Booster therapy for treating or preventing exacerbations of pulmonary hypertension symptoms

Abstract

A method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof includes administering to the subject a supplemental medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms. The subject is concurrently undergoing treatment with one or more primary medicaments for treating pulmonary hypertension. The supplemental medicament may include a dose of treprostinil comprising greater than 10 micrograms of treprostinil. The treprostinil of the supplemental medicament may be administered as a dry powder.

Description

Booster Therapy for Treating or Preventing Exacerbations of Pulmonary Hypertension SymptomsCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 749,296, filed January 24, 2025, all of which is incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure provides an improvement to the treatment of pulmonary hypertension, a condition that deteriorates the lives of many thousands of patients toward an untimely death. The present disclosure, in some embodiments, provides a booster therapy comprising one or more treatments for exacerbations of pulmonary hypertension symptoms administered to a subject who is undergoing or has undergone a background pulmonary hypertension therapy. In some embodiments, the present disclosure provides a booster therapy for the treatment of exacerbations of pulmonary hypertension symptoms that includes an inhalable treprostinil formulation that is administered to a subject in need thereof who is undergoing or has undergone a background pulmonary hypertension therapy. In some embodiments, the inhalable treprostinil formulation is a dry powder.BACKGROUND

[0003] Pulmonary hypertension (PH) is a condition characterized by high blood pressure in the pulmonary vessels. PH has several underlying causes. The World Health Organization (WHO) guidelines classify PH into five groups.• Group 1 : Pulmonary arterial hypertension (PAH),• Group 2: PH due to left heart disease,• Group 3: PH due to lung disease, e.g., chronic obstructive pulmonary disease (COPD) and pulmonary hypertension associated with interstitial lung disease (PH-ILD),DBl / 165834806.1 1• Group 4: PH due to chronic pulmonary obstructions, e.g., blood clots in the lungs, and• Group 5 : PH due to unknown causes.

[0004] PH initially presents as exertional dyspnea, lethargy, and fatigue and is often confused for other disease states. This confusion often leads to delayed diagnosis and treatment. As PH progresses, additional symptoms appear. Depending on the type of PH, these symptoms may include right ventricular failure, exertional chest pain (i.e., angina), exertional syncope, and peripheral edema. Diagnostic tools to identify PH as well as the WHO Group include right heart catheterization, echocardiogram, blood tests, x-rays, and computerized tomography (CT), among other things. Following diagnosis treatment is recommended to lower pulmonary pressures and treat symptoms. Although no cure exists for PH, treatment of PH is directed at improving hemodynamic measures and quality of life.

[0005] PH can limit a patient’s functionality and quality of life. These limitations may progress over the course of the disease. The New York Heart Association (NYHA) heart failure guidelines have been applied to PH to describe the severity of the disease state. Using this guideline, the severity may be classified as follows:• NYHA Class I: Subjects with no limitation of activities; they suffer no symptoms from ordinary activities.• NYHA Class II: Subjects with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.• NYHA Class III: Subjects with marked limitation of activity; they are only comfortable at rest.• NYHA Class IV: Subjects who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest.

[0006] WHO has also developed a PH-specific functional classification system that mirrors the NYHA guidelines. Under the WHO guidelines, severity is classified as follows:• WHO Class I: Subjects have no symptoms and no limitation of physical activity,DBl / 165834806.1 2• WHO Class II: Subjects have mild symptoms and slight limitation during ordinary physical activity,• WHO Class III: Subjects have marked symptoms with significant limitation during less- than-ordinary activity, and• WHO Class IV: Subjects have symptoms at rest and are unable to perform any physical activity without discomfort.

[0007] PAH and PH-ILD are two types of PH. PAH is classified as WHO Group 1. PH-ILD is classified as WHO Group 3.

[0008] PAH affects approximately 15 out of every one million individuals. There are approximately 1,000 new cases of PAH diagnosed in the United States each year. The mean age at diagnosis is between 50 and 65 years of age, although the disorder may present much earlier in childhood or even infancy. While gender-based prevalence estimates for PAH are variable, estimates for the overall prevalence of pulmonary hypertension (PH) in females is approximately twice that of males. PAH has several phenotypes including: idiopathic, heritable, associated PAH (PAH associated with other conditions), PAH with specific features, and persistent pulmonary hypertension of the newborn to name a few.

[0009] Pulmonary arterial hypertension is a serious, progressive, and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. Severe constriction of the blood vessels in the lungs leads to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated.Subjects with PAH suffer from extreme shortness of breath as the heart struggles to pump against these high pressures. Subjects with PAH typically develop significant increases in pulmonary vascular resistance (PVR) and sustained elevations in pulmonary artery pressure (PAP), which ultimately lead to right ventricular failure and death. Subjects diagnosed with PAH have a poor prognosis and equally compromised quality of life, with a mean life expectancy of 2 to 5 years from the time of diagnosis if untreated.

[0010] A variety of factors contribute to the pathogenesis of pulmonary hypertension including proliferation of pulmonary cells which can contribute to vascular remodeling (i.e.,DBl / 165834806.1 3hyperplasia). For example, pulmonary vascular remodeling occurs primarily by proliferation of arterial endothelial cells and smooth muscle cells of subjects with pulmonary hypertension. Overexpression of various cytokines is believed to promote pulmonary hypertension. Further, it has been found that pulmonary hypertension may rise from the hyperproliferation of pulmonary arterial smooth cells and pulmonary endothelial cells. Still further, advanced PAH may be characterized by muscularization of distal pulmonary arterioles, concentric intimal thickening, and obstruction of the vascular lumen by proliferating endothelial cells. Pietra et al., J. Am. Coll. Cardiol., 43:255-325 (2004).

[0011] Interstitial lung disease (ILD) is caused by inflammation and scarring of the lung tissue, fibrosis, making the lungs stiff and inefficient for oxygen exchange. These changes progress over the course of the disease leading to chronic hypoxia and increased lung pressures. There are over two-hundred lung disorders falling under ILD including COPD and PH-ILD. Approximately 3.5 to 15% of subjects with early stage ILD have PH. Approximately 30 to 50% of subjects having advanced stage ILD have PH. PH-ILD subjects are sicker and have a poorer prognosis than subjects with ILD alone. PH-ILD have a two-fold risk of death compared to PAH subjects.

[0012] Although treatments are available for PH, PAH and PH-ILD, subjects may experience transient symptom exacerbations when engaging in activities. Administration of a supplemental medicament may provide relief of these symptom exacerbations.SUMMARY OF THE INVENTION

[0013] The disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplemental medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms; wherein the subject is concurrently undergoing or has undergone treatment with one or more primary medicaments for treating pulmonary hypertension; wherein the supplemental medicament is physiologically effective following administration. In another aspect, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplemental medicament for treating, attenuating, DBl / 165834806.1 4and / or preventing one or more pulmonary hypertension symptoms; wherein the subject is simultaneously, serially, or alternately administered with one or more dosages of one or more primary medicaments for treating pulmonary hypertension; wherein the supplemental medicament is physiologically effective following administration.

[0014] In some embodiments, the primary medicament comprises a treatment for WHO Group 1 or WHO Group 3 pulmonary hypertension. In some embodiments, the supplemental medicament comprises a treatment for WHO Group 1 or WHO Group 3 pulmonary hypertension. In some embodiments, the pulmonary hypertension is NYHA Functional Classification Class I, Class II, Class III, or Class IV. In some embodiments, the pulmonary hypertension is WHO Functional Classification Class I, Class II, Class III, or Class IV.

[0015] In some embodiments, the supplemental medicament is physiologically effective in less than sixty minutes, less than thirty minutes, less than twenty minutes, less than fifteen minutes, less than ten minutes, less than five minutes, less than three minutes, less than two minutes, or less than one minute. In some embodiments, the primary medicament comprises 1, 2, 3, 4, or more medicaments. In some embodiments, the primary medicament comprises 1 or more, 2 or more, 3 or more, or 4 or more medicaments.

[0016] In some embodiments, the primary medicament comprises a prostacyclin analog, prostacyclin receptor agonist, endothelin receptor antagonist, phosphodiesterase-5 inhibitor, soluble guanylate cyclase stimulator, calcium channel blocker, activin signaling inhibitor, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the prostacyclin analog comprises epoprosterol, treprostinil, iloprost, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the prostacyclin analog comprises treprostinil, treprostinil prodrugs, pharmaceutically acceptable salts of treprostinil, or combinations thereof. In particular embodiments, the prostacyclin receptor agonist comprises selexipag, ralinepag, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the endothelin receptor antagonist comprises bosentan, ambrisentan, macitentan, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the phosphodiesterase-5 inhibitor comprises sildenafd, tadalafil, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. InDBl / 165834806.1 5particular embodiments, the soluble guanylate cyclase stimulator comprises riociguat, prodrugs thereof, or pharmaceutically acceptable salts thereof. In particular embodiments, the calcium channel blocker comprises amlodipine, nifedipine, diltiazem, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the activin signaling inhibitor comprises sotatercept, prodrugs thereof, or pharmaceutically acceptable salts thereof. In particular embodiments, the primary medicament comprises: an endothelin receptor antagonist, prodrugs thereof, or pharmaceutically acceptable salts thereof; and a phosphodiesterase-5 inhibitor, prodrugs thereof, or pharmaceutically acceptable salts thereof. In more particular embodiments, the primary medicament comprises at least one of: bosentan, ambrisentan, macitentan, prodrugs thereof, and pharmaceutically acceptable salts thereof; and at least one of: sildenafd, tadalafd, prodrugs thereof, and pharmaceutically acceptable salts thereof.

[0017] In some embodiments, the treprostinil, treprostinil prodrugs, or pharmaceutically acceptable salts of treprostinil, is administered via an aerosolized liposomal composition. In some embodiments, the aerosolized liposomal composition comprises one or more liposomes suspended in an external medium. In some embodiments, the one or more liposomes each comprise: a lipid bilayer comprising at least one vesicle-forming phospholipid; and an internal aqueous medium encapsulated by the lipid bilayer comprising treprostinil, and a pH gradient salt; wherein a weight ratio of treprostinil to the at least one vesicle-forming phospholipid is equal to or higher than about 0.035. In particular embodiments, the lipid bilayer further comprises a sterol selected from the group consisting of cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, and any combination thereof.

[0018] In some embodiments, the at least one vesicle-forming phospholipid comprises a first phospholipid and a second phospholipid. In particular embodiments, the first phospholipid is selected from the group consisting of a hydrogenated soybean phosphatidylcholine (HSPC), a distearoylphosphatidylcholine (DSPC), a dipalmitoylphosphatidylcholine (DPPC), a dimyristoylphosphatidylcholine (DMPC), and any combination thereof, and the second phospholipid is selected from the group consisting of a distearyloyl phosphatidylglycerol (DSPG), a dipalmitoylphosphatidylglycerol (DPPG), a dimyristoylphosphatidylglycerol (DMPG), a 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-Poly(ethylene glycol) (PEG- DSPE), and any combination thereof. In embodiments, the HSPC, DSPC, DPPC, DMPC, DSPG, DPPG, DMPG, PEG-DSPE is a salt. In embodiments, the HSPC, DSPC, DPPC, DMPC, DBl / 165834806.1 6DSPG, DPPG, DMPG, PEG-DSPEis a sodium salt. In embodiments, the DSPG is DSPG-Na. In some embodiments, the lipid bilayer includes a sterol comprising cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, and any combination thereof, but is not limited thereto. In an exemplary embodiment, the sterol is cholesterol. In some embodiments, the lipid bilayer comprises about 50-70 mole % of the first phospholipid, 20-45 mole % of the sterol, and 0.1-10 mole % of the second phospholipid. In other embodiments, the first phospholipid is HSPC, the sterol is cholesterol, and the second phospholipid is DSPG. In particular embodiments, the pH gradient salt comprises a bicarbonate salt. In particular embodiments, the one or more liposomes have a mean particle size of about 100 nm to about 200 nm and a poly dispersity index of less than 0.2.

[0019] In some embodiments, the primary medicament is administered via orally, parenterally, or by inhalation. In some embodiments, the primary medicament is parenterally administered by subcutaneous injection, intradermal injection, intramuscular injection, or intravenous injection. In particular embodiments, the primary medicament is administered by inhalation via a nebulizer or an inhaler. In some embodiments, the nebulizer comprises a jet, ultrasonic, or mesh nebulizer.

[0020] In some embodiments, the inhaler comprises a dry powder, metered dose inhaler, or soft mist inhaler.

[0021] In some embodiments, the primary medicament is administered orally as a tablet, a capsule, a pill, or a liquid formulation.

[0022] In some embodiments, the primary medicament is administered at least once a day, at least once a week, at least once every two weeks, at once every three weeks, at least once every four weeks, at least once every month, at least once every two months, at least once every three months, at least once every four months, at least once every five months, or at least once every six months.

[0023] In some embodiments, the primary medicament is administered not more than once a day, not more than twice a day, not more than three times a day, not more than once a week, not more than once every two weeks, not more than once every three weeks, not more than once every four weeks, not more than once every month, not more than once every two months, not more than once every three months, not more than once every four months, not more than once every five months, or not more than once every six months. In some embodiments, the primary DBl / 165834806.1 7medicament is administered once every 6 months, once every 5 months, once every 4 months, once every 3 months, once every 2 months, once every 1 month, once every 4 weeks, once every 3 weeks, once every 2 weeks, once every 1 week, once every 6 days, once every 5 days, once every 4 days, once every 3 days, once every 2 days, once every 1 day, once a day, twice a day, three times a day, four times a day, five times a day, or six times a day. The primary medicament may be administered continuously.

[0024] In some embodiments, the supplemental medicament comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof is administered as dry powder particles. In some embodiments, the dry powder particles have a mass median aerodynamic diameter from 1 micrometer to 5 micrometers. In some embodiments, the dry powder particles have a mass median aerodynamic diameter of 3 micrometers or less. In some embodiments, the dry powder particles are formed having a predetermined size range. In some embodiments, the dry powder particles comprise particles that are substantially uniform in shape. In some embodiments, each particle of the dry powder particles comprises the treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof and an excipient matrix. In some embodiments, the dry powder particles comprise about 1% by weight treprostinil. In some embodiments, the dry powder particles comprise about 0.5% by weight treprostinil. In some embodiments, the excipient matrix comprises fumaryl diketopiperazine. In some embodiments, the dry powder particles are contained in a single dose unit. In some embodiments, the single dose unit contains between about 10 and about 150 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof. In some embodiments, the single dose unit contains about 16 micrograms, about 26.5 micrograms, about 32 micrograms, about 48 micrograms, about 53 micrograms, about 64 micrograms, about 79.5 micrograms, or about 106 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

[0025] In some embodiments, the dry powder particles have a crystalline structure. In some embodiments, the dry powder particles have an amorphous structure. In some embodiments, the excipient matrix is configured to dissolve at pH values above 6.DBl / 165834806.1 8

[0026] In some embodiments, the supplemental medicament is administered as one or more doses of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof. In some embodiments, each dose comprises between 10 and 400 micrograms treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof. In some embodiments, each dose comprises about 212 micrograms, about 204 micrograms, about 200 micrograms, about 185.5 micrograms, about 175 micrograms, about 159 micrograms, about 153 micrograms, about 150 micrograms, about 132.5 micrograms, about 125 micrograms, about 106 micrograms, about 102 micrograms, about 100 micrograms, about 80 micrograms, about 79.5 micrograms, about 75 micrograms, about 64 micrograms, about 53 micrograms, about 51 micrograms, about 50 micrograms, about 48 micrograms, about 32 micrograms, about 26.5 micrograms, about 25 micrograms, about 16 micrograms, or about 10 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

[0027] In some embodiments, the supplemental medicament is administered via inhalation. In some embodiments, the supplemental medicament is administered via a nebulizer or an inhaler. In some embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, or a mesh nebulizer. In some embodiments, the inhaler is a dry powder inhaler, a metered dose inhaler, or a soft mist inhaler. In some embodiments, the supplemental medicament is administered as a therapeutically effective dose.

