Use of inhaled nitric oxide (iNO) for treating patients with sarcoidosis-associated pulmonary arterial hypertension (PH-SARC)

Abstract

Methods of treating patients with sarcoidosis-associated pulmonary arterial hypertension (PH-SARC) using inhaled nitric oxide (NO) are described.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 296,359, filed on January 4, 2022, entitled “Use of Inhaled Nitric Oxide for Decreasing Pulmonary Arterial Pressure and Pulmonary Vascular Resistance,” U.S. Provisional Application No. 63 / 341,986, filed on May 13, 2022, entitled “Use of Inhaled Nitric Oxide for Decreasing Pulmonary Arterial Pressure and Pulmonary Vascular Resistance,” and U.S. Provisional Application No. 63 / 342,535, filed on May 16, 2022, entitled “Use of Inhaled Nitric Oxide for Decreasing Pulmonary Arterial Pressure and Pulmonary Vascular Resistance,” all of which are incorporated herein by reference in their entirety.

[0003] field

[0004] The present application generally relates to devices and methods for administering nitric oxide, and in some embodiments, pulsed delivery of nitric oxide, to patients suffering from sarcoidosis-related pulmonary arterial hypertension (PH-SARC), and also generally relates to methods for administering nitric oxide, and in some embodiments, pulsed delivery of nitric oxide to the same patients to reduce pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR).

[0005] background

[0006] Nitric oxide (NO) is a gas that, when inhaled, serves to dilate blood vessels in the lungs to improve oxygenation of the blood and reduce pulmonary hypertension. Therefore, nitric oxide is provided as a therapeutic gas during the inspiratory breathing phase to patients with shortness of breath (dyspnea), fatigue, reduced exercise capacity, reduced oxygen saturation, and potentially other indications due to disease states such as pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other lung diseases.

[0007] Although NO can be therapeutically effective when administered under the proper conditions, it can also become toxic if not administered correctly. NO reacts with oxygen to form nitrogen dioxide (NO2), and NO2 can be formed when oxygen or air is present in the NO delivery catheter. NO2 is a toxic gas that can cause many side effects, and the Occupational Safety & Health Administration (OSHA) stipulates that the permissible exposure limit for general industry is only 5 ppm. Therefore, it is desirable to limit NO2 exposure during NO therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The following detailed description of embodiments for treating patients with PH-SARC associated with pulmonary hypertension using iNO will be better understood when read in conjunction with the accompanying drawings of exemplary embodiments. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown.

[0010] In the attached picture:

[0011] Figure 1 is a schematic diagram demonstrating an exemplary acute iNO dose-escalation study design, including examination of changes in mPAP, PCWP, CO, and PVR at various doses of inhaled nitric oxide (iNO).

[0012] Figure 2A-2H are graphs of experimental data demonstrating absolute changes from baseline hemodynamics associated with changes in PVR, mPAP, CO, and PCWP.

[0013] Details

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0015] Before describing several exemplary embodiments of the present disclosure, it is to be understood that the present disclosure is not limited to the details of construction or process steps set forth in the following description. The present disclosure is capable of other embodiments and can be practiced or carried out in various ways.

[0016] References throughout this specification to "one embodiment," "certain embodiments," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with that embodiment is included in at least one embodiment of the present disclosure. Thus, the appearance of phrases such as "in one or more embodiments," "in certain embodiments," "in one embodiment," or "in an embodiment" throughout this specification are not necessarily referring to the same embodiment of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0017] Although the present disclosure has been described herein with reference to specific embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It will be apparent to those skilled in the art that various modifications and changes may be made to the methods and apparatus of the present disclosure without departing from the spirit and scope of the present disclosure. Therefore, the present disclosure is intended to include modifications and changes within the scope of the appended claims and their equivalents.

[0018] definition

[0019] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein sufficient to affect the intended application, including but not limited to disease treatment. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated (e.g., the subject's weight, age, and sex), the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a specific response in the target cell (e.g., a decrease in platelet adhesion and / or cell migration). The specific dose will vary depending on the specific compound selected, the dosing regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system that carries the compound.

[0020] The term "therapeutic effect" as used herein includes therapeutic benefit and / or prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0021] When ranges are used herein to describe an aspect of the present disclosure, e.g., dosage ranges, the amounts of components of a formulation, etc., all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a numerical value or numerical range, the use of the term "about" means that the numerical value or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and therefore the numerical value or numerical range may vary. The variation is typically 0% to about 25%, 0% to about 20%, 0% to 15%, preferably 0% to 10%, and more preferably 0% to 5% of the specified numerical value or numerical range. The term "comprising" (and related terms such as "comprises" or "containing" or "having" or "including") includes embodiments such as any material composition, method, or process that is "consisting of" or "essentially consisting of" the features.

[0022] For the avoidance of doubt, it is intended herein that specific features (e.g., integers, properties, values, uses, diseases, chemical formulas, compounds or groups) described in conjunction with a particular aspect, embodiment or example of the present disclosure be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. These features may therefore be used in conjunction with any definition, claim or embodiment defined herein, as appropriate. All features disclosed in this specification (including any attached claims, abstracts and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, unless at least some of the features and / or steps in the combination are mutually exclusive. The present disclosure is not limited to any details of any disclosed embodiment. The present disclosure extends to any novel one or novel combination of the features disclosed in this specification (including any attached claims, abstracts and drawings), or to any novel one or any novel combination of the steps of any method or process disclosed thereby.

[0023] As used herein, the terms "pulmonary arterial hypertension associated with sarcoidosis (PH-SARC)" and "sarcoidosis-associated pulmonary arterial hypertension (SAPH)" are used interchangeably.

[0024] Sarcoidosis is characterized by the growth of inflammatory cells (granulomas), most often in the lungs or lymphatic tissue. The cause of sarcoidosis is unknown, but it is believed to be an immune response in genetically susceptible people to an unknown trigger, such as an infection or chemical. Symptoms include fatigue, weight loss, joint pain, dry eyes, swollen knees, blurred vision, shortness of breath, and a dry, hacking cough or skin lesions.

