Treatment methods for pulmonary hypertension

Abstract

According to embodiments of the present invention, a method for treating pulmonary hypertension comprises administering an effective amount of vardenafil, or a pharmaceutically acceptable salt or hydrate thereof, to a subject requiring such treatment. According to this method, vardenafil is administered by inhalation using a portable inhaler as needed, and the vasodilator is administered at least 2 to 30 minutes before physical activity.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 470,091, filed on 31 May 2023, for the title of the invention, “Methods for Treatment of Pulmonary Hypertension,” which is incorporated herein by reference in its entirety.

[0002] The present invention relates to methods and compositions useful in subjects suffering from pulmonary arterial hypertension, and to devices useful in combination with such methods and compositions. [Background technology]

[0003] Pulmonary hypertension (PH) is a rare disease defined by abnormally high pulmonary artery pressure and pulmonary vascular resistance (PVR). Group 1 PH, or pulmonary arterial hypertension (PAH), is a progressive disease of unknown etiology. It can be characterized by mean pulmonary artery pressure (mPAP) of 20 mmHg or higher, pulmonary capillary wedge pressure (PCWP) of 15 mmHg or lower, pulmonary vascular resistance (PVR) of 3 Wood Units or higher, and physiological changes in the pulmonary arteries. As the disease progresses, exercise tolerance decreases, and daily activities become increasingly difficult.

[0004] Currently, there is no cure for PAH. The disease is managed with approved treatments such as endothelin receptor agonists, phosphodiesterase 5 inhibitors (PDE5i), and prostacyclin analogs, which reduce symptoms over time and slow disease progression.

[0005] Because approved treatments cannot be used to treat acute symptoms themselves, managing acute symptoms triggered by daily activities remains a current challenge for patients living with PAH. Currently approved treatments for PAH are long-term treatments requiring multiple doses to alleviate symptoms and slow disease progression. Furthermore, despite ongoing advancements in these treatments, patients continue to experience significant declines in cardiac respiration fitness and exercise tolerance. These treatments are also associated with side effects that reduce patients' quality of life, including nausea, headache, and redness, as well as pain and infection at the injection site from infusion administration. These side effects are partly due to the doses required to achieve effective local drug concentrations in the pulmonary artery.

[0006] Therefore, there is an urgent and unmet clinical need for patient-as-needed (PRN) interventions for PAH that reduce acute symptoms and enable patients to engage in daily activities and exercise. [Overview of the project]

[0007] According to embodiments of the present invention, a method for treating pulmonary hypertension comprises administering an effective amount of vardenafil, or a pharmaceutically acceptable salt or hydrate thereof, to a subject requiring such treatment. According to this method, vardenafil is administered by inhalation using a portable inhaler as needed, and the vasodilator is administered at least 2 to 30 minutes before physical activity.

[0008] In one embodiment, administering vardenafil involves directing the vardenafil to the peripheral airways of the subject's lungs. In a further embodiment, a nominal dose of vardenafil of about 0.5 mg to about 1 mg is delivered to the subject by inhalation. In one embodiment of the present invention, a nominal dose of vardenafil of about 0.5 mg is delivered to the subject by inhalation. Alternatively, in one embodiment of the present invention, a nominal dose of vardenafil of about 1.0 mg is delivered to the subject by inhalation. [Modes for carrying out the invention]

[0009] This invention relates to methods and compositions useful in subjects suffering from PAH, and to devices useful in combination with such methods and compositions. The method involves administration of a phosphodiesterase type 5 inhibitor (PDE5i) by PRN inhalation. In some embodiments, the PDE5i is vardenafil.

[0010] The methods disclosed herein provide a pulmonary targeted therapy for patients with PAH, other forms of PH, or other lung disorders, delivered to the pulmonary vascular bed with minimal systemic exposure via a dry powder inhaler. Such appropriate inhalation dosing is characterized by good lung tolerance and near-total or no systemic exposure, and is useful for both targeted, long-term maintenance therapy and potential PRN use, delivered once, twice, three times, or more times daily.

[0011] PRN administration for PH, when convenient and portable, easily improves patients' short-term functional and exercise tolerance, enabling them to achieve daily activities of daily living or other more strenuous activities when they wish to. By avoiding systemic (enteral or parenteral) administration of vasodilators and the potential for airflow / perfusion mismatch associated with dose-limiting systemic side effects, the method of inhaled pulmonary vasodilators delivered by an easy-to-use portable inhaler provides improved function and quality of life for patients with limited effort due to PH and / or interstitial lung disease (ILD).

[0012] In some cases, self-administration of low-dose medications via inhalation, such as inhaled PDE5i like vardenafil as PRN therapy at the peak of long-term background therapy, can provide patients with improved exercise tolerance throughout the day while minimizing the risk of systemic side effects. PRN administration can propose drug products that effectively direct the pulmonary and pulmonary blood vessels while minimizing drug concentration in the systemic circulation, contributing to a reduction in systemic blood pressure. Aerosol administration also provides a rapid onset of action (comparable to infusion) compared to oral administration.

[0013] Inhalation of vasodilators for pre-radicular-weight neurotransmitter administration offers PH patients the opportunity to optimize their daily functioning by self-administering lower nominal doses of medication, which is preliminary to increased activity for complementary background therapy, leading to safe and effective improvements in daily functioning quality of life indices and metrics.

