Treatment of pulmonary arterial hypertension

Abstract

A novel method for treating pulmonary hypertension is provided, comprising monitoring a subject's mean pulmonary artery pressure, administering a first therapeutically effective amount of a pulmonary vasodilator when the subject's mean pulmonary artery pressure exceeds a threshold, and increasing the amount of pulmonary vasodilator administered until the mean pulmonary artery pressure is reduced.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 439,779, filed January 18, 2023, the entire contents of which are incorporated herein by reference.

[0002] Technical Field This application relates generally to the treatment of pulmonary hypertension. [Background technology]

[0003] Pulmonary arterial hypertension (PAH) is a rapidly progressive disease characterized by elevated mean pulmonary artery pressure (mPAP) >20 mmHg, leading to right ventricular (RV) dysfunction and death. It is characterized by elevated pressures in the pulmonary vasculature, which can lead to heart failure (2022 ESC / ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Eur Heart J. 2022;43(38):3618-373).

[0004] Pulmonary hypertension is classified into five groups: Group 1: pulmonary arterial hypertension (PAH); Group 2: PH associated with left heart disease; Group 3: PH associated with pulmonary disease and / or hypoxia; Group 4: PH associated with pulmonary artery obstruction; Group 5: PH of unclear mechanism and / or multifactorial

[0005] Currently, there are many approved products for specific types of pulmonary hypertension, including Group 1 (PAH). These products include products containing treprostinil as the active ingredient, such as Remodulin® (treprostinil) injection. When treprostinil is administered subcutaneously, it is generally desirable to administer the maximum tolerated dose of treprostinil to patients to achieve maximum therapeutic effect balanced against undesirable effects, such as pain at the site. There is a need to administer treprostinil to maximize therapeutic effect and minimize undesirable side effects.

[0006] A pilot study demonstrated the feasibility and safety of using the CardioMEMS™ HF System to remotely monitor mPAP and guide drug therapy in PAH (Am. J. Respir. Crit. Care Med., 2022 April 1; 205(7):751-760), while one study evaluated early, aggressive parenteral prostanoid therapy and showed that significant mPAP reduction led to significant improvements in RV function and long-term outcomes in PAH patients (J. Heart Lung Transplant, 2018;37:365-375). Summary of the Invention

[0007] One aspect of the present disclosure is directed to a method for treating pulmonary hypertension, comprising monitoring mean pulmonary artery pressure in a subject, and administering a therapeutically effective amount of a first pulmonary vasodilator to the subject when the mean pulmonary artery pressure in the subject exceeds a threshold. The method may further comprise administering increasing doses of the pulmonary vasodilator until the mean pulmonary artery pressure is reduced to a target level. In some embodiments, the subject is a human.

[0008] In some embodiments of the present disclosure, the pulmonary vasodilator comprises a prostanoid or prostacyclin. In yet another aspect, the pulmonary vasodilator comprises treprostinil, a salt or ester thereof. In yet another embodiment, the pulmonary vasodilator comprises a non-prostanoid IP receptor agonist, such as larinepag.

[0009] In some embodiments of the present disclosure, the subject's pulmonary artery pressure is monitored remotely. In yet other embodiments, the mean pulmonary artery pressure is monitored continuously. In some embodiments, the mean pulmonary artery pressure is monitored using a wireless pulmonary artery pressure sensor implanted in the subject.

[0010] In some embodiments of the present disclosure, the target level is less than 50 mmHg, or less than 40 mmHg, or less than 30 mmHg, or less than 25 mmHg. In still further embodiments, the threshold is greater than 20 mmHg, or greater than 30 mmHg, or greater than 40 mmHg. In some embodiments, the initial mean pulmonary artery pressure is greater than 35 mmHg.

[0011] In some embodiments of the present disclosure, the method includes monitoring the right ventricular structure of the subject. In yet another embodiment, the method further includes measuring the right ventricular ejection fraction after a first period of time following administration of a pulmonary vasodilator.

[0012] In some embodiments, the ejection fraction is measured by cMRI. In yet another embodiment, the method further comprises, consists of, or consists essentially of measuring the ratio of stroke volume to end-systolic volume. In yet another embodiment, the method comprises, consists of, or consists essentially of measuring the ratio of tricuspid annular plane systolic escape to pulmonary artery systolic pressure.

[0013] In some embodiments of the present disclosure, the subject has not previously received treatment for pulmonary hypertension or has received an endothelin receptor antagonist and / or a phosphodiesterase type 5 inhibitor for less than 24 months, or less than 18 months, or less than 12 months, or less than 6 months, or less than 3 months, or less than 1 month.

[0014] In some embodiments of the present disclosure, administering comprises intravenous administration. In yet another aspect, administering comprises administering by inhalation. In yet another aspect, administering comprises administering an oral formulation. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Throughout this specification, unless otherwise noted, the terms "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, such that a stated integer or group of integers may include one or more other unstated integers or groups of integers. Also, the term "or" is inclusive unless modified, for example, by "either." Thus, unless the context dictates otherwise, the word "or" means any one member of a particular list and includes any combination of members of that list. Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about."