[0025] Regarding the present disclosure, in certain embodiments, a dose of gas (e.g., NO) is administered to a patient during the patient's inhalation. In an embodiment, the dose of gas (e.g., NO) is administered to a patient in a pulsed form during the patient's inhalation. It has been surprisingly found that nitric oxide delivery can be precisely and accurately delivered within the total respiratory inspiratory time or a portion thereof, such as within the first 2 / 3 of the total respiratory inspiratory time, and the patient benefits from such delivery. Such delivery minimizes the risk of loss and harmful side effects of the drug product, improves the efficacy of the pulse dose, which in turn results in a lower total amount of NO that needs to be administered to the patient in order to produce an effect. Such delivery can be used to treat various diseases, such as, but not limited to, sarcoidosis-associated pulmonary hypertension (PH-SARC), including World Health Organization (WHO) Class IV pulmonary hypertension.

[0026] The effective dose of NO is based on many different variables, including the amount of drug and the timing of delivery. Several patents have been granted relating to NO delivery, including U.S. Patent Nos. 7,523,752; 8,757,148; 8,770,199; and 8,803,717, and design patent D701,963 for the design of a NO delivery device, all of which are incorporated herein by reference. In addition, there are pending applications relating to NO delivery, including US2013 / 0239963 and US2016 / 0106949, both of which are incorporated herein by reference. Even in view of these patents and pending disclosures, there is still a need for methods and devices for delivering NO in a precisely controlled manner to maximize the benefits of therapeutic doses and minimize potential harmful side effects for the treatment of sarcoidosis-related pulmonary arterial hypertension (PH-SARC).

[0027] Such precision has the further advantage that poorly ventilated lung areas are only partially exposed to NO. Such pulsed delivery can also reduce hypoxia and hemoglobin problems, while NO2 exposure is also more limited.

[0028] The device disclosed herein

[0029] In certain embodiments, the present disclosure includes a device, for example, a programmable device for delivering a dose of a gas (e.g., nitric oxide) to a patient in need thereof. The device may include a delivery portion, a cartridge containing a compressed gas for delivery to the patient, a breathing sensitivity portion for detecting the patient's breathing pattern (including a breathing sensitivity setting), at least one breathing detection algorithm for determining when to administer the compressed gas to the patient, and a portion for administering the dose of nitric oxide to the patient via a series of one or more pulses.

[0030] In certain embodiments, the cartridge is replaceable.

[0031] In certain embodiments, the delivery portion comprises one or more of a nasal cannula, a mask, a nebulizer, and a nasal inhaler. In certain embodiments, the delivery portion may further comprise a second delivery portion to allow for simultaneous administration of one or more other gases (e.g., oxygen) to the patient.

[0032] In certain embodiments, and as described in detail elsewhere herein, the device includes an algorithm, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, wherein the slope algorithm detects a breath when the rate of pressure drop reaches a predetermined threshold.

[0033] In one embodiment of the present disclosure, pulse dosing of gas can mechanically reduce, if not eliminate, the Venturi effect that is often problematic for other gas sensors. For example, in the absence of pulse dosing of the present disclosure, an O2 backpressure sensor may override the delivery of O2 when O2 is administered simultaneously with another gas such as NO.

[0034] Breathing patterns, detection and triggering

[0035] Breathing patterns vary based on the individual, time of day, activity level, and other variables; therefore, it is difficult to predetermine an individual's breathing pattern. A delivery system that delivers a therapeutic agent to a patient based on breathing patterns should therefore be able to address a range of potential breathing patterns in order to be effective.

[0036] In certain embodiments, the patient or individual can be of any age, however, in more specific embodiments, the patient is 16 years of age or older, or 18 years of age or older.

[0037] In one embodiment of the present disclosure, the breathing pattern includes a measure of total inspiratory time, which, as used herein, is determined for a single breath. However, depending on the context, "total inspiratory time" may also refer to the sum of all inspiratory times for all detected breaths during treatment. The total inspiratory time may be observed or calculated. In another embodiment, the total inspiratory time is based on the effective time of the simulated breathing pattern.

[0038] In one embodiment of the present disclosure, breath detection includes at least one, and in some embodiments at least two, independent triggers that work together, namely a breath level trigger and / or a breath slope trigger.

[0039] In one embodiment of the present disclosure, a respiration level trigger algorithm is used for respiration detection. The respiration level trigger detects respiration when a pressure threshold level (eg, a threshold negative pressure) is reached during inspiration.

[0040] In one embodiment of the present disclosure, a breath slope trigger detects a breath when the slope of the pressure waveform indicates inspiration. A breath slope trigger is more accurate than a threshold trigger in certain situations, particularly when used to detect short, shallow breaths.

[0041] In one embodiment of the present disclosure, the combination of these two triggers provides an overall more accurate breathing detection system, particularly when multiple therapeutic gases are administered to the patient simultaneously.

[0042] In one embodiment of the present disclosure, the breathing sensitivity control for detecting breathing level and / or breathing slope is fixed. In one embodiment of the present disclosure, the breathing sensitivity control for detecting breathing level or breathing slope is adjustable or programmable. In one embodiment of the present disclosure, the breathing sensitivity control for breathing level and / or breathing slope can be adjusted from the least sensitive to the most sensitive range, whereby the most sensitive setting detects breathing more sensitively than the least sensitive setting.

[0043] In certain embodiments using at least two triggers, the sensitivity of each trigger is set at different relative levels. In one embodiment using at least two triggers, one trigger is set at the highest sensitivity and the other trigger is set to less than the highest sensitivity. In one embodiment using at least two triggers and one trigger is a breathing level trigger, the breathing level trigger is set at the highest sensitivity.

[0044] Often not every inhalation / exhalation of a patient is detected for subsequent classification as an inhalation / exhalation event for a pulse of administered gas (eg NO). Detection errors may occur, particularly when multiple gases are administered to a patient simultaneously, such as NO and oxygen combination therapy.

[0045] Embodiments of the present disclosure, and particularly embodiments including a respiratory slope trigger alone or in combination with another trigger, can maximize the correct detection of inspiratory events to thereby maximize the effectiveness and efficiency of treatment while also minimizing waste caused by misidentification or timing errors.