[0028] In some embodiments, the supplemental medicament is administered after an onset of an increase in the severity of one or more pulmonary hypertension symptoms. In some embodiments, the one or more pulmonary hypertension symptoms is one or more of fatigue, dyspnea, palpitations, angina, swelling, cyanosis, dizziness, fainting, lightheadedness, or weakness. In some embodiments, the supplemental medicament is administered before performing an activity, wherein the activity may result in an increase in the severity of one or more pulmonary hypertension symptoms. In some embodiments, the activity may be a type of activity which previously resulted in an increase in the severity of one or more pulmonary hypertension symptoms in the subject. In some embodiments, the supplemental medicament is administered no more than four hours, no more than three hours, no more than two hours, no more than one hour, no more than thirty minutes, no more than fifteen minutes, no more than ten minutes, no more than five minutes, or no more than one minute prior to performing the activity. In some embodiments, the supplemental medicament is administered when initiating the activity. DBl / 165834806.1 9In some embodiments, the supplemental medicament is administered while engaged in the activity. In some embodiments, the supplemental medicament is administered after an increase in the severity of one or more pulmonary hypertension symptoms is detected (e.g., within 10 minutes of detection, within 5 minutes of detection, within 1 minute of detection, or within 30 seconds of detection). In some embodiments, the activity lowers the subject’s blood pressure. In some embodiments, the activity increases the subject’s heart rate. In some embodiments, the increase in the severity of one or more pulmonary hypertension symptoms presents as an acute pulmonary hypertension progression. In some embodiments, the supplemental medicament is administered intermittently to treat the transient increase in the severity of one or more pulmonary hypertension symptoms.BRIEF DESCRIPTION OF THE FIGURES

[0029] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention can be embodied in different forms and thus should not be construed as being limited to the illustrated embodiments set forth herein.

[0030] Figure 1 shows a three-dimensional rendering of a pollen particle according to an embodiment of the present invention.

[0031] Figure 2 is an SEM image showing pollen-shaped particles according to an embodiment of the present invention.DETAILED DESCRIPTION OF EMBODIMENTS

[0032] It has been found that a booster therapy may be useful in treating symptom exacerbations of PH (e.g., PAH, PH-ILD) symptoms in subjects who are undergoing or have undergone a primary pulmonary hypertension therapy. In some embodiments, the booster therapy may comprise administration of treprostinil in addition to or parallel with the primaryDBl / 165834806.1 10pulmonary hypertension therapy. Without wishing to be bound by theory, it is believed that some such booster therapies, e.g., treprostinil, may act as rapidly effective treatment suitable for intermittent use as a treatment for transient exacerbations of pulmonary hypertension symptoms or as a prophylaxis administered in anticipation of an exacerbation of pulmonary hypertension symptoms.Supplemental Medicament

[0033] In some embodiments, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplemental medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms; wherein the subject is administered the supplemental medicament while the subject is concurrently undergoing or has undergone treatment with one or more primary medicaments for treating pulmonary hypertension; wherein the supplemental medicament is physiologically effective following administration. In other embodiments, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplemental medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms; wherein the subject is simultaneously, serially, or alternately administered with one or more dosages of one or more primary medicaments for treating pulmonary hypertension; wherein the supplemental medicament is physiologically effective following administration.

[0034] In some embodiments, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms, comprising administering to a subject in need thereof who is undergoing or has undergone a primary dosage regimen comprising one or more medicaments for treating pulmonary hypertension: one or more booster dosages of a supplemental medicament as necessary to treat, attenuate, and / or prevent the exacerbation of one or more pulmonary hypertension symptoms. In other embodiments, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms, comprising administering to a subject in need thereof who is or has been administered one or more dosages of one or more primary medicaments for treating pulmonary hypertension: one or more booster dosages of a supplemental medicament asDBl / 165834806.1 11necessary to treat, attenuate, and / or prevent the exacerbation of one or more pulmonary hypertension symptoms, wherein the one or more booster dosages are administered simultaneously, serially, or alternately with the dosages of one or more primary medicaments.

[0035] In some embodiments, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms, comprising administering to a subject in need thereof who is undergoing or has undergone a primary dosage regimen comprising one or more medicaments for treating pulmonary hypertension: a booster therapy comprising one or more dosages of a supplemental medicament physiologically effective to treat, attenuate, and / or prevent one or more exacerbations of pulmonary hypertension symptoms. In other embodiments, the disclosure provides a method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms, comprising administering to a subject in need thereof who is or has been administered one or more dosages of one or more primary medicaments for treating pulmonary hypertension: a booster therapy comprising one or more dosages of a supplemental medicament physiologically effective to treat, attenuate, and / or prevent one or more exacerbations of pulmonary hypertension symptoms; wherein the booster therapy is administered simultaneously, serially, or alternately with the one or more dosages of one or more primary medicaments.

[0036] In some embodiments, the disclosure provides a method reducing the incidence of one or more pulmonary hypertension symptom exacerbations in a subject suffering from pulmonary hypertension, comprising administering to a subject in need thereof: one or more booster treatments comprising one or more dosages of a supplemental medicament to treat, attenuate, and / or prevent the exacerbation of pulmonary hypertension symptoms, wherein the one or more booster treatments are administered in combination with a background therapy for treating pulmonary hypertension comprising one or more primary medicaments. In other embodiments, the disclosure provides a method reducing the incidence of one or more pulmonary hypertension symptoms exacerbations in a subject suffering from pulmonary hypertension, comprising administering to a subject in need thereof: one or more booster treatments comprising one or more dosages of a supplemental medicament to treat, attenuate, and / or prevent the exacerbation of pulmonary hypertension symptoms, wherein the one or more booster treatments are administered simultaneously, serially, or alternately in combination with one or more dosages ofDBl / 165834806.1 12a background therapy for treating pulmonary hypertension comprising one or more primary medicaments.

[0037] As used herein, the expression “exacerbation of one or more pulmonary hypertension symptoms” (also referred to herein as “symptom exacerbation”) means an increase in the severity and / or frequency and / or duration of one or more symptoms or indicia of pulmonary hypertension. A “symptom exacerbation” also includes any deterioration in the respiratory or cardiovascular health of a subject that requires and or is treatable by a therapeutic intervention for pulmonary hypertension (e.g., prostacyclin analog, prostacyclin receptor agonist, endothelin receptor antagonist, phosphodiesterase-5 inhibitor, soluble guanylate cyclase stimulator, calcium channel blocker, activin signaling inhibitor, etc.). According to certain embodiments of the invention, a symptom exacerbation is defined as one or more of the following: (a) an increase in the frequency of a symptom or symptoms experienced by the subject; (b) an increase in the severity of a symptom or symptoms experienced by the subject; and (c) a worsening or deterioration of the subject’s physical condition.

[0038] In certain instances, a symptom exacerbation may be categorized as a “severe symptom exacerbation.” A severe symptom exacerbation means an incident requiring immediate intervention in the form of a rapidly physiologically effective treatment. The general expression “symptom exacerbation” therefore includes and encompasses the more specific subcategory of “severe symptom exacerbations.” Accordingly, the invention includes methods for reducing the incidence of severe symptom exacerbations in a subject in need thereof.

[0039] In some instances, treating or preventing exacerbations of one or more pulmonary hypertension symptoms includes reducing the incidence in exacerbations of pulmonary hypertension symptoms. A “reduction in the incidence” or “reducing the incidence” of exacerbations of one or more pulmonary hypertension symptoms means that a subject who has received a pharmaceutical composition of the present invention experiences fewer pulmonary hypertension symptom exacerbations (e.g., at least one fewer symptom exacerbation) after treatment than before treatment, experiences no pulmonary hypertension symptom exacerbations for at least one day (e.g., 1, 2, 3, 4, 5, 6, 7, or more days), or experiences pulmonary hypertension symptom exacerbations with an attenuated severity following initiation of treatment with aDBl / 165834806.1 13supplemental medicament of the present invention. A “reduction in the incidence” of a pulmonary hypertension symptom exacerbation alternatively means that, following administration of a supplemental medicament of the present invention, the likelihood that a subject experiences a pulmonary hypertension symptom exacerbation is decreased by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) as compared to a subject who has not received a supplemental medicament of the present invention.

[0040] In some embodiments, the supplemental medicament is formulated for faster release than the primary medicament. In other embodiments, the supplemental medicament is formulated for immediate release. In particular embodiments, the supplemental medicament is released over less than four hours. In particular embodiments, the supplemental medicament is released over less than three hours. In particular embodiments, the supplemental medicament is released over less than two hours. In particular embodiments, the supplemental medicament is released over less than one hour. In particular embodiments, the supplemental medicament is released over less than 30 minutes. In particular embodiments, the supplemental medicament is released over less than 15 minutes. In particular embodiments, the supplemental medicament is released over less than 5 minutes. In particular embodiments, the supplemental medicament is released over less than one minute. In some embodiments, the supplemental medicament provides rapid onset of action, releasing more than about 95% of the drug contained therein within a period of time selected from less than four hours, less than three hours, less than two hours, less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes, and less than one minute after administration. In some embodiments, the supplemental medicament provides rapid onset of action, releasing more than about 90% of the drug contained therein within a period of time selected from less than four hours, less than three hours, less than two hours, less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes, and less than one minute after administration. In particular embodiments, the supplemental medicament releases more than about 85% of the drug contained therein within a period of time selected from less than four hours, less than three hours, less than two hours, less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes, and less than one minute after administration. In particular embodiments, the supplemental medicament releases more than about 80% of the drug contained therein within a period of time selected from less than four hours, less than three hours, less than two hours, DBl / 165834806.1 14less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes, and less than one minute after administration. In particular embodiments, the supplemental medicament is physiologically effective within a period of time selected from less than four hours, less than three hours, less than two hours, less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes, and less than one minute after administration.

[0041] In some embodiments, the supplemental medicament comprises a prostacyclin analog, prostacyclin receptor agonist, endothelin receptor antagonist, phosphodiesterase-5 inhibitor, soluble guanylate cyclase stimulator, calcium channel blocker, activin signaling inhibitor, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0042] In some embodiments, the supplemental medicament comprises a prostacyclin analog. In other embodiments, the prostacyclin analog comprises epoprosterol, treprostinil, iloprost, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the prostacyclin analog comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof. In other embodiments, the prostacyclin receptor agonist comprises selexipag, ralinepag, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0043] In some embodiments, the supplemental medicament comprises an endothelin receptor antagonist. In other embodiments, the endothelin receptor antagonist comprises bosentan, ambri sentan, macitentan, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0044] In some embodiments, the supplemental medicament comprises a phosphodiesterase-5 inhibitor. In other embodiments, the phosphodiesterase-5 inhibitor comprises sildenafd, tadalafil, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0045] In some embodiments, the supplemental medicament comprises a soluble guanylate cyclase stimulator. In other embodiments, the soluble guanylate cyclase stimulator comprises riociguat, prodrugs thereof, or pharmaceutically acceptable salts thereof.DBl / 165834806.1 15

[0046] In some embodiments, the supplemental medicament comprises a calcium channel blocker. In other embodiments, the calcium channel blocker comprises amlodipine, nifedipine, diltiazem, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0047] In some embodiments, the supplemental medicament comprises an activin signaling inhibitor. In other embodiments, the activin signaling inhibitor comprises sotatercept, prodrugs thereof, or pharmaceutically acceptable salts thereof.

[0048] In some embodiments, the supplemental medicament comprises an endothelin receptor antagonist, prodrugs thereof, or pharmaceutically acceptable salts thereof, and a phosphodiesterase-5 inhibitor, prodrugs thereof, or pharmaceutically acceptable salts thereof. In other embodiments, the supplemental medicament comprises at least one of bosentan, ambri sentan, macitentan, and prodrugs and pharmaceutically acceptable salts of any thereof; at least one of sildenafil, tadalafil, and prodrugs and pharmaceutically acceptable salts of any thereof.Treprostinil

[0049] In some embodiments, the one or more booster dosages, booster therapy, or booster treatments comprise a supplemental medicament. In some embodiments, the supplemental medicament comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof.

[0050] Treprostinil is a chemically stable tricyclic benzidine prostanoid with vasodilator properties that is capable of reducing pulmonary vasoconstriction with minimal effects on systemic blood pressure. Treprostinil is a synthetic analog of prostacyclin (PGh) and the IUPAC name for treprostinil is (2-[[(lR,2R,3aS,9aS)-2-hydroxy-l-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid).

[0051] Treprostinil has been approved for the treatment of PAH under the trade names REMODULIN® (United Therapeutics Corporation; subcutaneous or IV infusion), TYVASO® (United Therapeutics Corporation; inhaled via ultrasonic, pulsed nebulization delivery device), TYVASO DPI® (United Therapeutics Corporation; inhaled via dry powder inhalation device)DBl / 165834806.1 16and ORENITRAM (United Therapeutics Corporation; oral tablet); YUTREPIA™ (Liquidia Technologies, Inc.; inhaled via dry powder inhalation device). TYVASO, TYVASO DPI, and YUTREPIA have also been approved for the treatment of PH-ILD. A booster therapy according to some embodiments of the present disclosure comprises administering the one or more background pulmonary hypertension therapies together or sequentially with an administration of a supplemental medicament comprising treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of treprostinil (e.g., treprostinil sodium). The treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof may be administered through one or more of the routes of administration previously mentioned (e.g., inhaled via a delivery device, oral administration, subcutaneous administration), and may be administered prior to, after, or concurrently with the administration of the one or more background pulmonary hypertension therapies. In some embodiments, the treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof is included in an inhalable dry powder drug product that is administered to the subject via a dry powder inhaler. In still further embodiments, the treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof is administered via inhalable liposomes. In some embodiments, in addition to administration of treprostinil, treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof, a background pulmonary hypertension therapy according to the present disclosure may include administration of one or more of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, prostacyclin receptor agonists, or other prostacyclin analogs that are useful for treating PH.

[0052] Unless specified otherwise, the use of the term “treprostinil” alone in the description of embodiments herein shall be understood to encompass treprostinil free acid, pharmaceutically acceptable salts of treprostinil, e.g., treprostinil sodium, treprostinil prodrugs, and amphiphilic treprostinil. In other embodiments, amphiphilic treprostinil may be particularly useful for loading into liposomes. In some embodiments, amphiphilic treprostinil may contain, for example, at least one functional group selected from the group consisting of a carboxyl group (- COOH) and a hydroxyl group (-OH), which is mostly soluble without forming insoluble crystals, precipitates or gels and is stable in alkaline solution. Treprostinil may also contain one or more functional groups in addition to the carboxylic functionality, although the presence of such functional group should not significantly alter the acidity of treprostinil from that of itsDBl / 165834806.1 17nonfunctionalized counterpart. According to some embodiments, the amphiphilic treprostinil may be biologically active in its protonated form or any salt forms thereof. A salt of an amphiphilic treprostinil may be accompanied by any pharmaceutically acceptable counterion which is in an aqueous soluble form.