[0016] Headings are provided for convenience only and should not be construed as limiting the invention in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims. In order that this disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0017] All numerical designations are approximations that may vary (+) or (-) by increments of 0.05%, 1%, 2%, 5%, 10%, or 20%. It is understood, although not always explicitly stated, that all numerical designations are preceded by the term "about." It is also understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such reagents are known in the art.

[0018] Another aspect of the present invention relates to a method for treating pulmonary hypertension, comprising monitoring the mean pulmonary artery pressure in a subject. Preferably, monitoring is performed at least once a week or at least once a month. In some embodiments, the present invention comprises administering a pulmonary vasodilator to the subject. In some embodiments, the pulmonary vasodilator is treprostinil or its derivative, or a pharmaceutically acceptable salt thereof.

[0019] In one embodiment, the method uses treprostinil sodium, which is currently marketed under various trade names and routes of administration: REMODULIN® (intravenous and subcutaneous), TYVASO® (inhalation), TYVASO DPI® (inhalation), or ORENITRAM® (oral). The U.S. FDA has approved treprostinil sodium for the treatment of pulmonary arterial hypertension in the following dosage concentrations: 1.0 mg / mL, 2.5 mg / mL, 5.0 mg / mL, and 10.0 mg / mL, as an injectable, inhaled, or oral formulation. The chemical structure of treprostinil sodium is:

[0020] [ka]

[0021] Treprostinil sodium is sometimes designated by the chemical names: (a) [(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid; or (b) 9-deoxy-2',9-α-methano-3-oxa-4,5,6-trino-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin F1. Treprostinil sodium is also known as UT-15; LRX-15; 15AU81; UNIPROST™; BW A15AU; and U-62,840. The molecular weight of treprostinil sodium is 390.52, and its empirical formula is C 23 H 34O5. Treprostinil, or 9-deoxy-2',9-α-methane-3-oxa-4,5,6-trino-3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin FI, is a prostacyclin analogue first described in U.S. Patent No. 4,306,075. U.S. Patent No. 5,153,222 describes the use of treprostinil for the treatment of pulmonary hypertension. Treprostinil is approved for both intravenous and subcutaneous administration, the latter avoiding the potential septic effects associated with continuous venous catheters. U.S. Patent Nos. 6,521,212 and 6,756,033 describe the administration of treprostinil by inhalation for the treatment of pulmonary hypertension, peripheral venous insufficiency, and other diseases and conditions. U.S. Patent No. 6,803,386 describes the administration of treprostinil to treat cancers such as lung cancer, liver cancer, brain cancer, pancreatic cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, and head and neck cancer. U.S. Patent Application Publication No. 2005 / 0165111 describes the treatment of ischemic lesions with treprostinil. U.S. Patent No. 7,199,157 discloses that treatment with treprostinil improves renal function. U.S. Patent Application Publication No. 2005 / 0282903 describes the treatment of neuropathic foot ulcers with treprostinil. U.S. Provisional Application No. 60 / 900,320, filed February 9, 2007, describes the treatment of pulmonary fibrosis with treprostinil.

[0022] Physiologically acceptable salts of treprostinil include salts derived from bases. Base salts include ammonium salts (such as quaternary ammonium salts), alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. In this specification, the term "acid derivatives" is used to refer to C1-4 alkyl esters and amides, including amides in which the nitrogen is optionally substituted with one or two C1-4 alkyl groups.

[0023] Quaternary ammonium salts can be formed, for example, by reaction with lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl and phenethyl bromides.

[0024] The amount of treprostinil or its derivative, or pharmaceutically acceptable salt thereof required in a medication or diagnostic aid according to the present invention to achieve the desired effect depends on many factors, such as the particular application, the nature of the particular compound used, the mode of administration, the concentration of the compound used, and the patient's weight and condition. The concentration of treprostinil or its pharmaceutically acceptable salt in solution ranges from about 500 pg / ml to about 2500 pg / ml, wherein the metered-dose inhaler delivers a single dose of 30 pg to 90 pg of treprostinil or its pharmaceutically acceptable salt per actuation. Described herein are methods for delivering a therapeutically effective amount of treprostinil to a subject, such as a human, in need thereof, comprising administering to the subject a formulation containing a therapeutically effective amount of treprostinil, its derivative, or a pharmaceutically acceptable salt thereof using a metered-dose inhaler. Treprostinil can be administered via a metered dose inhaler to subjects suffering from a condition or disease that can be treated with treprostinil, such as asthma, pulmonary hypertension, peripheral venous insufficiency, or pulmonary fibrosis.

