Treprostinil for use in the treatment of interstitial lung disease

Abstract

Methods for treating interstitial lung disease, reducing pulmonary function decline in subjects with interstitial lung disease (ILD), and increasing forced vital capacity (FVC) in subjects suffering from ILD are provided, which methods comprise administering treprostinil.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 011,810, filed Apr. 17, 2020, and U.S. Provisional Application No. 63 / 160,611, filed Mar. 12, 2021.

[0002] Field This application generally relates to methods of treating diseases with prostacyclin, and more specifically to methods of treating diseases with treprostinil.

Background Art

[0003] Background Interstitial lung disease (ILD) or diffuse parenchymal lung disease (DPLD) is a group of lung diseases that affect the interstitium (the tissue and space around the alveoli, including the air sacs of the lung). This is related to alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and extralymphatic tissues. This can occur when lung damage causes an abnormal healing response. Such an abnormal response can cause idiopathic pulmonary fibrosis (IPF). Currently, two drugs, nintedanib and pirfenidone, have been approved by the FDA as therapeutic agents for IPF, the most common form of PF. Currently, the average survival rate of patients with interstitial lung disease is 3 - 5 years (Meyer et al., 2017). There is a need to identify new pharmaceutical treatments for ILD.

Summary of the Invention

[0004] Summary In one aspect, a method of treating pulmonary hypertension resulting from a condition selected from chronic lung disease, hypoxia, and combinations thereof comprises administering to a subject having pulmonary hypertension resulting from a condition selected from chronic lung disease, hypoxia, and combinations thereof an effective amount of treprostinil, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0005] In one embodiment, a method is provided for treating interstitial lung disease (ILD) in a subject requiring treatment, comprising administering a therapeutically effective dose of treprostinil, its prodrug, salt, or ester to the subject. In one embodiment, the subject suffers from pulmonary hypertension associated with ILD.

[0006] In one embodiment, a method is provided for reducing impaired lung function in a subject with an intrapulmonary disease (ILD), comprising administering treprostinil, its prodrug, salt, or ester to the subject.

[0007] In one embodiment, a method is provided for increasing forced vital capacity (FVC) in a subject suffering from an intravascular lung disease (ILD), comprising administering treprostinil, its prodrug, salt, or ester to the subject. In some embodiments, administration of treprostinil, its prodrug, salt, or ester can result in an increase of at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, or at least 100% of FVC compared to the FVC before the initiation of treatment. FVC can be assessed before the initiation of treatment and at some intervals after the initiation of treatment. For example, the FVC before treatment can be compared to the FVC measured at 1 week, 4 weeks, 8 weeks, or 16 weeks after the initiation of treatment.

[0008] In some embodiments, administration of an effective amount of treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug can provide a statistically significant improvement in forced vital capacity (FVC) in subjects with conditions selected from chronic lung diseases such as ILD or IPF and / or hypoxia. For example, FVC may be higher in a subgroup of patients with chronic lung disease and / or hypoxia who are administered an effective dose of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, compared to a subgroup of patients with the same condition who are administered a placebo instead of treprostinil, for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks. For example, in a subgroup of patients with chronic lung disease and / or hypoxia who were administered an effective dose of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, FVC values ​​may be at least 10 ml, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 weeks after administration, compared to a subgroup of patients with the same condition who were administered a placebo instead of treprostinil. In patients with chronic lung disease and / or hypoxia, such as interstitial lung disease, FVC values ​​usually decrease over time if left untreated.Therefore, administration of an effective dose of treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt can increase the FVC value compared to the pre-administration FVC value, maintain the FVC value within 5%, 10%, or 20% of the pre-administration FVC value, or reduce the decrease in FVC value over time compared to the decrease in FVC value when an effective dose of treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt is not administered, for example, when a placebo is administered instead of treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt.

[0009] In some embodiments, ILD includes one or more of the following: idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), idiopathic organizing pneumonia (COP), lymphocytic interstitial pneumonia (LIP), sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, antisynthetase syndrome, silicosis, asbestosis, occupational lung disease, chronic hypersensitivity pneumonitis, idiopathic interstitial pneumonia (IIP), autoimmune ILD, lymphangioleiomyomatosis (LAM), Langerhans cell histiocytosis (LCH), drug-associated ILD, vasculitis, granulomatosis, and berylliumosis. In some embodiments, ILD includes IPF.

[0010] In some embodiments, ILD includes systemic sclerosis-associated interstitial lung disease (SSc-ILD).

[0011] In some embodiments, ILD is induced by antibiotics, chemotherapy, antiarrhythmic agents, coronavirus disease 2019 (COVID-19), atypical pneumonia, Pneumocystis pneumonia, tuberculosis (TB), Chlamydia trachomatis, respiratory syncytial virus, or lymphangiocarcinomatosis.

[0012] In some embodiments, the subject has one or more of the following conditions: surfactant-protein-B deficiency, surfactant-protein-C deficiency, ABCA3- deficiency, cerebropulmonary thyroid syndrome, congenital alveolar proteinosis, alveolar capillary dysplasia, telomerase reverse transcriptase mutation, telomerase RNA component mutation, telomere elongation helicase 1 regulator mutation, and poly(A)-specific ribonuclease mutation.

[0013] In some embodiments, the subject has one or more of the following symptoms: shortness of breath, fatigue, weight loss, dry cough, chest pain, and pulmonary hemorrhage. In some embodiments, after administration, the symptoms improve by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as measured by medically recognized techniques. In some embodiments, medically recognized techniques include one or more of the following: Modified Medical Research Council (MMRC) Dyspnea Scale, Modified Borg Dyspnea Scale (0-10), Calder Fatigue Scale, Weight Measurement Scale, Visual Analog Scale for Cough (VAS), King's Brief Interstitial Lung Disease Questionnaire, Leicester Cough Questionnaire (LCQ), Living with IPF (L-IPF, see Am J Respir Crit Care Med Vol 202, Iss 12, pp 1689-1697, December 15, 2020, etc.), computed tomography (CT) scan, X-ray, multiple magnetic resonance imaging (MRI), pulmonary function tests (PFT), spirometry, lung volume, maximal respiratory pressure, diffusion capacity, oxygen saturation reduction, and arterial blood gas assessment.

[0014] In some embodiments, treprostinil, its prodrug, salt, or ester is administered in a pharmaceutical composition comprising treprostinil, its prodrug, salt, or ester and a pharmaceutically acceptable carrier or excipient.

[0015] In some embodiments, administration includes at least one of oral, inhalation, subcutaneous, nasal, intravenous, intramuscular, sublingual, buccal, rectal, vaginal, and transdermal administration. In some embodiments, administration includes inhalation. In some embodiments, a single inhalation administration event includes 1 to 20 breaths, and at least one inhalation administration event is performed per day.

[0016] In some embodiments, the method comprises the administration of at least one additional activator for treating ILD. In some embodiments, the at least one additional activator includes a corticosteroid, mycophenolic acid, mycophenolate mofetil, azathioprine, cyclophosphamide, rituximab, pirfenidone, or nintedanib. In some embodiments, the at least one additional activator and treprostinil, its prodrug, salt, or ester are administered by a method selected from the group consisting of (a) simultaneously, (b) as a mixture, (c) separately and simultaneously or in parallel, and (d) separately and sequentially.

[0017] In some embodiments, administration is once, twice, three times, four times, five times, or six times per day. In some embodiments, administration is for a period selected from the group consisting of about 1 day, about 1 to about 3 days, about 3 to about 6 days, about 6 to about 9 days, about 9 to about 12 days, about 12 to about 15 days, about 15 to about 18 days, about 18 to about 21 days, about 21 to about 24 days, about 24 to about 27 days, about 27 to about 30 days, or about 30 days or more.

[0018] In some embodiments, a method for treating pulmonary hypertension resulting from a condition selected from chronic lung disease, hypoxia, and combinations thereof comprises administering an effective amount of treprostinil, its prodrug, or a pharmaceutically acceptable salt thereof to a subject with pulmonary hypertension resulting from a condition selected from chronic lung disease, hypoxia, and combinations thereof.

[0019] In some embodiments, the subject is human. [Brief explanation of the drawing]

[0020] [Figure 1] Figure 1 shows Kaplan-Meier plots of time to exacerbation of underlying pulmonary disease over a 16-week period of treprostinil treatment. CI represents the confidence interval, and HR represents the hazard ratio. For subjects who discontinued the study early, the time to the first clinical exacerbation event was censored at the last visit. For subjects who did not experience a clinical exacerbation event, the time to the first clinical exacerbation event was censored on the end of the study. (1) P-values ​​were calculated using a log-rank test stratified by baseline 6-minute walk distance category. (2) Hazard ratios, 95% CI, and p-values ​​were calculated using a proportional hazards model with treatment and baseline 6-minute walk distance (continuous) as explanatory variables.

[0021] [Figure 2] Figure 2 outlines the design of the clinical study shown in Example 3. Of the 462 patients screened for eligibility, 326 were randomized and received at least one dose of their assigned treprostinil or placebo (included in the intention-to-treat and safety populations). Of the randomized patients, 40 patients in the treprostinil group and 38 patients in the placebo group discontinued their assigned regimen prematurely. These patients were not excluded from the study but were encouraged to maintain and complete the evaluation until week 16. 33 patients in the treprostinil group and 35 patients in the placebo group discontinued participation in the study before week 16.

[0022] [Figure 3] Figure 3 shows the mean change from baseline in peak 6-minute walk distance up to week 16 in the clinical trial shown in Example 3. The mean (±SE) change from baseline (dashed line) in peak 6-minute walk distance over the 16-week trial period is shown. The data presented are for patients with available data (observed) and the results of two analytical methods used to account for missing data. The value shown at each data point indicates the number of patients evaluated at that time point. The primary analysis used the mixed model repeated measures (MMRM) method and assumed that the missing data were missing at random. This model included the change from baseline to peak 6-minute walk distance as the dependent variable, treatment, week, and the interaction of treatment as fixed effects, and baseline 6-minute walk distance as a covariate. A sensitivity analysis of the primary endpoint was performed using a multiple imputation approach with a multivariate normal imputation model using the Markov chain Monte Carlo (MCMC) method. The imputation model included treatment group, all scheduled visits, patient gender, and patient age at randomization. Confidence intervals were not adjusted for multiplicity and cannot be used to infer a definitive treatment effect.

[0023] [Figure 4] Figure 4 shows the treatment effect on 6-minute walk distance using mixed model repeated measures up to week 16. A longitudinal data analysis using mixed model repeated measures was also performed to evaluate the treatment difference in the change in peak 6-minute walk distance at week 16. Mixed model repeated measures included the change from baseline in peak 6-minute walk distance as the dependent variable, treatment, week, and the interaction of treatment as fixed effects, and baseline 6-minute walk distance as a covariate. Intra-subject error was modeled using an unstructured dispersion / covariance structure shared between treatment groups.

[0024] [Figure 5]Figure 5 shows a forest plot for subgroup analysis of peak 6-minute walk distance (meters) in week 16. 6MWD represents the 6-minute walk distance, CI represents the confidence interval, ILD represents interstitial lung disease, PH represents pulmonary hypertension, PVR represents pulmonary vascular resistance, LS represents the mean difference and its 95% confidence interval, and the p-value is from a mixed model repeated measures. The confidence intervals are not adjusted for multiplicity and cannot be used to infer a definitive treatment effect. For etiology, the "other" category includes chronic hypersensitivity pneumonitis and occupational lung diseases.