[0014] For example, methods and compositions for the treatment of pulmonary hypertension and other lung disorders, including methods and compositions with PDE5 inhibitors such as vardenafil, are disclosed in U.S. Patent No. 10,912,778, titled “Methods for Treatment of Pulmonary Hypertension,” which is incorporated herein by reference in its entirety.

[0015] PDE5i PDE5 inhibitors inhibit phosphodiesterase type 5 (PDE5) enzyme, which is also responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with a decrease in vascular endothelium in pulmonary vascular smooth muscle and, consequently, impaired nitric oxide (NO) release due to reduced cGMP concentration. PDE5 is the main phosphodiesterase in the pulmonary vascular bed. Inhibition of PDE5 by PDE5 increases cGMP concentration, leading to relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Suitable PDE5i class agents for use with embodiments of the present invention include sildenafil, tadalafil, vardenafil, avanafil, benzamidenafil, rodenafil, mirodenafil, udenafil, and zaprinast.

[0016] In connection with one embodiment of the present invention, the PDE5i agent is vardenafil (i.e., 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethylpiperazine, or a pharmaceutically acceptable salt thereof, such as monohydrochloride). Vardenafil, and other 2-phenyl-substituted imidazotriazinones, are described, for example, in U.S. Pat. Nos. 6,890,922, 7,122,540, 7,314,871, 7,704,999, and 7,696,206, all of which are incorporated herein by reference in their entirety. Vardenafil has been shown to be safe and effective in human patients with PAH when orally administered twice daily at a dose of 5 mg. Vardenafil has been shown to have characteristics superior to sildenafil and tadalafil for use as an inhalant, as described in International PCT Application No. WO / 2015 / 089105 and U.S. Patent Application No. 2016 / 0317542, both of which are incorporated herein by reference in their entirety, and is formulated as a dry powder and delivered by a dry powder inhaler device. Vardenafil is a high-affinity inhibitor of PDE5 (half-maximal inhibitory concentration [IC 50 0.091 ± 0.031).

[0017] Method of using PDE5i The therapeutic target for the vasodilators disclosed herein is smooth muscle cells within the pulmonary artery and small arterioles. One goal for a PRN therapeutic agent can be to maximize the delivery of the agent to the pulmonary artery while minimizing off-target delivery of the agent to the mouth and throat when swallowed, and minimizing concerns regarding safety and tolerability. Inhalation For therapeutic agents, improvement at the lung target can be achievable not only by more efficient drug delivery to the lung, but also by rational design and / or selection of the agent being delivered.

[0018] The goals of PRN therapeutics targeting the lung can be quite the opposite of those for oral therapeutics. For orally administered therapeutics, the goal is to maximize and maintain the concentration of the drug in the systemic circulation. This is achieved by maximizing oral bioavailability and then maintaining the systemic concentration of the "free" drug by minimizing protein binding and whole body clearance. In contrast, pulmonary PRN therapeutics strive to maximize residence time in the lung, either by prolonging receptor binding time, delaying dissolution of the drug into the epithelial lining fluid, or developing controlled release dosage forms (e.g., liposomes). Once absorbed into the systemic circulation, the goal is to minimize systemic effects by clearing the drug as quickly as possible and / or binding it to plasma proteins. Additionally, minimizing oral bioavailability is important to minimize the systemic concentration of the drug resulting from drug deposition in the upper airway after inhalation. Vardenafil has a slow dissociation rate and rapid clearance and is ideally suited for PRN use.

[0019] Inhalation device for PDE5i powder Transpulmonary administration provides non-invasive, direct targeting delivery of vasodilators to the site of action in the lung, thereby improving lung selectivity and reducing adverse events associated with off-target delivery. Portable aerosol delivery systems are particularly advantageous for PRN administration of vasodilators. For the purposes of the present disclosure, a "portable" inhaler refers to an inhaler that can easily fit into a pocket or wallet. A portable inhaler with a short administration time can be used unobtrusively in public spaces. The methods and compositions according to embodiments of the present invention can use a drug delivery device that is portable, simple, and convenient to use (e.g., does not require power, active agent reconstitution steps, and cleaning), enabling a short administration time and a low daily treatment burden.

[0020] Administration of the compositions disclosed herein can be effected by various classes of portable inhalers, including dry powder inhalers, pressurized metered dose inhalers, and smart mist inhalers.

[0021] In some cases, vasodilators can be delivered to patients using highly efficient dry powder inhalers (DPIs). In some cases, the inhalers are those described in U.S. Patent No. 8,651,104; U.S. Patent No. 8,561,609; U.S. Patent Application No. 2013 / 0213397; U.S. Patent Application No. 2015 / 0246189; U.S. Patent Application No. 2013 / 0340747; and U.S. Patent Application No. 2015 / 0314086, each of which is incorporated herein by reference for all purposes. Such inhalers can improve the delivery of many drugs, in some cases dry powder compositions of pure micronized drugs, including, for example, vardenafil, PDE5 inhibitors, or, for example, powdered vardenafil hydrochloride.