[0025] The daily dosage per patient for the treatment of pulmonary hypertension or conditions related to pulmonary hypertension can range from 25 μg to 250 mg per kilogram of body weight per day; 0.5 μg to 2.5 mg; or 7 μg to 285 μg per kilogram of body weight per day. For example, an intravenous dose ranging from 0.5 μg to 1.5 mg per kilogram of body weight per day may be conveniently administered as an infusion of 0.5 ng to 1.0 μg per kilogram of body weight per minute. One possible dosage is 2.5 ng / kg / min, increased weekly by 2.50 ng / kg / min over 12 weeks until a target dosage, such as 15 ng / kg / min, is reached. Suitable infusion solutions for this purpose include, for example, 10 ng to 1 μg per ml. Injectable ampoules contain, for example, 0.1 μg to 1.0 mg, while orally administrable unit dose formulations, such as tablets and capsules, contain, for example, 0.1 to 100 mg, typically 1 to 50 mg. For diagnostic purposes, a single unit dose formulation can be administered. In the case of physiologically acceptable salts, the weights indicated above refer to the weight of the active compound ion, i.e., the ion derived from Treprostinil.

[0026] In preparing the pharmaceutical or diagnostic aid (hereinafter referred to as "formulation") according to the present invention, treprostinil and / or its derivatives, and / or pharmaceutically acceptable salts thereof may be admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients in the formulation and not deleterious to the subject. The carrier may be solid or liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, e.g., a tablet, containing 0.05% to 95% by weight of the active compound. One or more of treprostinil or its derivatives, or pharmaceutically acceptable salts thereof, may be incorporated into the formulations of the present invention, which may be prepared by any of the well-known pharmaceutical techniques for admixing ingredients.

[0027] Formulations of the present invention include those suitable for parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), oral, inhalation (solid and liquid form), rectal, topical, buccal (e.g., sublingual) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the particular form of treprostinil, its derivative or its pharmaceutically acceptable salt.

[0028] Formulations of the present invention suitable for parenteral administration advantageously consist of a sterile aqueous preparation of treprostinil or a derivative thereof, or a pharmaceutically acceptable salt thereof, which preparation may be isotonic with the blood of the intended recipient. These preparations may be administered by subcutaneous injection, although administration may also be by intravenous, intramuscular, or intradermal injection. Such formulations may be conveniently prepared by mixing the compound with water or a glycine or citrate buffer and rendering the resulting solution sterile and isotonic with blood. Injectable formulations of the present invention contain 0.1-5% w / v of the active compound and may be administered at a rate of 0.1 ml / min / kg. Alternatively, the present invention may be administered at a rate of 0.625-50 ng / kg / min. Alternatively, the present invention may be administered at a rate of 10-15 ng / kg / min.

[0029] Formulations suitable for oral administration can be presented as discrete units such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of treprostinil or its derivatives or its pharmaceutically acceptable salts; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations can be prepared by any suitable pharmaceutical method, including the step of bringing into association the active compound with a suitable carrier (which may contain one or more accessory ingredients).

[0030] Treprostinil can be administered by inhalation, which means herein that a subject in need of the active ingredient(s) delivers the active ingredient or combination of active ingredients through the subject's respiratory tract, such as the subject's nose or mouth.

[0031] As used herein, a metered dose inhaler refers to a device capable of delivering a metered or bolus dose of a respiratory medication, such as treprostinil, to the lungs. An example of an inhalation device is a pressurized metered dose inhaler, i.e., a device that generates an aerosol cloud for inhalation from a solution and / or suspension of the respiratory medication in a chlorofluorocarbon (CFC) solution and / or a hydrofluoroalkane (HFA) solution. The inhalation device can also be a dry powder inhaler. In this case, the respiratory medication is inhaled in a solid formulation in the form of a powder, typically with a particle size of less than 10 micrometers or less than 5 micrometers.

[0032] The metered-dose inhaler can be a fine mist inhaler (SMI), and an aerosol cloud containing the respiratory medication can be generated by forcing a solution containing the respiratory medication through a nozzle or series of nozzles. Aerosol generation in an SMI can be achieved, for example, by mechanical, electromechanical, or thermomechanical processes. Examples of fine mist inhalers include the Respimat® inhaler (Boeringer Ingelheim GmbH), the AERx® inhaler (Aradigm Corp), the Mystic™ inhaler (Ventaira Pharmaceuticals, Inc.), and the Aira™ inhaler (Chrysalis Technologies Incorporated). For a review of fine mist inhaler technology, see, for example, M. Hindle, The Drug Delivery Companies Report, Autumn / Winter 2004, pp. 31-34. Aerosols for SMIs can be generated from a solution of the respiratory medication, which also contains pharmaceutically acceptable excipients. In this embodiment, the respiratory medication is treprostinil, its derivatives, or its pharmaceutically acceptable salts, and can be incorporated into the SMI as a solution. The solution can be, for example, a solution of treprostinil in water, ethanol, or a mixture thereof. Preferably, the diameter of the aerosol particles containing treprostinil is less than about 10 μm, or less than about 5 μm, or less than about 4 μm.