[0025] [Figure 6] Figure 6 shows the treatment effect of 6-minute walk distance using multiple imputation up to week 16. The multiple imputation approach uses a multivariate normal imputation model by Markov chain Monte Carlo method. The P-value is obtained from 100 multiple imputations using a Markov chain Monte Carlo evaluation by an ANCOVA model with the change in 6-minute walk distance from baseline as the dependent variable, treatment as the fixed effect, and the baseline 6-minute walk distance measurement as the covariate.

[0026] [Figure 7] Figure 7 shows the results of NT-proBNP (pg / mL) by study visit. CI represents the confidence interval, IQR represents the interquartile range, and NT-proBNP represents N-terminal pro-brain natriuretic peptide. As shown above, inhaled treprostinil was associated with a 42% decrease in NT-proBNP compared to placebo at week 16 (treatment ratio 0.58, 95% CI: 0.47, 0.72, P < 0.001). Only subjects with baseline NT-proBNP measurements are included in this analysis. The P-value, estimated treatment ratio, and associated 95% CI (LS mean difference is expressed as a ratio) are obtained from an analysis of covariance with the change from baseline in the log-transformed data of NT-proBNP as the dependent variable. The confidence intervals are not adjusted for multiplicity and cannot be used to infer a definitive treatment effect.

[0027] [Figure 8]Figure 8 shows the Hodges-Lehmann assessment of the treatment effect on 6-minute walk distance up to week 16. For subjects who withdrew early due to death, were unable to walk due to illness, or had no 6-minute walk distance measurement due to a clinical exacerbation event, the 6-minute walk distance was set to 0. For all other withdrawals without measurement, the last observation carried over to the next period was used for substitution. P-values ​​were obtained from non-parametric ANCOVA adjusted for the baseline 6-minute walk distance category.

[0028] [Figure 9] Figure 9 is a plot showing the relationship between treprostinil AUC0-5 and the doses of treprostinil inhalation powder (TreT) administered by a dry powder inhaler and treprostinil spray administered by a Tyvaso sprayer.

[0029] [Figure 10] Figure 10 is a plot showing the relationship between treprostinil Cmax and the doses of treprostinil inhalation powder (TreT) administered by a dry powder inhaler and treprostinil spray administered by a Tyvaso sprayer.

[0030] [Figure 11] Figure 11 shows a dry powder inhaler with a dosage cartridge for treprostinil inhalation powder (TreT).

[0031] [Figure 12] Figure 12 shows the design of the study in Example 5. During the optional extension phase (OEP), dose titration is encouraged. The dose of TreT is titrated upward to a clinically acceptable level to identify the maximum stable dose for each subject.

[0032] [Figure 13] Figure 13 shows several subjects for various maintenance TreT doses in OEP.

[0033] [Figure 14]Figure 14 shows the change in 6-minute walk distance (6MWD) relative to baseline as a function of the duration of TreT treatment.

[0034] [Figure 15] Figure 15 is a plot reporting participant satisfaction in the study of Example 5. [Modes for carrying out the invention]

[0035] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the relationship explicitly indicates otherwise. It should also be noted that claims can be drafted to exclude optional (optionally present) elements. Therefore, this statement is intended to serve as a prerequisite for the use of exclusive terms such as “solely” and “only” in relation to the enumeration of elements in the claims or the use of “negative” limitations.

[0036] When used herein, the terms “contains” or “composes” are intended to mean that compositions and methods include the enumerated elements but do not exclude other elements. A composition or method that “becomes essentially” of the elements as defined herein does not exclude other materials or processes that do not substantially affect the fundamental and novel properties of the claimed art. “Consists of” means the exclusion of other components and substantial method processes in excess of trace amounts. Embodiments defined by each of these transitional terms are within the scope of this art. When an embodiment is defined by one of these terms (e.g., “contains”), it should be understood that this disclosure also includes alternative embodiments such as “becomes essentially” and “consists of” for the said embodiment.

[0037] "Subject" refers to an animal, such as a mammal (including humans), that has been or is the subject of treatment, observation, or experimentation. "Subject" and "patient" may be used interchangeably unless otherwise indicated. The methods described herein may be useful in the treatment and / or veterinary applications of humans. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0038] The terms “therapeutic dose,” “effective dose,” and “pharmaceutical dose” are used interchangeably and refer to the amount of compound sufficient to provide the treatment as defined below when administered in one or more doses to a patient (e.g., a human) requiring such treatment. The therapeutic dose varies depending on the patient, the disease being treated, the patient’s weight and / or age, the severity of the disease, or the method of administration as determined by the qualified prescriber or caregiver. The therapeutic dose can be determined by titrating the dose upward from the starting dose, with respect to either the dose or the frequency of administration. In some embodiments, the therapeutic dose is determined by titrating the dose upward until the maximum tolerable dose for the individual subject is determined.

[0039] The terms “treatment” or “to treat” mean administering any of the compounds disclosed herein for the purpose of (i) delaying the onset of a disease, i.e., preventing or delaying the onset of the clinical symptoms of the disease; (ii) inhibiting the disease, i.e., preventing the manifestation of the clinical symptoms; and / or (iii) alleviating the disease, i.e., causing regression of the clinical symptoms or their severity.

[0040] The term "pulmonary fibrosis" refers to a condition characterized by scarring and thickening of the lungs. Symptoms include shortness of breath, fatigue, weakness, chronic dryness, dry cough, loss of appetite, and chest discomfort. Ultimately, the scars in the lungs are replaced by fibrous tissue, and the lungs lose their ability to deliver oxygen to the blood.

[0041] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this art belongs. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this art, but representative exemplary methods and materials are described herein.

[0042] All numerical values, including ranges, such as pH, temperature, time, concentration, dose, and molecular weight, are approximations that vary by (+) or (-) in increments of 0.05%, 1%, 2%, 5%, 10%, or 20%. While not always explicitly stated, it should be understood that all numerical specifications are preceded by the term "approximately."

[0043] Where a range of values ​​is provided, unless explicitly indicated otherwise, each intervening value up to one-tenth of the lower limit between the upper and lower limits of that range, and any other stated or intervening values ​​within that stated range, are included in this Art. The upper and lower limits of these smaller ranges may independently be included in smaller ranges and are included in this Art, subject to any specially excluded limitations within the stated range. Where a stated range includes one or both limits, a range that excludes one or both of the included limits is also included in this Art.

[0044] In one embodiment, the present disclosure provides a method for treating interstitial lung disease (ILD) in a subject requiring treatment, comprising administering a therapeutically effective amount of treprostinil, its prodrug, salt, or ester to the subject.

[0045] Treprostinil is used to treat pulmonary arterial hypertension. Treprostinil is a synthetic analog of prostacyclin (PGI2) with the following structure.

[0046] [ka]

[0047] Treprostinil, the active ingredient in Remodulin® (Treprostinil) Injection, Tyvaso® (Treprostinil) Inhalation Solution, and Orenitram® (Treprostinil) Extended-Release Tablets, is described in U.S. Patent No. 4,306,075. Methods for producing treprostinil and other prostacyclin derivatives are described, for example, in Moriarty et al.'s J. Org. Chem, 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374. U.S. Patent Nos. 6,441,245, 6,528,688, 6,700,025, 6,809,223, 6,756,117, 8,461,393, 8,481,782, 8,242,305, 8,497,393, 8,940,930, 9,029,607, 9,156,786, 9,388,154, 9,346,738, U.S. Published Patent Application Nos. This information is described in publications No. 2012-0197041, No. 2013-0331593, No. 2014-0024856, No. 2015-0299091, No. 2015-0376106, No. 2016-0107973, No. 2015-0315114, No. 2016-0152548 and No. 2016-0175319, and PCT publication numbers WO2016 / 0055819 and WO2016 / 081658.

[0048] Various uses and / or forms of treprostinil include, for example, U.S. Patent Nos. 5,153,222, 5,234,953, 6,521,212, 6,756,033, 6,803,386, 7,199,157, 6,054,486, 7,417,070, 7,384,978, 7,879,909, 8,563,614, 8,252,839, 8,536,363, 8,410,169, 8, No. 232,316, No. 8,609,728, No. 8,350,079, No. 8,349,892, No. 7,999,007, No. 8,658,694, No. 8,653,137, No. 9,029,607, No. 8,765,81 No. 3, No. 9,050,311, No. 9,199,908, No. 9,278,901, No. 8,747,897, No. 9,358,240, No. 9,339,507, No. 9,255,064, No. 9,278,902, No. 9 ,278,903, 9,758,465, 9,422,223, 9,878,972, 9,624,156, US Published Patent Application Nos. 2009-0036465, 2008-0200449, 2008-0280986, 2009-0124697, 2014-0275616, 2014-0275262, 2013-0184295, 2014-0323567, 2016-0030371, 20 This information is disclosed in specifications 16-0051501, 2016-0030355, 2016-0143868, 2015-0328232, 2015-0148414, 2016-0045470, 2016-0129087, 2017-0095432, 2018-0153847, and PCT publication numbers WO00 / 57701, WO20160105538, WO2016038532, and WO2018 / 058124.

[0049] A "prodrug" of treprostinil is a compound that is converted in vivo to treprostinil or its pharmaceutically active derivative, or PCT Publication No. WO2005 / 007081, U.S. Patent Nos. 7,384,978, 7,417,070, 7,544,713, 8,252,839, 8,410,169, 8,536,363, and 9,050,31 No. 1, No. 9,199,908, No. 9,278,901, No. 9,422,223, No. 9,624,156, No. 9,878,972, No. 9,371,264, No. 9, No. 394,227, No. 9,505,737, No. 9,758,465, No. 9,643,911, No. 9,701,616, No. 9,776,982, No. 9,845,305 , No. 9,957,200, No. 10,494,327, No. 10,053,414, No. 10,246,403, No. 10,344,012, No. 10,450,290, No. No. 10,464,877, No. 10,464,878, No. 10,703,706, No. 10,752,733, No. 9,255,064, No. 9,469,600, No. 10, This may refer to the compounds described in U.S. Patent Publications 010,518, 10,343,979, 10,526,274, U.S. Patent Publications 2018-0153847 and 2021-0054009, U.S. Provisional Patent Application 63 / 036,561 filed on 9 June 2020, and U.S. Provisional Patent Application 63 / 125,145 filed on 14 December 2020. Each of these is incorporated herein by reference in its entirety.

[0050] Prostacyclin is a small molecule that has been previously shown to cause dilation of large blood vessels, relaxation of smooth muscle, inhibition of smooth muscle proliferation, and inhibition of platelet aggregation, which is involved in the blood coagulation process. Similar effects of treprostinil at the microvascular level and in capillaries near the skin are thought to promote blood flow to the skin and help heal and / or prevent ischemic lesions or ulcers associated with scleroderma, Buerger's disease, Raynaud's disease, Raynaud's phenomenon, and other conditions.

[0051] The "ester" of treprostinyl is given by formula:

[0052] [ka] (In the above formula, R1 is H, an optionally substituted C1-C10 alkyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C2-C10 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl.) R2 and R3 are each independently -C(O)R4, and Each R4 is independently an optionally substituted C1-C10 alkyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C2-C10 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl. This can refer to a compound in which at least one of R1, R2, and R3 is not H.

[0053] "Optionally substituted" refers to a group selected from the group and the substitution forms of that group. Substituents may include any of the groups defined below. In one embodiment, substituents are selected from C1-C10 or C1-C6 alkyl, substituted C1-C10 or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C10 heterocyclyl, C1-C10 heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C6-C10 aryl, substituted C3-C8 cycloalkyl, substituted C2-C10 heterocyclyl, substituted C1-C10 heteroaryl, halo, nitro, cyano, -CO2H or their C1-C6 alkyl esters.

