Use of inhaled nitric oxide (iNO) to treat patients with pulmonary hypertension associated with sarcoidosis (PH-SARC)

Abstract

Methods are described for treating patients with pulmonary hypertension associated with sarcoidosis (PH-SARC) using inhaled nitric oxide therapy (iNO).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 296,359, entitled "Use of Inhaled Nitric Oxide for Decreasing Pulmonary Arterial Pressure and Pulmonary Vascular Resistance", filed January 4, 2022, U.S. Provisional Patent Application No. 63 / 341,986, entitled "Use of Inhaled Nitric Oxide for Decreasing Pulmonary Arterial Pressure and Pulmonary Vascular Resistance", filed May 13, 2022, and U.S. Provisional Patent Application No. 63 / 342,535, entitled "Use of Inhaled Nitric Oxide for Decreasing Pulmonary Arterial Pressure and Pulmonary Vascular Resistance", filed May 16, 2022, all of which applications are incorporated by reference in their entirety into this specification.

[0002]

[0002] This application relates generally to devices and methods for administering nitric oxide, and in some embodiments, pulsatile delivery of nitric oxide to patients with pulmonary hypertension associated with sarcoidosis (PH-SARC), and also generally to methods for administering nitric oxide, and in some embodiments, pulsatile delivery of nitric oxide to the same patients to reduce pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). [Background technology]

[0003]

[0003] Nitric oxide (NO) is a gas that, when inhaled, dilates the blood vessels in the lungs, improving blood oxygenation and reducing pulmonary hypertension. For this reason, nitric oxide is provided as a therapeutic gas during the inspiration phase in patients suffering from conditions such as shortness of breath (dyspnea), fatigue, reduced exercise capacity, oxygen desaturation, and possibly other indications due to pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis with emphysema (CPFE), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other pulmonary diseases.

[0004]

[0004] When administered under appropriate conditions, NO can be therapeutically effective, but it can also be toxic if not administered correctly. NO reacts with oxygen to form nitrogen dioxide (NO2), which can form if oxygen or air is present in the NO delivery tube. NO2 is a toxic gas that can cause many side effects, and the Occupational Safety & Health Administration (OSHA) has set a permissible exposure limit of only 5 ppm in general industry. For this reason, it is desirable to limit exposure to NO2 during NO therapy.

[0005]

[0005] The following detailed description of embodiments relating to the use of iNO to treat patients with pulmonary hypertension associated PH-SARC will be better understood when read in conjunction with the accompanying drawings of exemplary embodiments, it being understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown. [Brief description of the drawings]

[0006] [Figure 1]

[0007] FIG. 1 is a schematic diagram showing an exemplary acute iNO dose escalation study design, including examination of changes in mPAP, PCWP, CO and PVR across various doses of inhaled nitric oxide (iNO). [Figure 2-1]

[0008] Figures 2A-2H are graphs of the experimental data showing absolute changes from baseline hemodynamics associated with changes in PVR, mPAP, CO, and PCWP. [Figure 2-2] Figures 2A-2H are graphs of the experimental data showing absolute changes from baseline hemodynamics associated with changes in PVR, mPAP, CO, and PCWP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007]

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0008]

[0010] Before describing certain example embodiments of the present disclosure, it is to be understood that the disclosure is not limited to the details of construction or process steps set forth in the following description, as the disclosure is capable of other embodiments and of being practiced or carried out in various ways.

[0009]

[0011] References throughout this specification to "one embodiment," "a particular embodiment," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of phrases such as "in one or more embodiments," "in a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification do not necessarily refer 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.

[0010]

[0012] Although the present disclosure has been described herein with reference to specific embodiments, it should 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 variations can be made to the disclosed method and apparatus without departing from the spirit and scope of the present disclosure. Thus, the present disclosure is intended to cover modifications and variations that come within the scope of the appended claims and their equivalents.

[0011] definition

[0013] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein that is sufficient to affect the intended use, including, but not limited to, the treatment of a disease. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), the subject and condition to be treated (e.g., the subject's weight, age, and sex), the severity of the condition, the method of administration, and the like, and can be easily determined by one of ordinary skill in the art. The term also applies to a dose that will cause a particular response in target cells (e.g., reduced platelet adhesion and / or reduced cell migration). The specific dose will vary depending on the particular compound selected, the administration 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 through which the compound is delivered.