[0046] In certain embodiments, greater than 50% of the total number of inhalations of a patient are detected within the time frame of delivering gas to the patient. In certain embodiments, greater than 75% of the total number of inhalations of a patient are detected. In certain embodiments, greater than 90% of the total number of inhalations of a patient are detected. In certain embodiments, greater than 95% of the total number of inhalations of a patient are detected. In certain embodiments, greater than 98% of the total number of inhalations of a patient are detected. In certain embodiments, greater than 99% of the total number of inhalations of a patient are detected. In certain embodiments, 75% to 100% of the total number of inhalations of a patient are detected.

[0047] Dosage and administration schedule

[0048] In one embodiment of the present disclosure, the nitric oxide delivered to the patient is formulated to a concentration of about 3 to about 18 mg NO / liter, about 6 to about 10 mg / liter, about 3 mg NO / liter, about 6 mg NO / liter, about 15 mg NO / liter, or about 18 mg NO / liter. NO can be administered alone or in combination with alternative gas therapy. In certain embodiments, oxygen (e.g., concentrated oxygen) can be administered to the patient in combination with NO. In embodiments, NO is inhaled nitric oxide (iNO).

[0049] In one embodiment of the present disclosure, a certain volume of nitric oxide is administered (e.g., in a single pulse) in an amount of about 0.350 mL to about 7.5 mL per breath. In some embodiments, the volume of nitric oxide in a single pulse dose may be the same during a single course of treatment. In some embodiments, the volume of nitric oxide in some pulse doses may be different during a single time frame for delivering gas to a patient. In some embodiments, the volume of nitric oxide in each pulse dose may be adjusted with the monitored breathing pattern during a single time frame for delivering gas to a patient. In one embodiment of the present disclosure, on a per pulse basis, the amount of nitric oxide delivered to a patient in order to treat or alleviate symptoms of lung disease (in ng) ("pulse dose") is calculated as follows and rounded to the nearest nanogram value:

[0050] Dose mcg / kg-IBW / hr x ideal body weight in kg (kg-IBW) x ((1hr / 60min) x (1min / respiratory rate (bpm)) x (1,000ng / ug).

[0051] As an example, patient A, with an ideal body weight of 75 kg, has a respiratory rate of 20 breaths per minute (or 1200 breaths per hour) at a dose of 100 mcg / kg IBW / hr:

[0052] 100mcg / kg-IBW / hr x 75kg x (1hr / 1200 breaths) X (1,000ng / ug) = 6250ng / pulse

[0053] In certain embodiments, 60 / respiratory rate (ms) variable may also be referred to as dose event time (DoseEventTime). In another embodiment of the present disclosure, dose event time (DoseEventTime) is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds or 10 seconds.

[0054] In one embodiment of the present disclosure, a single pulse dose provides a therapeutic effect (e.g., a therapeutically effective amount of NO) to a patient. In another embodiment of the present disclosure, the sum of two or more pulse doses provides a therapeutic effect (e.g., a therapeutically effective amount of NO) to a patient.

[0055] In one embodiment of the present disclosure, at least about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 625, about 650, about 675, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 pulses of nitric oxide are administered to the patient per hour.

[0056] In one embodiment of the present disclosure, a nitric oxide therapy session is performed within a time frame. In one embodiment, the time frame is at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0057] In one embodiment of the present disclosure, nitric oxide treatment uses the time frame of the minimum course of treatment. In one embodiment of the present disclosure, the minimum course of treatment is about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes or about 90 minutes. In one embodiment of the present disclosure, the minimum course of treatment is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours or about 24 hours. In one embodiment of the present disclosure, the minimum course of treatment is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 18, or about 24 months.

[0058] In one embodiment of the present disclosure, the nitric oxide treatment course is administered once or multiple times per day. In one embodiment of the present disclosure, the nitric oxide treatment course may be once, twice, three times, four times, five times, six times, or more than six times per day. In one embodiment of the present disclosure, the treatment course may be administered monthly, biweekly, weekly, every other day, daily, or multiple times per day.

[0059] Timing of NO pulse

[0060] In one embodiment of the present disclosure, the breathing pattern is correlated to an algorithm to calculate the timing of administration of the nitric oxide dose.

[0061] The accuracy of detection of inhalation / inspiration events also allows timing of gas (eg NO) pulses to maximize their effectiveness by administering the gas within a specified time frame of the total inspiratory time of a single detected breath.

[0062] In one embodiment of the present disclosure, at least fifty percent (50%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time of each breath. In one embodiment of the present disclosure, at least sixty percent (60%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time. In one embodiment of the present disclosure, at least seventy-five percent (75%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time of each breath. In one embodiment of the present disclosure, at least eighty-five percent (85%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time of each breath. In one embodiment of the present disclosure, at least ninety percent (90%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time. In one embodiment of the present disclosure, at least ninety-two percent (92%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time. In one embodiment of the present disclosure, at least ninety-five percent (95%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time. In one embodiment of the present disclosure, at least ninety-nine percent (99%) of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time. In one embodiment of the present disclosure, 90% to 100% of the pulse dose of gas is delivered within the first 1 / 3 of the total inspiratory time.

[0063] In one embodiment of the present disclosure, at least seventy percent (70%) of the pulse dose is delivered to the patient within the first 1 / 2 of the total inspiratory time. In another embodiment, at least seventy-five percent (75%) of the pulse dose is delivered to the patient within the first 1 / 2 of the total inspiratory time. In one embodiment of the present disclosure, at least eighty percent (80%) of the pulse dose is delivered to the patient within the first 1 / 2 of the total inspiratory time. In one embodiment of the present disclosure, at least ninety percent (90%) of the pulse dose is delivered to the patient within the first 1 / 2 of the total inspiratory time. In one embodiment of the present disclosure, at least ninety-five percent (95%) of the pulse dose is delivered to the patient within the first 1 / 2 of the total inspiratory time. In one embodiment of the present disclosure, 95% to 100% of the pulse dose of gas is delivered within the first 1 / 2 of the total inspiratory time.