[0054] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Examples of this term include linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2), and neopentyl ((CH3)3CCH2-).

[0055] "Alkenyl" refers to a monovalent linear or branched hydrocarbyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, or preferably 2 to 4 carbon atoms, and having at least 1, preferably 1 to 2, vinyl (>C=C<) unsaturated sites. Such groups are exemplified, for example, by vinyl, allyl, and buto-3-en-1-yl. This term includes cis and trans isomers or mixtures thereof.

[0056] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, or preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2, acetylene (-C≡C-) unsaturated sites. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0057] "Substituting alkyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl This refers to an alkyl group having 1 to 5 substituents, preferably 1 to 3, or more preferably 1 to 2 substituents, selected from the group consisting of cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents are as defined herein.

[0058] "Substituted alkenyl" includes alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cyano This refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of chloroalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, provided that neither the hydroxyl nor the thiol substitution is bonded to a vinyl (unsaturated) carbon atom.

[0059] "Substituted alkynyl" is a compound of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, and This refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, except that neither the hydroxyl nor the thiol substitution is bonded to the acetylene carbon atom.

[0060] "Alkoxy" refers to the O alkyl group, where alkyl is defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0061] "Substituting alkoxy" refers to the group O (substituted alkyl), where substituted alkyl is defined herein.

[0062] "Acyl" refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. An example of an acyl group is the "acetyl" group CH3C(O)-.

[0063] "Acylamino" refers to the group -NR47C(O)alkyl, -NR47C(O)substituted alkyl, -NR47C(O)cycloalkyl, -NR47C(O)substituted cycloalkyl, -NR47C(O)cycloalkenyl, -NR47C(O)substituted cycloalkenyl, -NR47C(O) alkenyl, -NR47C(O) substituted alkenyl, -NR47C(O) alkynyl, -NR47C(O) substituted alkynyl, -NR47C(O) aryl, -NR47C(O) substituted aryl, -NR47C(O) This refers to heteroaryls, -NR47C(O)-substituted heteroaryls, -NR47C(O) heterocycles, and NR47C(O)-substituted heterocycles, where R47 is hydrogen or alkyl, and alkyls, substituted alkyls, alkenyls, substituted alkenyls, alkynyls, substituted alkynyls, cycloalkyls, substituted cycloalkyls, cycloalkenyls, substituted cycloalkenyls, aryls, substituted aryls, heteroaryls, substituted heteroaryls, heterocycles, and substituted heterocycles are as defined herein.

[0064] "Acyloxy" includes the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, and heteroaryl groups. -C(O)O-, substituted heteroaryl-C(O)O, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0065] "Amino" refers to the NH2 group.

[0066] "Substituting amino" refers to the group -NR48R49, where R48 and R49 are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, SO2 alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-substituted aryl, -S A substituted amino group is independently selected from the group consisting of O2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and SO2-substituted heterocyclic groups, where R48 and R49 are optionally bonded together with the nitrogen atoms to form a heterocyclic or substituted heterocyclic group, provided that R48 and R49 are not both hydrogen atoms, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein. When R48 is hydrogen and R49 is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R48 and R49 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it means that either R48 or R49 is hydrogen, but not both are hydrogen atoms. When referring to disubstituted amino acids, it means that neither R48 nor R49 are hydrogen atoms.

[0067] "Medically acceptable salts" may refer to physiologically acceptable salts of treprostinil, as well as non-physiologically acceptable salts of treprostinil. Medicinally acceptable salts of the compounds described herein include acid or base addition salts that are within the scope of the Art, retain the desired pharmacological activity, and are not biologically undesirable (e.g., the salt is not excessively toxic, allergenic, or irritating, and is bioavailable). When the compounds of the Art have a basic group, such as an amino group, medicatable salts can be formed with inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid), or acidic amino acids (e.g., aspartic acid and glutamic acid). When the compounds of this technology (treprostinyl, its esters, prodrugs, or derivatives) have an acidic group, such as a carboxylic acid group, they can form salts with metals such as alkalis and alkaline earth metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine, and ornithine). Such salts can be prepared in situ during the separation and purification of the compound, or by reacting the purified compound in free base or free acid form separately with the appropriate acid or base, and then separating the salts thus formed.

[0068] ILDs include idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), idiopathic organizing pneumonia (COP), lymphocytic interstitial pneumonia (LIP), sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, antisynthetase syndrome, silicosis, asbestosis, occupational lung disease, chronic hypersensitivity pneumonitis, idiopathic interstitial pneumonia (IIP), autoimmune ILDs, lymphangioleiomyomatosis (LAM), Langerhans cell histiocytosis (LCH), drug-associated ILDs, vasculitis, granulomatosis, and berylliumosis.

[0069] As used herein, “pulmonary function” refers to the lungs’ ability to absorb oxygen, expand, and contract. Pulmonary function, its decline, or mitigation of its decline can be assessed using medically recognized tools known to those skilled in the art. These methods include pulmonary function tests (PFT), spirometry, lung volume, maximal respiratory pressure, diffusion capacity, oxygen saturation reduction, and arterial blood gas analysis.

[0070] As used herein, “forced vital capacity” refers to the amount of air that can be forced out of the lungs after taking the deepest possible breath, as measured by spirometry.

[0071] Further aspects of the present invention relate to the use of treprostinil or its derivatives, prodrugs, esters or pharmaceutically acceptable salts thereof in the manufacture of agents for the treatment or prevention of interstitial lung disease or conditions associated with interstitial lung disease. In some embodiments, the agents are formulated for inhalation. When administered by inhalation, the formulation can be atomized or formulated for use in a dry powder inhaler (DPI).

[0072] The amount of treprostinil or its derivatives, or a pharmaceutically acceptable salt thereof, required by the method may depend on many factors, including the specific indication used, the properties of the specific compound used, the mode of administration, the concentration, and the subject's body weight and condition. The daily dose per subject for ILD or ILD-related conditions may range from 25 μg to 250 mg or 7 μg to 285 μg per kilogram of body weight per day. In some embodiments, the daily dose may range from about 150 μg to about 350 μg per day, about 200 μg to about 300 μg per day, or about 225 μg to about 275 μg per day. Intravenous doses in the range of 0.5 μg to 1.5 mg per kilogram of body weight per day may be administered as an infusion of 0.5 ng to 1.0 μg per kilogram of body weight per minute.

[0073] Treprostinil or its derivatives, prodrugs, esters, or pharmaceutically acceptable salts thereof can be administered using any appropriate treatment schedule. In some embodiments, the drug is administered multiple times a day (1, 2, 3, 4, or 5 times), and in other embodiments, the drug can be administered continuously, such as by using an infusion pump. The duration of treatment varies depending on the severity of the disease, the treatment goals, or the individual circumstances. In some embodiments, the duration of treatment is at least 1 week, at least 2 weeks, at least 4 weeks, at least 8 weeks, or at least 16 weeks. In some embodiments, the duration of treatment is indefinite, and for example, treatment can continue for the lifetime of the subject or until the symptoms of the disease fall below a certain threshold.

[0074] The pharmaceutical compositions (hereinafter referred to as "Formulations" or "Compositions") described herein or administered to subjects, comprising treprostinil and / or its prodrugs, esters, derivatives, and / or pharmaceutically acceptable salts thereof, may, in particular, be mixed with an acceptable carrier. The carrier may be compatible with any other components in the Formulation and may not be harmful to the subject. The carrier may be solid, liquid, or both. One or more of treprostinil or its derivatives, esters, prodrugs, or pharmaceutically acceptable salts thereof may be incorporated into the Formulations of the present invention. Suitable formulations for administration include those suitable for parenteral, oral, inhalation, rectal, topical, buccal, and transdermal administration.

[0075] Compositions administered parenterally may be isotonic with the blood of the intended recipient. They can be administered by subcutaneous, intravenous, intramuscular, or intradermal injection. Such formulations can be conveniently prepared by mixing the compound with water or glycine or citrate buffer, sterilizing the resulting solution, and making it isotonic with blood.

[0076] Formulations suitable for oral administration may be provided as capsules, cachets, lozenges or tablets, as powders or granules, as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, each containing a specific amount of treprostinil or its derivatives, prodrugs, esters, or pharmaceutically acceptable salts thereof. Examples of orally administered formulations include those described in U.S. Patents No. 7,384,978 and No. 8,747,897 (including commercially available Orenitram® (treprostinil) sustained-release tablets), the entirety of which disclosures are incorporated herein by reference. Generally, formulations of the present invention are prepared by homogeneously and tightly mixing treprostinil, its esters, prodrugs, or salts with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.

[0077] Formulations suitable for buccal (sublingual) administration include lozenges containing treprostinil or its derivatives, prodrugs, esters, or pharmaceutically acceptable salts thereof in a flavor base, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0078] Formulations suitable for rectal administration are preferably provided as unit-dose suppositories. These can be prepared by mixing treprostinil or its derivatives, prodrugs, esters, or pharmaceutically acceptable salts thereof with one or more solid carriers.

[0079] Topical and transdermal preparations may be ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Possible carriers include petrolatum, lanolin, polyethylene glycol, alcohol, and combinations thereof.

[0080] Treprostinyl, its prodrugs, esters, and salts are conveniently prepared by the same or similar methods as described in U.S. Patents No. 4,306,075, No. 6,528,688, and No. 6,441,245, and their disclosures are incorporated herein by reference.

[0081] In some embodiments of this method, the administered treprostinil is provided as a kit with instructions for use in the treatment of ILD. In certain kit embodiments, treprostinil or its derivatives, prodrugs, esters, or pharmaceutically acceptable salts thereof are in a form suitable for subcutaneous administration, serial subcutaneous infusion, intravenous administration, or inhalation. The subcutaneous formulation administered to the subject may include any of those described in U.S. Patent No. 7,999,007 (including the commercially available product Remodulin® (treprostinil) injection), the full disclosure of which is incorporated herein by reference. In other kit embodiments, treprostinil or its derivatives, or pharmaceutically acceptable salts thereof, are in an orally available form selected from the group consisting of tablets and capsules.

[0082] The efficacy of these methods against pulmonary fibrosis (PF) can be confirmed through animal models of PF, such as bleomycin and vanadium pentoxide (V2O5) models, as described in Bonner JC, Rice AB, Ingram JL, Moomaw CR, Nyska A, Bradbury A, Sessoms AR, Chulada PC, Morgan DL, Zeldin DC and Langenbach R, Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis, Am J Pathol 161: 459-470, 2002; 23; and Keerthisingam CB, Jenkins RG, Harrison NK, Hernandez-Rodriguez NA, Booth H, Laurent GJ, Hart SL, Foster ML and McAnulty RJ. Cyclooxygenase-2 deficiency leads to a loss of the antiproliferative response to transforming growth factor 31 beta in human fibrous lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. The entire text of Am J Pathol 158: 1411-1422, 2001 is incorporated herein by reference.

[0083] In preferred embodiments, treprostinil is administered by inhalation. Examples of inhalation compositions containing treprostinil include sprays, aerosols, and dry powder compositions. The compositions may contain a variety of excipients. The inhalable compositions administered may include any of those described in U.S. Patent No. 9,339,507 (including the commercially available product Tyvaso® (treprostinil) inhalation solution), WO2017192993, and WO2014085813, the entirety of which disclosures are incorporated herein by reference.