[0033] The concentration of treprostinil in an aerosolizable formulation, such as a solution, used in a metered-dose inhaler can range from about 500 pg / ml to about 2500 pg / ml, or from about 800 pg / ml to about 2200 pg / ml, or from about 1000 pg / ml to about 2000 pg / ml. In the present invention, the dose of treprostinil administered using a metered-dose inhaler in one actuation is about 30 pg to about 90 pg, or about 30 pg to about 60 pg.

[0034] Treprostinil can be administered in a single pump with a limited number of breaths taken by the patient.For example, treprostinil can be administered in 20 or less breaths, or 10 or less breaths, or 5 or less breaths.Preferably, treprostinil is administered in 3, 2 or 1 breaths.The total time of one administration pump can be less than 5 minutes, or less than 1 minute, or less than 30 seconds.Treprostinil can be administered once a day or several times a day.

[0035] Generally, the formulations of the present invention are prepared by uniformly and intimately mixing the active compound with a liquid carrier or a finely divided solid carrier, or both, and then molding the resulting mixture as needed.For example, tablets can be prepared by compressing or molding powder or granules containing the active compound, optionally with one or more accessory ingredients.Compressed tablets can be prepared by compressing a free-flowing compound, such as a powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and / or a surfactant / dispersant(s), using a suitable machine.Molded tablets can be produced by molding the powdered compound moistened with an inert liquid binder using a suitable machine.

[0036] Formulations suitable for buccal (sublingual) administration include troches comprising treprostinil or a derivative thereof, or a pharmaceutically acceptable salt thereof, in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0037] Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, which can be prepared by admixing treprostinil or its derivatives, or pharmaceutically acceptable salts thereof, with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0038] Formulations suitable for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that can be used include petrolatum, lanolin, polyethylene glycol, alcohol, and combinations of two or more thereof. The active compound is generally present in a concentration of 0.1 to 15% w / w, e.g., 0.5 to 2% w / w. Formulations for transdermal administration are typically administered by iontophoresis (see, e.g., Pharmaceutical Research, 3(6): 318 (1986)), typically in the form of treprostinil or a derivative or salt thereof, or an optionally buffered aqueous solution thereof. Suitable formulations consist of citrate or Bis / Tris buffer (pH 6) or ethanol / water, containing 0.1 to 0.2 M of the active ingredient.

[0039] In some embodiments, the method for treating pulmonary hypertension may further include administering at least one adjunct agent selected from the group consisting of sildenafil, tadalafil, calcium channel blockers (diltiazem, amlodipine, nifedipine), bosentan, sitaxsentan, ambrisentan, and pharmaceutically acceptable salts thereof. In some embodiments, the adjunct agent may be included in a treprostinil formulation and thus may be administered simultaneously with treprostinil using a metered dose inhaler. In some embodiments, the adjunct agent may be administered separately from treprostinil. In some embodiments, intravenous prostacyclin (Flolan), intravenous iloprost, or intravenous or subcutaneous treprostinil may be administered in addition to treprostinil administered by inhalation using a metered dose inhaler.

[0040] The compounds of the present invention are conveniently prepared by methods identical or analogous to those described in US Pat. No. 4,306,075, US Pat. No. 6,528,688 and US Pat. No. 6,441,245.

[0041] In certain kit embodiments, treprostinil or its derivative or its pharmaceutically acceptable salt is in a form suitable for subcutaneous administration, continuous subcutaneous infusion, intravenous administration, or inhalation. In other kit embodiments, treprostinil or its derivative or its pharmaceutically acceptable salt is in an orally available form selected from the group consisting of tablets and capsules. In other kit embodiments, the effective amount of treprostinil or its derivative or its pharmaceutically acceptable salt is at least 1.0 ng / kg body weight / min.

[0042] The formulations of the present invention can also be used to normalize biomarkers associated with lung disease. Lung disease and affected cells or tissues are associated with varying concentrations of proteins and cellular compounds. These compounds serve as biomarkers for assessing the severity and progression of disease. For example, matrix metalloproteinase 9 (MMP-9), angiopoietin-2 (Ang-2), vascular endothelial-derived growth factor (VEG-F), and platelet-derived growth factor (PDGF) are associated with lung disease and can be used in the present invention to monitor the progression of treatment with treprostinil or other pharmaceutical agents.