[0053] “Prodrug” is intended to describe a compound that may be converted under physiological conditions or by enzymatic or non-enzymatic hydrolysis, for example, to provide a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by enzymatic or non-enzymatic hydrolysis. The prodrug compound often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier, Amsterdam). The term “prodrug” is also intended to include any covalently bonded carriers, which release the active compound in vivo when administered to a subject.

[0054] The phrase “treprostinil prodrug” as used herein refers to any derivative of treprostinil that converts in whole or in part to treprostinil in vivo following administration. Treprostinil prodrugs may be administered orally, parenterally, or by inhalation. Parenteral administration of the prodrugs may be by subcutaneous injection, intradermal injection, intramuscular injection, or intravenous injection. The treprostinil prodrug may have reduced affinity for one or more of the IP, DP, or EP receptors locally at the site of injection as compared to treprostinil. In some embodiments, a “treprostinil prodrug” can be a treprostinil derivative with one or more hydroxyl groups of the treprostinil structure modified to have reduced affinity for one or more of the IP, DP or EP receptors as compared to treprostinil, but which can be converted in vivo into active treprostinil following administration and subsequent diffusion into the blood. In some embodiments, the treprostinil prodrug is completely or substantially converted in vivo to treprostinil outside the location of administration, such as in the bloodstream. Preferred treprostinil prodrug include amide, carbonate, or carbamate esters of treprostinil. In embodiments treprostinil is derivatized at one or more hydroxyl groups, including the hydroxyl group of the carboxyl group. In other embodiments, the carboxyl group is derivatized either separately or in conjunction with one or more hydroxyl groups. In some embodiments, the treprostinil prodrugDBl / 165834806.1 18has greater than 50%, 75%, 85%, 90%, 95%, or 98% conversion to treprostinil in vivo following administration. In some embodiments, this conversion takes place in 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hour, or 3 hours following administration. Treprostinil prodrug includes pharmaceutically acceptable salts of such prodrugs.Inhalation Powder Drug Product

[0055] In some embodiments, the treprostinil, treprostinil prodrug, or a pharmaceutically acceptable salt of treprostinil (e.g., treprostinil sodium) of the supplemental medicament is administered as an inhalation powder drug product. The inhalation powder drug product may include inhalable particles containing treprostinil and one or more excipients that may be administered to the subject via a dry powder inhaler. In some such embodiments, each particle includes treprostinil and the one or more excipients.

[0056] The inhalation powder drug of the supplemental medicament product according to certain aspects of the present disclosure provides a dry powder dosage form of treprostinil and excipients, where the treprostinil and excipients are formed into inhalable particles as described in U.S. Pat. Nos. 10,898,494, 11,712,442, 11,744,836, 11,744,835, 11,660,304, 12,390,475, all of which are incorporated by reference in their entirety herein. In some embodiments, the inhalable particles are filled into a capsule, for example, a hydroxypropyl methylcellulose (HPMC) capsule (size 3), cartridge, or other container configured for use with a dry powder inhaler for administration to a subject. In some embodiments, the dry powder of the supplemental medicament is a treprostinil / excipient matrix from which particles of precise size and shape are formed according to the methods herein. In one example, the particles of the dry powder comprise a shape corresponding generally to a rounded triangular shape having a volume, where the inner portion of the rounded triangular shape, in size, fits a 1 micrometer equilateral triangle (otherwise referred to as being pollen-shaped). A three-dimensional rendering of such a particle shape is depicted in Figure 1. In another embodiment, the pollenshape may be trefoil-shaped with an inscribed circle diameter of 1 micrometer, and a prescribed thickness of a value or range between 0.5 and 1 micrometer, or more preferred 0.7 micrometer. In addition, certain embodiments of the present drug product include particles having 0.5% by weight treprostinil in dose levels ranging from 25 micrograms to 150 micrograms treprostinilDBl / 165834806.1 19(e.g., 25 micrograms, 50 micrograms, 75 micrograms, 100 micrograms, 125 micrograms and 150 micrograms treprostinil). In further embodiments, a drug product according to the present disclosure may provide dose levels ranging from 150 micrograms to greater than 300 micrograms treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof (e.g., 175 micrograms, 200 micrograms, 225 micrograms, 250 micrograms, 275 micrograms, 300 micrograms, 325 micrograms, 350 micrograms treprostinil, 375 micrograms treprostinil, 400 micrograms treprostinil). In some embodiments, the treprostinil is included in the particles as a salt of treprostinil (e.g., treprostinil sodium). In further embodiments, a drug product according to the present disclosure may provide dose levels of 50 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 75 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 100 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 125 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 150 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 175 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1DBl / 165834806.1 20microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 200 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 225 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 250 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 275 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 300 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 325 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 350 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 375 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7DBl / 165834806.1 21micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil loaded into capsules for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide dose levels of 400 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil loaded into capsules for delivery to a subject in a dry powder.

[0057] According to the present disclosure, the particles of the supplemental medicament remain stable for long periods of time at relatively low humidity conditions. In some embodiments, the present disclosure provides dry powder particles packaged under sealed conditions that remain stable for more than 3 months at 40 degrees Celsius and 75 percent relative humidity.

[0058] The present disclosure, in some embodiments, also provides a dry formulation of treprostinil of the supplemental medicament, which upon delivery to a subject via the inhaled route, becomes soluble and pharmaceutically available in less than 10 seconds. In some embodiments, the dry formulation composition becomes soluble and pharmaceutically available in less than 5 seconds. In some embodiments, the dry formulation composition becomes soluble and pharmaceutically available in less than 2 seconds. In some embodiments, the dry formulation composition becomes soluble and pharmaceutically available in about 1 second. In some embodiments, the dry formulation composition becomes soluble and pharmaceutically available in less than 1 second. In some embodiments, the dry formulation composition becomes soluble and pharmaceutically available in less than about 0.5 seconds. Furthermore, the excipients in the dry particle formulation of the present disclosure maintain conditions during processing and storage such that the active agent remains in a state to become soluble in the lung conditions of a user.

[0059] An exemplary formulation of the supplemental medicament (also referred to herein as “LIQ861”), particle composition, particle geometry, packaging, device, delivery, stability, dose, and a description of the use are described in U.S. Pat. Nos. 10,898,494, 11,712,442, 11,744,836, 11,744,835, 11,660,304, 11,826,327, 12,390,475, all of which are herein incorporated by reference in their entirety. Methods and materials that may be used for fabricating the particlesDBl / 165834806.1 22according to embodiments of the present disclosure are further described and disclosed in issued patents and co-pending patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. Nos. 8,518,316; 8,444,907; 8,444,899; 8,420,124; 8,268,446; 8,263,129; 8,158,728; 8,128,393; 7,976,759; 9,214,590; 9,205,594; 8,662,878; 8,439,666;, 8,128,393;8,992,992; 9,545,737; and U.S. Pat. Application Publications Nos. 2013-0228950, 2013-0011618, , 2010-0003291, and 2009-0165320.

[0060] In some embodiments, a formulation of the supplemental medicament according to the present disclosure includes a drug substance (e.g., treprostinil, treprostinil sodium, treprostinil palmitil) together with one or more excipients. In some embodiments, the one or more excipients may include a bulking agent, a wetting agent, a hydrophobicity modifier, a pH modifier, a buffer component, or combinations thereof. Examples of such formulations according to certain specific embodiments are provided in the tables below.LIQ861 Drug Product-Intermediate Description for Active (LIQ861) Formulations (dihydrate form calculations)DBl / 165834806.1 23LTQ861 Drug Product-Intermediate Description for Active (LIQ861) Formulations (anhydrous form calculations)

[0061] The inhalation drug powder product of the supplemental medicament, in some embodiments, includes or consists of a dry powder dosage form of treprostinil and excipients that may be filled into, for example, a HPMC capsule (size 3) or other container for use with an inhaler (e.g., dry powder inhaler). The dry powder of the supplemental medicament, in some embodiments, is a treprostinil / excipient matrix from which particles of precise size (e.g., 1 pm) and shape (e.g., “pollen-shaped”). The “pollen-shaped” particles may also be described as trefoil-shaped, with an inscribed circle diameter of 1 pm, and a thickness of 0.7 pm. A three- dimensional rendering of such a particle shape is depicted in Figure 1. LIQ861 comprised drug product capsule strengths of 25 micrograms, 50 micrograms, and 75 micrograms treprostinil used in the first clinical study to investigate planned dose levels of 25 micrograms, 50 micrograms, 75 micrograms, 100 micrograms, 125 micrograms and 150 micrograms treprostinil. The 100 microgram, 125 microgram and 150 microgram doses may be made up of a combination of lower dose capsules. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 100 micrograms, 125 micrograms, 150 micrograms, 175 micrograms, 200 micrograms, 225 micrograms, 250 micrograms, 275 micrograms, 300 micrograms, 325 micrograms, or 350 micrograms treprostinil. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 25 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7DBl / 165834806.1 24micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 50 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 75 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 100 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 125 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 150 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 175 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 microgram treprostinil for delivery to a subject in a dry powder. In further embodiments, a drug product according to the present disclosure may provide capsules with dose levels of 200 micrograms treprostinil plus or minus 10 micrograms, 9 micrograms, 8 micrograms, 7 micrograms, 6 micrograms, 5 micrograms, 4 micrograms, 3 micrograms, 2 micrograms or 1 micrograms treprostinil for delivery to a subject in a dry powder. A summary of the LIQ861DBl / 165834806.1 25formulation, including powder composition, particle geometry, and a description of the dosing unit according to certain exemplary embodiments follows.LIQ861 Drug Product-Intermediate Description for Active (LIQ861) Formulations (dihydrate)Inhalation Drug Product Dosing Unit Description^Excipients only (no treprostinil). Abbreviations: HPMC. hydroxypropyl methylcellulose

[0062] According to some embodiments of the present disclosure, drug particles of the supplemental medicament are provided that include a composition having a target dose of 15 - 90 pg of delivered treprostinil to the subject. In some embodiments of the present disclosure the dose of treprostinil of the supplemental medicament provided to the subject can be, for example, 100 micrograms, 125 micrograms or 150 micrograms. In some embodiments of the present disclosure the dose of treprostinil provided to the subject, for example, can contain about 100 micrograms, about 125 micrograms, about 150 micrograms or about 175 micrograms. In some embodiments, each dose contains greater than or equal to 200 micrograms of treprostinil. InDB1 / 165834806.1 26some embodiments, each dose contains greater than or equal to 225 micrograms of treprostinil. In some embodiments, each dose contains greater than or equal to 250 micrograms of treprostinil. In some embodiments, each dose contains greater than or equal to 275 micrograms of treprostinil. In some embodiments, each dose contains greater than or equal to 300 micrograms of treprostinil. In some embodiments, each dose contains from about 10 micrograms to about 15 micrograms, 15 micrograms to about 20 micrograms, 20 micrograms to about 25 micrograms, 25 micrograms to about 30 micrograms, about 30 micrograms to about 35 micrograms, about 35 micrograms to about 40 micrograms, about 40 micrograms to about 45 micrograms, about 45 micrograms to about 50 micrograms, about 50 micrograms to about 55 micrograms, about 55 micrograms to about 60 micrograms, about 60 micrograms to about 65 micrograms, about 65 micrograms to about 70 micrograms, about 70 micrograms to about 75 micrograms, about 75 micrograms to about 80 micrograms, about 80 micrograms to about 85 micrograms, about 85 micrograms to about 90 micrograms, about 90 micrograms to about 95 micrograms, about 95 micrograms to about 100 micrograms, or about 100 micrograms to about 105 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 110 micrograms, 110 micrograms to about 120 micrograms, 120 micrograms to about 130 micrograms, 130 micrograms to about 140 micrograms, about 140 micrograms to about 150 micrograms, about 150 micrograms to about 160 micrograms, about 160 micrograms to about 170 micrograms, about 170 micrograms to about 180 micrograms, about 180 micrograms to about 190 micrograms, about 190 micrograms to about 200 micrograms, about 200 micrograms to about 210 micrograms, about 210 micrograms to about 220 micrograms, about 220 micrograms to about 230 micrograms, about 230 micrograms to about 240 micrograms, about 240 micrograms to about 250 micrograms, about 250 micrograms to about 260 micrograms, about 260 micrograms to about 270 micrograms, about 270 micrograms to about 280 micrograms, about 280 micrograms to about 290 micrograms, about 290 micrograms to about 300 micrograms, about 300 micrograms to about 310 micrograms, about 310 micrograms to about 320 micrograms, about 320 micrograms to about 330 micrograms, about 330 micrograms to about 340 micrograms, or about 340 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 25 micrograms to about 400 micrograms of treprostinil. In some embodiments, each dose contains from about 25 micrograms to about 350 micrograms of treprostinil. In some embodiments, eachDBl / 165834806.1 27dose contains from about 25 micrograms to about 300 micrograms of treprostinil. Tn some embodiments, each dose contains from about 50 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 225 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 250 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 275 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 50 micrograms to about 75 micrograms of treprostinil. In some embodiments, each dose contains from about 50 micrograms to about 100 micrograms of treprostinil. In some embodiments, each dose contains from about 50 micrograms to about 150 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 100 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 125 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 150 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 175 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 200 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 225 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 75 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 125 micrograms of treprostinil. In someDBl / 165834806.1 28embodiments, each dose contains from about 100 micrograms to about 150 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 175 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 200 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 225 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 100 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 150 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 175 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 200 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 225 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 125 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 175 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 200 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 225 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 150 micrograms to about 350 micrograms ofDBl / 165834806.1 29treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 200 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 225 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 175 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 225 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 200 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 225 micrograms to about 250 micrograms of treprostinil. In some embodiments, each dose contains from about 225 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 225 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 225 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 225 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 250 micrograms to about 275 micrograms of treprostinil. In some embodiments, each dose contains from about 250 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 250 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 250 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 275 micrograms to about 300 micrograms of treprostinil. In some embodiments, each dose contains from about 275 micrograms to about 325 micrograms of treprostinil. In some embodiments, each dose contains from about 275 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 300 micrograms to about 325DBl / 165834806.1 30micrograms of treprostinil. Tn some embodiments, each dose contains from about 300 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 325 micrograms to about 350 micrograms of treprostinil. In some embodiments, each dose contains from about 350 micrograms to about 375 micrograms of treprostinil. In some embodiments, each dose contains from about 375 micrograms to about 400 micrograms of treprostinil. In some embodiments, each dose contains about 26.5 micrograms, about 53 micrograms, about 79.5 micrograms, about 106 micrograms, about 132.5 micrograms, about 159 micrograms, about 185.5 micrograms, about 212 micrograms, about 238.5 micrograms, about 265 micrograms, about 291.5 micrograms, about 318 micrograms, about 344.5 micrograms, about 371 micrograms, or about 397.5 micrograms of treprostinil.