[0084] One or more excipients of the pharmaceutical composition according to the present invention may have a water solubility of more than 5 g / l, often more than 100 g / l. They are preferably selected from sugars, salts, or amino acids and have the dual function of minimizing the effect of the inhaled composition on the cellular outcome of the fluid. With respect to the composition in solid-dry form, the excipients also form a solid matrix in which treprostinil, its prodrug, ester, salt, or derivative is dispersed.

[0085] The composition may include, for example, excipients such as lactose and corn starch, flow promoters such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. Sweeteners and / or flavoring agents may be added if desired. Exemplary excipients, but not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO3), cremophor, carbohydrates, starches (e.g., corn starch), inorganic salts, antibacterial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium stearate or magnesium stearate), flow promoters such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, and combinations thereof. Other examples of soluble excipients that can be used in compositions according to the present invention include alitame, acesulfame potassium, aspartame, saccharin, sodium saccharin, sodium cyclamate, sucralose, trerose, xylitol, citric acid, tartaric acid, cyclodextrin, dextrin, hydroxyethylcellulose, gelatin, malic acid, maltitol, maltodextrin, maltose, polydextrose, tartaric acid, sodium bicarbonate or potassium bicarbonate, sodium chloride or potassium chloride, sodium citrate or Examples include potassium citrate, phospholipids, lactose, sucrose, glucose, fructose, mannitol, sorbitol, natural amino acids, alanine, glycine, serine, cysteine, phenylalanine, tyrosine, tryptophan, histidine, methionine, threonine, valine, isoleucine, leucine, arginine, lysine, aspartic acid, glutamic acid, asparagine, glutamine, proline, their salts, and possible simple chemical modifications thereof such as N-acetylcysteine ​​and carbocysteine.

[0086] Preferred soluble excipients include alkali metal salts such as sodium chloride or potassium chloride, and sugars such as lactose. Specific carbohydrate excipients include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, melegitose, maltodextrin, dextran, and starch; and algitols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, and myo-inositol.

[0087] As far as the hollow morphology of the dried powder particles is concerned, the composition requires the presence of a soluble excipient, preferably a sugar such as lactose, that can form a particle skeleton that generates highly porous particles during the preparation of the composition and at the start of the solvent evaporation stage during spray drying.

[0088] In some embodiments, the excipients include surfactants. The surfactant in the composition can be selected from various classes of surfactants for pharmaceutical applications.

[0089] Surfactants suitable for use in the present invention are generally all substances characterized by medium or low molecular weight, comprising a hydrophobic moiety that readily dissolves in organic solvents but is poorly soluble or insoluble in water, and a hydrophilic (or polar) moiety that is poorly soluble or insoluble in organic solvents but readily soluble in water. Surfactants are classified according to their polar moiety. Therefore, surfactants having a negatively charged polar moiety are called anionic surfactants, and cationic surfactants have a positively charged polar moiety. Uncharged surfactants are generally called nonionic, while surfactants that are both positively and negatively charged are called amphoteric. Examples of anionic surfactants are fatty acid salts (well-known as soaps), sulfates, sulfate ethers, and phosphate esters. Cationic surfactants are often based on polar groups containing amino groups. The most common nonionic surfactants are based on polar groups containing oligo(ethylene oxide) groups. Amphoteric surfactants are generally characterized by polar groups formed by quaternary amines and sulfate or carboxyl groups.

[0090] Specific examples of this application include the following surfactants: benzalkonium chloride, cetrimide, sodium docusate, glyceryl monolaurate, sorbitan esters, sodium lauryl sulfate, polysorbate, phospholipids, and bile salts.

[0091] Nonionic surfactants such as polysorbates and polyethylene and polyoxypropylene block copolymers, known as "poloxamers," can be used. Polysorbates are described in the CTFA International Cosmetic Ingredient Dictionary as mixtures of sorbitol and sorbitol anhydrous fatty acid esters condensed with ethylene oxide. Particularly preferred are nonionic surfactants of the series known as "Tween®," especially the surfactant polyoxyethylene sorbitan known as "Tween® 80." Additional exemplary excipients include other polysorbates, such as surfactants such as "Tween® 20," and Pluronic® (both available from BASF, Mount Olive, NJ), such as F68 and F88, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamine), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents such as EDTA, zinc, and other suitable cations.

[0092] The presence of a surfactant, preferably Tween® 80, may be necessary to reduce the static charge present in compositions where it is absent, and to maintain a uniform solid state without powder flow and initial crystallization. According to the present invention, phospholipids are included in the above-mentioned surfactant or excipient.

[0093] The inhaled formulation to be administered may contain a hydrophobic substance to reduce its sensitivity to humidity. Such a hydrophobic substance is preferably leucine, which facilitates the deaggregation of particles.

[0094] In the case of manufacturing solid products in powder form, this can be done using various techniques well established in the pharmaceutical industry. Preparation of fine particles by spray drying represents a preferred method according to the present invention. In the case of industrial production, this technique is undoubtedly preferred over freeze-drying. Freeze-drying is currently the most expensive drying process in terms of both the equipment used, yield, and production time.

[0095] The pharmaceutical composition according to the present invention may contain other components such as pH buffers and preservatives. Examples of buffers, though not limited to them, include citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, monobasic sodium phosphate, dibasic sodium phosphate, and combinations thereof.

[0096] Furthermore, the administered composition may optionally contain one or more acids or bases. Non-limiting examples of usable acids include those selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Non-limiting examples of suitable bases include those selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

[0097] Excipients may include antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0098] In relation to the compositions of the present invention, the term "dry powder" refers to compositions in the form of powder, granules, tablets, or any other solid form that has humidity to ensure the chemical stability of the composition over time. More precisely, the term "dry" refers to a solid composition with a water content of less than 10% w / w, usually less than 5%, and preferably less than 3%.

[0099] The amount of any excipient in the dry powder composition of the present invention can vary over a wide range. The amount of any individual excipient in the composition varies depending on the role of the excipient, the dosage requirements of the active ingredient, and the specific needs of the composition. However, generally, the excipient is present in the composition in an amount of about 1% to about 99% by mass, preferably about 5% to about 98% by mass, and more preferably about 15% to about 95% by mass. Generally, the amount of excipient present in the composition of the present disclosure is selected from: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by mass.

[0100] The treprostinil composition to be administered may be provided as a kit comprising a metered-dose inhaler containing a pharmaceutical composition comprising treprostinil or its derivatives, esters, prodrugs, or pharmaceutically acceptable salts thereof. Such a kit may further include instructions on how to use the metered-dose inhaler for inhaling treprostinil. Such instructions may include, for example, information on how to regulate the patient's respiration and how to operate the inhaler. The kit can be used by subjects such as humans suffering from interstitial lung disease (ILD) that can be treated with treprostinil. In some cases, the kit is a kit for treating ILD and includes (i) a metered-dose inhaler containing a pharmaceutical composition comprising treprostinil or its derivatives, esters, prodrugs, or pharmaceutically acceptable salts thereof, and (ii) instructions for the use of the metered-dose inhaler containing treprostinil in the treatment of pulmonary hypertension.

[0101] This disclosure also provides a method for treating pulmonary hypertension resulting from a condition selected from chronic lung disease and / or hypoxia (low oxygen levels), comprising administering an effective amount of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its prodrug to a subject such as a human with such pulmonary hypertension. Pulmonary hypertension due to chronic lung disease and / or hypoxia belongs to Group 3 pulmonary hypertension according to the World Health Organization (WHO) classification.

[0102] Chronic lung diseases include obstructive lung diseases such as chronic obstructive pulmonary disease (COPD) and emphysema, which narrow the airways in the lungs and make it difficult to exhale; restrictive lung diseases such as interstitial lung disease or pulmonary fibrosis, which cause difficulty in lung expansion during inhalation; sleep apnea; prolonged residence in high-altitude areas; and various combinations of the above conditions.

[0103] In some embodiments, chronic lung diseases include idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis (e.g., respiratory bronchiolitis associated with interstitial lung disease), desquamative interstitial pneumonia, acute interstitial pneumonia, chronic hypersensitivity pneumonitis, occupational lung disease, pulmonary fibrosis, emphysema, connective tissue disease, or any combination of the above conditions.

[0104] In some embodiments, administration of an effective amount of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its prodrug can result in an increase in the 6-minute walk distance (6MWD) value, i.e., the 6MWD value before administration, in subjects with pulmonary hypertension resulting from a condition selected from chronic lung disease and / or hypoxia, and such increase may be statistically significant. For example, the 6MWD value may be statistically significantly increased at least 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks, or 20 weeks, or 24 weeks, or 28 weeks, or 32 weeks, or 36 weeks, or 40 weeks, or 44 weeks, or 48 weeks, or 52 weeks after administration. In some embodiments, the administration can result in an increase of at least 5m, at least 10m, or at least 15m of 6MWD compared to the baseline 6MWD value at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks after administration. In some embodiments, the administration can result in an increase of at least 5m, at least 10m, at least 15m, at least 18m, or at least 20m of 6MWD compared to the baseline 6MWD value at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks after administration.

[0105] In some embodiments, administration of an effective amount of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its prodrug can reduce the plasma concentration of NT-proBNP in subjects with pulmonary hypertension resulting from a condition selected from chronic lung disease and / or hypoxia, compared to baseline NT-proBNP plasma concentration, i.e., the NT-proBNP plasma concentration before administration, and the reduction can be statistically significant. For example, NT-proBNP plasma concentrations may decrease statistically significantly at least 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after administration. In some embodiments, the administration can result in a decrease of at least 50 pg / ml, at least 100 pg / ml, at least 150 pg / ml, at least 200 pg / ml, at least 250 pg / ml, at least 300 pg / ml, or at least 350 pg / ml in NT-proBNP plasma concentration compared to baseline NT-proBNP plasma concentration at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks after administration.

[0106] In some embodiments, administration of an effective amount of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its prodrug to subjects with pulmonary hypertension due to chronic lung disease may result in a reduction of some exacerbations of the chronic lung disease, and such reduction may be statistically significant. For example, certain exacerbations of chronic lung disease may be reduced in a subgroup of patients with pulmonary hypertension due to chronic lung disease who were administered an effective dose of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks, compared to a subgroup of patients with the same condition who were administered a placebo instead of treprostinil. For example, certain exacerbations may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%. Exacerbations may include acute, clinically significant respiratory deterioration characterized by new, widespread evidence of alveolar abnormalities.

[0107] In some embodiments, administration of an effective amount of treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug to subjects with chronic lung disease and / or pulmonary hypertension due to hypoxia can result in a reduction of several clinical exacerbation events, the reduction being statistically significant. For example, in a subgroup of patients with pulmonary hypertension due to chronic lung disease and / or hypoxia, administered an effective dose of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 14 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks, several clinical exacerbation events may be reduced compared to a subgroup of patients with the same condition who were administered placebo instead of treprostinil. For example, several clinical exacerbation events may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%. Clinical deterioration events may include one or more of the following: hospitalization due to cardiopulmonary indication, a decrease in 6MWD of more than 15% from baseline, death, or lung transplantation.