[0022] In a particular embodiment, a method for aerosolizing a dry powder composition is provided. As a first step, a carrier-based powder pharmaceutical composition comprising a vasodilator (e.g., a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof) is provided. In a second step, an inhaler can be provided, comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable and reciprocating along the longitudinal axis of the dispersion chamber. The first and second steps can be performed in any order or simultaneously. In a third step, an airflow is induced through an exhaust channel, causing air and the powder pharmaceutical composition to enter the dispersion chamber from the inlet, vibrating the actuator within the dispersion chamber, and assisting the distribution of the powder pharmaceutical composition from the outlet for delivery to a target through the outlet. In some cases, the powdered drug may be stored in a storage compartment (of the inhaler), and the powder pharmaceutical composition is transferred from the storage compartment through the inlet to the dispersion chamber. In a particular case, the inlet may be in fluid communication with the first chamber, and the powder pharmaceutical composition is received in the first chamber and then enters the dispersion chamber through the inlet.

[0023] In practice, patients can plant an aerosolizing device by puncturing a container that holds the formulation (such as a capsule or blister), or they can transfer the drug from the powder reservoir of the device to the inhalation portion and then inhale it. Upon inhalation by the patient, the powder is drawn through the inhaler device, where entrainment of the powder leads to fluidization and deaglomeration of the powder agglomerate into respiratory dust. This approach may be useful for effectively dispersing two- and three-component carrier-based compositions, as well as formulations containing modified particles.

[0024] Examples of devices for use in administering dry powder compositions include, but are not limited to, dry powder inhalers and metered-dose inhalers such as TWISTHALER® (Merck), DISKUS® (GSK), HANDIHALER® (BI), AEROLIZER®, TURBUHALER® (AstraZeneca), FLEXHALER® (AstraZeneca), NEOHALER® (BREEZHALER®) (Novartis), PODHALER® (Novartis), EASYHALER® (Orion), NOVOLIZER® (Meda Pharma), and ROTAHALER® (GSK). As is well known to those skilled in the art, various devices have a variety of performance characteristics, particularly based on device resistance, deaggregation mechanism, adhesion of the drug to the internal flow path, and patient adaptation and inhalation ability.

[0025] In some embodiments, a dry powder composition may be administered using a dry powder inhaler, which includes a dry powder crusher, also known as a powder dispersion mechanism. Exemplary powder dispersion mechanisms are described in their entirety in U.S. Patent Applications 2013 / 0340754 and 2013 / 0340747, which are incorporated herein by reference. In some cases, such a powder dispersion mechanism may include beads placed within a chamber, which are arranged and configured to include a rapid, quick, or otherwise abrupt expansion of the flow upon entering the chamber. Generally, the chamber may be connected to any form or type of dose-limiting system or source that supplies the powder activator to the chamber.

[0026] In some cases, the powder dispersion mechanism can be connected to a dry powder inhaler, such as a commercially available device. The dispersion mechanism (dispersion chamber) may be adapted to receive an aerosolized powder activator from an inlet channel, such as the one described by reference herein, for example, U.S. Patent Application No. 2013 / 0340754. The powder dispersion mechanism (dry powder crusher) may be adapted to receive at least a portion of the aerosolized powder activator from a first chamber of the inhaler. The powder dispersion mechanism may comprise a dispersion chamber capable of holding an actuator that is movable within the dispersion chamber along a longitudinal axis. The dry powder inhaler may include an outlet channel through which air and powder activator exit the inhaler and are delivered to a target. The geometry of the inhaler may be such that a flow profile is generated within the dispersion chamber, causing vibration of the actuator along a longitudinal axis, and the vibration actuator can efficiently disperse the powdered drug received in the dispersion chamber for delivery to the patient through the outlet channel.

[0027] In certain cases, a dry powder inhaler system can be used to aerosolize and administer a dry powder composition. The dry powder inhaler system may comprise a container containing a certain amount of powdered activator. The dry powder inhaler system may comprise an inlet channel adapted to receive air and powdered activator from the container. The dry powder inhaler system may comprise a first chamber adapted to receive air and powdered activator from the inlet channel. The volume of the first chamber may be greater than the volume of the inlet channel. The dry powder inhaler system may comprise a dispersion chamber adapted to receive air or powdered drug from the first chamber. The dispersion chamber may hold an actuator that is movable within the dispersion chamber along a longitudinal axis. The dry powder inhaler system may comprise an outlet channel through which air and powdered activator exit the dispersion chamber and are delivered to the patient. The geometry of the system may be such that a flow profile is generated within the system that causes vibration of the actuator along a longitudinal axis, and the vibration actuator can efficiently disperse the powdered drug received in the dispersion chamber for delivery to the patient through the outlet channel.

[0028] Dosage and Administration Compositions and methods according to embodiments of the present invention can provide dose-administration without strict treatment regimens. Furthermore, medications designed for use "as needed" can provide a significant boost to patients who have poor adherence to long-term medication regimens, or to patients who, while well-adhered, lack exercise tolerance at various times of the day as a result of their treatment regimens. In addition, PRN therapies can reduce or otherwise improve symptoms in patients who have missed doses, while still allowing them to maintain their planned treatment regimen. The use of PRN therapies can simplify medication consultations for missed doses. For example, if a dose is missed, a patient can receive a consultation to administer a certain dose of PRN therapy and then resume their usual treatment schedule for long-term medication.