[0012]

[0014] As used herein, the term "therapeutic benefit" encompasses therapeutic benefit and / or prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0013]

[0015] When ranges are used herein to describe aspects of the present disclosure, such as, for example, dosage ranges, amounts of components of a formulation, etc., all combinations and subcombinations of the ranges and specific embodiments thereof are intended to be included. The use of the term "about" when referring to a number or numerical range means that the number or numerical range referred to is an approximation within experimental variation (i.e., within statistical experimental error), and thus, the number or numerical range may vary. This 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 number or numerical range mentioned above. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments such as, for example, embodiments of any composition of matter, any method, or any process that "consists of" or "consists essentially of" the described features.

[0014]

[0016] For the avoidance of doubt, it is intended herein that a particular feature (e.g., integer, property, value, use, disease, formula, compound, or group) described in connection with a particular aspect, embodiment, or example of the present disclosure should be understood to be applicable to any other aspect, embodiment, or example described herein, unless inconsistent therewith. Thus, such features may be used where appropriate in connection with any of the definitions, claims, or embodiments defined herein. All of the features disclosed herein (including any accompanying claims, abstract, and figures), and / or all of the steps of any method or process disclosed similarly, may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. The present disclosure is not limited to any details of any of the disclosed embodiments. The present disclosure extends to any novel or any novel combination of the features disclosed herein (including any accompanying claims, abstract, and figures), or any novel or any novel combination of the steps of any method or process disclosed similarly.

[0015]

[0017] As used herein, the terms "sarcoidosis-associated pulmonary hypertension (PH-SARC)" and "sarcoidosis-associated pulmonary hypertension (SAPH)" are used interchangeably.

[0016]

[0018] Sarcoidosis is characterized by the proliferation of inflammatory cells (granulomas), most commonly occurring in the lungs or lymphatic tissue. The cause of sarcoidosis is unknown, but it is thought to be an immune response to an unknown trigger, such as an infection or chemical, in genetically predisposed individuals. Symptoms may include fatigue, weight loss, joint pain, dry eyes, swollen knees, blurred vision, shortness of breath, a dry cough, or skin lesions.

[0017]

[0019] In accordance with the present disclosure, in certain embodiments, a dose of gas (e.g., NO) is administered to a patient during inspiration by the patient. In embodiments, a dose of gas (e.g., NO) is administered to a patient in pulses during inspiration by the patient. Surprisingly, it has been found that delivery of nitric oxide can be precise and accurate over the total respiratory inspiration time or a portion thereof, such as the first two-thirds, and that the patient benefits from such delivery. Such delivery, which minimizes the risk of pharmaceutical loss and adverse side effects, increases the effectiveness of pulse administration, which in turn results in a smaller overall amount of NO that needs to be administered to the patient to be effective. Such delivery is useful for the treatment of various diseases, such as, but not limited to, pulmonary hypertension associated with sarcoidosis (PH-SARC), including World Health Organization (WHO) Groups I-V pulmonary hypertension.

[0018]

[0020] Effective administration of NO is based on many different variables, including the amount of drug and the timing of delivery.Several patents related to NO delivery have been granted, including U.S. Patent Nos. 7,523,752, 8,757,148, 8,770,199, and 8,803,717, and Design Patent No. D701,963 for the design of NO delivery devices, all of which are incorporated herein by reference.In addition, there are pending applications related to NO delivery, including US2013 / 0239963 and US2016 / 0106949, both of which are incorporated herein by reference.In light of these patents and pending publications, there remains a need for methods and devices that deliver NO in a precisely controlled manner to maximize the benefits of therapeutic doses and minimize potentially harmful side effects in the treatment of pulmonary hypertension associated with sarcoidosis (PH-SARC).

[0019]

[0021] Such precision has the added advantage that only portions of poorly ventilated lung regions are exposed to NO. Hypoxia and hemoglobin disturbances may also be reduced using such pulsed delivery, but exposure to NO2 is also more limited. Devices of the present disclosure

[0022] In certain embodiments, the disclosure includes a device, e.g., a programmable device for delivering a dose of gas (e.g., nitric oxide) to a patient in need thereof. The device may include a delivery portion, a drug cartridge containing compressed gas for delivery to the patient, a breath sensing portion for detecting the patient's breathing pattern including a breath sensitivity setting, at least one breath detection algorithm for determining when to administer 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.