[0108] In some embodiments, administration of an effective amount of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its prodrug may result in an improvement in forced vital capacity (FVC) in subjects with pulmonary hypertension resulting from a condition selected from chronic lung disease and / or hypoxia, and such improvement may be statistically significant. For example, FVC may be higher in a subgroup of patients with pulmonary hypertension due to chronic lung disease and / or hypoxia who received a placebo instead of treprostinil when administered an effective dose of treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks. For example, in a subgroup of patients with pulmonary hypertension due to chronic lung disease and / or hypoxia, FVC levels may increase by at least 10 ml, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 weeks after administration, compared to a subgroup of patients with the same condition who received placebo instead of treprostinil. In patients with chronic lung disease and / or hypoxia, such as interstitial lung disease, FVC levels usually decrease over time if left untreated.Therefore, administration of an effective dose of treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt can increase the FVC value compared to the pre-administration FVC value, maintain the FVC value within 5%, 10%, or 20% of the pre-administration FVC value, or reduce the decrease in FVC value over time that would occur if an effective dose of treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt were not administered, compared to such a decrease in FVC when a placebo is administered instead of treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt.

[0109] In some embodiments, treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug may be administered by inhalation, which may be, for example, oral inhalation or nasal inhalation. In some embodiments, treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug may be administered by an inhalation device, which may be, for example, a pulse inhalation device such as a metered-dose inhaler and / or pulse nebulizer. Pulse inhalation devices are disclosed, for example, in U.S. Patent Application Publication No. 20080200449, U.S. Patent No. 9,358,240, U.S. Patent No. 9,339,507, U.S. Patent No. 10,376,525 and U.S. Patent No. 10,716,793, each of which is incorporated herein by reference in its entirety.

[0110] In some embodiments, inhalation devices, such as pulse inhalation devices, may include solutions or suspensions containing treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. For example, such solutions or suspensions may be used for aerosolization or atomization by inhalation devices, such as nebulizers and / or metered-dose inhalers. One example of a solution may be the commercially available product Tyvaso®. The concentration of treprostinil in such solutions can vary. In some embodiments, the treprostinil concentration may be 200 μg / ml to 2000 μg / ml, or 300 μg / ml to 1500 μg / ml, or 400 μg / ml to 1200 μg / ml, or any value or sub-range within these ranges. For example, in certain embodiments, the treprostinil concentration may be 600 μg / ml.

[0111] In some embodiments, the inhalation device, such as a pulse inhalation device, may be a dry powder inhaler that can contain a dry powder composition or formulation comprising treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. For example, a dry powder inhaler and a dry powder composition or formulation comprising treprostinil are disclosed in WO2019 / 237028, which is incorporated herein by reference in its entirety. In some embodiments, in addition to treprostinil, its prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the dry powder composition may further contain (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP).

[0112] Treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug may be administered by inhalation in a single administration event, which may involve a limited number of breaths (or inhalations) by the subject. For example, in some embodiments, the number of breaths in a single administration event may not exceed 20 breaths (or inhalations), 19 breaths (or inhalations), 18 breaths (or inhalations), 17 breaths (or inhalations), 16 breaths (or inhalations), 15 breaths (or inhalations), 14 breaths (or inhalations), 13 breaths (or inhalations), 12 breaths (or inhalations), 11 breaths (or inhalations), 10 breaths (or inhalations), 9 breaths (or breaths (or inhalations) inhalations), 8 breaths (or inhalations), 7 breaths (or inhalations), 6 breaths (or inhalations), 5 breaths (or inhalations), 4 breaths (or inhalations), 3 breaths (or inhalations), 2 breaths (or inhalations), or 1 breath (or inhalation).

[0113] The dose of treprostinil, its prodrug, its pharmaceutically acceptable salt, or its prodrug administered by inhalation in a single dose event can vary. In some embodiments, the single-dose event dose can be 7.5 μg to 100 μg, or 10 μg to 100 μg, or 15 μg to 100 μg, 15 μg to 90 μg, or 15 μg to 75 μg, or 30 μg to 75 μg, or any value or sub-range within these ranges.

[0114] The number of single-dose events per day for administering treprostinil, its prodrug, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its prodrug by inhalation can vary. For example, the number of single-dose events per day can be 1, 2, 3, 4, 5, or 6.

[0115] The table below shows exemplary doses of treprostinil in dry powder formulations usable with dry powder inhalers, and how they compare to the dose of treprostinil in Tyvaso® inhalation solution.

[0116] [Table 1]

[0117] All disclosures of the publications cited above are expressly incorporated herein by reference in their entirety, just as each is incorporated by reference individually.

[0118] The examples described herein are illustrative of the present invention and are not intended to limit it. Different embodiments of the present invention have been described in accordance with the present invention. Many modifications and variations can be made to the techniques described and illustrated herein without departing from the spirit and scope of the present invention. Therefore, it should be understood that the examples are merely illustrative and do not limit the scope of the present invention. [Examples]

[0119] Example 1: Results of inhaled treprostinil on underlying pulmonary diseases Exacerbation of underlying pulmonary disease is defined as an acute, clinically significant respiratory deterioration characterized by new, widespread evidence of alveolar abnormalities (Collard et al., 2016). This example demonstrates that treatment with inhaled treprostinil significantly reduced exacerbation of the patient's underlying pulmonary disease.

[0120] Participants with underlying pulmonary disease were treated with inhaled treprostinil for 16 weeks. Participants began inhaling either treprostinil or placebo four times daily, in three breaths (18 mcg) (during waking hours). The study drug dose was maximized throughout the study. Dose escalation (one additional breath four times daily) could be performed up to every three days, to a target dose regimen of nine breaths four times daily (54 mcg) and a maximum dose of twelve breaths four times daily (72 mcg), as long as it was clinically acceptable. Participants were evaluated during screening and baseline to determine their eligibility for the study. If eligible, five treatment-phase visits were required at weeks 4, 8, 12, 15, and 16 (final study visit). Early termination (ET) visits were conducted for participants who discontinued treatment before week 16. Where applicable, all evaluations planned for the final week 16 visit were performed during the ET visit. Participants were contacted at least once a week by telephone or email to assess their tolerance to changes in the investigational drug, adverse events (AEs), and concomitant medications.

[0121] Efficacy evaluation consisted of 6MWD, plasma NT-proBNP concentration, and time to clinical worsening. Exploratory endpoints included SGRQ, changes in DSP, time to exacerbation of underlying disease, and pulmonary function tests. Safety evaluation consisted of incidence of AEs, vital signs, clinical laboratory parameters, ECG parameters, hospitalization due to cardiopulmonary disease indications, exacerbation of underlying pulmonary disease, and oxygen load.

[0122] Treatment significantly reduced the incidence of underlying disease exacerbations during the 16-week treatment period (26.4% in the treprostinil inhalation group vs. 38.7% in the placebo group, p=0.018), and reduced the risk of underlying disease exacerbations (hazard ratio 0.66, i.e., a 34% reduction in risk), as shown in Figure 1.

[0123] Furthermore, the following FVC-indicating data were obtained from this study. The overall results from the treatment intention group among patients treated with inhaled treprostinil were as follows:

[0124] Overall ITT FVC was 28.47 mL and 44.40 mL in weeks 8 and 16. % predicted FVC in week 8 (1.79%, p=0.0139) and week 16 (1.80%, p=0.0277) Subset IIP Ethology: 46.48 mL and 108.18 mL in weeks 8 and 16 (p=0.0229) % predicted FVC in week 8 (1.95%, p=0.0373) and week 16 (2.88%, p=0.0096) Subset IPF Ethology: 84.52 mL and 168.52 mL in weeks 8 and 16 (p=0.0108) % predicted FVC in week 8 (2.54%, p=0.0380) and week 16 (3.50%, p=0.0147) Nintedanib: Approximately 109 mL at week 52 of IPF (predicted 3.2%) Pirfenidone: Approximately 153-193 mL at week 52 of IPF

[0125] Placebo-corrected, rate of decrease (not improvement) Compared to the known treatments for ILD shown above (nintedanib and pirfenidone), inhaled treprostinil achieves comparable efficacy with a shorter treatment duration.

[0126] Pulmonary function tests were performed first as part of the safety assessment during the study (safety population). The results showed that most PFT parameters remained stable in the study subjects, but a significant improvement in FVC (% predicted) was observed in the inhaled treprostinil group at week 16 (median improvement of 1.0% compared to a 1.0% decrease in the placebo group). As a result, a post-hoc MMRM analysis of FVC data was performed on the ITT population, and the results are shown in Table 1 (ITT population), Table 2 (pH ILD etiology of IIP), and Table 3 (for subjects with IPF).

[0127] [Table 2]

[0128] [Table 3]

[0129] [Table 4]

[0130] Treatment with inhaled treprostinil resulted in improvements of 28.47 mL and 44.40 mL in FVC at weeks 8 and 16, respectively. These improvements were statistically significant when expressed as % predicted FVC at week 8 (1.79%, p=0.0139) and week 16 (1.80%, p=0.0277).

[0131] When FVC was analyzed by pH-ILD etiology of IIP, treatment with inhaled treprostinil resulted in improvements of 46.48 mL and 108.18 mL compared to placebo at weeks 8 and 16, respectively (p=0.0229). The group difference in % predicted FVC was statistically significant at week 8 (1.95%, p=0.0373) and week 16 (2.88%, p=0.0096).

[0132] Further analysis of FVC in subjects with IPF etiology (using only IIP subjects from the ITT population) showed that treatment with inhaled treprostinil resulted in improvements of 84.52 mL and 168.52 mL compared to placebo at weeks 8 and 16, respectively (p=0.0108). The group difference in % predicted FVC was statistically significant at week 8 (2.54%, p=0.0380) and week 16 (3.50%, p=0.0147).

[0133] Example 2 The following predictive case evaluates the efficacy of treprostinil in the treatment of chronic fibrous interstitial lung disease (CF-ILD), including IPF, chronic hypersensitivity pneumonitis (CHP), and idiopathic interstitial lung disease (IIP), including environmental / occupational fibrous lung disease.

[0134] Patients may be treated with inhaled treprostinil for up to 15 respiratory QIDs based on tolerance. The primary efficacy endpoint is evaluated as the change in FVC (absolute or % predicted) from baseline to week 24 of treatment. Parameters that may be evaluated include time to exacerbation of underlying lung disease, 6-meter walk distance test (6MWD), all-cause mortality / survival rate, time to death, additional analysis of FVC (e.g., absolute and relative changes), change in SpO2 from baseline, pulmonary diffusion capacity to carbon monoxide (DLCO), NT-proBNP, and King's Brief Interstitial Lung Disease Questionnaire.

[0135] References 1.Collard et al., American Journal of Respiratory and Critical Care Medicine, Volume 194 Number 3, pg. 265. 2. Meyer et al., (2017-04-03). Therapeutics and Clinical Risk Management. 13: 427-437.

[0136] Example 3: Inhalation of treprostinil in pulmonary hypertension due to interstitial lung disease

[0137] Currently, there are no approved treatments for pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil in patients with this condition are unknown.

[0138] method We enrolled patients with interstitial lung disease and pulmonary hypertension (as demonstrated by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive either inhaled treprostinil administered via an ultrasonic pulsed delivery nebulizer at a maximum of 12 breaths four times daily (72 μg total) or placebo. The primary efficacy endpoint was the difference between the two treatment groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary endpoints included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at week 16 and at clinical exacerbation.

[0139] result A total of 326 patients were randomized, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least squares mean difference in the change from baseline in 6-minute walk distance between the treprostinil and placebo groups was 31.12 m (95% confidence interval [CI], 16.85–45.39, P<0.001). NT-proBNP levels increased 46% in the placebo group compared to a 15% decrease in the inhaled treprostinil group (treatment ratio 0.58, 95% CI 0.47–0.72, P<0.001). Clinical exacerbations occurred in 37 patients (22.7%) in the treprostinil group compared to 54 patients (33.1%) in the placebo group (hazard ratio, 0.61, 95% CI, 0.40–0.92, P=0.04 by log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea.