[0029] Upon administration of a PRN dosage form according to an embodiment of the present invention, the patient may begin to feel a rapid relief of symptoms, and in some cases, the relief may be felt essentially immediately. The PRN dosage form according to an embodiment of the present invention can have its action rapidly initiated, for example, in less than 15 minutes, less than 10 minutes, or less than 5 minutes, to the maximum concentration of the drug achieved in circulation. Furthermore, pharmacodynamic effects (e.g., improved hemodynamics, gas exchange, and symptom relief) may occur within, for example, 30 minutes, and measurable improvement may occur within 15 or 10 minutes after administration.

[0030] As described herein, inhalation of vasodilators is appropriate for a period of well less than one hour to the vasodilator. max This value can provide a rapid onset of action. For example, inhaled vardenafil can be administered intrapulmonaryly within 2 minutes. max It has the following characteristics: In contrast to common oral vasodilators, max The values ​​are typically in the range of 2 to 8 hours. While intravenous injections provide immediate drug concentrations in circulation, they are not as suitable as PRN treatments because dose delivery is highly invasive, leading to high systemic drug levels and significant adverse events, and the procedure is inconvenient, as patients cannot be administered as needed without the use of a complex pump system.

[0031] Importantly, PRN therapeutic agents according to embodiments of the present invention can provide symptom relief and improved exercise tolerance for a period long enough to complete the target activity. Generally, the duration of action is at least one hour and can extend to more than two hours, more than three hours, or even longer.

[0032] PRN therapies according to embodiments of the present invention can maximize the amount of drug delivered to the pulmonary artery while minimizing off-target drug delivery (e.g., gastrointestinal and systemic delivery), thereby minimizing safety and tolerability challenges. Targeted delivery to the lungs is maximized by aerosol administration via oral inhalation. Given that the drug is administered on top of background therapy, a superior adverse event profile is a particularly important advantage of PRN therapies. Injectable solutions lead to higher systemic concentrations of the drug, which can result in significant adverse events, making them less suitable for PRN administration.

[0033] In a method according to an embodiment of the present invention, when physical activity such as exercise, walking, going to a store, or other activity is anticipated in a patient, a PRN formulation containing only a vasodilator (e.g., a PDE5i agent) or a combination of a vasodilator and a second agent (either formulated together or packaged separately) may be administered by inhalation. Typically, the patient may be administered the formulation(s) 2 to 30 minutes before such activity. These doses may be administered to the patient in addition to any long-term therapy being taken, for example. The administration of a vasodilator, or a combination of the above-mentioned agents, can be low enough not to cause significant additional side effects to the patient's standard drug regimen, but nevertheless, it can be sufficient to transiently dilate the pulmonary blood vessels for at least 30 minutes to at least 6 hours, thereby improving the patient's exercise tolerance and enabling them to complete desired activities of daily living (ADL).

[0034] In some embodiments, the PRN therapeutic agent comprises one or more activators in a nominal dose ranging from 0.1 to 5.0 mg (e.g., 0.15 to 0.5 mg). In some embodiments, the PRN therapeutic agent comprises one or more activators in a nominal dose ranging from 0.02 to 1.0 mg (e.g., 0.04 to 0.1 mg). As a non-limiting example, the nominal dose of vardenafil (in its basic form) for an inhaled PRN therapeutic agent, formulated in a carrier-based formulation and delivered by a capsule-based dry powder inhaler, may typically range from about 0.1 mg to about 2.0 mg (e.g., 0.15 to 0.50 mg).

[0035] For example, formulations with various dosages can be conceivable, including formulations containing an activator of PDE5i delivered to the lungs in inhalation doses ranging from 0.01 mg to 5 mg.

[0036] For example, the PDE5i inhalation doses are 0.01mg-0.5mg, 0.01mg-1mg, 0.01mg-2mg, 0.025mg-0.5mg, 0.025mg-1mg, 0.025mg-2mg, 0.05mg-0.5mg, 0.05mg-1mg, 0.05mg-2mg, 0.075mg-0.5mg, 0.075mg-1mg, 0.075mg-2mg, 0.1mg-0.25mg, 0.1mg-0.5mg, 0.1mg-1mg, 0.1mg-2mg, 0.1mg-3mg, 0.1mg-4mg, 0.25mg-0.5mg, 0.25mg-0.75mg, 0.25mg-1mg, 0.25mg-1.5mg, 0.25mg-2mg. The doses can range from mg, 0.25mg to 3mg, 0.25mg to 4mg, 0.5mg to 0.75mg, 0.5mg to 1mg, 0.5mg to 2mg, 0.5mg to 1mg, 0.5mg to 2mg, 0.5mg to 3mg, 0.5mg to 4mg, 0.75mg to 1mg, 0.75mg to 2mg, 0.75mg to 1mg, 0.75mg to 2mg, 0.75mg to 3mg, 0.75mg to 4mg, 1mg to 1.5mg, 1mg to 2mg, 1mg to 2.5mg, 1mg to 3mg, 1mg to 3.5mg, 1mg to 4mg, 2mg to 3mg, 2mg to 4mg, 0.5mg to 4.5mg, 2mg to 5mg, and doses within 25% of these ranges. In some such embodiments, the PDE5i agent is vardenafil.

