median (range) dose immediately prior to transition was 24 (6-40) ng / kg / min. In the study, maximum parenteral dose was achieved initially, and titration was similar among participants who initiated transition to oral treprostinil at week 4 compared with week 8, suggesting that week 4 or earlier is an appropriate time for patients to titrate to therapeutic SC or IV doses.

[0047] During the transition visit (weeks 2, 4, or 8), participants were transitioned if they achieved a minimum parenteral treprostinil dosage of 20 ng / kg / min and were deemed suitable for transition based on physician assessment.During the transition visit (weeks 2, 4, or 8), participants were transitioned if they achieved a minimum parenteral treprostinil dosage of 20 ng / kg / min.

[0048] Conversion from parenteral to oral treprostinil could occur over 1 to 21 days in an inpatient or outpatient setting. More than half of patients (55%) were converted to oral treprostinil in an outpatient setting over a mean duration of 5.6 days (± 2.3). The remaining 45% were converted in an inpatient setting over a mean duration of 1.7 days (± 0.5). A post-conversion visit occurred 1 to 2 weeks after initiating the transition. The mean (SD) TDD at the post-conversion visit was 16.6 (8.1) mg. At the end of the study, 79.3% of participants achieved an oral treprostinil dose of at least 12 mg TDD 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) at week 16. The mean (SD) oral treprostinil exposure time was 64 (16) days throughout the study.

[0049] From the post-transition visit through week 16, many participants (13 of 28) continued to titrate oral treprostinil beyond their post-transition visit, while 9 participants maintained and 6 participants reduced their oral treprostinil dosage. No participants returned to parenteral treprostinil after receiving oral treprostinil.

[0050] While participants were on parenteral treprostinil, 69%, 55%, and 34% of participants in the protocol-compliant population (n=29) received ondansetron, acetaminophen, and loperamide for prostacyclin-related nausea / vomiting, headache, and diarrhea, respectively. When on oral treprostinil, 48%, 38%, and 38% of participants used ondansetron, acetaminophen, and loperamide, respectively. Overall, the use of all concomitant medications decreased after the transition from parenteral to oral treprostinil. Secondary outcome measures Adverse events

[0051] All patients who initiated parenteral treprostinil reported at least one treatment-emergent AE. Table 4 shows the AEs experienced by patients during the parenteral treprostinil phase, transition phase, and oral treprostinil phase. Adverse effects not included in Table 4 occurred in at least 10% of patients and included decreased appetite, joint pain, decreased digestive function, abdominal pain, infusion site irritation, back pain, dyspnea, muscle spasms, peripheral edema, and dizziness. During parenteral treprostinil induction, the most bothersome AE was acromioclavicular pain, followed by jaw pain, headache, and diarrhea; all except diarrhea improved to "not at all bothersome" on a present adverse effect scale (1 corresponding to "it bothers me a lot" and 4 to "not bothersome at all") after transition to oral treprostinil. Diarrhea and nausea became the most bothersome AEs after transition to oral treprostinil. The number of patients experiencing prostanoid-related AEs was similar between the parenteral and oral treprostinil phases, with the exception of increased facial flushing and decreased headache after transition.

[0052] [Table 4] Clinical parameters and risk assessment

[0053] At the transition visit, the median (IQR) values ​​for 6MWD, NT-proBNP, tricuspid annular systolic excursion (TAPSE), and right atrial area for the protocol-compliant population were 377 (318, 453) m, 186 (110, 724) ng / L, 18.1 (14.8 of 20.9) mm, and 19.3 (16.0, 26.7) cm, respectively. 2 Of the 29 patients, 76% had improved WHO FC, 21% had maintained it, and 3% had worsened it at their transition visit. Overall, the clinical changes outlined above improved from baseline to transition (Table 1).

[0054] At week 16, multiple clinical measures improved from baseline measurements (Tables 1 and 5, Figures 1 and 2). Patients demonstrated clinical improvement in echocardiographic parameters. From baseline to week 16, the median change in RA area was -2.9 cm. 2 (IQR -6.6, 1.5; p=0.0102) and 17.5cm at 16 weeks. 2 A median RA area of ​​13.8 (IQR 13.8, 20.5) was achieved (Figure 1D). RA area was measured using end-diastolic area. In addition to RA area, several other echocardiographic parameters had numerically favorable changes. Table 5 shows the changes in echocardiographic parameters for patients in the study. The median change from baseline to week 16 in cardiac output was +0.5 L / min (IQR -0.4, 1.4), the median change in tricuspid annular 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).

[0055] [Table 5]

[0056] The WHO-FC system has functional classes I to IV, with lower FC (e.g., I) indicating less severe disease. From baseline to week 16, there was an overall shift toward less severe FC symptoms, with 68% of patients improving in FC and only one patient worsening (p<0.0001). From baseline to week 16, the percentage of patients classified as FC I increased from 0% to 46% (Figure 1A).

[0057] Patients demonstrated 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). The median Borg dyspnea score improved from 4 (IQR 3, 6) to 3 (IQR 1, 4) at week 16, with a median change from baseline of -1 (IQR -3, 0; p = 0.0009). From baseline to week 16, improvements were seen in most domains of the PAHSS, including fatigue, dyspnea, edema, orthopnea, and dizziness; there were minimal changes in chest pain and syncope. Quality of life significantly improved, as measured by a median change from baseline in the emPHasis-10 score of -3 (p = 0.0001). At week 16, the median NT-proBNP 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 ).