[0140] conclusion In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline compared to placebo, as assessed using a 6-minute walk test.

[0141] Precapillary pulmonary hypertension is defined as elevated mean pulmonary artery pressure and pulmonary vascular resistance.1 In the World Health Organization (WHO) classification of pulmonary hypertension, precapillary pulmonary hypertension caused by lung disease is classified as Group 3. The most common lung diseases associated with Group 3 pulmonary hypertension are chronic obstructive pulmonary disease and interstitial lung disease.

[0142] Pulmonary hypertension is reported in up to 86% of patients with interstitial lung disease and is associated with reduced exercise capacity, increased need for oxygen supplementation, decreased quality of life, and premature death.2–4 Despite the global prevalence of pulmonary hypertension due to interstitial lung disease and its inadequate clinical course, there are currently no approved treatments for these patients. Although data are limited, approved treatments for pulmonary hypertension in group 1 (pulmonary arterial hypertension) are being used to treat pulmonary hypertension in group 3.5 Previous studies of vasodilator therapy have shown conflicting results. The largest trial to date evaluated the soluble guanylate cyclase stimulant riociguat in a patient population with pulmonary hypertension in group 3 and was discontinued early due to significant harm.6

[0143] Treprostinil is a stable analog of prostacyclin that promotes direct vasodilation of the pulmonary and systemic arterial vascular beds and inhibits platelet aggregation.7 Inhaled treprostinil formulations have previously been shown to improve exercise capacity after 12 weeks of treatment in patients with pulmonary hypertension in group 1.8 Data from a previously completed pilot study suggest that inhaled treprostinil may improve hemodynamic and functional capacity in patients with pulmonary hypertension in group 3.9-12 Therefore, the objective of the INCREASE trial was to evaluate the safety and efficacy of inhaled treprostinil in patients with hypertension due to interstitial lung disease.

[0144] Test design and supervision INCREASE was a multicenter, randomized, double-blind, placebo-controlled trial. It was monitored by an independent data and safety monitoring committee and conducted in accordance with the guidelines for best practice clinical trials.

[0145] Test group The study population consisted of patients aged 18 years or older diagnosed with interstitial lung disease based on evidence of diffuse parenchymal lung disease by computed tomography (not centrally determined) of the chest performed within 6 months prior to randomization. Confirmation of group 3 pulmonary hypertension by right heart catheterization was required within 1 year prior to randomization. Group 3 pulmonary hypertension was defined by pulmonary vascular resistance greater than 3 Wood units, pulmonary capillary wedge pressure less than 15 mmHg, and mean pulmonary artery pressure greater than 25 mmHg. Patients with group 3 pulmonary hypertension due to connective tissue disease also needed to have a baseline forced vital capacity less than 70%. Eligible patients also needed to walk at least 100m during the 6-minute walk test. Patients receiving drug therapy for underlying lung disease (i.e., pirfenidone or nintedanib) needed to have received a stable dose for at least 30 days prior to randomization. Patients who had received approved treatment for pulmonary arterial hypertension within 60 days prior to randomization were ineligible for enrollment. Written informed consent was obtained from all patients.

[0146] [Table 5]

[0147] Test Procedure Within 30 days of screening, eligible patients were randomly assigned in a 1:1 ratio to receive either inhaled treprostinil (Tyvaso, United Therapeutics) or placebo in a double-blind manner. Randomization based on sorted blocks was stratified by baseline 6-minute walk distance (≤350m vs >350m) and conducted via an interactive web response system.

[0148] Inhaled treprostinil (0.6 mg per milliliter) was administered at a rate of 6 μg per breath using an ultrasound-guided pulsed delivery nebulizer. Placebo was administered similarly as a visually identical solution. The initial dose of the investigational drug (3 breaths) was administered in the clinic, followed by an observation period of at least 1 hour. The doses of treprostinil or placebo were adjusted, and dose escalations (one additional breath per day, four times daily) were performed every 3 days, with a target dose of 9 breaths per day, four times daily, and a maximum dose of 12 breaths per day. Researchers adjusted the doses on an individual patient basis to achieve the maximum tolerated dose leading to functional improvement.

[0149] Test evaluation A 6-minute walk test was performed, and laboratory data were collected at baseline, weeks 4, 8, 12, and 16, or at early discontinuation of treprostinil or placebo. Each 6-minute walk test was performed 10–60 minutes after the most recent dose of the active drug or placebo, which is the peak time for plasma treprostinil exposure. Trough tests were performed at week 15, at least 4 hours after participants received their dose of treprostinil or placebo, and at week 16, at least 24 hours prior to the test. Pulse oximetry was performed immediately before, during, and after each 6-minute walk test. Measurement of N-terminal pro-B natriuretic peptide (NT-proBNP) levels and pulmonary function tests were performed at baseline and at weeks 8 and 16 (or at early discontinuation) after patients had recovered from the 6-minute walk test. The St. George's Respiratory Questionnaire (SGRQ), a measure of quality of life, was completed at baseline and at week 16 or early discontinuation.

[0150] Measurement of results The primary endpoint of the trial was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary efficacy endpoints were analyzed using the following hierarchical trial procedure: change in NT-proBNP from baseline to week 16, time to clinical deterioration, change in 6-minute walk distance at peak plasma treprostinil levels at week 12, and change in 6-minute walk distance at traftreprostinil levels at week 15. Time to clinical deterioration was assessed from the time of randomization until the patient withdrew from the trial and was defined as the time until any of the following events occurred: hospitalization for cardiopulmonary symptoms, a greater than 15% decrease in 6-minute walk distance from baseline directly related to the disease under study, in two consecutive hospital visits at least 24 hours apart, death from any cause, or lung transplantation.

[0151] The exploration endpoints were the change in peak 6-minute walk distance between week 4 and week 8, quality of life as measured using the SGRQ at week 16, and the product of distance and saturation at week 16 (calculated by multiplying the total walking distance during the 6-minute walk by the lowest oxygen saturation measurement). The safety endpoint included exacerbations of underlying pulmonary conditions reported by researchers, defined as adverse events, abnormal clinical laboratory findings, oxygen load and supplemental oxygen demand as measured by pulse oximetry (SpO2), changes in pulmonary function test results, hospitalization for cardiopulmonary symptoms, and acute clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormalities.

[0152] statistical analysis Initial estimates suggested that if 266 patients were randomly assigned in a 1:1 ratio to receive either inhaled treprostinil or placebo, the trial would have at least 90% power at a significance level of 0.05 (two-sided), and assuming a standard deviation of 75m, it would detect a 30m difference between groups in the change in peak 6-minute walk distance from baseline at week 16. To compensate for the approximately 15% of participants who discontinued the trial, 314 patients would need to be enrolled.

[0153] In the primary efficacy analysis, missing data were assumed to be randomly missing, and the change in 6-minute walk distance was analyzed using a mixed-model repeated measures method. This model included baseline 6-minute walk distance as a covariate, with the change from baseline to peak 6-minute walk distance as the dependent variable, and treatment, weekly, and treatment-by-treatment interactions as fixed effects. Sensitivity analysis of the primary endpoint was performed using a multiple imputation approach with a multivariate normal imputation model using Markov chain Monte Carlo. The imputation model included treatment group, all scheduled visits, patient sex, and patient age at randomization. If the primary efficacy endpoint result was significant, the secondary efficacy endpoint was evaluated according to a hierarchical study procedure. Confidence intervals were not adjusted for multiplicity and cannot be used to predict the definitive treatment effect of the secondary efficacy endpoint.

[0154] result

[0155] patient Of the 462 patients screened for eligibility, 326 were enrolled in 93 centers and randomly assigned to receive either placebo (163 patients) or inhaled treprostinil (163 patients) (Figure 2). Baseline characteristics were similar in the two groups (Table 4). The mean age of the patients was 66.5 years, 46.9% were female, and the most common diagnosis was idiopathic interstitial pneumonia (44.8%). At baseline, the mean 6-minute walk distance was 259.6 m, the mean pulmonary vascular resistance was 6.2 Wood units, and the mean NT-proBNP level was 1832.9 pg / ml.

[0156] Exposure and follow-up Patients in the treprostinil group received a median of 11 inhalations (66 μg) per session, four times daily, at week 12, and 12 inhalations (72 μg) per session at week 16. The percentage of patients in this group receiving 10–12 inhalations (60–72 μg) per session was 57.0% at week 12 and 57.8% at week 16. Patients in the placebo group received a median of 12 inhalations per session at weeks 12 and 16.

[0157] Of the 40 patients (24.5%) assigned to receive inhaled treprostinil and the 38 patients (23.3%) assigned to placebo, early discontinuation of the assigned regimen occurred. These patients were encouraged to remain in the trial and complete the evaluation by week 16, and 33 patients in the treprostinil group and 35 patients in the placebo group discontinued participation in the trial. The reasons for discontinuation are shown in Figure 2.

[0158] Primary terminus Figure 2 shows the mean change in 6-minute walk distance within the groups. Mixed model repeated measures analysis showed that the least squares mean difference in the change from baseline in peak 6-minute walk distance between the treprostinil and placebo groups was 31.12 m (95% confidence interval [CI], 16.85–45.39, P<0.001) (Table 5 and Figure 4). Similar effects were observed across subgroups, including those defined by disease cause and severity (measured by baseline 6-minute walk distance), baseline hemodynamics, and treatment group (Figure 5). Furthermore, when analyzed by multiple imputation using Markov chain Monte Carlo, the between-group difference in the change from baseline in peak 6-minute walk distance at week 16 was significant (30.97 m, 95% CI, 16.53–45.41, 95% CI, 16.53–45.41, P<0.001) (Figure 6).

[0159] [Table 6]

[0160] *Unless otherwise specified, plus or minus values ​​represent the mean ± SE. For secondary endpoints, confidence intervals (CI) are not adjusted for multiplicity and cannot be used to predict definitive therapeutic effects. NT-proBNP represents the N-terminal pro-B type natriuretic peptide. †The effect of inhaled treprostinil on the change in 6-minute walk distance compared to placebo was evaluated using a mixed model repeated measures with the change from baseline in peak 6-minute walk distance as the dependent variable, treatment, week, and treatment-specific interactions as fixed effects, baseline 6-minute walk distance as a covariate, and subjects as a random effect. The results are shown in Figures S1 and S3. ‡This is the difference in the least squares mean between the groups. The effect of inhaled treprostinil compared to placebo on log-transformed NT-proBNP changes was assessed using a mixed model repeated measures with log-transformed NT-proBNP change from baseline as the dependent variable, treatment, week-by-week, and treatment-by-treatment interactions as fixed effects, and log-transformed baseline NT-proBNP as the covariate. The ratio to baseline is the least squares mean of the change from baseline in the log-transformed data. Changes in plasma NT-proBNP concentrations from baseline up to week 16 were evaluated in 156 patients in the treprostinil group and 160 patients in the placebo group. This is the treatment ratio, which is the ratio of the proportions between two treatment groups. **This is a hazard ratio calculated from a Cox proportional hazards model. P-values ​​were calculated using a log-rank test stratified by baseline 6-minute walk distance category.** ††The p-value was obtained from 100 multiple imputations using Markov chain Monte Carlo estimation with analysis of covariance (ANCOVA) modeling, with the change from baseline in peak 6-minute walk distance as the dependent variable, treatment as a fixed effect, and baseline 6-minute walk distance as the covariate.