[0020]

[0023] In certain embodiments, the drug cartridge is replaceable.

[0021]

[0024] In certain embodiments, the delivery portion includes one or more of a nasal cannula, a face mask, a nebulizer, and a nasal inhaler. In certain embodiments, the delivery portion may further include a second delivery portion that allows one or more other gases (e.g., oxygen) to be simultaneously administered to the patient.

[0022]

[0025] In certain embodiments, and as detailed elsewhere herein, the device includes an algorithm that uses one or both of a threshold sensitivity and a slope algorithm, where the slope algorithm detects a breath when the rate of pressure drop reaches a predefined threshold.

[0023]

[0026] Mechanically, in certain embodiments of the present disclosure, the pulse dose of gas can reduce the Venturi effect that would normally cause problems in other gas sensors if not vented. For example, without the pulse dose of the present disclosure, an O2 backpressure sensor can disable the delivery of O2 when O2 is administered simultaneously with another gas, such as NO.

[0024] Breathing Patterns, Detection, and Triggering

[0027] Breathing patterns vary based on the individual, time of day, level of activity, and other variables. This makes it difficult to predetermine an individual's breathing pattern. Therefore, a delivery system that delivers therapy to a patient based on breathing patterns should be able to address a range of possible breathing patterns in order to be effective.

[0025]

[0028] In certain embodiments, the patient or individual may be of any age, but in more particular embodiments, the patient is 16 years of age or older or 18 years of age or older.

[0026]

[0029] In certain embodiments of the present disclosure, a breathing pattern, as used herein, includes a measurement of total inspiration time determined for a single breath. However, depending on the context, "total inspiration time" may also refer to the sum of all inspiration times in all breaths detected during therapy. Total inspiration time may be observed or calculated. In another embodiment, total inspiration time is a time verified based on a simulated breathing pattern.

[0027]

[0030] In certain embodiments of the present disclosure, breath detection includes at least one trigger, and in some embodiments includes at least two separate triggers that work together: a breath level trigger and / or a breath slope trigger.

[0028]

[0031] In one embodiment of the present disclosure, a breath level trigger algorithm is used for breath detection. The breath level trigger detects a breath when a threshold level of pressure (e.g., a threshold negative pressure) is reached during inspiration.

[0029]

[0032] In an embodiment of the present disclosure, the respiratory slope trigger detects a breath when the slope of the pressure waveform indicates an inhalation. The respiratory slope trigger can be more accurate than the threshold trigger in some cases, especially when used to detect short, shallow breaths.

[0030]

[0033] In certain embodiments of the present disclosure, the combination of these two triggers provides a generally more accurate breath detection system, especially when multiple therapeutic gases are being administered to the patient simultaneously.

[0031]

[0034] In certain embodiments of the present disclosure, the breath sensitivity control for detecting breath level and / or breath slope is fixed. In certain embodiments of the present disclosure, the breath sensitivity control for detecting either breath level or breath slope is adjustable or programmable. In certain embodiments of the present disclosure, the breath sensitivity control for detecting breath level and / or breath slope is adjustable ranging from a minimum sensitivity to a maximum sensitivity, where the maximum sensitivity setting is more sensitive to detecting breaths than the minimum sensitivity setting.

[0032]

[0035] In certain embodiments where at least two triggers are used, the sensitivity of each trigger is set at a different relative level. In one embodiment where at least two triggers are used, one trigger is set to maximum sensitivity and the other trigger is set to less than maximum sensitivity. In one embodiment where at least two triggers are used and one trigger is a breath level trigger, the breath level trigger is set to maximum sensitivity.

[0033]

[0036] Often, not all of a patient's inhalations / breaths are detected and classified as inhalation / breath events for a pulsed administration of gas (e.g., NO). Detection errors can occur, especially when multiple gases are administered to the patient simultaneously, for example, in combination therapy with NO and oxygen.

[0034]

[0037] The embodiments of the present disclosure, and particularly those incorporating a respiratory slope trigger, either alone or in combination with another trigger, can maximize correct detection of inspiration events, thereby maximizing the effectiveness and efficiency of therapy while minimizing waste due to misidentification or errors in timing.