[0037] In some cases, the PDE5i composition is 0.01 mg, 0.25 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.225 mg, 0.25 mg, 0.275 mg, 0.3 mg, 0.325 mg, 0.35 mg, 0.375 mg, 0.4 mg, 0.425 mg, 0.45 mg, 0.5 mg, 0.525 mg, 0.55 mg, 0.575 mg, 0.6 mg, 0.625 mg, 0.65 mg, 0.6 75mg, 0.7mg, 0.725mg, 0.75mg, 0.775mg, 0.8mg, 0.825mg, 0.85mg, 0.875mg, 0.9mg, 0.925mg, 0.95mg, 0.975mg, 1.0mg, 1.1mg, 1 .15mg, 1.2mg, 1.25mg, 1.3mg, 1.35mg, 1.4mg, 1.45mg, 1.5mg, 1.55mg, 1.6mg, 1.65mg, 1.7mg, 1.75mg, 1.8mg, 1.85mg, 1.9mg, 1. 95mg, 2.0mg, 2.1mg, 2.15mg, 2.2mg, 2.25mg, 2.3mg, 2.35mg, 2.4mg, 2.45mg, 2.5mg, 2.55mg, 2.6mg, 2.65mg, 2.7mg, 2.75mg, 2. 8mg, 2.85mg, 2.9mg, 2.95mg, 3.0mg, 3.1mg, 3.15mg, 3.2mg, 3.25mg, 3.3mg, 3.35mg, 3.4mg, 3.45mg, 3.5mg, 3.55mg, 3.6mg, 3.65 Inhalation doses may be 3.7 mg, 3.75 mg, 3.8 mg, 3.85 mg, 3.9 mg, 3.95 mg, 4.0 mg, 4.1 mg, 4.15 mg, 4.2 mg, 4.25 mg, 4.3 mg, 4.35 mg, 4.4 mg, 4.45 mg, 4.5 mg, 4.55 mg, 4.6 mg, 4.65 mg, 4.7 mg, 4.75 mg, 4.8 mg, 4.85 mg, 4.9 mg, 4.95 mg, or 5.0 mg, or doses up to 25% of any of these doses. In some such embodiments, the PDE5i agent is vardenafil.

[0038] In some cases, the PDE5i composition contains at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, Inhalation doses may be 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5 mg. In some cases, the PDE5i composition may be present in amounts less than approximately 0.1 mg, less than approximately 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg Inhalation doses of 1 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5 mg may be available. In some cases, subjects may receive a daily inhalation dose of 0.25 mg to 1 mg, 0.1 mg to 4 mg, 0.1 mg to 2 mg, or 1 mg to 4 mg of the PDE5i composition, or doses less than 25% of these ranges. In some such embodiments, the PDE5i agent is vardenafil.

[0039] In some cases, the PDE5i composition contains at least approximately 0.001 mg, 0.0025 mg, 0.005 mg, 0.0075 mg, 0.01 mg, 0.0125 mg, 0.015 mg, 0.0175 mg, 0.02 mg, 0.025 mg, 0.0275 mg, 0.03 mg, 0.0325 mg, 0.035 mg, 0.0375 mg, 0.04 mg, 0.0425 mg, 0.05 mg, 0.0525 mg, 0.055 mg, 0.0575 mg, 0.06 mg, 0.0625 mg, 0.065 mg, 0.0675 mg, 0.07 mg, and 0.0725 mg. The inhalation doses may be 0.075 mg, 0.0775 mg, 0.08 mg, 0.0825 mg, 0.085 mg, 0.0875 mg, 0.09 mg, 0.0925 mg, 0.095 mg, 0.0975 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.225 mg, 0.25 mg, 0.275 mg, 0.3 mg, 0.325 mg, 0.35 mg, 0.375 mg, 0.4 mg, 0.425 mg, 0.45 mg, 0.475 mg, 0.5 mg, or doses up to 25% of any of these doses. In some such embodiments, the PDE5i agent is vardenafil.

[0040] In some cases, the PDE5i composition is present in amounts of approximately 0.001 mg, 0.0025 mg, 0.005 mg, 0.0075 mg, 0.01 mg, 0.0125 mg, 0.015 mg, 0.0175 mg, 0.02 mg, 0.025 mg, 0.0275 mg, 0.03 mg, 0.0325 mg, 0.035 mg, 0.0375 mg, 0.04 mg, 0.0425 mg, 0.05 mg, 0.0525 mg, 0.055 mg, 0.0575 mg, 0.06 mg, 0.0625 mg, 0.065 mg, 0.0675 mg, 0.07 mg, 0.0725 mg, 0. Inhalation doses may be 0.75 mg, 0.0775 mg, 0.08 mg, 0.0825 mg, 0.085 mg, 0.0875 mg, 0.09 mg, 0.0925 mg, 0.095 mg, 0.0975 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.225 mg, 0.25 mg, 0.275 mg, 0.3 mg, 0.325 mg, 0.35 mg, 0.375 mg, 0.4 mg, 0.425 mg, 0.45 mg, 0.475 mg, less than 0.5 mg, or within 25% of any of these doses. In some cases, subjects may receive daily inhalation doses of 0.003 mg to 1 mg, 0.015 mg to 0.75 mg, 0.075 mg to 0.375 mg, or 0.075 mg to 0.75 mg, or doses less than 25% of these ranges. In some such embodiments, the PDE5i drug is vardenafil.

[0041] The terms "nominal dose" or "total dose" refer to the total amount or mass of the active ingredient packaged or portioned for administration to a subject. For example, the nominal dose is the total amount of active ingredient contained in capsules for use with an inhaler.