[0063] In some embodiments, a subject may be provided with one, two, three, four, or more doses of treprostinil per day. In some embodiments, a subject may be provided up to one, two, three, or four doses of treprostinil per day. Each dose of treprostinil of the supplemental medicament may be contained in a single capsule according to some embodiments, for example, a HPMC capsule (size 3). In other embodiments, a dose of treprostinil may be made up of a combination of various dose capsules. Under the present disclosure, the dry powder particles of the supplemental medicament provide significantly higher dose levels to be safely administered than currently marketed products, such as for example, up to 100 micrograms of treprostinil per dosing, up to 125 micrograms of treprostinil per dosing and up to 150 micrograms of treprostinil per dosing. The higher levels of dosing were surprisingly demonstrated in the first clinical trial of LIQ861. In alternative embodiments, a subject may be provided with up to 200 micrograms of treprostinil per dosing and up to 300 micrograms of treprostinil per dosing as surprisingly demonstrated in pre-clinical toxicology studies using LIQ861.Excipients

[0064] According to some embodiments of the present disclosure, the dry powder (anhydrous) of the supplemental medicament is comprised of particles that include, for example, the following excipients: trehalose, polysorbate 80, L-leucine, sodium citrate, and sodium chloride. In some embodiments, the ratio of treprostinil sodium and excipients is 0.581:92.32:2.19:4.39:0.26:0.25 (wt:wt solids) treprostinil sodium:trehalose:polysorbateDBl / 165834806.1 3180:leucine:sodium citrate: sodium chloride. A summary of the function, quantity, and compendial status of these excipients is provided herein.

[0065] The excipients were selected based upon the following functional requirements for the formulation:• Trehalose Dihydrate: Trehalose comprises the bulk of the particle and was selected because it is a non-reducing sugar with a high glass transition temperature. Trehalose is an example of a non-reducing sugar (as opposed to lactose, which is a reducing sugar) that can be used in the present disclosure. Trehalose is more chemically compatible with compounds containing primary amines, such as leucine.• Ultra-Pure Polysorbate 80 (Ultra-Pure Tween 80): Polysorbate 80 is added as a processing aide / wetting agent to facilitate particle manufacturing. In some embodiments, Polysorbate 80 is a particle processing aide and enables film generation during particle manufacture by decreasing dewetting, leading to uniform particle morphology.• L-leucine: Leucine is added as a hydrophobicity and surface modifier to reduce the hygroscopicity of the particle and improve aerosol efficiency. L-leucine is an example of a formulation additive to reduce hygroscopicity to improve stability of the final drug product powder.• Sodium chloride and sodium citrate: Sodium citrate and sodium chloride are used to buffer the stock solution used in the manufacturing process and to help control acidity in the particle. Sodium chloride and sodium citrate are examples of buffers that help maintain pH and control ionization / acidity of the formulation. In some embodiments of the present disclosure, pH is maintained between about pH 6.0 and 7.2. In addition to the active pharmaceutical ingredient (e.g., treprostinil) the present drug particle comprises a bulking agent, wetting agent, hydrophobicity modifier, pH modifier and buffer. In some embodiments, the present drug particle comprises, along with the active ingredients, a bulking agent, hydrophobicity controlling agent, and a pH controlling agent.

[0066] According to another embodiment of the present disclosure, LIQ861 of the supplemental medicament contains six ingredients as follows: treprostinil sodium :trehalose DBl / 165834806.1 32dihydrate:leucine:polysorbate 80:sodium citrate dihydrate: sodium chloride at ratios of 0.53:92.97:4:2:0.27:0.23. At an example treprostinil dose level of 100 pg / day of the present disclosure drug particles, a subject would receive the following daily excipient doses:• 18.6 mg of trehalose dihydrate. Assuming a subject weighs 60 kg and has a lung mass of 1000 g, this is equivalent to 310 pg / kg and 18.6 pg / g of lung.• 0.4 mg of polysorbate 80. Assuming a subject weighs 60 kg and has a lung mass of 1000 g, this is equivalent to 6.7 pg / kg and 0.4 pg / g of lung.• 0.8 mg of leucine. Assuming a subject weighs 60 kg and has a lung mass of 1000 g, this is equivalent to 13.3 pg / kg and 0.8 pg / g of lung.• 0.05 mg of sodium citrate and 0.05 mg of sodium chloride. Assuming a subject weighs 60 kg and has a lung mass of 1000 g, this is equivalent to 0.83 pg / kg for each compound and 0.05 pg / g of lung for each compound.Physiochemical and Biological Properties

[0067] The “pollen-shaped” LIQ861 particles of the supplemental medicament according to certain embodiments have an aerodynamic size to enable efficient delivery to the pulmonary arterioles (1 < MMAD < 5pm) with a high fine particle fraction (FPF) to limit oropharyngeal deposition. A scanning electron microscopy (SEM) image of the “pollen-shaped” feature is provided in Figure 2. Example aerosol data for the active particles are also provided in the table below.

[0068] During the development of the LIQ861 formulation, the applicants tested other possible particle shapes and sizes (e.g., 1.5 pm donut, 3.0 pm donut). Based upon these studies, the applicants observed that the “pollen-shaped” feature resulted in a greater FPF, reduced MMAD, acceptable emitted dose (ED), and dose uniformity characteristics when compared to other features both with and without treprostinil.Representative Aerosol Data (NGI) for Active ParticlesDBl / 165834806.1 33Abbreviations: NGI. Next Generation Impactor™, MSP Corp.; MMAD, mass median aerodynamic diameter; GSD, geometric standard deviation; ED, emitted dose; FPF, fine particle fraction; wt, weight.Manufacture

[0069] In an embodiment, the particles of the supplemental medicament are made by molding the materials intended to make up the particles in mold cavities.

[0070] In some embodiments, the molds can be polymer-based molds and the mold cavities can be formed into any desired shape and dimension. Uniquely, as the particles of the supplemental medicament are formed in the cavities of the mold, the particles are highly uniform with respect to shape, size, and composition. Due to the consistency among the physical and compositional makeup of the particles of the present compositions, the compositions of the present disclosure provide highly uniform release rates and dosing ranges. Methods and materials that may be used for fabricating the particles according to embodiments of the present disclosure are further described and disclosed in issued patents and co-pending patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. Nos. 8,518,316; 8,444,809; 8,444,907; 8,420,124; 8,268,446; 8,263,129; 8,158,728; 8,128,393;7,976,759, 9,214,590, 9,205,594, 8,662,878, 8,439,666, 8,128,393, 8,992,992, 9,545,737; and U.S. Pat. Application Publications Nos. 2013-0228950, 2013-0011618, , 2010-0003291, 2009- 0165320.Batch-to-Batch Uniformity of Drug Particles

[0071] In some embodiments, the particle uniformity from batch-to-batch provides the present disclosure with an unexpected and exceptional advantage over the prior art. In certain embodiments, the uniformity within any given batch is unexpected and exceptionally advantageous over the prior art. The present disclosure includes highly conserved batch uniformity as shown in the following data. See the table below.DBl / 165834806.1 34Uniformity: Sample aerosol data (NGI) for active particlesIn the example shown, fine particle fraction remained within plus / minus 1 percent within a single batch run when sampled at the beginning, middle, and end of the run.Other Excipients

[0072] In some alternative embodiments, treprostinil of the supplemental medicament may be included in inhalable dry powder particles having an excipient matrix that includes or consists essentially of fumaryl diketopiperazine (FDKP). FDKP, bis-3,6(4-fumarylaminobutyl)-2,5- diketopiperazine, is a fumaramide derivative of diketopiperazine, which has shown to be highly soluble at pH values above 6. In some embodiments, particles including FDKP may have a crystalline structure. In other embodiments, particles including FDKP may have an amorphous structure.

[0073] In some such embodiments, particles of the supplemental medicament including FDKP and treprostinil may be formed by mixing a solution of treprostinil (e.g., treprostinil in ethyl alcohol) and a suspension of FDKP microcrystalline particles which is then spray dried to form inhalable powder particles. Methods and materials that may be used for fabricating the particles according to embodiments of the present disclosure are further described and disclosed in issued patents, each of which is incorporated herein by reference in its entirety: U.S. Pat. Nos.10,130,685; U.S. 10,421,729; and U.S. 10,772,883; U.S. Pat. Pub. Nos. 2017-0216538, and 2019-0321290.

[0074] In some embodiments, the inhalable dry powder particles of the supplemental medicament are contained in single-dose cartridges. In other embodiments, the single-dose cartridges comprise about 1% treprostinil. In other embodiments, the single-dose cartridges DBl / 165834806.1 35comprise about 16 micrograms, about 32 micrograms, about 48 micrograms, or about 64 micrograms of treprostinil. In other embodiments, the single-dose cartridges comprise treprostinil adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP). In particular embodiments, the single-dose cartridge comprises about 1.6 mg, about 3.2 mg, about 4.8 mg, or about 6.4 mg of dry powder particles. In some embodiments, the inhalable dry powder particles of the supplemental medicament are administered via inhalation. In other embodiments, the inhalable dry powder particles of the supplemental medicament are administered at least once a day, at least twice a day, at least three times a day, or at least four times a day.Background or Primary Pulmonary Hypertension Therapy

[0075] In some embodiments, the background therapy or primary dosage regimens comprises a primary medicament. In some embodiments, the primary medicament comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof.

[0076] In some embodiments, the primary medicament comprises a prostacyclin analog, prostacyclin receptor agonist, endothelin receptor antagonist, phosphodiesterase-5 inhibitor, soluble guanylate cyclase stimulator, calcium channel blocker, activin signaling inhibitor, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0077] In some embodiments, the primary medicament comprises a prostacyclin analog. In other embodiments, the prostacyclin analog comprises epoprosterol, treprostinil, iloprost, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof. In particular embodiments, the prostacyclin analog comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof. In other embodiments, the prostacyclin receptor agonist comprises selexipag, ralinepag, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0078] In some embodiments, the background therapy or primary dosage regimens comprises one or more primary medicaments. In some embodiments, the primary medicament comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof.DBl / 165834806.1 36

[0079] In some embodiments, the primary medicament comprises an endothelin receptor antagonist (ERA). In other embodiments, the endothelin receptor antagonist comprises bosentan, ambrisentan, macitentan, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0080] In some embodiments, the primary medicament comprises a phosphodiesterase-5 inhibitor (PDE5). In other embodiments, the phosphodiesterase-5 inhibitor comprises sildenafd, tadalafil, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0081] In some embodiments, the primary medicament comprises a soluble guanylate cyclase stimulator. In other embodiments, the soluble guanylate cyclase stimulator comprises riociguat, prodrugs thereof, or pharmaceutically acceptable salts thereof.

[0082] In some embodiments, the primary medicament comprises a calcium channel blocker. In other embodiments, the calcium channel blocker comprises amlodipine, nifedipine, diltiazem, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

[0083] In some embodiments, the primary medicament comprises an activin signaling inhibitor. In other embodiments, the activin signaling inhibitor comprises sotatercept, prodrugs thereof, or pharmaceutically acceptable salts thereof.

[0084] In some embodiments, the primary medicament comprises an endothelin receptor antagonist, prodrugs thereof, or pharmaceutically acceptable salts thereof, and a phosphodiesterase-5 inhibitor, prodrugs thereof, or pharmaceutically acceptable salts thereof. In other embodiments, the supplemental medicament comprises at least one of bosentan, ambrisentan, macitentan, and prodrugs and pharmaceutically acceptable salts of any thereof; at least one of sildenafil, tadalafil, and prodrugs and pharmaceutically acceptable salts of any thereof.

[0085] For example, in some embodiments, the one or more primary medicaments and their route of administration can include one or more of:• ERAs: bosentan (oral), ambrisentan (oral); and macitentan (oral);• PDE5 inhibitors: sildenafil (oral, intravenous (IV)) and tadalafil (oral);DBl / 165834806.1 37• Soluble Guanylate Cyclase (sGC) Stimulators: riociguat (oral);• Prostacyclin Receptor Agonists: selexipag (oral); and ralinepag (oral); and / or• Prostacyclin Analogs: epoprostenol (IV), iloprost (inhaled), and treprostinil (oral, subcutaneous IV and inhaled).

[0086] In some embodiments, the one or more primary medicaments include administration of treprostinil, treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the one or more primary medicaments include one or more of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, prostacyclin receptor agonists, or other prostacyclin analogs.

[0087] In some embodiments, the primary medicament is formulated for extended release. In other embodiments, the primary medicament comprises an extended-release formulation. An extended-release formulation is designed to gradually release the active ingredient over a specific period of time. Extended-release formulations have also been described as sustained release, sustained action, prolonged action, controlled release, time-released, and long-acting. An extended-release formulation is a formulation designed to release the medication in a controlled manner during an extended period of time, at a predetermined rate, duration, and location following administration. Extended-release formulations can allow for reduction in dose frequency, which may enhance convenience and thereby improve adherence.Liposomal Treprostinil Composition

[0088] In some embodiments, the background pulmonary hypertension therapy comprises administering treprostinil or amphiphilic treprostinil, wherein the treprostinil is administered in a pharmaceutical composition including one or more liposomes containing the treprostinil or amphiphilic treprostinil. In some embodiments, the pharmaceutical composition further includes an external medium, and the one or more liposomes are suspended in the external medium. In some embodiments, the pharmaceutical composition including the one or more liposomes may be administered to the subject via inhalation. In some such embodiments, the pharmaceutical composition including the one or more liposomes may be administered to the subject via a nebulizer, e.g., a vibrating mesh nebulizer.DBl / 165834806.1 38

[0089] In some particular embodiments, the booster therapy is administered concurrently or sequentially with a pharmaceutical composition containing one or more liposomes suspended in an external medium, each liposome comprising: (a) an external lipid bilayer including at least one vesicle-forming phospholipid; and (b) an internal aqueous medium, comprising treprostinil or amphiphilic treprostinil and a salt to provide a pH gradient between the internal aqueous medium and the external medium (hereafter “pH gradient salt”). In some embodiments, the weight ratio of treprostinil or amphiphilic treprostinil to the at least one vesicle-forming phospholipid (i.e., Treprostinil / phospholipid, T / P ratio) is equal to or higher than about 0.035. In some embodiments, the liposome is formulated such that about less than 60% of the treprostinil or amphiphilic treprostinil is released within 2 hours after the administration of the pharmaceutical composition. In some embodiments, the liposome is formulated such that more than 80% of the treprostinil or amphiphilic treprostinil is released more than 2 hours to about 72 hours after the administration of the pharmaceutical composition.

[0090] In an exemplary embodiment, the liposomes are suspended in an external medium and the pH of the external medium is above the pKaof treprostinil. In another exemplary embodiment, pH of the internal aqueous medium is at least 0.1 unit or at least 1 unit higher than the pH of the external medium. In yet another embodiment, the encapsulation efficiency of treprostinil is above about 80%, about 85%, about 90% or about 95%.

[0091] In some embodiments, the treprostinil-to-phospholipid ratio is equal to or higher than about 0.035, about 0.036, about 0.037, about 0.038, about 0.039, about 0.040, about 0.041, about 0.042, about 0.043, about 0.044, about 0.045, about 0.046, about 0.047, about 0.048, about 0.049, about 0.050, about 0.051, about 0.052, about 0.053, about 0.054, about 0.055, about 0.056, about 0.057, about 0.058, about 0.059 or about 0.060.