[0064] In one embodiment of the present disclosure, at least ninety percent (90%) of the pulse dose is delivered within the first 2 / 3 of the total inspiratory time. In one embodiment of the present disclosure, at least ninety five percent (95%) of the pulse dose is delivered within the first 2 / 3 of the total inspiratory time. In one embodiment of the present disclosure, 95% to 100% of the pulse dose is delivered within the first 2 / 3 of the total inspiratory time.

[0065] When combined, the administration of multiple pulse doses within a therapy session / time frame may also meet the above ranges. For example, when combined, greater than 95% of all pulse doses administered during a therapy session are administered within the first 2 / 3 of all inspiratory times for all detected breaths. In a more precise embodiment, when combined, greater than 95% of all pulse doses administered during a therapy session are administered within the first 1 / 3 of all inspiratory times for all detected breaths.

[0066] Under the high precision of the detection method disclosed in the present invention, the pulse dose can be applied within any specified time window of inspiration. For example, the pulse dose can be applied to the first 1 / 3, the middle 1 / 3 or the last 1 / 3 of the patient's inspiration. Alternatively, the first 1 / 2 or the last 1 / 2 of the inspiration can be used as the target of the pulse dose application. In addition, the target of application can be changed. In one embodiment, the first 1 / 3 of the inspiration time can be used as the target of one or a series of inspirations, wherein the second 1 / 3 or the last 1 / 2 can be used as the target of one or a series of subsequent inspirations during the same or different treatment courses. Alternatively, after the first 1 / 4 of the inspiration time has passed, the pulse dose starts and lasts for the middle 1 / 2 (the next two 1 / 4s), and the goal can be to end the pulse dose at the beginning of the last 1 / 4 of the inspiration time. In some embodiments, the pulse can be delayed by 50, 100 or 200 milliseconds (ms), or a range of about 50 to about 200 milliseconds.

[0067] The use of pulse doses during inspiration reduces exposure of poorly ventilated lung regions and alveoli to pulse doses of gas, such as NO. In one embodiment, less than 5% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 10% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 15% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 20% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 25% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 30% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 50% of poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 60% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 70% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 80% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 90% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO.

[0068] Treatment

[0069] In one aspect of the present disclosure, a method of treating sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof is described. In another embodiment, a method for reducing pulmonary vascular resistance (PVR) in a patient suffering from or at risk of developing and / or developing sarcoidosis-related pulmonary arterial hypertension (PH-SARC), for example, as compared to a baseline level, is provided. In another embodiment, a method of reducing mean pulmonary arterial pressure (mPAP) in a patient suffering from or at risk of developing and / or developing sarcoidosis-related pulmonary arterial hypertension (PH-SARC), for example, as compared to a baseline level, is provided. In some embodiments, the method comprises comparing the PVR and / or mPAP to a baseline level. In some embodiments, the method comprises administering iNO, optionally supplementing the iNO administration with oxygen. In one embodiment of the present disclosure, iNO is administered according to the pulsed regimen discussed herein. In one embodiment of the present disclosure, iNO is administered using Device (Bellerophon Therapeutics) delivers iNO to a patient. In one embodiment, the patient suffers from or is at risk of developing and / or developing sarcoidosis-associated pulmonary hypertension (PH-SARC). In one embodiment, the patient has a low risk of developing and / or developing sarcoidosis-associated pulmonary hypertension (PH-SARC). In one embodiment, the patient has a moderate risk of developing and / or developing sarcoidosis-associated pulmonary hypertension (PH-SARC). In one embodiment, the patient has a high risk of developing and / or developing sarcoidosis-associated pulmonary hypertension (PH-SARC). In one embodiment, the patient suffers from or is at risk of developing and / or developing pulmonary hypertension (PH). In one embodiment, the patient has a low risk of developing and / or developing pulmonary hypertension (PH). In one embodiment, the patient has a moderate risk of developing and / or developing pulmonary hypertension (PH). In one embodiment, the patient has a high risk of developing and / or developing pulmonary hypertension (PH). In some embodiments, pulmonary hypertension is selected from WHO Class I, WHO Class II, WHO Class III, WHO Class IV, and WHO Class V pulmonary hypertension. In some embodiments, the pulmonary hypertension is WHO Class V pulmonary hypertension.

[0070] In one embodiment, iNO is administered to a patient daily for a period of at least about 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours for a period of at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks. In one embodiment, iNO is administered to a patient for 8 weeks. In another embodiment, iNO is administered to a patient for 16 weeks. In one embodiment of the present disclosure, a course of nitric oxide therapy is performed within a certain time frame. In one embodiment, the time frame is at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0071] In one embodiment of the present disclosure, nitric oxide treatment uses the time frame of the minimum course of treatment. In one embodiment of the present disclosure, the minimum course of treatment is about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes or about 90 minutes. In one embodiment of the present disclosure, the minimum course of treatment is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours or about 24 hours. In one embodiment of the present disclosure, the minimum course of treatment is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 18, or about 24 months.

[0072] In one embodiment of the present disclosure, iNO is administered at a dose of about 10mcg / kg ideal body weight (IBW) / hr to about 200mcg / kg IBW / hr or more. In one embodiment, iNO is administered at a dose of about 20mcg / kg IBW / hr to about 150mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 25mcg / kg IBW / hr to about 100mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 30mcg / kg IBW / hr to about 75mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 25mcg / kg IBW / hr to about 50mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 30mcg / kg IBW / hr to about 45mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 25mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 30mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 35mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 40mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 45mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 50mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 55mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 60mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 65mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 70mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 75mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 80mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 85mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 90mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 95mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 100mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 105mcg / kg IBW / kg. In one embodiment, iNO is administered at a dose of about 110mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 115mcg / kg IBW / hr.In one embodiment, iNO is administered at a dose of about 120mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 125mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 130mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 135mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 140mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 145mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 150mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 155mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 160mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 165mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 170mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 175mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 180mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 185mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 190mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 195mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 200mcg / kg IBW / hr.