[0042] Example 1 RT234 represents a drug / device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers vardenafil, a phosphodiesterase-5 inhibitor, to the lungs via inhalation and has been shown to reduce pulmonary vascular resistance (PVR) in patients with PAH. This embodiment describes a study to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH.

[0043] This prospective, multicenter, open-label, two-cohort, dose-escalation phase IIb trial will evaluate the safety and efficacy of RT234 in complete exercise parameters in patients with PAH. Eligible patients for enrollment are those with a right heart catheterization (RHC) confirmed diagnosis of PAH, a 6-minute walk distance of ≥150 m, a minute ventilation / carbon dioxide production (VE / VCO2) gradient of ≥36, and who have received up to three stable oral and / or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, divided into two dose cohorts. Cohort 1 will receive 0.5 mg of RT234, and Cohort 2 will receive 1.0 mg of RT234. Each cohort will contain two subgroups based on the number of PAH background medications received (up to two and three). The clinical trial will evaluate the change from baseline in peak oxygen consumption (VO2), the change in 6-minute walking distance, and the pharmacokinetic and safety profiles of a single dose of RT234 during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg of RT234 in patients.

[0044] To be eligible for inclusion in the clinical trial, patients must be between 18 and 80 years of age (inclusive) and have one of the following: (1) idiopathic, class I, or familial PAH; (2) PAH associated with connective tissue disease; or (3) HIV; simple congenital systemic-pulmonary splitting more than one year after postoperative repair; or a diagnosis of PAH confirmed by right heart catheterization (RHC) in response to exposure to drugs, chemicals, and toxins; and patients must have ventilation / perfusion scans, computed tomography angiography, or pulmonary angiography excluding long-term thromboembolic pulmonary hypertension; and meet the following conditions: (1) disease-specific background PAH treatment at least three months prior to the CPET procedure. A previous diagnosis of PAH accompanied by (2) stable PAH without significant adjustments, and (3) stable doses of prednisone (or other corticosteroid at doses less than 20 mg / day) for more than 30 days prior to reference CPET; below: (1) Forced expiratory volume per second (FEV1) of 60% or more expected, (2) Forced expiratory vital capacity (FVC) of 60% or more expected, and (3) Pulmonary function tests (PFT) within 6 months prior to the start of screening or during the screening period that meet the following criteria: (1) mPAP ≥ 20 mmHg (at rest), and (2) 300 ≤ PVR < 500 dyn / s cm -5 In this case, PCWP of 12 mmHg or less, or ventricular end-diastolic pressure, or PVR of ≥ 500 dyn·s cm -5 In this case, PCWP or LVEDP of ≤15 mmHg, and if PCWP is unavailable, in the absence of left atrial dysfunction, mean left arterial pressure (mLAP) or LVEDP of ≤15 mmHg or ≤12 mmHg, and PVR > 3 Wood units or > 240 dyn·s cm. -5 The following conditions must be met: a diagnosis of PAH and a documented RHC performed before consistent screening; functional class II-IV symptomatology of the WHO / New York Heart Association; and ≤35 kg m -2must have a BMI of; must be receiving a stable PAH disease-specific background therapy of up to three oral and / or inhaled therapies; must have a 6MWD of ≥150 m; must have a minute ventilation (VE) / carbon dioxide production (VCO2) gradient of ≥36 during the reference CPET; and the maximum effort during the reference CPET must reach a peak respiratory exchange ratio (RER) of ≥1.0. If the patient is receiving subsequent concomitant medications that can affect PAH, the patient must have been receiving a stable therapeutic dose for at least one month prior to screening, and the dose must be maintained through (1) vasodilators, (2) digoxin, (3) L-arginine supplements, (4) anticoagulants (the anticoagulant state needs to be maintained / stabilized in the therapeutic range for at least one month prior to screening). Stability can be defined as no change in PAH-specific drug therapy within 1 of the 3-month screening visit and during the study period, and no change in the dose of the PAH-specific drug(s) within 1 month of screening. A BMI of 36.0 kg m -2 Individuals above can be considered as inclusion criteria for the clinical trial.

[0045] Criterion for screening includes: standard systemic hypotension defined as mean arterial pressure < 50 mmHg or maximal systolic blood pressure < 90 mmHg; a history of uncontrolled hypertension or current uncontrolled hypertension defined as SBP greater than 175 mmHg or seated diastolic blood pressure greater than 110 mmHg; a history of uncontrolled long-term asthma; patients unable to use or potentially unable to use an inhaler; intravenous inotropic agent requirements within 30 days prior to the reference CPET procedure; use of parenteral PAH medication; use of riociguat as background PAH therapy within one month prior to the start of screening, or from during the study until the end of visit 4; use of oral, topical, or inhaled nitrates within two weeks prior to the reference CPET procedure; and Child-Pugh Portal hypertension, portal hypertension, or chronic liver disease measured as B or C; a history of atrial septal defect repair; a known history of uncorrected right-to-left shunt; clinically relevant persistent patent foramen ovale; or known Eisenmenger physiology; paroxysmal or uncontrolled atrial fibrillation; chronic renal insufficiency; serum alanine aminotransferase or aspartate aminotransferase at more than three times the upper limit of the normal range; 50,000 μL at screening. -1 Less than 9 gdL of platelets at screening. -1 Patients with hemoglobin levels below a certain level; or those with evidence or a history of left-sided heart disease and / or clinically significant heart disease, will be excluded from the trial.