[0043] In certain embodiments, mean pulmonary artery pressure is monitored by a CARDIOMEMS unit or device capable of remote, continuous, and real-time monitoring of mean pulmonary artery pressure. In one embodiment, one exemplary active system and sensor suitable for measuring hemodynamic parameters is a CARDIOMEMS pressure sensor. As described in U.S. Pat. No. 7,699,059, entitled "Implantable Wireless Sensor," and U.S. Pat. No. 7,679,355, entitled "Communication with an Implantable Wireless Sensor," which are incorporated herein by reference in their entireties, these pressure sensors are MEMS-based pressure sensors configured to be implanted in the pulmonary artery, more specifically, in the distal pulmonary artery branch, either with a RHC or as part of a graft such as an AAA stent graft. Cardiomec pressure sensors are further configured to be selectively energized with RF energy to return high-fidelity dynamic pressure information at high frequencies from precisely selected locations within the patient's body. In one aspect, advantages of the CardioMems pressure sensor when used in therapeutic development are that the system is wireless, the pressure sensor is non-invasive after initial implantation, the pressure sensor is small enough to be implanted in a desired range of lumens and locations within the patient, and the pressure sensor can be permanently or long-term implanted.

[0044] Another advantage of CARDIOMEMS pressure sensors is that they allow measurements during ambulatory activities outside of a hospital, which is more representative of the patient's lifestyle. Because CARDIOMEMS pressure sensors are noninvasive after implantation, ambulatory use is provided, and the CARDIOMEMS sensor can be selectively energized via an easy-to-use RF transmitter within an external, noninvasive device that energizes the sensor. In another aspect, the CARDIOMEMS pressure sensor is configured to wirelessly communicate pressure data to a node local to the patient, which is configured to transmit the information over a network to a front-end computer system with little or no patient involvement.

[0045] In some embodiments, the mean pulmonary artery pressure can be obtained remotely from the patient outside the hospital. For example, the desired physiological information can be obtained via a wireless sensor implanted within the patient, such as an exemplary CARDIOMEMS pressure sensor implanted in the patient's pulmonary artery.

[0046] In some embodiments, an initial dose of a pulmonary vasodilator (e.g., treprostinil) is administered to the subject, and the effect of the pulmonary vasodilator on mean pulmonary artery pressure is monitored. The mean pulmonary artery pressure can be monitored continuously, remotely, or at various intervals. Upon detecting a change or improvement (i.e., a decrease) in the mean pulmonary artery pressure, the dose of the pulmonary vasodilator can be increased or decreased depending on the subject's response to the vascular control until the subject's mean pulmonary artery pressure reaches a target level. In this way, the method of the claimed invention provides patient-specific optimization of dosage.

[0047] The disclosures of all publications cited above are expressly incorporated by reference herein in their entireties to the same extent as if each was individually incorporated by reference.

[0048] The examples described herein are illustrative of the present invention and are not intended to be limiting thereto. 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 illustrative only and do not limit the scope of the present invention.

[0049] Pharmaceutical Composition Treprostinil may be provided in the form of a pharmaceutical composition, which may contain pharmaceutically acceptable carriers, excipients, binders, diluents, etc. Such pharmaceutical compositions may be prepared by methods known in the art, such as granulation, mixing, dissolving, encapsulation, lyophilization, emulsification, or excipient processes. The compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, and solutions. The compositions may be formulated for a variety of administration routes, such as oral, transmucosal, rectal, transdermal, or subcutaneous administration, as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular, or intracerebroventricular injection. Treprostinil may be administered by any of the above routes, and may be administered locally rather than systemically, for example, as an injection or sustained-release formulation.

[0050] In one embodiment, the pharmaceutical composition may comprise a treprostinil prodrug and a carrier such as sterile water. In some embodiments, the treprostinil prodrug is formulated for subcutaneous administration, and such formulations may or may not contain m-cresol or another preservative.

[0051] Treprostinil described herein can be used to treat pulmonary hypertension. In some embodiments, treprostinil can be used to treat PAH. In some embodiments, treprostinil can be used to treat one or more of WHO Group 1-5 pulmonary hypertension, e.g., Group 1 pulmonary arterial hypertension. In some embodiments, treprostinil can be used to treat pulmonary hypertension classified into multiple WHO groups but sharing common features, e.g., responsiveness to vascular factors. Similarly, treprostinil described herein can be used to treat any disease or condition for which treprostinil is indicated or useful. Treprostinil can be administered as the sole therapeutic agent or in addition to other active agents, including treprostinil. In certain embodiments, treprostinil can be administered in combination with one or more additional active agents. In some embodiments, such one or more additional active agents can also be administered with treprostinil using a metered-dose inhaler. In some embodiments, such one or more additional active agents can also be administered separately from treprostinil. The particular additional active agent that may be administered in combination with treprostinil may depend on the particular disease or condition for which treprostinil is administered to treat or prevent. In some cases, the additional active agent may be a cardiovascular agent such as a calcium antagonist, a phosphodiesterase inhibitor, an endothelial antagonist, or an antiplatelet agent.