[0035]

[0038] In certain embodiments, greater than 50% of the patient's total number of inspirations over a time frame for gas delivery to the patient are detected. In certain embodiments, greater than 75% of the patient's total number of inspirations are detected. In certain embodiments, greater than 90% of the patient's total number of inspirations are detected. In certain embodiments, greater than 95% of the patient's total number of inspirations are detected. In certain embodiments, greater than 98% of the patient's total number of inspirations are detected. In certain embodiments, greater than 99% of the patient's total number of inspirations are detected. In certain embodiments, between 75% and 100% of the patient's total number of inspirations are detected.

[0036] Dosage and Administration Regimen

[0039] In certain embodiments of the present disclosure, nitric oxide delivered to a patient is formulated at a concentration of about 3 to about 18 mg NO per liter, about 6 to about 10 mg NO per liter, about 3 mg NO per liter, about 6 mg NO per liter, about 15 mg NO per liter, or about 18 mg NO per liter. NO may be administered alone or in combination with an alternative gas therapy. In certain embodiments, oxygen (e.g., concentrated oxygen) may be administered to a patient in combination with NO. In embodiments, the NO is inhaled nitric oxide (iNO).

[0037]

[0040] In certain embodiments of the present disclosure, a volume of nitric oxide is administered in an amount of about 0.350 mL to about 7.5 mL per breath (e.g., in a single pulse). In some embodiments, the volume of nitric oxide in each pulse dose during the course of a single session may be the same. In some embodiments, the volume of nitric oxide in several pulse doses during a single time frame for delivering gas to a patient may vary. In some embodiments, the volume of nitric oxide in each pulse dose may be adjusted while monitoring breathing patterns during the course of a single time frame for delivering gas to a patient. In certain embodiments of the present disclosure, the amount of nitric oxide (ng) delivered to a patient per pulse ("pulse dose") for purposes of treating or alleviating symptoms of a pulmonary disease is calculated as follows, rounded to the nearest nanogram: Dose mcg / kg-IBW / hour x ideal body weight kg (kg-IBW) x ((1 hour / 60 minutes) / (1 minute / respiration rate (bpm)) x (1,000ng / ug).

[0038]

[0041] As an example, patient A on a dose of 100mcg / kg IBW / hr has an ideal body weight of 75kg and a respiratory rate of 20 breaths per minute (or 1200 breaths per hour): 100mcg / kg-IBW / hr x 75kg x (1hr / 1200 breaths) x (1,000ng / ug) = 6250ng per pulse.

[0039]

[0042] In certain embodiments, the variable 60 / respiratory rate (min) may be referred to as the administration event time. In another embodiment of the present disclosure, the administration event time is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, or 10 seconds.

[0040]

[0043] In some embodiments of the disclosure, a single pulse dose provides a therapeutic benefit (e.g., a therapeutically effective amount of NO) to a patient. In other embodiments of the disclosure, a total of two or more pulse doses provides a therapeutic benefit (e.g., a therapeutically effective amount of NO) to a patient.

[0041]

[0044] In certain embodiments 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 a patient every hour.

[0042]

[0045] In certain embodiments of the present disclosure, the nitric oxide therapy sessions occur over 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.

[0043]

[0046] In some embodiments of the present disclosure, nitric oxide therapy is administered during the shortest treatment course time frame.In some embodiments of the present disclosure, the shortest treatment course 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 some embodiments of the present disclosure, the shortest treatment course 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 certain embodiments 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.

[0044]

[0047] In some embodiments of the present disclosure, nitric oxide therapy sessions are performed one or more times per day. In some embodiments of the present disclosure, nitric oxide therapy sessions may be performed one, two, three, four, five, six, or more than six times per day. In some embodiments of the present disclosure, therapy sessions may be performed monthly, biweekly, weekly, every other day, daily, or multiple times per day.

[0045] NO Pulse Timing

[0048] In one embodiment of the present disclosure, breathing patterns are correlated with an algorithm to calculate when to administer a dose of nitric oxide.

[0046]

[0049] The accuracy of detecting inhalation / inhalation events is further maximized by timing the gas (e.g., NO) pulse to administer gas at a specific time window in the total inhalation time of a single detected breath.