[0161] Secondary and search endpoint Patients assigned to inhaled treprostinil showed significant improvement at each secondary endpoint compared to patients assigned to placebo (Table 5). NT-proBNP levels, assessed by the least squares mean of log-transformed ratios to baseline levels at week 16, decreased 15% from baseline in the inhaled treprostinil group and increased 46% from baseline in the placebo group (treatment ratio, 0.58, 95% CI, 0.47–0.72, P<0.001) (Figure 7). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group compared to 54 patients (33.1%) in the placebo group (hazard ratio, 0.61, 95% CI, 0.40–0.92, P=0.04 by log-rank test) (Figure 1). The least-squares mean change in peak 6-minute walk distance from baseline up to week 12 was 31.29 m greater in the treprostinil group than in the placebo group (P<0.001), and the change in trough 6-minute walk distance from baseline up to week 15 was 21.99 m greater in the treprostinil group (P=0.004). There were no significant differences between the groups in patient-reported quality of life as assessed by the SGRQ, or in the product of distance and saturation at week 16.

[0162] Safe Terminus [Table 7]

[0163] *The p-value was calculated using Fisher's exact test. ‡The most frequently occurring adverse events, occurring in 10% or more of patients in either group of the safety population, are shown. This includes all patients who were randomized and received at least one dose of treprostinil or placebo.

[0164] The most frequently reported adverse events were cough, headache, shortness of breath, dizziness, nausea, fatigue, and diarrhea (Table 6). Most of these events were mild to moderate in severity.

[0165] Serious adverse events occurred in 23.3% of patients who received inhaled treprostinil and in 25.8% of patients who received placebo. Serious adverse events were not reported significantly more frequently in the treprostinil group than in the placebo group.

[0166] Patients in the treprostinil group experienced significantly fewer exacerbations of underlying pulmonary disease than those in the placebo group (43 [26.4%] vs 63 [38.7%], P=0.02, Fisher's direct test). Patients in the treprostinil group had fewer initial clinical exacerbations requiring hospitalization for cardiopulmonary symptoms than those in the placebo group (18 [11.0%] vs 24 [14.7%], P=0.41). Inhaled treprostinil did not adversely affect test variables of pulmonary function during the study. There were no significant treatment-related changes in pulse oximetry or supplemental oxygen use in either group during the study period.

[0167] Consideration Pulmonary hypertension often complicates the treatment of patients with interstitial lung disease, associated with worsening functional status, increased need for oxygen supplementation, and poorer outcomes.3,13 In the INCREASE trial, patients treated with inhaled treprostinil showed significant improvement in exercise capacity, as evidenced by changes in 6-minute walk distance. Treatment with inhaled treprostinil was associated with a lower risk of clinical worsening compared to patients receiving placebo, decreased NT-proBNP levels over a 16-week treatment period, and less worsening of underlying lung disease. The safety profile of inhaled treprostinil observed in this vulnerable patient population was similar to that reported in previous studies. The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. Use of inhaled treprostinil was not associated with decreased lung function.

[0168] Patients with group 3 pulmonary hypertension are often treated with systemic pulmonary vasodilators, which are currently approved only for the treatment of group 1 pulmonary hypertension. However, there are concerns that such drugs may worsen the ventilation-perfusion matching in patients with group 3 pulmonary hypertension. Inhaled agents have the advantage of preferentially redirecting blood flow to the most ventilation-perfused lung units, reducing the risk of ventilation-perfusion mismatching.9,14 Indeed, previous studies of inhaled treprostinil in patients with group 3 pulmonary hypertension have shown that such patients experience improvements in functional class and 6-minute walk distance without adverse effects on peripheral oxygen saturation, reinforcing the idea that ventilation-perfusion matching does not change or improves with inhaled treprostinil.10 Similarly, in the current trial, we found no evidence of worsening oxygen load. This further alleviates concerns about ventilation-perfusion mismatching.

[0169] The INCREASE trial was not without its limitations. The trial period was short, and 21% of patients discontinued the trial early (before week 16). Furthermore, events of clinical exacerbation and worsening of underlying pulmonary disease were reported by the researchers and were not adjudicated by an independent review board. Finally, the magnitude of the favorable therapeutic effect of inhaled treprostinil on 6-minute walk distance is similar to the estimated clinically significant minimum difference in this trial in patients with pulmonary disease (21.7–37m in Nathan et al.'s study and 24–45m in du Bois et al.'s study)15,16.

[0170] This study demonstrated that in patients with pulmonary hypertension due to interstitial lung disease, treatment with inhaled treprostinil improved exercise capacity, as indicated by an improvement in 6-minute walk distance by the end of a 16-week treatment period. Furthermore, treatment with inhaled treprostinil was associated with a lower risk of clinical worsening, reduced NT-proBNP levels, and less exacerbation of underlying lung disease compared to placebo treatment.

[0171] Supplementary Information [Table 8]

[0172] DLCO, lung diffusion capacity, FEV1, forced expiratory volume in one second, FVC, forced vital capacity, NT-proBNP, N-terminal pro-brain natriuretic peptide, TLC, total vital capacity *N=156 Inhaled treprostinil, N=160 Placebo

[0173] Table 8. St. George's Respiratory Questionnaire Results The St. George's Respiratory Questionnaire has a score range of 0 to 100, with higher scores indicating greater impairment, and the smallest clinically significant difference being 4 points.

[0174] [Table 9]

[0175] ANCOVA, analysis of covariance, CI, confidence interval, LS, mean, least squares mean, SD, standard deviation, SE, standard error

[0176] Changes from baseline in the total score and each of the three domain scores were analyzed by parametric ANCOVA without imputation of missing data.

[0177] The confidence intervals are not adjusted for multiplicity and cannot be used to predict definitive treatment effects.

[0178] [Table 10]

[0179] ANCOVA, analysis of covariance, CI, confidence interval, LS mean, least squares mean, SD, standard deviation, SE, standard error, SpO2, peripheral capillary oxygen load saturation

[0180] The change in the distance-saturation product is the product of the walking distance and minimum SpO2 recorded during the 6-minute walk test.7 The change from baseline in the distance-saturation product up to week 16 was analyzed by parametric ANCOVA without substituting missing values ​​for the distance-saturation product.

[0181] The confidence intervals are not adjusted for multiplicity and cannot be used to predict definitive treatment effects.

[0182] [Table 11-1] [Table 11-2]

[0183] [Table 12-1] [Table 12-2]

[0184] CI, confidence interval, DLCO, lung diffusion capacity for carbon monoxide, FEV1, forced expiratory volume in one second, FVC, forced vital capacity, TLC, total vital capacity, LS mean, least squares mean, SE, standard error, TLC, total vital capacity

[0185] The mean LS (SE), P-value, estimated difference (SE), and associated 95% CI are from a mixed model repeated measures, with the dependent variable being the change from baseline in pulmonary function test parameters, the fixed effects being treatment, week, and weekly treatment interaction, the covariate being baseline measurement, and the random effect being subject. Within-subject error was modeled using an unstructured variance / covariance structure shared between treatment groups.

[0186] Confidence intervals and p-values ​​are not adjusted for multiplicity and cannot be used to predict definitive treatment effects.

[0187] [Table 13]

[0188] SD, standard deviation, SpO2, peripheral capillary oxygen load saturation *The p-value is calculated from an analysis of covariance with the change from before walking as the dependent variable, treatment as a fixed effect, and baseline SpO2 as a covariate.

[0189] [Table 14]

[0190] Subjects that did not use oxygen supplementation were coded as 0 in the summary. Subjects who received oxygen supplementation during the baseline 6-minute walk test continued to receive the same flow rate in all subsequent 6-minute walk test assessments. *The p-value is calculated from an analysis of covariance with the change from baseline as the dependent variable, treatment as a fixed effect, and baseline oxygen use as a covariate.

[0191] References 1.Simonneau G, et al Eur Respir J 2019;53: 1801913. 2.Nathan SD. Int J Clin Pract Suppl 2008;160:21-8. 3.Nathan SD, et al. Clin Chest Med 2013;34:695-705. 4.King CS, et al. Chest 2020;158:1651-64. 5. Trammell AW, et al. Pulm Circ 2015;5:356-63. 6.Nathan SD, et al. Lancet Respir Med 2019;7:780-90. 7. Whittle BJ, et al. Biochem Pharmacol 2012;84:68-75. 8.McLaughlin VV, et al. J Am Coll Cardiol 2010;55:1915- 22. 9.Faria-Urbina M, et al. Lung 2018;196:139-46. 10. Agarwal M, et al. J Heart Lung Transplant 2015;34: Suppl:S343. abstract. 11.Bajwa AA, et al. Pulm Circ 2017;7:82-8. 12. Wang L, et al. Int J Chron Obstruct Pulmon Dis 2017;12:3353-60. 13. Lettieri CJ, et al. Respir Med 2006;100:1734-41. 14. Dernaika TA, et al. Respiration 2010; 79:377-82. 15.Nathan SD, et al. Respir Med 2015;109:914-22. 16.du Bois RM, et al. Am J Respir Crit Care Med 2011;183:1231-7.

[0192] Example 4. Aerosolized and inhaled powder treprostinil A randomized, crossover study (6x6 Williams design) involving 36 healthy volunteers, consisting of six treatments, six durations, and six sequences, compared treprostinil inhaled via a Tyvaso® inhaler with treprostinil inhalation powder (TreT) administered via a dry powder inhaler (U.S. Patent Application Publication No. 20190321290). Four participants discontinued the study early (COVID-19, n=2; participant dropout, n=1; non-compliance with study requirements, n=1).

[0193] [Table 15]

[0194] [Table 16]

[0195] [Table 17]

[0196] conclusion AUC0-5 was generally similar at all dose levels for TreT and Tyvaso. The Cmax value for TreT was slightly higher than that of Tyvaso across the entire dose comparison. The AE profile was consistent with known prostacyclin effects and previous studies of Tyvaso. Between-subject variability for both AUC0-5 and Cmax was approximately half that of Tyvaso for TreT. AUC0-5 and Cmax for TreT and Tyvaso increased almost proportionally to the dose. Median Tmax: approximately 10 minutes for TreT and approximately 10–15 minutes for Tyvaso.

[0197] Example 5. Aerosolized and inhaled powder treprostinil, safety evaluation Primary objective: To evaluate the safety and tolerability of treprostinil inhalation powder (TreT) administered via a dry powder inhaler, such as the one shown in Figure 11, in patients with pulmonary hypertension (PAH) currently being treated with Tyvaso® (treprostinil inhalation solution administered via a nebulizer).

[0198] Secondary purpose: To evaluate the systemic exposure and pharmacokinetics (PK) of treprostinil in patients with PAH when delivered as Tyvaso® and TreT. To evaluate the 6-minute walk distance (6MWD) at baseline and after 3 weeks of treatment with TreT. To evaluate patient satisfaction and preference for TreT using the Inhaled Treprostinil Device Preference Questionnaire (PQ-ITD). To evaluate patient-reported PAH symptoms and effects using the PAH-Symptoms and Effects Questionnaire (PAH-SYMPACT).

[0199] Eligibility criteria: Diagnosis of WHO Group I PAH The subjects had to have started Tyvaso at least 3 months prior to baseline and had to start with a stable Tyvaso regimen (no dose change within 30 days of baseline visit) (6-12 breaths per minute on QID). Background therapy for PAH (e.g., endothelin receptor antagonist or phosphodiesterase-5 inhibitor or both), stable dose for at least 30 days prior to screening. Exclude other prostacyclin analogs or agonists (selexipag, epoprostenol, iloprost, or beraprost). During screening, individuals classified as WHO functional class IV will be excluded. The subject is unable to perform inhalation techniques that meet the inspiratory training standards. Conditions that limit the ability to walk or complete a 6MWT are excluded (baseline 6MWD > 150m). Exclude patients who initiated pulmonary rehabilitation within 12 weeks prior to their baseline visit. Figure 12 shows the study design. Table 16 presents information on Tret and Tyvaso dosages.