[0046] Once patient eligibility is confirmed, the study begins with a screening visit (visit 1) and continues for 28-3 days prior to the reference CPET visit (Figure 2). The screening visit (visit 1) includes two 6-minute walk tests (6MWTs) conducted at least 2 days apart, or at least 2 hours apart on the same day, if permissible by the patient (this is due to the learning effect associated with the 6MWT, and the relative difference between the two measurements must be within 15%). The reference 6MWD is determined by averaging the two screening 6MWDs. If the relative difference between the two measurements exceeds 15%, a third MWT is performed. If a third 6MWT is performed, the reference 6MWD is determined by averaging the two longest 6MWTs. Urine or serum pregnancy tests can also be performed at screening visit 1. The patient's height can also be obtained at screening visit 1.

[0047] At the CPET reference visit (visit 2; day 1), registered patients return to the testing center for pre-test examinations, reference CPET to measure peak oxygen consumption (VO2), and post-test examinations. Eligible patients whose reference CPET is deemed evaluable by the CPET central laboratory enter the treatment period (visits 3 and 4) for administration of RT234, as well as post-administration CPET and 6MWT. Prothrombin time-to-international normalized ratio can also be tested in patients receiving oral vitamin K antagonists.

[0048] At the CPET procedure visit (visits 3 and 8), patients return to the study facility for pre-CPET examinations and a single dose of RT234 (0.5 mg for cohort 1 and 1.0 mg for cohort 2), where these are administered with the support of the research team. CPET is performed 30 minutes after administration, at approximately the same time (within 2 hours) on each visit, followed by post-study monitoring. The primary endpoint may be the change in peak VO2 from day 1 to day 8 (30 minutes after administration). Urine or serum pregnancy tests may also be performed at visit 3.

[0049] At the 6MWT procedure visit (visit 4; day 15), the patient undergoes a pre-6MWT assessment and receives a single dose of RT234. The patient undergoes the 6MWT 30 minutes after administration, followed by post-test examinations. Plasma samples for PK analysis are collected before and after RT234 administration at visits 3 and 4. Urine or serum pregnancy tests may also be performed at visit 4.

[0050] RT234 will be administered to the patient only between visits 3 and 4 (Figure 1); the patient will not use RT234 at any other time. Once all trials are completed between visits 3 and 4, the patient will remain at the clinic for 4 hours for PK sampling and safety monitoring, and safety monitoring will continue for 30 days after visit 4. Visit 5 (within a 45 ± 3 day window) will be accompanied by a safety follow-up telephone response survey.

[0051] For statistical analysis, the estimated total sample size was 86 enrolled patients with a 5% dropout rate, and the calculated sample size was 17 and 26 patients per dose cohort (0.5 and 1.0 mg) with up to two and three background doses, respectively. A two-sided t-test on one sample (0.05 significance and 80% power) was used to test the null hypothesis of no change in peak VO2 from baseline to post-administration, measured during CPET performed 30 minutes after RT234 administration. For patients with up to two and three background doses in each dose cohort, the estimated mean change from baseline was 1.5 and 1.2 mL of O2 kg, respectively. -1 ·minute -1 This is 2 mL of O2·kg -1 ·minute -1 The standard deviation is estimated for each dose cohort and background medication group.

[0052] A primary efficacy analysis was performed using an improved mITT analysis set that included all treated patients in the baseline and post-baseline follow-up of peak VO2. This mITT analysis set serves as the basis for all efficacy analyses. A single-sample t-test (assuming peak VO2 follows a normal distribution) was used to repeat the analysis procedure with the protocol-following analysis set (all mITT patients who did not experience any major protocol violations) to test the two-sided null hypothesis (significant difference of 0.05) of no change in peak VO2. The 95% CI for peak VO2 is derived from the t-test if normality analysis is not excluded. If normality analysis is excluded, the median change in peak VO2 is measured by 95% CI estimation using a single-sample Wilcoxon signed-rank test.

[0053] A secondary efficacy analysis is performed using the mITT analysis set, and this is repeated using the analysis set described in the protocol for the primary efficacy analysis.

[0054] The PK parameters of vardenafil, and the relationship between vardenafil exposure and changes in CPET parameters and 6MWD, will also be measured. Plasma samples will be collected on visits 3 and 4, before RT234 administration; 3, 15, and 30 minutes after administration; immediately after the end of the exercise period; and at 45, 75, 120, 180, and 240 minutes after administration. Vardenafil concentrations will be measured in the PK samples as described above. The estimators of the PK parameters are T max , C max , the area under the curve (AUC) from time 0 to the last measurable concentration. 0-Last ), AUC from 0 to infinity (AUC 0-Inf ), and half-life (t 1 / 2 ) includes. Regarding CPET, exposure-response analysis is AUC 0-Last Furthermore, based on the change from baseline in peak VO2 measured during CPET 30 minutes after RT234 administration, the exposure-response analysis for the 6MWT was performed using AUC. 0-Last Furthermore, this is based on the change from a baseline of 6MWD (average of 6MWD screened) to 6MWD 30 minutes after RT234 administration.