[0073] In one embodiment of the present disclosure, oxygen is also administered to the patient together with iNO. In one embodiment of the present disclosure, oxygen is administered at most 20 liters / minute. In one embodiment of the present disclosure, oxygen is administered at most 1 liter / minute, 2 liters / minute, 3 liters / minute, 4 liters / minute, 5 liters / minute, 6 liters / minute, 7 liters / minute, 8 liters / minute, 9 liters / minute, 10 liters / minute, 11 liters / minute, 12 liters / minute, 13 liters / minute, 14 liters / minute, 15 liters / minute, 16 liters / minute, 17 liters / minute, 18 liters / minute, 19 liters / minute or 20 liters / minute. In one embodiment of the present disclosure, oxygen is administered according to a doctor's prescription. In some embodiments, the patient is experiencing long-term oxygen therapy (LTOT).

[0074] In some embodiments, the method for treating sarcoidosis-related pulmonary hypertension (PH-SARC) in a patient in need further comprises treating and / or reducing the severity of one or more symptoms associated with PH-SARC. Non-limiting examples of symptoms include reducing pulmonary vascular resistance (PVR) and reducing mean pulmonary arterial pressure (mPAP), wherein the symptoms are reduced compared to baseline levels. In some embodiments, the method for treating sarcoidosis-related pulmonary hypertension (PH-SARC) in a patient in need further comprises maintaining the severity of one or more symptoms associated with PH-SARC. Non-limiting examples of symptoms include reducing pulmonary vascular resistance (PVR) and reducing mean pulmonary arterial pressure (mPAP).

[0075] In one non-limiting embodiment, the baseline level can be determined by measuring and / or calculating the level (eg, PVR, mPAP) in a patient or group of patients (eg, one or more patients with PH-SARC) prior to administration of iNO.

[0076] In some embodiments, pulmonary vascular resistance (PVR) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more compared to baseline levels. In some embodiments, pulmonary vascular resistance (PVR) is reduced by at least about 20% compared to baseline levels.

[0077] In some embodiments, mean pulmonary artery pressure (mPAP) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more compared to baseline levels. In some embodiments, mean pulmonary artery pressure (mPAP) is reduced by at least about 10% compared to baseline levels.

[0078] In one aspect, the methods disclosed herein for treating sarcoidosis-associated pulmonary arterial hypertension (PH-SARC) in a patient in need thereof do not cause or result in the occurrence of and / or provide a reduction in the severity of treatment-emergent adverse events (AEs) compared to other forms of treatment. In some embodiments, treatment-emergent adverse events (AEs) include those associated with device defects.

[0079] In embodiments, the methods disclosed herein for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof do not cause or result in symptoms and / or provide a reduction in the severity of symptoms that may be due to rebound associated with acute withdrawal of iNO, compared to other nitric oxide treatments. Non-limiting examples of symptoms that may be due to rebound associated with acute withdrawal of iNO: systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, tachypnea, near syncope, and syncope.

[0080] In embodiments, the methods disclosed herein for treating sarcoidosis-associated pulmonary arterial hypertension (PH-SARC) in a patient in need thereof result in maintaining vital signs and / or other parameters, e.g., compared to baseline levels. In embodiments, vital signs and / or other parameters are adversely affected by administration of other types of treatments compared to baseline levels. Non-limiting examples of other parameters include changes in oxygen saturation, cardiac output (CO), and pulmonary capillary wedge pressure (PCWP). In embodiments, the method further comprises maintaining resting cardiac output (CO) compared to baseline levels. In embodiments, the method further comprises maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

[0081] In one embodiment of the present disclosure, other parameters that can be used to evaluate the effect of iNO include the time to clinical improvement and the time to clinical deterioration. In patients treated with iNO, it is expected that the time taken to see clinical improvement is shortened and the time taken to see clinical deterioration is prolonged. Patient-related outcome measurements (PRO) can also be used to evaluate the effect of iNO. PRO is measured in the form of a questionnaire, which provides the subject's views on overall quality of life. Non-limiting examples of PRO include St. George's Respiratory Questionnaire (SGRQ) and University of California, San Diego Shortness of Breath Questionnaire (UCSD SOBQ), Kings Sarcoidosis Questionnaire (KSQ), Fatigue Assessment Scale (FAS) and emPHasis 10. These questionnaires are standard questionnaires used in the art and are well-known and clinically accepted. For patients receiving iNO treatment, it is expected that the scores of these PROs are improved.

[0082] Actigraphy

[0083] The present disclosure also relates to a method of improving or maintaining activity level, or preventing a decrease in activity level, in a patient suffering from or at risk of developing and / or developing sarcoidosis-associated pulmonary arterial hypertension (PH-SARC). The method comprises using actigraphy to monitor and measure changes in activity level.

[0084] In an embodiment, actigraphy involves the use of a wearable activity monitor, similar to a pedometer or accelerometer, or a three-axis accelerometer, Actigraph GT9X or It measures activity parameters. Such activity monitors evaluate activity and measure activity parameters of the user. Activity parameters measured include total activity, non-sedentary activity, moderate activity, moderate to vigorous physical activity (MVPA), steps, calories, metabolic equivalent units (METs), sleep, heart rate, oxygen saturation, calories burned, six-minute walk distance (6MWD) test, and other types of activity and / or daily activity parameters.

[0085] In one embodiment of the present disclosure, the activity level is monitored and measured uninterruptedly in a time period. In one embodiment of the present disclosure, the activity level is monitored and measured intermittently in a time period. In one embodiment, the activity level is monitored and measured every day for at least about 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours, for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks or 26 weeks. In another embodiment, activity levels are monitored and measured daily for a period of at least about 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours, for a period of at least about 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In another embodiment, activity levels are monitored only during the patient's wakefulness. In one embodiment, activity levels are measured in a continuous manner throughout the wakefulness period. In another embodiment, the patient can remove the device for certain activities, so activity levels are measured in a discontinuous manner during the wakefulness period. In another embodiment, the wakefulness period is at least 10 hours. In another embodiment, the wakefulness period is at least 8 hours. In another embodiment, the wakefulness period is at least 12 hours. In another embodiment, the wakefulness period is at least 14 hours.