[0200] [Table 18]

[0201] [Table 19]

[0202] [Table 20]

[0203] [Table 21]

[0204] Of the 51 enrolled subjects, the assigned TreT doses for the 3-week treatment period were 32 μg for 2 subjects, 48 ​​μg for 27 subjects, and 64 μg for 22 subjects. 49 enrolled subjects entered the optional extension phase (OEP). Figure 13 shows some subjects with various maintenance TRET doses in the OEP.

[0205] Figure 14 shows the change in 6-minute walk distance (6MWD) relative to baseline as a function of the duration of TreT treatment. The change in 6MWD from baseline over the entire TreT period showed a significant improvement at week 3 (an increase of 11.5 m, p=0.0217). The improvement in 6MWD over the entire TreT period was maintained in the optional extension phase.

[0206] Patient-reported outcome indicators The Patient-Reported Quotient-Induced Disease (PQ-ITD) is a patient-reported outcome questionnaire used to assess patient satisfaction and preference for inhaled treprostinil devices. The PQ-ITD was administered at baseline to evaluate the Tyvaso inhalation system and at week 3 to evaluate the TreT inhaler.

[0207] The distribution of responses to each question in the PQ-ITD significantly improved between baseline (Tyvaso nebulizer) and week 3 (TreT inhaler) (p ≤ 0.0003). Overall satisfaction with the TreT inhaler significantly improved at week 3 compared to satisfaction with the Tyvaso nebulizer at baseline (Figure 14) (95.7%, p < 0.0001).

[0208] PAH SYMPACT: PAH-SYMPACT is a well-validated patient-reported outcome questionnaire given to assess the symptoms and effects of PAH. PAH-SYMPACT includes four domains (cardiopulmonary symptoms, cardiovascular symptoms, physical effects, and cognitive / emotional effects) and was given at baseline, week 3, and week 11.

[0209] Analysis of PAH SYMPACT data reported by patients revealed a trend towards improvement in both week 3 and week 11 of the subjects who received TreT.

[0210] Mean changes from baseline were low in all domain scores of PAH-SYMPACT at both weeks (range: -0.05 to -0.22), with significant improvements in physical effects (range: -1.1 to 1.0, p=0.0438) and cognitive / emotional effects (range: -1.3 to 0.5, p=0.0048) at week 3.

[0211] [Table 22]

[0212] [Table 23]

[0213] [Table 24]

[0214] conclusion The transition from Tyvaso to TreT was safe and well-tolerated in this study. Most adverse events (AEs) were mild to moderate in severity and occurred at a frequency consistent with those observed in other inhaled treprostinil studies in PAH patients.

[0215] The following was observed in patients who switched from Tyvaso to TreT after 3 weeks of TreT administration. Significant improvement in 6MWD at week 3 (an increase of 8.0m, p=0.0217). As of December 23, 2020 (data cutoff date), the overall improvement in 6MWD for TreT patients, along with the preference for TreT inhaler use, maintained significant OEP satisfaction (PQ-ITD).

[0216] There was a significant improvement in the PAH impact score and a trend toward improvement in the PAH symptom score (PAH SYMPACT).

[0217] Additional Embodiments 1. A method for treating interstitial lung disease (ILD) or pulmonary fibrosis in a subject requiring treatment, comprising administering a therapeutically effective amount of treprostinil, its prodrug, salt, or ester to the subject. 2. A method for reducing impaired lung function in subjects with interstitial lung disease (ILD) or pulmonary fibrosis, comprising administering treprostinil, its prodrug, salt, or ester to the subject. 3. A method for increasing forced vital capacity (FVC) in a subject suffering from ILD or pulmonary fibrosis, comprising administering treprostinil, its prodrug, salt, or ester to the subject. 4. The method according to any one of Embodiments 1 to 3, wherein ILD includes one or more of the following: idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), idiopathic organizing pneumonia (COP), lymphocytic interstitial pneumonia (LIP), sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, antisynthetase syndrome, silicosis, asbestosis, occupational lung disease, chronic hypersensitivity pneumonitis, idiopathic interstitial pneumonia (IIP), autoimmune ILD, lymphangioleiomyomatosis (LAM), Langerhans cell histiocytosis (LCH), drug-associated ILD, vasculitis, granulomatosis, and berylliumosis. 5. The method according to Embodiment 4, wherein ILD includes IPF. 6. The method according to any one of Embodiments 1 to 5, wherein ILD includes systemic sclerosis-associated interstitial lung disease (SSc-ILD). 7. The ILD is the method according to any one of embodiments 1 to 6, induced by antibiotics, chemotherapy, antiarrhythmic drugs, coronavirus disease 2019, severe acute respiratory syndrome, pneumocystis pneumonia, tuberculosis (TB), chlamydia trachomatis, respiratory syncytial virus or lymphangioleiomyomatosis. 8. The subject has one or more of surfactant protein-B deficiency, surfactant protein-C deficiency, ABCA3-deficiency, cerebro-lung-thyroid syndrome, congenital alveolar proteinosis, alveolar capillary dysplasia, mutations in telomerase reverse transcriptase, mutations in telomerase RNA component, mutations in regulators of telomere elongation helicase 1, and mutations in poly(A)-specific ribonuclease, and is the method according to any one of embodiments 1 to 7. 9. The subject has one or more of the symptoms of shortness of breath, fatigue, weight loss, dry cough, chest pain and pulmonary hemorrhage, and is the method according to any one of embodiments 1 to 8. 10. After administration, the symptoms are improved by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100% as measured by a medically approved technique, and is the method according to embodiment 9. 11. The medically approved technique includes one or more of the Modified Medical Research Council (MMRC) dyspnea scale, Modified Borg dyspnea scale (0-10), Calder fatigue scale, weight measurement scale, cough visual analog scale (VAS), King's Brief Interstitial Lung Disease Questionnaire, Leicester Cough Questionnaire (LCQ), computed tomography (CT) scan, X-ray, magnetic resonance imaging (MRI), pulmonary function test (PFT), spirometry, lung volume, maximum inspiratory pressure, diffusion capacity, reduction of oxygen saturation and arterial blood gas evaluation, and is the method according to embodiment 10. 12. The method according to any one of embodiments 1 to 11, wherein treprostinil, its prodrug, salt or ester is administered in a pharmaceutical composition comprising treprostinil, its prodrug, salt or ester and a pharmaceutically acceptable carrier or excipient. 13. The method according to any one of claims 1 to 12, wherein the administration comprises at least one of oral, inhalation, subcutaneous, nasal, intravenous, intramuscular, sublingual, buccal, rectal, vaginal and transdermal administration. 14. The method according to any one of claims 1 to 13, wherein the administration comprises inhalation. 15. The method according to any one of claims 1 to 14, wherein at least one inhalation administration event comprises 1 to 20 breaths. 16. The method according to any one of claims 1 to 15, comprising administering at least one additional active agent for treating ILD. 17. The method according to claim 16, wherein the at least one additional active agent comprises a corticosteroid, mycophenolic acid, mycophenolate mofetil, azathioprine, cyclophosphamide, rituximab, pirfenidone or nintedanib. 18. The at least one additional active agent and treprostinil, its prodrug, salt or ester are (a) simultaneously, (b) as a mixture, (c) separately and simultaneously or concurrently, and, (d) separately and sequentially, administered by a method selected from the group consisting of, the method according to claim 16 or 17. 19. The method according to any one of claims 1 to 18, wherein the administration is once, twice, three times, four times, five times or six times a day. 20. The method according to any one of claims 1 to 19, wherein the administration is for a period selected from the group consisting of about 1 day, about 1 day to about 3 days, about 3 days to about 6 days, about 6 days to about 9 days, about 9 days to about 12 days, about 12 days to about 15 days, about 15 days to about 18 days, about 18 days to about 21 days, about 21 days to about 24 days, about 24 days to about 27 days, about 27 days to about 30 days, or about 30 days or more. 21. The method according to any one of Embodiments 1 to 20, wherein the subject is a human. 22. The method according to any one of Embodiments 1 to 21, which results in an increased FVC compared to the FVC at the start of administration or before the start of administration. 23. The method according to Embodiment 22, wherein the administration results in an increase in FVC 16 weeks after the start of administration compared to FVC at the start of administration or before the start of administration. 24. The method according to any one of embodiments 22 to 23, wherein the increase in FVC is at least 20%. 25. The method according to Embodiment 24, wherein the increase in FVC is at least 75%.

[0218] While the above refers to certain preferred embodiments, it will be understood that the present invention is not so limited. Those skilled in the art will notice that various modifications can be made to the disclosed embodiments, and that such modifications are intended to fall within the scope of the present invention.

[0219] All publications, patent applications, and patents cited herein are incorporated herein by reference in their entirety.

Claims

1. A pharmaceutical composition for reducing the risk of exacerbation of an underlying lung disease in patients with pulmonary hypertension associated with interstitial lung disease, comprising at least 18 micrograms of an effective amount up to the maximum tolerated dose of treprostinil or a pharmaceutically acceptable salt thereof in a single dose event, administered by inhalation to patients with pulmonary hypertension associated with interstitial lung disease.

2. The pharmaceutical composition according to claim 1, wherein the inhalation is performed using a sprayer.

3. The pharmaceutical composition according to claim 1, wherein the inhalation is performed using a dry powder inhaler.

4. The pharmaceutical composition according to claim 1, wherein the patient receives up to four single-dose events per day.

5. The pharmaceutical composition according to claim 1, wherein the single dose event is at least 18 micrograms and up to 72 micrograms.

6. The pharmaceutical composition according to claim 1, wherein the administration increases the patient's forced vital capacity.

7. The pharmaceutical composition according to claim 1, wherein the administration provides a statistically significant improvement in the patient's forced vital capacity eight weeks after the start of administration.

8. The pharmaceutical composition according to claim 1, wherein the administration provides a statistically significant improvement in the patient's forced vital capacity 16 weeks after the start of administration.

9. A pharmaceutical composition for increasing forced vital capacity in patients with pulmonary hypertension associated with interstitial lung disease, comprising an effective amount of at least 18 micrograms up to the maximum tolerated dose of treprostinil or a pharmaceutically acceptable salt thereof in a single dose event, administered by inhalation to patients with pulmonary hypertension associated with interstitial lung disease.

10. The pharmaceutical composition according to claim 9, wherein the administration results in an increase in forced vital capacity compared to the forced vital capacity at the start of administration or before the start of administration.

11. The pharmaceutical composition according to claim 10, wherein the administration results in an increase in forced vital capacity at 8 weeks after the start of administration compared to the forced vital capacity at the start of administration or before the start of administration.

12. The pharmaceutical composition according to claim 10, wherein the administration results in an increase in forced vital capacity 16 weeks after the start of administration, compared to the forced vital capacity at the start of administration or before the start of administration.

13. The pharmaceutical composition according to claim 1, wherein the inhalation is performed using a sprayer.

14. The pharmaceutical composition according to claim 1, wherein the inhalation is performed using a dry powder inhaler.

15. The pharmaceutical composition according to claim 1, wherein the patient receives up to four single-dose events per day.

16. The pharmaceutical composition according to claim 1, wherein the single dose event is at least 18 micrograms and up to 72 micrograms.

Images