[0092] In some embodiments, the pharmaceutical composition reduces the burst release of treprostinil in the upper respiratory track (about less than 60% of the treprostinil or amphiphilic treprostinil is released within 2 hours after the administration), including the oral cavity, the nasopharynx, and the larynx above the vocal cords. As a result, the side effects of the treprostinil in the upper respiratory track, such as cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis, and wheezing, are reduced compared to that of a pharmaceutical compositionDBl / 165834806.1 39wherein the treprostinil-to-phospholipid ratio is lower than about 0.035. In yet another exemplary embodiment, the pharmaceutical composition extends the release of treprostinil or amphiphilic treprostinil from more than 2 hours to at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours at least 16 hours, at least 24 hours, at least 48 hours or at least 72 hours after the administration of the pharmaceutical composition (i.e., more than 80% of the treprostinil is released more than 2 hours to about 72 hours after the administration) and reduces the dosing frequency.Liposomal components

[0093] The term “liposome” as used herein refers to microscopic vesicles or particles made up of one or more lipid bilayers enclosing an internal aqueous medium. To form liposomes, the presence of at least one “vesicle-forming lipid” is needed, which is an amphipathic lipid capable of either forming or being incorporated into a lipid bilayer. Any suitable vesicle-forming lipid may be used to form the lipid bilayer constituting the liposomes. Vesicle-forming lipid includes, but not limited to, phospholipids such as phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (Pl), phosphatidic acid (PA), phosphatidylethanolamine (PE) or phosphatidyl serine (PS), and charged lipids, such as a positively charge lipid or a negatively charged lipid.

[0094] The lipid bilayer of the liposome includes at least one vesicle-forming lipid and may include a sterol, which is selected from the group consisting of cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, and any combination thereof, but is not limited thereto. In an exemplary embodiment, the sterol is cholesterol.

[0095] In some embodiments, the vesicle-forming lipid is a mixture of a first phospholipid and a second phospholipid. In certain embodiments, the first phospholipid is a phosphatidylcholine (PC), which is selected from the group consisting of hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl phosphatidylcholine (DPPC), distearyloyl phosphatidylcholine (DSPC), diarachidoyl phosphatidylcholine, dimyristoyl phosphatidylcholine (DMPC), egg phosphatidylcholine (EPC), soy phosphatidylcholine (SPC), oleoyl palmitoyl phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC), dipetroselinoyl phosphatidylcholine, palmitoylelaidoyl phosphatidylcholine,DBl / 165834806.1 40palmitoyloleoyl phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), diundecanoyl phosphatidylcholine, didecanoyl phosphatidylcholine, dinonanoyl phosphatidylcholine, and any combination thereof. In some embodiments, the second phospholipid is a polyethylene glycol modified phospholipid, containing a polyethylene glycol having a molecular weight of about 500 to about 10,000 daltons, such as l,2-distearoly-.s / / -glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (DSPE-PEG2000), a negatively charged phospholipid, such as distearyloyl phosphatidylglycerol (DSPG), Dipalmitoylphosphatidylglycerol (DPPG) or dimyristoylphosphatidylglycerol (DMPG) or (DOPG). In an exemplary embodiment, the mole percent of the first phospholipid: cholesterol: the second phospholipid is 50-70: 20-45: 0.1-10, 50-70: 20-45: 0.5-8 or 55-65:25-40:1-6.

[0096] In other embodiments, the vesicle-forming lipids are a mixture of a first phospholipid and a charged lipid. In an exemplary embodiment, vesicle-forming lipids are a mixture of a first phospholipid, a second phospholipid and a charged lipid. The charged lipid, includes stearylamine, l,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 3I3-[N-(N',N'- dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), N4-Cholesteryl-Spermine (GE67), dimethyldioctadecylammonium (DDAB), l,2-di-O-octadecenyl-3 -trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or combination thereof. In another exemplary embodiment, the mole percent of the first phospholipid: cholesterol: charged lipid is 50-70: 20-45: 0.1-10, 50-70: 20-45: 0.5-8 or 55-65:25-40: 1-6.

[0097] In some embodiments, the liposome includes an external lipid bilayer that includes or consists of HSPC, cholesterol, and a DSPG. In some embodiments, the liposome includes an external lipid bilayer that includes or consists of HSPC, cholesterol, and DSPE-PEG2000. In an embodiment, the mole % of HSPC, cholesterol, and a DSPG in the lipid bilayer is 50-70: 20-45: 0.1-10, 50-70: 20-45: 0.1-5 or 55-65:25-40:0.5-8. In one example embodiment, the mole % of HSPC, cholesterol, and DSPG in the lipid bilayer is about 59:40: 1.5. In another embodiment, the mole % of HSPC, cholesterol and DSPE-PEG2000 in the lipid bilayer is 50-70: 20-45: 0.1-10, 50-70: 20-45: 0.1-5 or 55-65:25-40:0.5-8. In another embodiment, the mole % of DPPC:Chol:DSPE-PEG2000 in the lipid bilayer is 50-70: 20-45: 0.5-8, 50-70: 20-45: 0.1-5 or 55-65:25-40:1-6.DBl / 165834806.1 41

[0098] In some embodiments, the lipid bilayer of the liposomes may also include at least one vesicle-forming lipid and a surfactant, which can be a non-ionic surfactant, a cationic surfactant or a zwitterionic surfactant. A non-ionic surfactant has no formally charged groups in its head. A cationic surfactant carries a net positive charge in its head. A zwitterion surfactant is electrically neutral but carries formal positive and negative charges on different atoms.

[0099] Non limiting examples of non-ionic surfactant include non-ionic water soluble mono-, di-, and tri-glycerides; non-ionic water soluble mono- and di-fatty acid esters of polyethyelene glycol; non-ionic water soluble sorbitan fatty acid esters (e.g. sorbitan monooleates such as TWEEN 20 (polyoxyethylene 20 sorbitan monooleate), SPAN 80; non-ionic water soluble triblock copolymers (e.g., poly(ethyleneoxide) / poly-(propyleneoxide) / poly(ethyleneoxide) triblock copolymers such as POLOXAMER 406 (PLURONIC F-127), or derivatives thereof.

[0100] Non-limiting examples of cationic surfactant include dimethyldialkylammonium bromide or dodecyltrimethylammonium bromide.

[0101] Non limiting examples of zwitterionic surfactant include 3-(N,N-dimethyl palmitylammonio)-propanesulfonate.

[0102] In some embodiments, the liposomes are substantially free of detergent or an ionophore, which is a compound capable of facilitating the transport of H+or OH' across the liposome membrane.

[0103] A solvent for dissolving a vesicle-forming lipid for the preparation of liposomes can be used, for example, methanol, ethanol, ether, and combinations thereof. Optionally, the solvent can be removed by a supercritical fluid later, and is preferably used in a minimum amount so as to decrease the time for performing an organic solvent removing step.

[0104] According to certain embodiments, the liposomes are prepared in a medium containing a salt to provide a pH gradient between the internal aqueous medium and the external medium of the liposome. When the vesicle-forming lipid is in contact with a medium containing the pH gradient salt, a liposome suspension is formed.DBl / 165834806.1 42

[0105] In some embodiments, the liposome in the suspension is subjected to size reduction. A liposome's size is typically referred to as its diameter. Liposome size reduction can be accomplished by a number of methods, such as extrusion, sonication, homogenization techniques or milling techniques, which are well known and can be performed by persons skilled in the art. Extrusion includes passing liposomes, under pressure, one or more times through filters having defined pore sizes. The filters are generally made of polycarbonate, but can also be made of any durable material which does not interact with the liposomes and which is sufficiently strong to allow extrusion under sufficient pressure. The size of the liposomes can be reduced by sonication, which employs sonic energy to disrupt or shear liposomes that will spontaneously reform into smaller liposomes. For example, sonication can be conducted by immersing a glass tube containing the liposome suspension into the sonic epicenter produced in a bath-type sonicator, or a probe type sonicator may be used in which the sonic energy is generated by vibration of a titanium probe in direct contact with the liposome suspension. In the present disclosure, the liposomes generally have a diameter of about 50 nm to 500 nm, such as about 500 nm or less, about 400 nm or less, about 300 nm or less, about 200 nm or less or about 100 nm or less.

[0106] After sizing, the concentration of the pH gradient salt in the external medium is adjusted to provide a pH gradient between the internal aqueous medium and the external medium, which can be carried out by a number of ways, for example, by exchanging the external medium with a suitable buffer lacking the pH gradient salts such as citric acid buffer (H3C6H5O) and phosphoric acid buffer (H3PO4), by methods such as diafiltration, dialysis, ultrafiltration, or tangential flow filtration.

[0107] The pH gradient salt provides a lower outside and a higher inside pH gradient between the external medium and the internal aqueous medium of the liposomes. In one embodiment, the pH of the internal aqueous medium is at least 0.1 unit higher than the pH of the external medium. In another embodiment, the pH of the internal aqueous medium is at least 1 unit higher than the pH of the external medium. In yet another embodiment, the pH of the internal aqueous medium is about 7, 8, 9 or 10 and the pH of the external medium is less than 7, less than 6, less than 5, less than 4, less than 3, about 3-7, about 3.5-6.5, or about 4-6. In yet another exemplary embodiment, the pH of the external medium is above the pKaof treprostinil.DBl / 165834806.1 43

[0108] The prepared liposome can be stored for substantial periods of time prior to treprostinil or amphiphilic treprostinil loading and administration to a subject. For example, liposomes can be stored at refrigerated conditions for substantial periods of time prior to treprostinil loading. Alternatively, liposomes can be dehydrated, stored, and subsequently rehydrated and loaded with treprostinil, prior to administration. Liposomes may also be dehydrated after being loaded with treprostinil. Dehydration can be performed by a number of methods available and known in the art. In some embodiments, liposomes are dehydrated using standard freeze-drying apparatus i.e. dehydration under low pressure conditions. Also, liposomes can be frozen e.g. using liquid nitrogen. Saccharides can be added to the liposomal environment, e.g., to the buffer containing the liposomes, prior to dehydration, to ensure stability and integrity of the liposome during dehydration. Examples of saccharides include but are not limited to maltose, lactose, sucrose, trehalose, dextrose, sorbitol, mannitol, xylitol, or a combination thereof.

[0109] A liposome suspension having a T / P ratio of equal to or higher than about 0.035 as described above are ready for treprostinil or amphiphilic treprostinil loading. Typically, treprostinil or amphiphilic treprostinil is added to the external medium of the liposome and the resultant suspension is incubated, allowing diffusion of treprostinil or amphiphilic treprostinil into the internal aqueous medium of the liposome and until a desired loading concentration and encapsulation efficiency (the percentage of the internal / encapsulated amount of treprostinil relative to the total amount of treprostinil in the composition) is achieved.Association between treprostinil to phospholipid ratio and controlled release profile

[0110] According to some embodiments, a pH gradient salt is used to provide a pH gradient between the intra- and extra-liposomal compartments and allow the loading of treprostinil into the internal aqueous medium, and not entrapped within the liposomal membrane or associated with external surface of the lipid bilayer.

[0111] Non limiting examples of pH gradient salt include a weak acid salt (such as carboxylic acid salt or bicarbonate salt) or an amino acid (such as a polar amino acid).

[0112] Bicarbonate salt may refer to a pharmaceutically acceptable salt compound including a bicarbonate anion and a cationic component. In one embodiment, the cationic component of theDBl / 165834806.1 44salt compound is a metal. Non-limiting examples of the metal include a Group IA or ITA metal, such as potassium (K), sodium (Na), calcium (Ca), magnesium (Mg), cesium (Cs), and lithium (Li) or a metal other than Group IA or IIA metal, such as ferrous iron (Fe) and nickel (Ni).Examples of bicarbonate salt include, but not limited to, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, lithium bicarbonate, nickel bicarbonate, ferrous iron bicarbonate or any combination thereof. In some embodiments, the bicarbonate salt is sodium bicarbonate.

[0113] Carboxylic acid salt includes, but not limited to, formate, acetate, propionate, butyrate, isobutyrate, valerate, isovalerate or a combination thereof. In one exemplary embodiment, the acetate is sodium acetate, calcium acetate, or a combination thereof.

[0114] In one embodiment, the pH gradient salt is a polar amino acid, including a neutral polar amino acid (Tyrosine, Asparagine, Glutamine, Cysteine, Serine, Threonine), a basic polar amino acid (Arginine, Lysine, Histidine), an acidic polar amino acid (Aspartate, Glutamate) or a combination thereof. The following table shows the classification of 20 amino acids:

[0115] In certain embodiments, the pH gradient salt is not phosphate. In an exemplary embodiment, the pH gradient salt is bicarbonate. In another exemplary embodiment, the pH gradient salt is acetate.

[0116] In some embodiments, a counter ion is selected to accompany the pH gradient salt to maintain a stable pH gradient such that the interaction between the counter ion with the pH gradient salt together achieve the optimal effect of the pH gradient salt, i.e., encapsulating a high concentration of treprostinil in the internal aqueous medium of the liposome and / or extending theDBl / 165834806.1 45release rate of the same from the liposome. It will be appreciated that after the pH gradient is established, excess counter ions within the liposome provide a wealth of hydroxide and these counter ions alone are membrane-impermeant. Treprostinil in its neutral form can permeate the lipid bilayer under the incubation conditions during liposome loading, and de-protonates in response to the counter ions. The de-protonated treprostinil does not readily permeate across the liposome bilayer. In certain embodiments, the counter ion may be an ion of alkali metals.

[0117] In certain embodiment, the internal aqueous medium is substantially free of precipitates, crystals, or gels. The internal aqueous medium is considered to be substantially free of precipitates, crystals, or gels if no such precipitates, crystals or gels are visible on electron microscopy with at least 5000x, 8000x, lOOOOx, 12000x, 15000x or 20000x magnification.

[0118] The pharmaceutical compositions of the present disclosure having a specific range of a treprostinil-to-phospholipid ratio reduces the burst release of the encapsulated treprostinil or amphiphilic treprostinil and hence reduce the side effect of the treprostinil or amphiphilic treprostinil. Furthermore, sufficient amount of treprostinil or amphiphilic treprostinil for a desired therapeutic effect is released from the pharmaceutical composition and the release profile is extended compared to that of the pharmaceutical composition with the treprostinil-to- phospholipid ratio falling outside the specific range of this disclosure. This claimed treprostinil- to-phospholipid ratio unexpectedly extends the release of the entrapped treprostinil or amphiphilic treprostinil from the liposomal composition while reducing the side effects of treprostinil or amphiphilic treprostinil, without the use of a detergent or an ionophore (such as calcium ionophore) for the release profile described herein.

[0119] As used herein, the term “burst release” refers to rapid and / or somewhat uncontrolled release of treprostinil or amphiphilic treprostinil from the pharmaceutical composition within 2 hours of administration of the pharmaceutical composition. In certain embodiments, less than about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39% or about 38% of the encapsulated treprostinil or amphiphilic treprostinil is released within about 2 hours of drug administration.DBl / 165834806.1 46

[0120] As used herein, the term “extended release” can be used interchangeably with “controlled release”, “delayed release”, “modified release”, “prolonged release”, “programmed release”, “time release”, “rate controlled” or “sustained release” refers, in the present context, to the release of encapsulated treprostinil or amphiphilic treprostinil during a period of more than 2 hours to about 72 hours after the administration of the pharmaceutical composition. In some embodiments, less than 60% of the encapsulated treprostinil or amphiphilic treprostinil is released within 2 hours of administration and a total of more than 80% of the encapsulated treprostinil or amphiphilic treprostinil is released by 72 hours after the administration of the pharmaceutical composition.