[0047]

[0050] In certain embodiments of the present disclosure, at least fifty percent (50%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the present disclosure, at least sixty percent (60%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the present disclosure, at least seventy-five percent (75%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the present disclosure, at least eighty-five percent (85%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the present disclosure, at least ninety percent (90%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In certain embodiments of the present disclosure, at least ninety-two percent (92%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In certain embodiments of the present disclosure, at least ninety-five percent (95%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In certain embodiments of the present disclosure, at least ninety-nine percent (99%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In certain embodiments of the present disclosure, between 90% and 100% of the pulse dose of gas is delivered over the first third of the total inspiration time.

[0048]

[0051] In certain embodiments of the present disclosure, at least seventy percent (70%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In yet another embodiment, at least seventy-five percent (75%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the present disclosure, at least eighty percent (80%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the present disclosure, at least ninety percent (90%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the present disclosure, at least ninety-five percent (95%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the present disclosure, between 95% and 100% of the pulse dose of gas is delivered over the first half of the total inspiration time.

[0049]

[0052] In certain embodiments of the present disclosure, at least ninety percent (90%) of the pulse dose is delivered over the first two-thirds of the total inspiration time. In certain embodiments of the present disclosure, at least ninety-five percent (95%) of the pulse dose is delivered over the first two-thirds of the total inspiration time. In certain embodiments of the present disclosure, between 95% and 100% of the pulse dose is delivered over the first two-thirds of the total inspiration time.

[0050]

[0053] When counted, administration of multiple pulse doses over a therapy session / time frame may also fall within the above range.For example, when counted, more than 95% of all pulse doses administered during a therapy session are administered over the first two-thirds of the total inspiration time of all detected breaths.In a more accurate embodiment, when counted, more than 95% of all pulse doses administered during a therapy session are administered over the first one-third of the total inspiration time of all detected breaths.

[0051]

[0054] Given the high accuracy of the detection method of the present disclosure, the pulse dose can be administered during any particular time window of inspiration. For example, the pulse dose can be administered in the first third, middle third, or last third of the patient's inspiration. Alternatively, the first half or second half of inspiration can be targeted for administering the pulse dose. Furthermore, the target for administration can be changed. In one embodiment, the first third of inspiration time can be targeted for one or a series of inspirations, where the second third or second half can be targeted for a subsequent one or a series of inspirations during the same or different therapy session. Alternatively, the pulse administration can be scheduled to start after the first quarter of inspiration time has elapsed, continue for the middle half (next two quarters), and end at the beginning of the last quarter of inspiration time. In some embodiments, the pulse may be delayed by 50, 100, or 200 milliseconds (ms), or may be delayed in the range of about 50 to about 200 ms.

[0052]

[0055] Utilizing pulsed dosing during inhalation reduces exposure of poorly ventilated lung regions and alveoli from exposure to pulsed gas, e.g., NO. In one embodiment, less than 5% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 10% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 15% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 20% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 25% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 30% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 50% of the 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.

[0053] Treatment method

[0056] In one aspect of the disclosure, a method is described for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need of such treatment. In another embodiment, a method is provided for reducing pulmonary vascular resistance (PVR) in a patient having or at risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC), e.g., compared to a baseline level. In another embodiment, a method is provided for reducing mean pulmonary artery pressure (mPAP) in a patient having or at risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC), e.g., compared to a baseline level. In some embodiments, the method includes comparing PVR and / or mPAP to a baseline level. In some embodiments, the method includes administration of iNO, optionally supplementing the iNO administration with oxygen. In certain embodiments of the disclosure, iNO is administered according to a pulsed regimen discussed herein. In certain embodiments of the disclosure, iNO is delivered to the patient using an INOpuls® device (Bellerofon Therapeutics). In certain embodiments, the patient has or is at risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC). In certain embodiments, the patient has a low risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC). In certain embodiments, the patient has a moderate risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC). In certain embodiments, the patient has a high risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC). In certain embodiments, the patient has or is at risk of having and / or developing pulmonary hypertension (PH). In certain embodiments, the patient has a low risk of having and / or developing pulmonary hypertension (PH). In certain embodiments, the patient has a moderate risk of having and / or developing pulmonary hypertension (PH).In certain embodiments, the patient has and / or is at high risk of developing pulmonary hypertension (PH). In some embodiments, the pulmonary hypertension is selected from WHO Group I, WHO Group II, WHO Group III, WHO Group IV, and WHO Group V pulmonary hypertension. In some embodiments, the pulmonary hypertension is WHO Group V pulmonary hypertension.