[0055] Planned PK parameters (T max , C max AUC 0-Last AUC 0-Inf , and t 1 / 2 The PK parameters are calculated for treated patients with available PK measurements, using a standard linear trapezoidal transformation for all available drug concentration measurements. The PK parameters are summarized using standard descriptive statistics (mean, median, n, standard deviation, minimum, maximum, and coefficient of variation), along with 90% confidence intervals where appropriate.

[0056] The primary efficacy endpoint is the change from baseline in peak oxygen consumption (VO2), measured during CPET 30 minutes after a single dose of 0.5 or 1.0 mg of RT234. Secondary efficacy endpoints include: change from baseline 6MWD (average of two 6MWDs at screening) to 6MWD measured 30 minutes after RT234 administration; change from baseline to post-administration in minute VE / VCO2 during CPET; change from baseline to post-administration in the partial pressure response of end-tidal carbon dioxide peak (i.e., maximum level during CPET) to exercise; change from baseline to post-administration during the exercise period of CPET; and Modified Borg Dyspnea Scale. The measures investigated by score include: changes from baseline to post-administration in peak perceived dyspnea during CPET; changes from baseline to post-administration in the patient's overall impression of severity (PGI-S) to CPET (assessed before CPET, after a 2-minute cool-down following treadmill exercise with a mask, and then at 5-minute intervals [7, 12, and 17 minutes] without a mask); and changes from screening to post-administration in PGI-S for 6MWT (assessed before 6MWT and 2 minutes after completion of 6MWT).

[0057] Appearance evaluation items may include, for example, the percentage of patients showing improvement in their risk category (low, moderate, or high) relative to the VE / VCO2 gradient criteria during CPET from baseline to post-administration, and changes in the following additional CPET parameters from baseline to post-administration: electrocardiogram (ECG) response to exercise, VO2 at the ventilation threshold, change in respiratory exchange ratio at peak VO2, SBP response to exercise, pulse oximetry response to exercise, non-peak Modified Borg Dyspnea Scale Score throughout exercise (non-peak every minute during CPET and for 6 minutes after CPET), Borg rating of perceived exercise intensity throughout exercise (every 2 minutes during CPET and for 6 minutes after CPET), Duke Activity Status Index (can be measured for 10 minutes after CPET), and Angina Scale (every 2 minutes during CPET and for 6 minutes after CPET, or, if indicated, until symptom recovery).

[0058] Safety investigations will involve the assessment of the adverse event profile and acute physical and cardiac symptoms following a single dose (0.5 or 1.0 mg) of RT234. The incidence and severity of TATEs will be summarized according to the National Cancer Institute's General Terminology Standards (current edition) for Systemic Organ Classes and Basic Terms, Adverse Events, Grades, and Causality (investigative treatments, and related / unrelated contributions to the investigational drug product). Changes in vital signs (blood pressure [BP], heart rate, respiratory rate, body temperature, and pulse oximetry) will be monitored, and a physical examination and 12-lead electrocardiogram (ECG) will be performed to measure changes from baseline to post-administration. Past medical history includes any signs, symptoms, or events the patient has experienced since a previous study visit. Vital signs can be tested after 5 minutes of rest (seated). Vital signs must be obtained before any blood draw. Vital signs can also be measured during and after CPET. Heart rate can be measured by continuous ECG monitoring during and for 6 minutes after CPET. Blood pressure can be measured every 2 minutes during CPET and for 6 minutes after CPET. Pulse oximetry can be measured every minute during CPET and for 6 minutes after CPET. Vital signs can be measured during the 6MWT procedure at the hospital visit (before administration of RT234; 5 and 15 minutes after administration; before the 6MWT at 30 minutes after administration; and at 60 and 120 minutes after administration).

[0059] Example 2 This embodiment describes a study to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH. The only difference between this embodiment and the study in Example 1 is that the study involves an estimated sample size of 37 patients, and the patients are divided into three dose cohorts. Cohort 1 consists of an estimated 7 patients receiving 0.5 mg of RT234, Cohort 2 consists of an estimated 15 patients receiving 1.0 mg of RT234, and Cohort 3 consists of an estimated 15 patients receiving 2.0 mg of RT234. In addition, patients with a baseline peak VO2 greater than 15 mL / mg / kg are excluded from this study. In all other major aspects, this embodiment is the same as the study in Example 2.

Claims

1. A method for treating pulmonary hypertension, comprising administering an effective amount of vardenafil, or a pharmaceutically acceptable salt or hydrate thereof, to a subject requiring such treatment. The aforementioned vardenafil is administered by inhalation using a portable inhaler as needed. The method involves administering the vardenafil at least 2 to 30 minutes before physical exercise.

2. The method according to claim 1, wherein administering the vardenafil includes directing the vardenafil towards the peripheral airways of the lungs of the subject.

3. The method according to claim 2, wherein vardenafil in a nominal dose of approximately 0.5 mg to approximately 1.0 mg is delivered to the subject upon inhalation.

4. The method according to claim 3, wherein a nominal dose of vardenafil of approximately 0.5 mg is delivered to the subject upon inhalation.

5. The method according to claim 3, wherein a nominal dose of vardenafil of approximately 1.0 mg is delivered to the subject upon inhalation.

6. The method according to claim 2, wherein vardenafil in a nominal dose of approximately 0.5 mg to approximately 2.0 mg is delivered to the subject upon inhalation.

7. The method according to claim 6, wherein a nominal dose of vardenafil of approximately 2.0 mg is delivered to the subject upon inhalation.

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