[0121] In certain embodiments, the pharmaceutical composition has a release profile wherein less than about 60%, 55%, 50%, 45%, 40% or 35% by weight of the entrapped treprostinil or amphiphilic treprostinil is released within 2 hours from the time of drug administration. In certain other embodiments, the pharmaceutical composition has a release profile wherein more than about 90%, 85%, 80%, 75%, 70%, 65%, 60% or 55% by weight of the entrapped treprostinil or amphiphilic treprostinil is released from the liposome, more than 2 hours to 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, or 72 hours from the time of drug administration.Preparation of Treprostinil Liposomal Composition

[0122] In some embodiments, a liposomal colloidal suspension may be prepared using ethanol injection technique. In one example, all lipid ingredients including a first phospholipid (e.g., HSPC), cholesterol and a second phospholipid (e.g., DSPE-PEG2000, DSPG) at a molar ratio of 3:2:0.075 were dissolved in 2.86 mL of ethanol solution at approximately 60°C. The resultant lipid solution was then injected into 17.14 mL of sodium bicarbonate solution (400 mM; pH 8.5) and was stirred at 60°C for liposome hydration. The mixture was extruded 6 to 10 times through polycarbonate membranes with specific pore sizes (0.2 micrometer and / or 0.1 micrometer, respectively), to obtain a suspension of liposomes having a mean particle size around 100 nm to 200 nm and a poly dispersity index (PDI) of <0.2. Subsequently, the suspension of liposomes was dialyzed with a tangential flow filtration system against 50 mM of sodium citrate buffer (pH 5.5) to form a transmembrane pH gradient between the internal aqueous medium of the liposome andDBl / 165834806.1 47the external medium (i.e., a higher inside and lower outside pH gradient). The suspension of liposomes with transmembrane pH gradient was stored at 4°C before drug loading process.

[0123] Treprostinil (purchased from Cayman Chemical, USA) was dissolved in 50 mM of sodium citrate aqueous solution, then added into the suspension of liposomes at a given treprostinil-to-phospholipid ratio and incubated at 40°C for 30 min. The resultant mixture was adjusted with sodium citrate buffer (pH 5.5) to obtain a liposomal treprostinil composition having a pH of 5.5 and a phospholipid concentration of 8.59 mg / mL.Example Liposomal Treprostinil Composition

[0124] A treprostinil liposomal composition for administration according to certain exemplary embodiments include the following components:DBl / 165834806.1 48qs = quantum satis (quantity sufficient for);'Trisodium citrate dihydrate and citric acid monohydrate are buffer ingredients to control the pH and are not required to be proportional.Administration of Liposomal Treprostinil Composition

[0125] In some embodiments, the liposomal treprostinil compositions described herein may be administered to the subject via inhalation. In some such embodiments, the liposomal treprostinil compositions may be administered via a vibrating-mesh nebulizer, for example, a breath- activated vibrating-mesh nebulizer. In some embodiments, the vibrating-mesh nebulizer is configured to aerosolize the liposomal treprostinil composition to produce aerosol particles having a MMAD of about 3.0 micrometers to about 5.0 micrometers. In some embodiments, the liposomal treprostinil composition may be contained in one or more ampoules, vials bottles, or other suitable containers that in turn may be used to fill the medicine chamber of the vibratingmesh nebulizer for administration to the subject.

[0126] In some embodiments, the liposomal treprostinil compositions may be administered once a day, twice a day (BID), three times a day, or four times per day (QID) to a subject via inhalation. In some embodiments, for example, the liposomal treprostinil composition is administered at a dose of about 40 microgram treprostinil to about 400 microgram treprostinil, twice a day. In some embodiments, the dosing may be titrated over time such that the dose of liposomal treprostinil compositions administered to a subject is gradually increased until a predetermined maximum dose is reached or until adverse reactions are encountered. In some embodiments, the doses may be increased at regular intervals, for example, every day, every two days, every three days, every four days, every five days, every six days, every 7 days (weekly), every two weeks, every three weeks, or every four weeks. For example, the dosing scheme according to some embodiments may be as follows:DBl / 165834806.1 49

[0127] In some embodiments, the administration of the booster dosage occurs after administration of at least one dose of the liposomal treprostinil composition. In some embodiments, the administration of the booster dosage occurs before administration of at least one dose of the liposomal treprostinil composition. In some embodiments, the administration of the one or more booster dosage occurs concurrently with the administration of at least one dose of the liposomal treprostinil composition. In some embodiments, where the dose of the liposomal treprostinil composition is titrated, the administration of the booster dosage occurs after or concurrently with the administration of the highest dose of the liposomal treprostinil composition.Treprostinil Prodrugs

[0128] In some embodiments, a booster therapy according to some embodiments of the present disclosure comprises administering the one or more booster dosages together or sequentially with an administration of a background pulmonary hypertension therapy. In some embodiments, the one or more booster dosages comprises a treprostinil prodrug. In some embodiments, the background pulmonary hypertension therapy comprises administering one or more dosages of a treprostinil prodrug. Non-limiting examples of treprostinil prodrugs are described below.

[0129] In some embodiments, the treprostinil prodrug is a compound of Formula (I)DBl / 165834806.1 50(Ij

[0130] wherein R1is an optionally substituted, unbranched C2-25 alkyl, or an optionally substituted, branched C2-25 alkyl. In some embodiments, R1is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. In other embodiments, the tresprostinil prodrug is formulated as a dry powder composition comprising (a) from about 0.1 wt % to about 3 wt % of a compound of Formula (I) or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof,; (b) from about 0.01 wt % to about 3 wt % of distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), (c) from about 10 wt % to about 50 wt % of leucine, and the balance being (d) a sugar selected from the group consisting of trehalose and mannitol; wherein the entirety of (a), (b), (c), and (d) is 100 wt %. In particular embodiments, R1is linear tetradecyl, linear pentadecyl, linear heptadecyl, linear octadecyl, or linear hexadecyl.

[0131] In some embodiments, the treprostinil prodrug is a compound of Formula (II), i.e. treprostinil palmitil wherein R1 is substituted with a straight chain, non-substituted hexadecyl alkane.00

[0132] In some embodiments, the treprostinil prodrug is administered by aerosolizing a dry powder composition comprising treprostinil. In other embodiments, the aerosolized dry powder DB1 / 165834806.1 51composition is administered to the lungs of the subject via inhalation. In particular embodiments, the aerosolized dry powder composition is administered at least once-a-day, twice-a-day, or three-times-a-day. In preferred embodiments, the aerosolized dry powder composition is administered once-a-day, twice-a-day, or three-times-a-day.Methods of TreatmentAdministration Regimens

[0133] The primary medicament and supplemental medicament each may be administered using various methods. The method of administration will be dependent on several factors including physical form, bioavailability, pharmacological profile, and toxicology to name a few.

[0134] In certain embodiments, the primary and / or supplemental medicament can be administered orally, e.g., in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of an agent as an active ingredient. An agent may also be administered as a bolus, electuary or paste.

[0135] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), one or more therapeutic compounds of the present disclosure may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; andDBl / 165834806.1 52(10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fdlers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0136] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.[00137J Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0138] The primary and / or supplemental medicament may be injected. In embodiments, the medicament is administered parenterally. In other embodiments, the medicament is administered via subcutaneous injection. In other embodiments, the medicament is administered via intradermal injection. In other embodiments, the medicament is administered via intramuscular injection. In other embodiments, the medicament is administered via intravenous injection. In other embodiments, the medicament is self-administered.

[0139] The primary and / or supplemental medicament may be administered via inhalation. In some embodiments, the primary and / or supplemental medicament is administered via a nebulizer or an inhaler. In some embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, or a mesh nebulizer. In some embodiments, the inhaler is a dry powder inhaler, a metered dose inhaler, or a soft mist inhaler.DBl / 165834806.1 53

[0140] In part, the present disclosure relates to methods of treating or preventing exacerbations of one or more pulmonary hypertension symptoms. In some embodiments, the disclosure contemplates methods of treating one or more complications of pulmonary hypertension (e.g., smooth muscle and / or endothelial cell proliferation in the pulmonary artery, angiogenesis in the pulmonary artery, dyspnea, chest pain, pulmonary vascular remodeling, right ventricular hypertrophy, and pulmonary fibrosis) comprising administering to a subject in need thereof a supplemental medicament. In some embodiments, the disclosure contemplates methods of preventing one or more complications of pulmonary hypertension comprising administering to a subject in need thereof a supplemental medicament. In some embodiments, the disclosure contemplates methods of treating or preventing exacerbations of one or more pulmonary hypertension symptoms comprising administering to a subject in need thereof a supplemental medicament. To prevent a disorder or condition can refer to a treatment that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated subject relative to an untreated control subject, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control subject.[00141 J In some embodiments, the present disclosure relates to methods of treating or preventing exacerbations of one or more pulmonary hypertension symptoms disclosed herein. In embodiments, the disorder is interstitial lung disease. In some embodiments, the interstitial lung disease is pulmonary fibrosis. In some embodiments, the interstitial lung disease is caused by any one of the following: silicosis, asbestosis, berylliosis, hypersensitivity pneumonitis, drug use (e.g., antibiotics, chemotherapeutic drugs, anti arrhythmic agents, statins), systemic sclerosis, polymyositis, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, an infection (e.g., atypical pneumonia, pneumocystis pneumonia, tuberculosis, Chlamydia trachomatis, and / or respiratory syncytial virus), lymphangitic carcinomatosis, cigarette smoking, or developmental disorders. In some embodiments, the interstitial lung disease is idiopathic (e.g., sarcoidosis, idiopathic pulmonary fibrosis, Hamman-Rich syndrome, and / or anti synthetase syndrome). In particular embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis.

[0142] Treating can include amelioration or elimination of the condition once it has been established. In either case, prevention or treatment may be discerned in the diagnosis provided byDBl / 165834806.1 54a physician or other health care provider and the intended result of administration of the therapeutic agent.

[0143] In general, treatment or prevention of symptom exacerbations as described in the present disclosure is achieved by administering a supplemental medicament. An effective amount of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A therapeutically effective amount of an agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent to elicit a desired response in the individual. A prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0144] The terms “subject,” an “individual,” or a “subject” are interchangeable throughout the specification and generally refer to mammals. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and nonhuman primates such as apes and monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the subject is a mammal. In other embodiments, the subject is human. In particular embodiments, the subject is a human suspected of having or diagnosed as having one or more forms of pulmonary hypertension.

[0145] In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the progression rate and / or severity of one or more complications of pulmonary hypertension), including transitory symptom exacerbations, comprising administering to a subject in need thereof a medicament. In some embodiments, the method relates to pulmonary hypertension subjects that have pulmonary arterial hypertension. In some embodiments, the method relates to pulmonary hypertension subjects that have pulmonary hypertension with left heart disease. In some embodiments, the method relates to pulmonary hypertension subjects that have lung disease and / or hypoxemia. In some embodiments, the method relates to pulmonary hypertension subjects that have chronic thrombotic and / or embolic disease. In some embodiments, the method relates to pulmonary hypertension subjects that have sarcoidosis, histiocytosis X, or lymphangiomatosis and compression of pulmonary vessels. In someDBl / 165834806.1 55embodiments, the method relates to pulmonary hypertension associated with interstitial lung disease.

[0146] In certain aspects, the disclosure relates to methods of treating or preventing exacerbations of one or more pulmonary hypertension symptoms comprising administering to a subject in need thereof a supplemental medicament. In some embodiments, the method relates to reducing the incidence of one or more pulmonary hypertension symptom exacerbations in a subject suffering from pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of fatigue experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of dyspnea experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of palpitations experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of angina experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of swelling experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of cyanosis experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of dizziness experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of fainting experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of lightheadedness experienced by subject with pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the severity of weakness experienced by subject with pulmonary hypertension. In some embodiments, the method relates to increasing physical activity of a subject having pulmonary hypertension. In some embodiments, the method relates to treating, preventing, or reducing the progression rate and / or severity of chest pain in a pulmonary hypertension subject.

[0147] In certain aspects, the disclosure relates to methods of increasing exercise capacity in a subject having pulmonary hypertension comprising administering to a subject in need a supplemental medicament. In some embodiments, exercise capacity for a subject on the primaryDBl / 165834806.1 56and supplemental medicament may be greater than the exercise capacity of a subject on the primary medicament alone. Any suitable measure of exercise capacity can be used. For example, exercise capacity in a 6-minute walk test (6 MWT), which measures how far the subject (e.g., human subject) can walk in 6 minutes, i.e., the 6-minute walk distance (6 MWD), is frequently used to assess pulmonary hypertension severity and disease progression. The Borg dyspnea index (BDI) is a numerical scale for assessing perceived dyspnea (breathing discomfort). It measures the degree of breathlessness, for example, after completion of the 6 MWT, where a BDI of 0 indicates no breathlessness and 10 indicates maximum breathlessness. In some embodiments, the method relates to increasing 6 MWD by at least 10 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 20 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 30 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 40 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 50 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 60 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 70 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 80 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 90 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to increasing 6 MWD by at least 100 meters in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 0.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 1 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 1.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 2 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 2.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 3 index points in the subject having pulmonary hypertension. In some embodiments, the method relatesDBl / 165834806.1 57to lowering BDT by at least 3.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 4 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 4.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 5.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 6 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 6.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 7 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 7.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 8 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 8.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 9 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 9.5 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by at least 3 index points in the subject having pulmonary hypertension. In some embodiments, the method relates to lowering BDI by 10 index points in the subject having pulmonary hypertension.

[0148] In certain aspects, the disclosure relates to methods of treating or preventing exacerbations of one or more pulmonary hypertension symptoms (e g., treating, preventing, or reducing the severity of fatigue, dyspnea, palpitations, angina, swelling, cyanosis, dizziness, fainting, lightheadedness, or weakness) comprising administering to a subject in need thereof a supplemental medicament, wherein the subject has Class I, Class II, Class III, or Class IV pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to a subject that has Class I pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to a subject that has Class II pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to a subject that has Class III pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates DBl / 165834806.1 58to a subject that has Class TV pulmonary hypertension as recognized by the WHO. Tn some embodiments, the method relates to preventing or delaying subject progression from Class I pulmonary hypertension to Class IT pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to promoting or increasing subject regression from Class IT pulmonary hypertension to Class I pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to a subject that has Class ITT pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to preventing or delaying subject progression from Class II pulmonary hypertension to Class III pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to promoting or increasing subject regression from Class III pulmonary hypertension to Class II pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to promoting or increasing subject regression from Class III pulmonary hypertension to Class I pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to a subject that has Class IV pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to preventing or delaying subject progression from Class III pulmonary hypertension to Class IV pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to promoting or increasing subject regression from Class IV pulmonary hypertension to Class 111 pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to promoting or increasing subject regression from Class IV pulmonary hypertension to Class II pulmonary hypertension as recognized by the WHO. In some embodiments, the method relates to promoting or increasing subject regression from Class IV pulmonary hypertension to Class I pulmonary hypertension as recognized by the WHO.