[0054]

[0057] In one embodiment, the patient is administered iNO 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, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours per day 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, the patient is administered iNO for 8 weeks. In another embodiment, the patient is administered iNO for 16 weeks. In some embodiments of the present disclosure, the nitric oxide therapy sessions occur over 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.

[0055]

[0058] In some embodiments of the present disclosure, nitric oxide therapy is administered during the shortest treatment course time frame.In some embodiments of the present disclosure, the shortest treatment course 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 some embodiments of the present disclosure, the shortest treatment course 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 certain embodiments 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.

[0056]

[0059] In certain embodiments of the present disclosure, iNO is administered at a dose ranging from about 10 mcg / kg ideal body weight (IBW) / hr to about 200 mcg / kg IBW / hr or more. In one embodiment, iNO is administered at a dose ranging from about 20 mcg / kg IBW / hr to about 150 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose ranging from about 25 mcg / kg IBW / hr to about 100 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose ranging from about 30 mcg / kg IBW / hr to about 75 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose ranging from about 25 mcg / kg IBW / hr to about 50 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose ranging from about 30 mcg / kg IBW / hr to about 45 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 25 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 30 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 35 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 40 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 45 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 50 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 55 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 60 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 65 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 70 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 75 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 80 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 85 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 90 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 95 mcg / kg IBW / hr.In one embodiment, iNO is administered at a dose of about 100 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 105 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 110 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 115 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 120 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 125 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 130 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 135 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 140 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 145 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 150 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 155 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 160 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 165 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 170 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 175 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 180 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 185 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 190 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 195 mcg / kg IBW / hr. In one embodiment, iNO is administered at a dose of about 200 mcg / kg IBW / hr.

[0057]

[0060] In some embodiments of the present disclosure, the patient is also administered oxygen with iNO. In some embodiments of the present disclosure, oxygen is administered at up to 20 L / min. In some embodiments of the present disclosure, oxygen is administered at up to 1 L / min, 2 L / min, 3 L / min, 4 L / min, 5 L / min, 6 L / min, 7 L / min, 8 L / min, 9 L / min, 10 L / min, 11 L / min, 12 L / min, 13 L / min, 14 L / min, 15 L / min, 16 L / min, 17 L / min, 18 L / min, 19 L / min, or 20 L / min. In some embodiments of the present disclosure, oxygen is administered as prescribed by a physician. In some embodiments, the patient is receiving long-term oxygen therapy (LTOT).

[0058]

[0061] In some embodiments, the method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need of treatment further comprises treating and / or reducing the severity of one or more symptoms associated with PH-SARC. Non-limiting examples of symptoms include a reduction in pulmonary vascular resistance (PVR) and a reduction in mean pulmonary artery pressure (mPAP), which symptoms are reduced compared to baseline levels. In some embodiments, the method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need of treatment further comprises maintaining the severity of one or more symptoms associated with PH-SARC. Non-limiting examples of symptoms include a reduction in pulmonary vascular resistance (PVR) and a reduction in mean pulmonary artery pressure (mPAP).

[0059]

[0062] In a non-limiting embodiment, baseline levels can be determined by measuring and / or calculating levels (e.g., PVR, mPAP) of a patient or patient cohort (e.g., one or more patients with PH-SARC) prior to administration of iNO.

[0060]

[0063] 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, hi some embodiments, pulmonary vascular resistance (PVR) is reduced by at least about 20% compared to baseline levels.

[0061]

[0064] In some embodiments, the 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, the mean pulmonary artery pressure (mPAP) is reduced by at least about 10% compared to baseline levels.

[0062]

[0065] In one aspect, 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 the occurrence of treatment-emergent adverse events (AEs) and / or reduce the severity of treatment-emergent adverse events (AEs) as compared to other forms of treatment. In some embodiments, treatment-emergent adverse events (AEs) include those associated with device defects.

[0063]

[0066] 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 attributable to rebound associated with acute withdrawal of iNO and / or reduce the severity of symptoms attributable to rebound associated with acute withdrawal of iNO compared to other nitric oxide therapies. Non-limiting examples of symptoms attributable to rebound associated with acute withdrawal of iNO include: systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, shortness of breath, presyncope, and syncope.