[0086] In one embodiment of the present disclosure, the activity level is improved compared to the baseline activity level. In one embodiment, the baseline activity level is monitored and measured for at least one week before the vasodilator is administered. In another embodiment, the baseline activity level is monitored or measured for about 1 day to about 14 days, about 1 day to about 10 days, about 1 day to about 7 days, or about 1 day to about 5 days. In another embodiment, the baseline activity level is monitored or measured for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In one embodiment of the present disclosure, the baseline activity is monitored or measured for about 7 days. In one embodiment of the present disclosure, the baseline activity level is monitored or measured every day for a period of about 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In one embodiment of the present disclosure, the baseline activity is monitored or measured while the subject is awake. In one embodiment of the present disclosure, the baseline activity is monitored or measured while the subject is asleep. In one embodiment of the present disclosure, the baseline activity is monitored or measured over several hours while the subject is awake and asleep.

[0087] In one embodiment, the activity level is improved compared to the baseline activity level. In one embodiment, the activity level improves by about 1% to about 50%. In another embodiment, the activity level improves by about 1% to about 25% compared to the baseline activity level. In another embodiment, the activity level improves by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25% compared to the baseline activity level. In another embodiment, the activity level improves by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% compared to the baseline activity level.

[0088] In another embodiment of the present disclosure, the activity level is maintained compared to the baseline activity level. In another embodiment, the activity level does not decrease compared to the baseline activity level. In another embodiment, the activity level of the treated patient decreases less over time compared to an untreated or placebo patient. In one embodiment, the activity level of the treated patient decreases by about 5%, while the activity level of the placebo or untreated patient decreases by about 20% or more.

[0089] In one embodiment of the present disclosure, the subject wears an actigraph monitor on the non-dominant arm. The wrist acceleration is continuously measured by the monitor. The monitor records triaxial acceleration at 30 Hz. The algorithm converts the acceleration measurements into minute-by-minute activity counts. Each minute is classified as an activity level based on established and effective cutoff points. The algorithm can also determine wearing time, calories, and other parameters. Daily activity data is converted to weekly activity levels to allow data comparison. Predetermined filters are used to ensure that only compliant data is analyzed. Such filters can include a minimum number of "wearawake" minutes (e.g., at least 600 minutes) to ensure compliance, and have at least three compliant days for a compliant week. The filter can be based on industry standards for actigraph analysis.

[0090] The counts can be converted to activity levels in a variety of ways. For example, the average of the counts provides a direct measure of physical activity. Each minute of the day can be converted to activity intensity to be able to determine the amount of time spent in sedentary, light, moderate, and vigorous activity as shown in Table A:

[0091] Table A: Examples of physical activity parameters

[0092]

[0093] Example

[0094] Embodiments encompassed herein are now described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein.

[0095] Example 1: INO pulse in patients with sarcoidosis-associated pulmonary hypertension (SAPH) requiring supplemental oxygen Phase 2 trial

[0096] Sarcoidosis patients may develop pulmonary hypertension (PH), which is associated with impaired quality of life and limitations in activities of daily living. This phase 2 trial was designed to determine the safety and clinical efficacy of pulsatile iNO, a potent and well-established vasodilator, in patients with sarcoidosis-associatedwith PH and to evaluate the safe and effective dose of iNO in subjects on long-term oxygen therapy (LTOT) with probable or definite sarcoidosis-associatedwith PH. Figure 1 Shows an exemplary study design.

[0097] Patients with sarcoidosis and PH on prior right heart catheterization (RHC) or echocardiography were enrolled in a two-part open-label study. Patients underwent RHC to establish baseline hemodynamics, including mean pulmonary artery pressure (mPAP), cardiac output (CO), pulmonary wedge pressure (PCWP), and derived pulmonary vascular resistance (PVR).

[0098] Patients were administered acute ascending doses of pulsed iNO via an INO pulse device, starting at 30 mcg / kg ideal body weight / hr (iNO30) and increasing to 125 mcg / kg ideal body weight / hr (iNO 125) to evaluate the effect of each dose level on hemodynamic parameters. Patients were treated with each dose of iNO for 10 minutes with a 10 minute washout between doses.

[0099] Each dose level was followed by a washout period. All hemodynamic waveforms were reviewed by a blinded hemodynamic core lab to determine end-tidal PAP and PCWP. Following the acute vasodilator study, subjects were eligible to participate in a long-term open-label extension study at the iNO dose found to be most beneficial as measured by RHC, as determined by the investigator.

[0100] Table 1A and Table 1B show the subject demographics describing the 8 patients included in the study.

[0101] Table 1A: Baseline patient demographics

[0102]

[0103] Table 1B: Patient Demographics

[0104] Age (years) 61.1(11.37) male(%) 37.5％ *FEV1 (% predicted) 50％(11％) *FVC (% predicted) 64％(18％) *DLCO (% predicted) 35％(11％) *LTOT(L / min) 3.0(1.1％)

[0105] Means (standard deviations) reported based on available preliminary data. *7 of 8 data points were available at the time of analysis.

[0106] Table 2 shows the baseline hemodynamic parameters.

[0107] Table 2: Baseline hemodynamic parameters

[0108]

[0109] Table 3 shows the changes in hemodynamic parameters from baseline.

[0110]

[0111] During the treatment visit in Part 1 of the study, subjects were admitted to the cardiac catheterization suite / ICU / CCU and a Swan Ganz catheter was inserted and monitored during acute exposure to iNO at 30, 45, 75, 125 mcg / kg IBW / hr. Hemodynamic changes were monitored during this part of the study. The primary endpoint of Part 1 of the study was to evaluate the change in mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and pulmonary vascular resistance (PVR) at iNO 30, 45, 75, 125 mcg / kg IBW / hr compared to baseline. Safety endpoints included the incidence and severity of treatment-emergent adverse events (AEs), including those related to device defects, symptoms potentially due to rebound associated with acute withdrawal of iNO: systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, tachypnea, near syncope, and syncope, and changes in oxygen saturation and vital signs.