[0149] In some embodiments, administration of the supplemental medicament decreases fatigue in the subject. In some embodiments, administration of the supplemental medicament decreases fatigue in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases dyspnea in the subject. In some embodiments, administration of the supplemental medicament decreases dyspnea in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases palpitations in the subject. In some embodiments, administration of the supplementalDBl / 165834806.1 59medicament decreases palpitations in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases angina in the subject. In some embodiments, administration of the supplemental medicament decreases angina in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases swelling in the subject. In some embodiments, administration of the supplemental medicament decreases swelling in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases cyanosis in the subject. In some embodiments, administration of the supplemental medicament decreases cyanosis in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases dizziness in the subject. In some embodiments, administration of the supplemental medicament decreases dizziness in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases fainting in the subject. In some embodiments, administration of the supplemental medicament decreases fainting in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases lightheadedness in the subject. In some embodiments, administration of the supplemental medicament decreases lightheadedness in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, administration of the supplemental medicament decreases weakness in the subject. In some embodiments, administration of the supplemental medicament decreases weakness in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%).

[0150] In some embodiments, the subject has a 6-minute walk distance from 150 to 400 meters. In some embodiments, the method increases the subject's 6-minute walk distance by at least 10 meters (e.g., at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, or more than 400 meters). In some embodiments, the subject has a blood hemoglobin level DBl / 165834806.1 60between about 8 and 15 g / dl. In some embodiments, the method delays clinical worsening of pulmonary arterial hypertension. In some embodiments, the method delays clinical worsening of pulmonary hypertension in accordance with the NYHA's functional classification system for pulmonary hypertension. In some embodiments, the method reduces the risk of hospitalization for one or more complications associated with pulmonary arterial hypertension.

[0151] In some embodiments, the subject has pulmonary arterial hypertension and has Functional Class II or Class III pulmonary hypertension in accordance with the NYHA's functional classification system for pulmonary hypertension. In some embodiments, the subject has pulmonary arterial hypertension that is classified as one or more subtypes selected from the group consisting of: idiopathic or heritable pulmonary arterial hypertension, drug- and / or toxin- induced pulmonary hypertension, pulmonary hypertension associated with connective tissue disease, and pulmonary hypertension associated with congenital systemic-to-pulmonary shunts at least 1 year following shunt repair. In some embodiments, the subject has been treated with one or more vasodilators.[00152J In some embodiments, the subject has pulmonary hypertension associated with interstitial lung disease. In other embodiments, the subject has pulmonary arterial hypertension.Dosing Regimen for Administration of Primary Medicaments and Supplemental Medicaments

[0153] According to certain embodiments, methods of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject include administering to the subject one or more doses of a supplemental medicament. In some embodiments, the one or more doses of the supplemental medicament is administered concurrently with a background therapy or primary dosage regimens comprising one or more dosages of a primary medicament. In some embodiments, the one or more doses of the supplemental medicament is administered sequentially with one or more dosages of one or more primary medicaments. In some embodiments, the one or more doses of the supplemental medicament is administered after administration of one or more dosages of one or more primary medicaments to the subject. In some embodiments, the supplemental medicament may be self-administered by the subject as dry powder particles via a dry powder inhaler. In some embodiments, the supplemental DBl / 165834806.1 61medicament is administered via a nebulizer. In some embodiments, the one or more dosages of a primary medicament may be administered to the subject via injection (e.g., subcutaneous injection, intradermal injection, intramuscular injection, or intravenous injection or infusion).

[0154] In some embodiments, the supplemental medicament is administered intermittently to treat the transient increase in the severity of one or more pulmonary hypertension symptoms.

[0155] In some embodiments, the supplemental medicament is administered to the subject after the subject experiences a symptom exacerbation. In some embodiments, the supplemental medicament is administered in anticipation of a symptom exacerbation. In some embodiments, the supplemental medicament is administered to the subject before the subject engages in an activity that may result in a symptom exacerbation. In other embodiments, the activity that may result in a symptom exacerbation is a physical activity, emotional activity, or mental activity.

[0156] In other embodiments, the activity that may result in a symptom exacerbation is a moderately strenuous activity. A moderately strenuous activity may be an activity requiring between 3 and less than 6 metabolic equivalents (METs). One MET corresponds to the amount of oxygen consumed while sitting at rest. These activities require the subject to consume three to six times more oxygen than the subject consumes at rest. While performing a moderately strenuous activity, the subject may experience a heart rate of between 50 to 70% of the subject’s maximum heart rate. Examples of moderate physical activities include sweeping the floor, walking briskly, slow dancing, vacuuming, washing windows, shooting a basketball.

[0157] In embodiments, the activity is a strenuous activity due to the subject’s disease state and may not be considered a strenuous activity for subjects with a less advanced disease or subjects without pulmonary hypertension. A strenuous activity may be an activity requiring 6 or more METS. Vigorous activities require the highest amount of oxygen consumption to complete the activity. These activities require the subject to consume more than six times more oxygen than the subject consumes at rest. While performing a strenuous activity, the subject may experience a heart rate of over 70% of the subject’s maximum heart rate. Examples of vigorous physical activities include running (faster than 5 miles per hour), swimming, shoveling, soccer, jumping rope, and carrying heavy loads.DBl / 165834806.1 62

[0158] In other embodiments, the activity that may result in a symptom exacerbation is a vigorous activity. In other embodiments, the activity that may result in a symptom exacerbation is a stressful activity.Administration / Regimens of Primary Medicament

[0159] In some embodiments, the primary medicament may be administered by the subject orally, intravenously, subcutaneously, or by inhalation. In other embodiments, the primary medicament is administered by inhalation via a nebulizer, e.g., a breath-actuated vibrating-mesh nebulizer. In some embodiments, the primary medicament is administered by inhalation via dry powder inhaler. In some embodiments, primary medicament administered to the subject via injection (e.g., subcutaneous injection, intradermal injection, intramuscular injection, or intravenous injection). In some embodiments, the primary medicament is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, the primary medicament is administered not more than once a day, not more than twice a day, not more than three times a day, or not more than four times a day. In some embodiments, the primary medicament is administered daily, every other day, every two days, or every three days. In some embodiments, the primary medicament is administered not more than daily, not more than every other day, not more than every two days, or not more than every three days. In some embodiments, the primary medicament is administered weekly, every other week, every two weeks, or every three weeks. In some embodiments, the primary medicament is administered not more than weekly, not more than every other week, not more than every two weeks, or not more than every three weeks. In some embodiments, the primary medicament is administered monthly, every other month, every two months, every three months, every four months, every five months, or every six months. In some embodiments, the primary medicament is administered not more than monthly, not more than every other month, not more than every two months, not more than every three months, not more than every four months, not more than every five months, or not more than every six months.

[0160] The term “concurrent” or “concurrently” means at or about the same time. The terms “concurrent” and “concurrently” are synonymous with “simultaneous” and “simultaneously.” Concurrent administration of a treatment means administration of two or more treatments at or about the same time. Typically, concurrent administration with two or more treatments (e.g., anDBl / 165834806.1 63inhalation treatment and a fusion protein) occurs between 0 and 10 days. Typically, concurrent administration occurs no longer than about 7 days apart, such as about 5 days, preferably no later than about 3 days, such as within 24 hours, such as within about 8 hours or less. Commonly, concurrent administration of two or more treatments occurs within about 2 hours or less, such that the first and at least second treatments are administered within a period of 2 hours, a period of 1 hour, or within about 30 minutes, or about 10 minutes. In some instances, concurrent administration is performed at the same time, e.g., in one or more administrations. In other instances, administration of concurrent treatments may be performed at different times, e.g., administration of one medicament according to one dosing schedule and administration of a second medicament according to a second dosing schedule. For example, one medicament dosing schedule may be once a month and the second medicament dosing schedule may be daily. A subject may have one or more primary medicaments administered concurrently. A supplemental medicament may be administered concurrently with one or more primary medicaments.

[0161] The term “physiologically effective” means having a therapeutic effect on the condition intended to be treated or prevented. An administered medicament is physiologically effective when it has attenuated or improved symptoms of pulmonary hypertension or treated underlying causes of symptoms of pulmonary hypertension.

[0162] In some embodiments, the supplemental medicament is physiologically effective after administration in a shorter amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 5% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 10% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 15% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 20% the amount of time than the primary medicament is physiologically effective after administration. In particularDBl / 165834806.1 64embodiments, the supplemental medicament is physiologically effective after administration in less than 25% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 30% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 35% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 40% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 45% the amount of time than the primary medicament is physiologically effective after administration. In particular embodiments, the supplemental medicament is physiologically effective after administration in less than 50% the amount of time than the primary medicament is physiologically effective after administration.

[0163] In some embodiments, the supplemental medicament is physiologically effective less than 120 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 105 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 90 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 75 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 60 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 50 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 40 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 30 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 20 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 10 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 5 minutes after administration. In some embodiments, the supplemental medicament is physiologically effective less than 1 minute after administration. In some embodiments, the supplemental medicament is physiologically effective less than 45 DBl / 165834806.1 65seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 30 seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 15 seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 5 seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 4 seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 3 seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 2 seconds after administration. In some embodiments, the supplemental medicament is physiologically effective less than 1 second after administration.

[0164] In some embodiments, the primary medicament is regularly administered according to a dosing regimen described herein. In some embodiments, the supplemental medicament is not regularly administered according to a dosing regimen. In particular embodiments, the supplemental medicament is administered before an activity that may exacerbate one or more pulmonary hypertension symptoms. In particular embodiments, the supplemental medicament is administered after an exacerbation of one or more pulmonary hypertension symptoms. In particular embodiments, the primary medicament and supplemental medicament administration is exemplified in the Table below. Administration of the supplemental medicament immediately before an anticipated activity means administration of the supplemental medicament less than 30 seconds before the anticipated activity. Administration of the supplemental medicament immediately after onset of symptom exacerbations means administration of the supplemental medicament less than 30 seconds after the onset of symptom exacerbations.DBl / 165834806.1 66DB1 / 165834806.1 67DB1 / 165834806.1 68DB1 / 165834806.1 69DB1 / 165834806.1 70DB1 / 165834806.1 71DB1 / 165834806.1 72DB1 / 165834806.1 73DB1 / 165834806.1 74DB1 / 165834806.1 75DB1 / 165834806.1 76DB1 / 165834806.1 77DB1 / 165834806.1 78

[0165] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concepts thereof. It is to be understood that the embodiments and claims disclosed herein are not limited in their application to the details of construction and arrangement of the components set forth in the description and illustrated in the drawings. Rather, the description and the drawings provide examples of the embodiments envisioned. The embodiments and claims disclosed herein are further capable of other embodiments and of being practiced and carried out in various ways.

[0166] Unless specifically set forth herein, the terms “a”, “an” and “the” are not limited to one element but instead should be read as meaning “at least one”. Further, unless specifically set forth herein, a disclosed or claimed method should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be varied.EXAMPLESExample 1

[0167] A subject with NYHA Functional Class II PAH is undergoing a background therapy comprising an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. The subject begins to experience fatigue, dyspnea, palpitations, or angina while taking a moderately strenuous hike. The subject takes a prostacyclin analog via inhaler. The subject’s symptoms are attenuated within 10 minutes.DBl / 165834806.1 79Example 2

[0168] The subject of Example 1 is planning on taking a moderately strenuous hike. Based on previous experience of symptom exacerbation during such a hike, the subject of Example 1 takes a prostacyclin analog via inhaler about 10 minutes prior to beginning the hike. The subject does not experience an exacerbation of pulmonary hypertension symptoms during the hike.Example 3

[0169] A subject with NYHA Functional Class II PAH is undergoing a background therapy comprising an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. The subject begins to experience fatigue, dyspnea, palpitations, or angina while taking a moderately strenuous hike. The subject takes treprostinil via inhaler. The subject’s symptoms are attenuated within 10 minutes. The table below shows various endothelin receptor / phosphodiesterase-5 inhibitor primary medicament combinations and possible treprostinil supplemental medicament doses.Example 4

[0170] The subject of Example 3 is planning on taking a moderately strenuous hike. Based on previous experience of symptom exacerbation during such a hike, the subject takes treprostinil via inhaler about 10 minutes before beginning the hike. The subject does not experience an exacerbation of pulmonary hypertension symptoms during the hike. The table below showsDBl / 165834806.1 80various endothelin receptor / phosphodiesterase-5 inhibitor primary medicament combinations and possible treprostinil supplemental medicament doses.Example 5

[0171] A subject with NYHA Functional Class II PH-ILD, is undergoing a background therapy comprising twice-a-day administration of liposomal treprostinil. The subject begins to experience fatigue, dyspnea, palpitations, or angina while taking a moderately strenuous hike. The subject takes a prostacyclin analog via inhaler. The subject’s symptoms are attenuated within 10 minutes.Example 6

[0172] A subject with NYHA Functional Class II PH-ILD, is undergoing a background therapy comprising twice-a-day administration of liposomal treprostinil. Prior to beginning a moderately strenuous hike, the subject takes a prostacyclin analog via inhaler about 10 minutes before beginning the hike. The subject does not experience a symptom exacerbation.Example 7

[0173] A subject with NYHA Functional Class III PAH is undergoing a background therapy comprising an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor and inhaled treprostinil. The subject begins to experience fatigue, dyspnea, palpitations, or angina whileDBl / 165834806.1 81undertaking day to day activities. The subject takes a supplemental medicament prostacyclin analog via inhaler. The subject’s symptoms are attenuated within 10 minutes.Example 8

[0174] A subject with NYHA Functional Class III PAH is undergoing a background therapy comprising an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor and inhaled treprostinil. The subject plans on folding laundry, an activity that exacerbated pulmonary hypertension symptoms in the past. The subject takes a supplemental medicament prostacyclin analog via inhaler about 10 minutes before the activity. The subject does not experience a symptom exacerbation while folding laundry.DBl / 165834806.1 82

Claims

CLAIMS1. A method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplemental medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms;wherein the subject is concurrently undergoing treatment with one or more primary medicaments for treating pulmonary hypertension;wherein the supplemental medicament is physiologically effective following administration of the supplemental medicament.

2. A method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplemental medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms;wherein the subject is simultaneously, serially, or alternately administered one or more dosages of one or more primary medicaments for treating pulmonary hypertension;wherein the supplemental medicament is physiologically effective following administration of the supplemental medicament.

3. The method of Claim 2, wherein the patient is undergoing treatment with one or more primary medicaments for treating pulmonary hypertension.

4. The method of any one of Claims 1-3, wherein the primary medicament comprises a treatment for WHO Group 1 or WHO Group 3 pulmonary hypertension.

5. The method of any one of Claims 1-4, wherein the supplemental medicament comprises a treatment for WHO Group 1 or WHO Group 3 pulmonary hypertension.

6. The method of any one of Claims 1-5, wherein the pulmonary hypertension is NYHA Functional Classification Class I, Class II, Class III, or Class IV.

7. The method of any one of Claims 1-5, wherein the pulmonary hypertension is WHO Functional Classification Class I, Class II, Class III, or Class IV.DBl / 165834806.1 838. The method of Claim 1-7, wherein the supplemental medicament is physiologically effective in less than sixty minutes.

9. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than thirty minutes.

10. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than twenty minutes.

11. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than fifteen minutes.

12. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than ten minutes.

13. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than five minutes.

14. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than three minutes.

15. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than two minutes.

16. The method of Claim 8, wherein the supplemental medicament is physiologically effective in less than one minute.

17. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 45 seconds after administration.

18. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 30 seconds after administration.

19. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 15 seconds after administration.DBl / 165834806.1 8420. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 5 seconds after administration.

21. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 4 seconds after administration.

22. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 3 seconds after administration.

23. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 2 seconds after administration.

24. The method of Claim 8, wherein the supplemental medicament is physiologically effective less than 1 second after administration.

25. The method of Claims 1-24, wherein the primary medicament comprises 1, 2, 3, 4, or more medicaments.

26. The method of Claims 1-25, wherein the primary medicament comprises 2 or more medicaments.

27. The method of Claims 1-26, wherein the primary medicament comprises 3 or more medicaments.

28. The method of Claims 1-27, wherein the primary medicament comprises 4 or more medicaments.

29. The method of any one of Claims 1-28, wherein the primary medicament comprises a prostacyclin analog, prostacyclin receptor agonist, endothelin receptor antagonist, phosphodiesterase-5 inhibitor, soluble guanylate cyclase stimulator, calcium channel blocker, activin signaling inhibitor, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

30. The method of Claim 29, wherein the primary medicament comprises a prostacyclin analog.DBl / 165834806.1 8531. The method of Claim 30, wherein the prostacyclin analog comprises epoprosterol, treprostinil, iloprost, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

32. The method of Claim 31, wherein the prostacyclin analog comprises treprostinil, treprostinil prodrugs, pharmaceutically acceptable salts of treprostinil, or combinations thereof.

33. The method of Claim 29, wherein the primary medicament comprises a prostacyclin receptor agonist.

34. The method of Claim 33, wherein the prostacyclin receptor agonist comprises selexipag or ralinepag.

35. The method of Claim 29, wherein the primary medicament comprises an endothelin receptor antagonist.

36. The method of Claim 35, wherein the endothelin receptor antagonist comprises bosentan, ambrisentan, macitentan, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

37. The method of Claim 29, wherein the primary medicament comprises a phosphodiesterase-5 inhibitor.

38. The method of Claim 37, wherein the phosphodiesterase-5 inhibitor comprises sildenafil, tadalafil, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

39. The method of Claim 29, wherein the primary medicament comprises a soluble guanylate cyclase stimulator.

40. The method of Claim 39, wherein the soluble guanylate cyclase stimulator comprises riociguat, prodrugs thereof, or pharmaceutically acceptable salts thereof.

41. The method of Claim 29, wherein the primary medicament comprises a calcium channel blocker.DBl / 165834806.1 8642. The method of Claim 41, wherein the calcium channel blocker comprises amlodipine, nifedipine, diltiazem, prodrugs thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

43. The method of Claim 29, the primary medicament comprises an activin signaling inhibitor.

44. The method of Claim 43, wherein the activin signaling inhibitor comprises sotatercept, prodrugs thereof, or pharmaceutically acceptable salts thereof.

45. The method of Claim 29, wherein the primary medicament comprises:an endothelin receptor antagonist, prodrugs thereof, or pharmaceutically acceptable salts thereof; anda phosphodiesterase-5 inhibitor, prodrugs thereof, or pharmaceutically acceptable salts thereof.

46. The method of Claim 45, wherein the primary medicament comprises at least one of: bosentan, ambrisentan, macitentan, prodrugs thereof, and pharmaceutically acceptable salts thereof; and at least one of: sildenafil, tadalafil, prodrugs thereof, and pharmaceutically acceptable salts thereof.

47. The method of Claim 32, wherein the treprostinil, treprostinil prodrugs, or pharmaceutically acceptable salts of treprostinil, is administered via an aerosolized liposomal composition.

48. The method of Claim 47, wherein the aerosolized liposomal composition comprises one or more liposomes suspended in an external medium.

49. The method of Claim 48, wherein the one or more liposomes each comprise:a lipid bilayer comprising at least one vesicle-forming phospholipid; andan internal aqueous medium encapsulated by the lipid bilayer comprising treprostinil, and a pH gradient salt;wherein a weight ratio of treprostinil to the at least one vesicle-forming phospholipid is equal to or higher than about 0.035.DBl / 165834806.1 8750. The method of Claim 49, wherein the lipid bilayer further comprises a sterol selected from the group consisting of cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, and any combination thereof.

51. The method of any one of Claims 49 or 50, wherein the at least one vesicle-forming phospholipid comprises a first phospholipid and a second phospholipid.

52. The method of Claim 51, wherein the first phospholipid is selected from the group consisting of HSPC, DSPC, DPPC, DMPC, and any combination thereof, and the second phospholipid is selected from the group consisting of DSPG, DPPG, DMPG, PEG-DSPE, and any combination thereof.

53. The method of Claims 51 or 52, wherein the lipid bilayer comprises about 50-70 mole % of the first phospholipid, 20-45 mole % of the sterol, and 0.1-10 mole % of the second phospholipid.

54. The method of any one of Claims 51 or 52, wherein the first phospholipid is HSPC, the sterol is cholesterol, and the second phospholipid is DSPG.

55. The method of any one of Claims 49 to 54, wherein the pH gradient salt comprises a bicarbonate salt.

56. The method of any one of Claims 48 to 55, wherein the one or more liposomes have a mean particle size of about 100 nm to about 200 nm and a poly dispersity index of less than 0.2.

57. The method of any one of Claims 1-46, wherein the primary medicament is administered orally, parenterally, or by inhalation.

58. The method of Claim 57, wherein the primary medicament is parenterally administered by subcutaneous injection, intradermal injection, intramuscular injection, or intravenous injection.

59. The method of Claim 57, wherein the primary medicament is administered by inhalation via a nebulizer or an inhaler.DBl / 165834806.1 8860. The method of Claim 59, wherein the nebulizer comprises a jet, ultrasonic, or mesh nebulizer.

61. The method of Claim 59, wherein the inhaler comprises a dry powder, metered dose, or soft mist inhaler.

62. The method of Claim 57, wherein the primary medicament is administered orally as a tablet, a capsule, a pill, or a liquid formulation.

63. The method of any one of Claims 1-62 wherein the primary medicament is administered at least once a day, at least once a week, at least once every two weeks, at once every three weeks, at least once every four weeks, at least once every month, at least once every two months, at least once every three months, at least once every four months, at least once every five months, or at least once every six months.

64. The method of any one of Claims 1-62 wherein the primary medicament is administered not more than once a day, not more than twice a day, not more than three times a day, not more than once a week, not more than once every two weeks, not more than once every three weeks, not more than once every four weeks, not more than once every month, not more than once every two months, not more than once every three months, not more than once every four months, not more than once every five months, or not more than once every six months.

65. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 6 months.

66. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 5 months.

67. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 4 months.

68. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 3 months.DBl / 165834806.1 8969. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 2 months.

70. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 1 month.

71. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 4 weeks.

72. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 3 weeks.

73. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 2 weeks.

74. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 1 week.

75. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 6 days.

76. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 5 days.

77. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 4 days.

78. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 3 days.

79. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 2 days.

80. The method of any one of Claims 1-64, wherein the primary medicament is administered once every 1 day.DBl / 165834806.1 9081. The method of any one of Claims 1-64, wherein the primary medicament is administered twice a day.

82. The method of any one of Claims 1-64, wherein the primary medicament is administered three times a day.

83. The method of any one of Claims 1-64, wherein the primary medicament is administered four times a day.

84. The method of any one of Claims 1-64, wherein the primary medicament is administered five times a day.

85. The method of any one of Claims 1-64, wherein the primary medicament is administered six times a day.

86. The method of any one of claims 1-64, wherein the primary medicament is administered continuously.

87. The method of any one of Claims 1-86, wherein the supplemental medicament comprises treprostinil, a treprostinil prodrug, or a pharmaceutically acceptable salt of any one thereof.

88. The method of Claim 87, wherein the treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof is administered as dry powder particles.

89. The method of Claim 88, wherein the dry powder particles have a mass median aerodynamic diameter from 1 micrometer to 5 micrometers.

90. The method of Claim 88, wherein the dry powder particles have a mass median aerodynamic diameter of 3 micrometers or less.

91. The method of any one of Claims 88-90, wherein the dry powder particles are formed having a predetermined size range.

92. The method of any one of Claims 88-91, wherein the dry powder particles comprise particles that are substantially uniform in shape.DBl / 165834806.1 9193. The method of any one of Claims 88-92, wherein each particle of the dry powder particles comprises the treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof and an excipient matrix.

94. The method of Claim 93, wherein the dry powder particles comprise about 0.5 to about 1% by weight treprostinil.

95. The method of Claim 93 or 94, wherein the excipient matrix comprises fumaryl diketopiperazine.

96. The method of any one of Claims 88-95, wherein the dry powder particles are contained in a single dose unit.

97. The method of Claim 96, wherein the single dose unit contains between about 10 and about 150 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

98. The method of Claim 97, wherein the single dose unit contains about 16 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

99. The method of Claim 97, wherein the single dose unit contains about 26.5 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

100. The method of Claim 97, wherein the single dose unit contains about 32 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

101. The method of Claim 97, wherein the single dose unit contains about 48 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

102. The method of Claim 97, wherein the single dose unit contains about 53 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

103. The method of Claim 97, wherein the single dose unit contains about 64 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.DBl / 165834806.1 92104. The method of Claim 97, wherein the single dose unit contains about 79.5 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

105. The method of Claim 97, wherein the single dose unit contains about 106 micrograms of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

106. The method of anyone of Claim 88, wherein the dry powder particles have a crystalline structure.

107. The method of Claim 88, wherein the dry powder particles have an amorphous structure.

108. The method of any one of Claims 93-105, wherein the excipient matrix is configured to dissolve at pH values above 6.

109. The method of any one of Claims 1-108, wherein the supplemental medicament is administered as one or more doses of treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

110. The method of Claim 109, wherein each dose comprises between 10 and 400 micrograms treprostinil, treprostinil prodrug, or pharmaceutically acceptable salt of any one thereof.

111. The method of claim 110, wherein each dose comprises 212 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

112. The method of claim 110, wherein each dose comprises 204 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

113. The method of Claim 110, wherein each comprises about 200 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

114. The method of claim 110, wherein each dose comprises 185.5 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

115. The method of Claim 110, wherein each dose comprises about 175 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.DBl / 165834806.1 93116. The method of claim 110, wherein each dose comprises 159 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

117. The method of claim 110, wherein each dose comprises 153 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

118. The method of Claim 110, wherein each dose comprises about 150 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

119. The method of claim 110, wherein each dose comprises 132.5 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

120. The method of Claim 110, wherein each dose comprises about 125 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

121. The method of claim 110, wherein each dose comprises 106 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

122. The method of claim 110, wherein each dose comprises 102 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

123. The method of Claim 110, wherein each dose comprises about 100 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

124. The method of claim 110, wherein each dose comprises 80 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

125. The method of claim 110, wherein each dose comprises 79.5 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

126. The method of Claim 110, wherein each dose comprises about 75 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

127. The method of claim 110, wherein each dose comprises 64 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.DBl / 165834806.1 94128. The method of claim 110, wherein each dose comprises 53 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

129. The method of claim 110, wherein each dose comprises 51 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

130. The method of Claim 110, wherein each dose comprises about 50 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

131. The method of claim 110, wherein each dose comprises 48 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

132. The method of claim 110, wherein each dose comprises 32 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

133. The method of claim 110, wherein each dose comprises 26.5 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

134. The method of Claim 110, wherein each dose comprises about 25 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

135. The method of claim 110, wherein each dose comprises 16 micrograms of the treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

136. The method of Claim 110, wherein each dose comprises about 10 micrograms treprostinil, the treprostinil prodrug, or the pharmaceutically acceptable salt of any one thereof.

137. The method of any one of Claims 1-136, wherein the supplemental medicament is administered via inhalation.

138. The method of Claim 137, wherein the supplemental medicament is administered via a nebulizer or an inhaler.

139. The method of Claim 138, wherein the nebulizer is a jet nebulizer, an ultrasonic nebulizer, or a mesh nebulizer.DBl / 165834806.1 95140. The method of Claim 138, wherein the inhaler is a dry powder inhaler, a metered dose inhaler, or a soft mist inhaler.

141. The method of any one of Claims 1-140, wherein one or more primary medicaments are administered as a therapeutically effective dose.

142. The method of any one of Claims 1-141, wherein the supplemental medicament is administered after an onset of an increase in the severity of one or more pulmonary hypertension symptoms.

143. The method of Claim 142, wherein the one or more pulmonary hypertension symptoms is one or more of fatigue, dyspnea, palpitations, angina, swelling, cyanosis, dizziness, fainting, lightheadedness, or weakness.

144. The method of any one of Claims 1-143, wherein the supplemental medicament is administered before performing an activity, wherein the activity may result in an increase in the severity of one or more pulmonary hypertension symptoms.

145. The method of Claim 144, wherein the one or more pulmonary hypertension symptoms is one or more of fatigue, dyspnea, palpitations, angina, swelling, cyanosis, dizziness, fainting, lightheadedness, or weakness.

146. The method of Claim 144 or 145, wherein the supplemental medicament is administered no more than four hours prior to performing the activity.

147. The method of any one of Claims 144-146, wherein the supplemental medicament is administered no more than three hours prior to performing the activity.

148. The method of any one of Claims 144-147, wherein the supplemental medicament is administered no more than two hours prior to performing the activity.

149. The method of any one of Claims 144-148, wherein the supplemental medicament is administered no more than one hour prior to performing the activity.DBl / 165834806.1 96150. The method of any one of Claims 144-149, wherein the supplemental medicament is administered no more than thirty minutes prior to performing the activity.

151. The method of any one of Claims 144-150, wherein the supplemental medicament is administered no more than fifteen minutes prior to performing the activity.

152. The method of any one of Claims 144-151, wherein the supplemental medicament is administered no more than ten minutes prior to performing the activity.

153. The method of any one of Claims 144-152, wherein the supplemental medicament is administered no more than five minutes prior to performing the activity.

154. The method of any one of Claims 144-153, wherein the supplemental medicament is administered no more than one minute prior to performing the activity.

155. The method of any one of Claims 144-154, wherein the supplemental medicament is administered when initiating the activity.

156. The method of any one of Claims 144-155, wherein the activity lowers the subject’s blood pressure.

157. The method of any one of Claim 144-155, wherein the activity increases the subject’s heart rate.

158. The method of any one of Claims 1-157, wherein the increase in the severity of one or more pulmonary hypertension symptoms presents as an acute pulmonary hypertension progression.

159. The method of any one of Claims 1-158, wherein the supplemental medicament is administered intermittently to treat or attenuate a transient increase in the severity of one or more pulmonary hypertension symptoms.

160. A method of treating or preventing exacerbations of one or more pulmonary hypertension symptoms in a subject in need thereof, comprising administering to the subject a supplementalDBl / 165834806.1 97medicament for treating, attenuating, and / or preventing one or more pulmonary hypertension symptoms;wherein the subject has undergone treatment with one or more primary medicaments for treating pulmonary hypertension;wherein the supplemental medicament is physiologically effective following administration of the supplemental medicament.DBl / 165834806.1 98

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