[0064]

[0067] In an embodiment, the method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need of such treatment disclosed herein results in the maintenance of vital signs and / or other parameters, e.g., compared to baseline levels. In an embodiment, the vital signs and / or other parameters are adversely affected by administration of other types of treatment, 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 an embodiment, the method further comprises maintaining resting cardiac output (CO) compared to baseline levels. In an embodiment, the method further comprises maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

[0065]

[0068] In certain embodiments of the present disclosure, other parameters useful for assessing the efficacy of iNO include time to clinical improvement and time to clinical deterioration. Patients treated with iNO are expected to have a shorter time to clinical improvement and a longer time to clinical deterioration. Patient related outcome measures (PROs) are also useful for assessing the efficacy of iNO. PROs are measured in the form of questionnaires and provide a subject's perspective on their overall quality of life. Non-limiting examples of PROs include the St. George Respiratory Questionnaire (SGRQ) and the University of California, San Diego Shortness of Breath Questionnaire (UCSD SOBQ), King Sarcoidosis Questionnaire (KSQ), Fatigue Assessment Scale (FAS), and emPHasis10. These questionnaires are standard questionnaires used in the art, well known, and clinically accepted. Improvements in both scores of these PROs are expected for patients undergoing iNO therapy.

[0066] Actigraphy

[0069] The present disclosure also relates to a method of improving or maintaining activity levels or preventing a decline in activity levels in a patient having or at risk of having and / or developing pulmonary hypertension associated with sarcoidosis (PH-SARC), the method comprising using actigraphy to monitor and measure changes in activity levels.

[0067]

[0070] In an embodiment, actigraphy involves the use of a wearable activity monitor similar to a pedometer or accelerometer, or a triaxial accelerometer, Actigraph GT9X, or FITBIT®, to measure activity parameters. Such activity monitors assess activity and measure activity parameters of the user. Activity parameters measured include general 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, 6-minute walk distance (6MWD) test, and other types of activity and / or daily activity parameters.

[0068]

[0071] In some embodiments of the present disclosure, activity level is monitored and measured continuously for a period of time.In some embodiments of the present disclosure, activity level is monitored and measured intermittently for a period of time.In one embodiment, activity level is monitored and measured for a period of at least about 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks, and for a period of at least about 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 weeks, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours per day. In another embodiment, the activity level is monitored and measured for a period of at least about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day for a period of at least about 1, 2, 3, 4, 5, or 6 months. In another embodiment, the activity level is monitored only during the time the patient is awake. In one embodiment, the activity level is measured in a continuous manner throughout the awake period. In another embodiment, the patient can remove the device for certain activities, and thus the activity level is measured in a non-continuous manner throughout the awake period. In another embodiment, the awake period is at least 10 hours. In another embodiment, the awake period is at least 8 hours. In another embodiment, the awake period is at least 12 hours. In another embodiment, the awake period is at least 14 hours.

[0069]

[0072] In certain embodiments of the present disclosure, the activity level is improved compared to the baseline activity level. In certain embodiments, the baseline activity level is monitored and measured for at least one week prior to administration of the vasodilator. In other embodiments, the baseline activity level is monitored or measured for about 1 to about 14 days, about 1 to about 10 days, about 1 to about 7 days, or about 1 to about 5 days. In other embodiments, the baseline activity level is monitored or measured for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In certain embodiments of the present disclosure, the baseline activity is monitored or measured for about 7 days. In some embodiments of the present disclosure, the baseline activity level is monitored or measured for a period of about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day.In some embodiments of the present disclosure, the baseline activity is monitored or measured while the subject is awake.In some embodiments of the present disclosure, the baseline activity is monitored or measured while the subject is asleep.In some embodiments of the present disclosure, the baseline activity is monitored or measured during the time the subject is awake and asleep.

[0070]

[0073] In one embodiment, the activity level is improved compared to the baseline activity level. In one embodiment, the activity level is improved by about 1% to about 50%. In another embodiment, the activity level is improved by about 1% to about 25% compared to the baseline activity level. In another embodiment, the activity level is improved 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 is improved by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the baseline activity level.