[0052] For oral, buccal, or sublingual administration, solid dosage forms can include powders, suspensions, granules, tablets, pills, capsules, gelcaps, caplets, and the like. These can be prepared, for example, by mixing one or more treprostinil prodrugs or pharmaceutically acceptable salts thereof with at least one additive or excipient, such as starch. Suitable additives or excipients can be sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methylcellulose, hydroxypropylmethylcellulose, and / or polyvinylpyrrolidone. Optionally, the oral dosage form may contain other ingredients that aid administration, such as an inert diluent, or a lubricant such as magnesium stearate, or a preservative such as paraben or sorbic acid, or an antioxidant such as ascorbic acid, tocopherol or cysteine, a disintegrant, a binder, a thickener, a buffer, a sweetener, a flavoring or an odorant. In addition, dyes or pigments may be added for identification. Tablets may further be treated with suitable coating materials known in the art.

[0053] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which may contain inert diluents such as water.Pharmaceutical preparations can be prepared as liquid suspensions or solutions using sterile liquids such as oils, water, alcohols and combinations thereof, but are not limited to these.For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents and emulsifying agents may be added.

[0054] As mentioned above, suspension may contain oil.Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.Suspension preparation may also contain fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.Suspension preparation may also contain alcohol such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.Ethers, for example, poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension preparation, but are not limited to these.

[0055] Injectable dosage forms generally include aqueous or oily suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents.Injectable dosage forms can also be in the form of a solution phase or suspension prepared using a solvent or diluent.Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic saline solution.Alternatively, sterile oils can be used as solvents or suspending agents.Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.

[0056] For injection, the pharmaceutical preparation may be a powder suitable for reconstitution with an appropriate solution, as described above. Examples of these include, but are not limited to, freeze-dried, rotary-dried, or spray-dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. The compound may be formulated for parenteral administration by injection, such as bolus injection or continuous infusion. The unit dosage form for injection may be an ampule or a multi-dose container. In addition to the above representative dosage forms, pharmaceutically acceptable excipients and carriers are commonly known to those skilled in the art and can be used. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0057] Treprostinil prodrugs can be formulated into formulations suitable for parenteral administration, which can consist of a sterile aqueous preparation of the treprostinil prodrug or a pharmaceutically acceptable salt thereof, where the preparation can be isotonic with the blood of the intended recipient. These preparations can be administered by subcutaneous injection, but administration can also be by intravenous, intramuscular, or intradermal injection. Such formulations can be conveniently prepared by mixing the compound with water or a glycine or citrate buffer and rendering the resulting solution sterile and isotonic with blood. Injectable formulations can contain 0.1-5% w / v of treprostinil based on the weight of the prodrug and can be administered at a rate of 0.1 ml / min / kg. Alternatively, the prodrug can be administered at a rate of 0.625-50 ng / kg / min based on the weight of treprostinil in the prodrug. Alternatively, the prodrug can be administered at a rate of 10-15 ng / kg / min based on the weight of treprostinil in the prodrug.

[0058] In some embodiments, the concentration of the treprostinil prodrug in a formulation for parenteral administration, such as intravenous or subcutaneous infusion (including continuous subcutaneous infusion), can be 0.0005 to 30 mg / mL, or 0.0007 to 50 mg / mL, or 0.001 to 15 mg / mL, or any value or subrange within these ranges. Exemplary concentrations include 0.1 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, or 10 mg / mL.

[0059] In some embodiments, formulations of treprostinil prodrugs for parenteral administration, such as intravenous infusion or subcutaneous infusion (including continuous subcutaneous infusion), can be prepared by mixing the prodrug with a vehicle such as a buffer solution. In certain embodiments, the vehicle can be a phosphate-containing vehicle, i.e., at least one phosphate, for example, a dibasic phosphate, such as dibasic sodium phosphate or dibasic potassium phosphate, or a tribasic phosphate, such as tribasic sodium phosphate or potassium phosphate. In certain embodiments, the vehicle can also contain a halogen salt, such as a chloride salt, which can be, for example, sodium chloride or potassium chloride. A halogen salt, such as sodium chloride, can be used to adjust the strong acidity of the vehicle. In certain embodiments, it may be preferable that the phosphate and the halogen salt have the same cation. For example, when the phosphate is sodium phosphate, such as tribasic sodium phosphate or tribasic sodium phosphate, the halogen salt can be a sodium halide salt, such as sodium chloride. Similarly, when the phosphate is potassium phosphate, such as tribasic potassium phosphate or tribasic potassium phosphate, the halogen salt can include a potassium halide salt, such as potassium chloride. The solvent in the vehicle may include water. In certain embodiments, water may be the only solvent in the vehicle. However, in certain embodiments, the vehicle may include one or more additional solvents in addition to water. In some embodiments, the additional solvent may be a preservative such as m-cresol.