[0058] 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 to week 16 of -1 (IQR -3, 0; p=0.0006).

[0059] Improvements were also seen in the 2015 ESC / ERS risk stratification for FC, 6MWD, NT-proBNP, and RA area (Figures 2A–2D). The percentage of patients in the low-risk stratum for all four variables increased at week 16, most notably for NT-proBNP and RA area, where the percentage of patients in the low-risk stratum nearly doubled. Accordingly, the percentage of patients in the intermediate- and high-risk stratum decreased at week 16. From baseline to week 16, the percentage of patients who switched to the low-risk stratum for FC, NT-proBNP, 6MWD, and RA area was 39%, 39%, 15%, and 35%, respectively. Only one patient worsened in risk stratification for each variable. equivalent

[0060] The technology should not be limited by the specific embodiments described herein, which are intended as individual examples of individual aspects of the technology. Many modifications and variations of the technology can be made without departing from the spirit and scope of the technology, as will be apparent to those skilled in the art. In addition to the methods and devices described herein, functionally equivalent methods and devices within the scope of the technology will be apparent to those skilled in the art from the above description. Such modifications and variations are intended to be within the scope of the technology. It is to be understood that the technology is not limited to particular methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0061] In addition, those skilled in the art will recognize that when features or aspects of the present disclosure are described in terms of a Markush group, the present disclosure is thereby also described in terms of any individual member or subgroup of members of that Markush group.

[0062] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a description, all ranges disclosed herein also include any and all possible subranges and combinations of those subranges. Any described range can be readily recognized as sufficiently described and fully allowing for the same range to be broken down into at least 2, 3, 4, 5, 10, etc. divisions. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, a middle third, a higher third, etc. As will also be understood by those skilled in the art, all terms, such as "up to," "at least," "greater than," "less than," etc., refer to ranges that are inclusive of the recited numbers and can subsequently be broken down into subranges as described above.

[0063] All numerical designations, including ranges, e.g., pH, temperature, time, concentration, amount, and molecular weight, are approximations that are varied (+) or (-) by 10%, 1%, or 0.1%, where appropriate. It is understood, although not always explicitly stated, that all numerical designations may be preceded by the term "about." It is also understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0064] All patents, patent applications, provisional applications and publications described or cited herein are hereby incorporated by reference in their entirety, including all figures and tables, to the extent they do not contradict the explicit teachings of this specification.

Claims

1. 1. A method of treating pulmonary hypertension comprising administering to a subject suffering from pulmonary hypertension a first therapeutically effective amount of a parenteral therapeutic agent for treating pulmonary hypertension, followed by administration of an orally administered therapeutic agent for treating pulmonary hypertension, wherein the first therapeutically effective amount of the parenteral therapeutic agent is sufficient to allow for an increased dose of the subsequently administered orally administered therapeutic agent compared to a subject not previously treated with the parenteral therapeutic agent.

2. 10. The method of claim 1, wherein the first therapeutically effective amount of a parenteral therapeutic agent is parenteral prostacyclin.

3. 3. The method of claim 2, wherein the parenteral prostacyclin is parenteral treprostinil, a salt, an ester, or a prodrug thereof.

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

5. 4. The method of claim 3, wherein the parenteral treprostinil is subcutaneous treprostinil.

6. 4. The method of claim 3, wherein the parenteral treprostinil is initiated at a dosage of 2 ng / kg / min.

7. 4. The method of claim 3, wherein the parenteral treprostinil is titrated to a minimum of 20 ng / kg / min over at least two weeks.

8. 4. The method of claim 3, wherein the parenteral treprostinil is titrated to a minimum of 20 ng / kg / min over a period of about 2 weeks to about 8 weeks.

9. 10. The method of claim 1, wherein the orally administered therapeutic agent is an oral dosage form of treprostinil, a salt, an ester, or a prodrug thereof.

10. 10. The method of claim 9, wherein the oral dosage form of treprostinil is administered twice daily.

11. 10. The method of claim 9, wherein the oral dosage form of treprostinil is administered three times daily.

12. 10. The method of claim 9, wherein the oral dosage form of treprostinil is titrated from an initial oral dosage of 1 mg per day to a maximum of at least 12 mg per day over a period of up to 21 days.

13. 10. The method of claim 9, wherein the oral dosage form of treprostinil is titrated from an initial oral dosage of 0.5 mg per day to a maximum of at least 12 mg per day over a period of up to 21 days.

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

15. The method of claim 1, wherein the subject's right atrial area is reduced.

16. 10. The method of claim 1, wherein the subject's 6-minute walk distance is increased.

17. 2. The method of claim 1, wherein the pulmonary hypertension is pulmonary arterial hypertension.

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

19. 20. The method of claim 18, wherein the additional therapeutic agent treats pulmonary hypertension.

20. 19. The method of claim 18, wherein the additional therapeutic agents comprise an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, and a soluble guanylate cyclase stimulator.

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

22. 10. The method of claim 1, wherein the therapeutically effective amount of a parenteral therapeutic agent is an inhaled prostacyclin.

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

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