[0112] All 8 PH-Sarc patients were dose-escalated to receive at least 75mcg / kg, and 7 patients were titrated to the highest dose of each regimen of 125mcg / kg. As determined by the blinded core lab, all 8 patients showed a decrease in mPAP and PVR in iNO doses from iNO30 to iNO125. The baseline median mPAP of the group was 37.2mmHg, which decreased by 6-10% in doses from iNO30 to iNO125. The baseline median PVR of the group was 329 dynes*sec*cm-5, with the iNO45 dose showing a median decrease of 20% (-54% to +22%). Increasing the dose to the iNO125 dose resulted in a median decrease of 29% (-43% to -5%, p=0.02 vs. baseline and previous dose). No adverse events or serious adverse events related to iNO were reported.

[0113] Hemodynamic changes were measured as absolute changes from baseline in PVR, mPAP, CO, and PCWP (eg, Figure 2A-2D ) and % change (as shown in Figure 2E-2H). The depicted analysis shows changes relative to baseline (box and whisker plots provide medians, IQRs, and minimum / maximum values). Statistical analysis based on the Wilcoxon Log Rank Test was evaluated between baseline and each dose and between each dose and each previous dose, and no correction for multiplicity was made. All 8 subjects showed reductions in mPAP and PVR across the dose range, with mPAP reaching statistical significance at the iNO30 dose compared to baseline, and PVR reaching statistical significance at the iNO125 dose compared to baseline and compared to the previous dose of iNO75. CO and PCWP remained stable at all doses, and iNO was well tolerated at all doses. The median mPAP reduction was 6.3% to 10.6%, with an IQR of 10% to 15.8%. The reduction in mPAP reached statistical significance (p<0.05) at the iNO30 dose, however, due to the small data set, it did not reach statistically significant levels of change relative to baseline or previous dose at any of the remaining doses. Cardiac output values ​​remained stable at all doses, with no significant changes observed at any dose of iNO.

[0114] The median reduction in PVR was 7.0% to 28.7% with an IQR of 10.6% to 37.7%. Given the overlap in the interquartile ranges between doses and due to the small sample size, no dose was identified as clearly superior, however, a statistically significant reduction in PVR was demonstrated at the iNO125 dose compared to baseline (p<0.05) and the previous dose of iNO75.

[0115] Although preferred embodiments of the present disclosure are shown and described herein, some of the embodiments are provided by way of example only and are not intended to otherwise limit the scope of the present disclosure. Various alternatives to the described embodiments of the present disclosure may be used to practice the invention.

Claims

1. A method of treating sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering inhaled nitric oxide (iNO) to the patient.

2. A method of treating sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the iNO is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

3. The method of claim 2, wherein detecting a breathing pattern comprises using at least one trigger selected from a breathing level trigger and a breathing slope trigger.

4. The method of claim 2 or 3, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, wherein the slope algorithm detects breathing when the rate of pressure drop reaches a predetermined threshold.

5. The method according to any one of claims 1-4, wherein the treatment further comprises reducing pulmonary vascular resistance (PVR) and / or reducing mean pulmonary artery pressure (mPAP) compared to baseline levels.

6. The method of claim 5, wherein pulmonary vascular resistance (PVR) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more, optionally at least about 20%, compared to baseline levels.

7. The method of claim 5 or 6, wherein mean pulmonary artery pressure (mPAP) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more, optionally at least about 10%, compared to baseline levels.

8. The method according to any one of claims 1-7, further comprising maintaining resting cardiac output (CO) and / or maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

9. The method of any one of claims 1-8, wherein delivery of a dose of iNO occurs within the first 1 / 3 of the total inspiratory time, the first 2 / 3 of the total inspiratory time, or the first 1 / 2 of the total inspiratory time.

10. The method of any one of claims 1-9, wherein delivery of at least 50% of the iNO dose occurs within the first 1 / 3 of the total inspiratory time, delivery of at least 90% of the iNO dose occurs within the first 2 / 3 of the total inspiratory time, and / or delivery of at least 70% of the iNO dose occurs within the first 1 / 2 of the total inspiratory time.

11. The method of any one of claims 1-10, wherein the nitric oxide is delivered as a series of pulses over a period of time.

12. The method according to any one of claims 1-11, wherein the pulmonary hypertension is selected from WHO class I, WHO class II, WHO class III, WHO class IV and WHO class V pulmonary hypertension, optionally WHO class V pulmonary hypertension.

13. The method of any one of claims 1-12, wherein the patient is undergoing long-term oxygen therapy (LTOT).

14. The method of any one of claims 1-13, wherein the inhaled nitric oxide is administered at a dose ranging from about 20 mcg / kg IBW / hr to about 150 mcg / kg IBW / hr.

15. The method of claim 14, wherein the iNO dose is selected from the group consisting of about 30 mcg / kg IBW / hr, about 45 mcg / kg IBW / hr, about 75 mcg / kg IBW / hr, and about 125 mcg / kg IBW / hr.

16. The method of any one of claims 1-15, wherein the iNO dose is about 45 mcg / kg IBW / hr.

17. The method of any one of claims 1-15, wherein the iNO dose is about 125 mcg / kg IBW / hr.

18. A method of reducing pulmonary vascular resistance (PVR) in a patient having or at risk for developing sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the nitric oxide is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

19. A method of reducing mean pulmonary arterial pressure (mPAP) in a patient having or at risk for developing sarcoidosis-associated pulmonary hypertension (PH-SARC) in a patient in need thereof, the method comprising administering inhaled nitric oxide (iNO) to the patient, wherein the nitric oxide is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

20. The method of claim 18 or 19, wherein detecting a breathing pattern comprises using at least one trigger selected from a breathing level trigger and a breathing slope trigger.

21. The method of any one of claims 18-20, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, wherein the slope algorithm detects respiration when the rate of pressure drop reaches a predetermined threshold.

22. The method of any one of claims 18, 20 or 21, wherein pulmonary vascular resistance (PVR) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% or more, optionally at least about 20%, compared to baseline levels.

23. The method of any one of claims 19-21, wherein mean pulmonary artery pressure (mPAP) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more, optionally at least about 10%, compared to baseline levels.