[0060] Preferably, the vehicle is isotonic with the blood of a patient, such as a human. The term isotonic means that the osmolality and ionic concentration of the vehicle match those of a patient, such as a human. Non-limiting examples of vehicles include phosphate buffered saline, an aqueous salt solution containing disodium hydrogen phosphate, sodium chloride, and in some formulations, potassium chloride and potassium dihydrogen phosphate. Other examples include a vehicle containing 20 mM dibasic sodium phosphate and 125 mM sodium chloride, and a vehicle containing 15 mM tribasic sodium phosphate, 125 mM sodium chloride, and 0.3% w / w m-cresol.

[0061] Treatment method One aspect of the present disclosure is directed to a method for treating pulmonary hypertension, comprising, consisting of, or consisting essentially of, monitoring mean pulmonary artery pressure in a subject.The method further comprises, or essentially consists of, administering a first therapeutically effective amount of a pulmonary vasodilator or its ester or salt to the subject when the mean pulmonary artery pressure in the subject exceeds a threshold.The method further comprises, consists of, or essentially consists of increasing the dosage of the pulmonary vasodilator or its ester or salt until the mean pulmonary artery pressure is reduced to a target level.In some embodiments, the subject is a human.

[0062] In some aspects of the disclosure, the pulmonary vasodilator consists of, consists of, or consists essentially of a prostanoid or prostacyclin, hi yet other aspects, the pulmonary vasodilator consists of, consists of, or consists essentially of treprostinil.

[0063] In some embodiments of the present disclosure, the subject's pulmonary artery pressure is monitored remotely. In yet other embodiments, the mean pulmonary artery pressure is monitored continuously. In some embodiments, the mean pulmonary artery pressure is monitored using a wireless pulmonary artery pressure sensor implanted in the subject.

[0064] In some embodiments of the present disclosure, the target level is less than 50 mmHg, or less than 40 mmHg, or less than 30 mmHg, or less than 25 mmHg. In still further aspects, the threshold is greater than 20 mmHg, or greater than 30 mmHg, or greater than 40 mmHg. In some aspects, the initial mean pulmonary artery pressure is greater than 35 mmHg.

[0065] In some embodiments of the present disclosure, the method comprises, consists of, or consists essentially of monitoring the right ventricular structure of the subject.In yet another embodiment, the method further comprises, consists of, or consists essentially of measuring the right ventricular ejection fraction after a first period of time after administration of treprostinil, its ester, or salt.

[0066] In some embodiments, the ejection fraction is measured by cMRI. In yet another embodiment, the method further comprises, consists of, or consists essentially of measuring the ratio of stroke volume to end-systolic volume. In yet another embodiment, the method comprises, comprises, or essentially comprises measuring the ratio of tricuspid annular plane systolic stretch to pulmonary artery systolic pressure.

[0067] In some embodiments of the present disclosure, the subject has not previously received treatment for pulmonary hypertension or has received an endothelin receptor antagonist and / or a phosphodiesterase type 5 inhibitor for less than 24 months, or less than 18 months, or less than 12 months, or less than 6 months, or less than 3 months, or less than 1 month.

[0068] In some embodiments of the present disclosure, administering consists of, consists of, or consists essentially of intravenous administration. In yet other aspects, administering consists of, consists of, or consists essentially of administration by inhalation. In yet other embodiments, administering consists of, consists of, or consists essentially of administering an oral formulation.

[0069] Administration can be by the routes described above, or, for example, orally, intravenously, intraarterially, intramuscularly, nasally, rectally, vaginally, or subcutaneously. In some embodiments, the composition is administered by injection. In some embodiments, administration is orally. In some embodiments, administration is subcutaneously.

[0070] In some embodiments, the administration results in no or less pain at the injection site compared to administration of treprostinil. Pain, or its reduction, can be assessed by any medically recognized method known in the art, such as a numeric rating scale (NRS), a visual analog scale (VAS, i.e., the Wong-Baker pain scale), the FLACC scale, the CRIES scale, the COMFORT scale, the McGill pain scale, the Manoski scale, or other categorical scales. Compared to injection of treprostinil, injection of the prodrug results in 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% less pain, as measured by a medically recognized method.

[0071] The subject to be treated may be a human, dog, cat, bird, non-human primate, cow, or horse. In some embodiments, the subject is a human. In some embodiments, the subject is a human who is uncooperative or afraid of injections, such as a child or a demented elderly subject.

[0072] The embodiments described herein are further illustrated by, but in no way limited to, the following examples. [Example]

[0073] method The ARTISAN (Afterload Reduction To Improve Right Ventricular Structure And Function) clinical trial (NCT 05203510) is a prospective, multicenter, open-label study evaluating the efficacy of early and rapid treprostinil therapy to reduce mPAP and reverse RV remodeling in PAH. Patients were newly treated for PAH or had been treated with an endothelin receptor antagonist and / or a phosphodiesterase type 5 inhibitor for less than 6 months, had mPAP >35 mmHg, and were in WHO functional class II or III. Based on mPAP assessment, parenteral treprostinil was initiated, followed by oral treprostinil with continued dose titration to further reduce mPAP. mPAP was closely monitored using the CardioMEMS HF system, and RV structure and function were monitored with cardiac magnetic resonance imaging (cMRI) and echocardiography.

[0074] result Approximately 50 patients will be enrolled. The primary endpoint is change in RV ejection fraction from baseline to 12 months as measured by cMRI. Key secondary endpoints include mPAP, clinical improvement, the ratio of stroke volume to end-systolic volume measured by cMRI, the ratio of tricuspid annular plane systolic amplitude to pulmonary artery systolic pressure measured by echocardiography, and survival to 36 months.

[0075] Treprostinil's primary mechanism of action is direct vasodilation of the pulmonary arterial vascular bed and inhibition of smooth muscle cell proliferation. Treprostinil's mechanism of anti-remodeling action in human pulmonary artery smooth muscle cells may be beneficial for patients with PAH, reducing pulmonary arterial wall remodeling (PPloS One. 2018;13(11):e0205195). Following early first-line treprostinil treatment with rapid dose escalation to reduce mean pulmonary arterial pressure (mPAP) to less than 35 mmHg, aiming for mPAP normalization, and monitoring with the CardioMEMS HF System, subjects demonstrated significant improvement in RV function as assessed by the primary endpoint. Normalization of mPAP and reversal or improvement of RV function, measured by RV ejection fraction, may be associated with prolonged survival and favorable outcomes compared with untreated controls. These results suggest that mPAP reduction through the use of pulmonary vasodilators may be a novel treatment approach to improve patient survival and outcomes. Specifically, the effects of pulmonary vasodilators, monitored in real time with the CardioMEMS HF System, may be an effective strategy in lowering mPAP to reverse RV remodeling and improve survival in populations suffering from pulmonary hypertension (Life, 2023; 13, 1202; see also Heart 2023; 0:1-7).

[0076] Although certain preferred embodiments have been referred to above, it will be understood that the present invention is not so limited. Those skilled in the art will recognize that various modifications can be made to the disclosed embodiments, and that such modifications are intended to be within the scope of the present invention.

[0077] All publications, patent applications and patents cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A method of treating pulmonary hypertension, comprising: monitoring mean pulmonary artery pressure in the subject; administering to the subject a first therapeutically effective amount of a pulmonary vasodilator, or an ester or salt thereof, when the mean pulmonary artery pressure in the subject exceeds a threshold value; administering increasing doses of a pulmonary vasodilator or an ester or salt thereof until the mean pulmonary artery pressure is reduced to a target level. A method comprising:

2. 10. The method of claim 1, wherein the pulmonary vasodilator is a prostanoid or prostacyclin.

3. 10. The method of claim 1, wherein the pulmonary vasodilator is treprostinil.

4. 10. The method of claim 1, wherein the mean pulmonary artery pressure in the subject is monitored remotely.

5. 10. The method of claim 1, wherein mean pulmonary artery pressure is continuously monitored.

6. 10. The method of claim 1, wherein the mean pulmonary artery pressure is monitored using a wireless pulmonary artery pressure sensor implanted in the subject.

7. 10. The method of claim 1, wherein the target level is less than 50 mmHg, or less than 40 mmHg, or less than 30 mmHg, or less than 25 mmHg.

8. 2. The method of claim 1, wherein the threshold is 20 mmHg or greater, or 30 mmHg or greater, or 40 mmHg or greater.

9. The method of claim 1 , further comprising monitoring a right ventricular structure of the subject.

10. 10. The method of claim 1, further comprising measuring right ventricular ejection fraction after a first period of time after administration of treprostinil, an ester or a salt thereof.

11. 11. The method of claim 10, wherein the ejection fraction is measured by cMRI.

12. The method of claim 1 , further comprising measuring the ratio of stroke volume to end-systolic volume.

13. 10. The method of claim 1, further comprising measuring the ratio of tricuspid annular plane systolic stretch to pulmonary artery systolic pressure.

14. 10. The method of claim 1, wherein the subject has not previously received treatment for pulmonary hypertension or has received an endothelin receptor antagonist and / or a phosphodiesterase type 5 inhibitor for less than 24 months, or less than 18 months, or less than 12 months, or less than 6 months, or less than 3 months, or less than 1 month.

15. 10. The method of claim 1, wherein the initial mean pulmonary artery pressure is greater than 35 mmHg.

16. 10. The method of claim 1, wherein the administering comprises intravenous administration.

17. 10. The method of claim 1, wherein administering comprises administering by inhalation.

18. 10. The method of claim 1, wherein administering comprises administering an oral formulation.

19. The method of claim 1 , wherein the subject is a human.

20. 10. The method of claim 1, wherein the right ventricular ejection fraction does not change by more than 15 mmHg during administration.

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