24. The method of any one of claims 18-23, further comprising maintaining resting cardiac output (CO) and / or maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

25. The method of any one of claims 18-24, wherein delivery of a dose of iNO occurs within the first 1 / 3 of the total inspiratory time, the first 2 / 3 of the total inspiratory time, or the first 1 / 2 of the total inspiratory time.

26. The method of any one of claims 18-25, wherein delivery of at least 50% of the iNO dose occurs within the first 1 / 3 of the total inspiratory time, delivery of at least 90% of the iNO dose occurs within the first 2 / 3 of the total inspiratory time, and / or delivery of at least 70% of the iNO dose occurs within the first 1 / 2 of the total inspiratory time.

27. The method of any one of claims 18-26, wherein nitric oxide is delivered as a series of pulses over a period of time.

28. The method according to any one of claims 18-27, wherein the pulmonary hypertension is selected from WHO class I, WHO class II, WHO class III, WHO class IV and WHO class V pulmonary hypertension, optionally WHO class V pulmonary hypertension.

29. The method of any one of claims 18-28, wherein the patient is undergoing long-term oxygen therapy (LTOT).

30. The method of any one of claims 18-29, wherein the inhaled nitric oxide is administered at a dose ranging from about 20 mcg / kg IBW / hr to about 150 mcg / kg IBW / hr.

31. The method of claim 30, wherein the iNO dose is selected from the group consisting of about 30 mcg / kg IBW / hr, about 45 mcg / kg IBW / hr, about 75 mcg / kg IBW / hr, and about 125 mcg / kg IBW / hr.

32. The method of any one of claims 18-31, wherein the iNO dose is about 45 mcg / kg IBW / hr.

33. The method of any one of claims 18-31, wherein the iNO dose is about 125 mcg / kg IBW / hr.

34. The method of any one of claims 1-33, wherein the patient is at low risk, intermediate risk, or high risk of developing and / or developing pulmonary hypertension (PH).

35. The method of any one of claims 1-34, wherein the method further comprises preventing a decline in, maintaining or improving one or more activity levels of the patient.

36. The method of claim 35, wherein the one or more activity levels are selected from total activity, non-sedentary activity, moderate activity, moderate to vigorous physical activity (MVPA), steps, calories, metabolic equivalent units (METs), sleep, heart rate, oxygen saturation, calories burned, six-minute walk distance (6MWD) test, and other types of activity and / or daily activity parameters.

37. A method of treating sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the iNO is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide of about 45 mcg / kg IBW / hr; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

38. A method of treating sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the iNO is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide of about 125 mcg / kg IBW / hr; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

39. A method of reducing pulmonary vascular resistance (PVR) in a patient having or at risk for developing sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the nitric oxide is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide of about 45 mcg / kg IBW / hr; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

40. A method of reducing pulmonary vascular resistance (PVR) in a patient having or at risk for developing sarcoidosis-related pulmonary arterial hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the nitric oxide is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide of about 125 mcg / kg IBW / hr; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

41. A method of reducing mean pulmonary arterial pressure (mPAP) in a patient having or at risk for developing sarcoidosis-associated pulmonary hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the nitric oxide is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide of about 45 mcg / kg IBW / hr; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

42. A method of reducing mean pulmonary arterial pressure (mPAP) in a patient having or at risk for developing sarcoidosis-associated pulmonary hypertension (PH-SARC) in a patient in need thereof, the method comprising administering to the patient inhaled nitric oxide (iNO), wherein the nitric oxide is delivered in a pulsed manner as follows: a. Detecting the patient's breathing pattern, including the total inspiratory time of a single breath; b. correlating the breathing pattern with an algorithm to calculate the timing of administration of a dose of nitric oxide of about 125 mcg / kg IBW / hr; and c. delivering nitric oxide to the patient in a pulsed manner during a portion of the total inspiratory time.

43. The method of any one of claims 37-42, wherein detecting a breathing pattern comprises using at least one trigger selected from a breathing level trigger and a breathing slope trigger.

44. The method of any one of claims 37-43, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, wherein the slope algorithm detects respiration when the rate of pressure drop reaches a predetermined threshold.

45. The method of any one of claims 39, 40, 43 or 44, wherein pulmonary vascular resistance (PVR) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% or more, optionally at least about 20%, compared to baseline levels.

46. ​​The method of any one of claims 41-44, wherein mean pulmonary arterial pressure (mPAP) is reduced by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more, optionally at least about 10%, compared to baseline levels.

47. The method of any one of claims 37-46, further comprising maintaining resting cardiac output (CO) and / or maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

48. The method of any one of claims 37-47, wherein delivery of a dose of iNO occurs within the first 1 / 3 of the total inspiratory time, the first 2 / 3 of the total inspiratory time, or the first 1 / 2 of the total inspiratory time.

49. The method of any one of claims 37-48, wherein delivery of at least 50% of the iNO dose occurs within the first 1 / 3 of the total inspiratory time, delivery of at least 90% of the iNO dose occurs within the first 2 / 3 of the total inspiratory time, and / or delivery of at least 70% of the iNO dose occurs within the first 1 / 2 of the total inspiratory time.

50. The method of any one of claims 37-49, wherein nitric oxide is delivered as a series of pulses over a period of time.

51. The method according to any one of claims 37-50, wherein the pulmonary hypertension is selected from WHO class I, WHO class II, WHO class III, WHO class IV and WHO class V pulmonary hypertension, optionally WHO class V pulmonary hypertension.

52. The method of any one of claims 37-51, wherein the patient is undergoing long-term oxygen therapy (LTOT).

53. The method of any one of claims 37-52, wherein the patient is at low risk, intermediate risk, or high risk of developing and / or pulmonary hypertension (PH).

54. The method of any one of claims 37-53, wherein the method further comprises preventing a decline in, maintaining or improving one or more activity levels of the patient.

55. The method of claim 54, wherein the one or more activity levels are selected from total activity, non-sedentary activity, moderate activity, moderate to vigorous physical activity (MVPA), steps, calories, metabolic equivalent units (METs), sleep, heart rate, oxygen saturation, calories burned, six-minute walk distance (6MWD) test, and other types of activity and / or daily activity parameters.

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