[0071]

[0074] In another embodiment of the present disclosure, activity level is maintained compared to baseline activity level.In another embodiment, activity level is not decreased compared to baseline activity level.In another embodiment, activity level decreases less over time in treated patients than in untreated patients or placebo patients.In one embodiment, activity level decreases about 5% in treated patients, while activity level decreases about 20% or more in placebo patients or untreated patients.

[0072]

[0075] In one embodiment of the present disclosure, a subject wears an actigraphy monitor on the non-dominant arm. Wrist acceleration is continuously measured by the monitor. The monitor records 3-axis acceleration at 30 Hz. An algorithm converts the acceleration measurements into minutes of activity. Each minute is classified into an activity level based on established and validated cut points. The algorithm may also determine wear time, calories, and other parameters. Daily activity data is converted to weekly activity levels to allow comparison of the data. Predefined filters are utilized to ensure that only adherence data is analyzed. Such filters may include a minimum number of "wake-to-wear" minutes to ensure adherence (e.g., at least 600 minutes) and at least three adherence days in a complaint week. Filters may be based on industry standards used for actigraphy analysis.

[0073]

[0076] Counts can be converted to activity levels in multiple ways. For example, the average count provides a direct measure of physical activity. As shown in Table A, each minute of the day can be converted to an activity intensity to determine the amount of time spent in sedentary, light, moderate, and vigorous activity. [Table A]

[0074]

[0078] The embodiments encompassed herein will now be described with reference to the following examples, which 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 as encompassing any and all variations that become evident as a result of the teachings presented herein.

[0075] Example 1: Phase 2 Study of INOpulse in Patients with Sarcoidosis-Associated Pulmonary Hypertension (SAPH) Requiring Supplemental Oxygen

[0079] Patients with sarcoidosis may develop pulmonary hypertension (PH), which is associated with reduced quality of life and limitations in activities of daily living. The Phase 2 study was designed to determine the safety and clinical efficacy of pulsed iNO, a potent and well-established vasodilator, in patients with sarcoidosis-associated PH, as well as to evaluate a safe and effective dose of iNO in subjects with possible or confirmed sarcoidosis-associated pulmonary hypertension receiving long-term oxygen therapy (LTOT). Figure 1 shows an exemplary study design.

[0076]

[0080] Patients with sarcoidosis and previous right heart catheterization (RHC) or echocardiography-proven PH 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), and pulmonary wedge pressure (PCWP), and to derive pulmonary vascular resistance (PVR).

[0077]

[0081] Patients were administered acutely incremental doses of pulsed iNO via the INOpulse device, starting at 30 mcg / kg ideal body weight / hour (iNO30) and increasing to 125 mcg / kg ideal body weight / hour (iNO125), to assess the effect of each dose level on hemodynamic parameters. Patients were treated with iNO for 10 minutes per dose, with a 10-minute washout between doses.

[0078]

[0082] Dosing at each dose level was followed by a washout period. All hemodynamic waveforms were reviewed by a blinded hemodynamic core laboratory to determine end-tidal PAP and PCWP. After the acute vasodilator study, subjects were eligible to participate in a long-term open-label extension study at the dose of iNO found to be most beneficial by RHC measurements, as determined by the investigator.

[0079]

[0083] Tables 1A and 1B show the subject demographics of the eight patients enrolled in this study.

[0080] [Table 1-1]

[0081] [Table 1-2]

[0082] [Table 1-3]

[0084] Table 2 shows the baseline hemodynamic parameters.

[0083] [Table 2]

[0085] Table 3 shows the changes from baseline hemodynamic parameters.

[0084] [Table 3]

[0086] During the treatment visit for part 1 of the study, subjects were admitted to the cardiac catheterization lab / ICU / CCU, had a Swan-Ganz catheter inserted, and were monitored during acute exposure to iNO at 30, 45, 75, and 125 mcg / kg IBW / hr. Hemodynamic changes were monitored during this portion of the study. The primary endpoints for part 1 of the study were to evaluate the change in mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and pulmonary vascular resistance (PVR) with iNO 30, 45, 75, and 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 failure, symptoms attributable to rebound associated with acute withdrawal of iNO: systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, shortness of breath, near-syncope, and syncope, as well as changes in oxygen saturation and vital signs.

[0085]

[0087] All eight PH-Sarc patients received dose escalation to at least 75 mcg / kg, and seven were titrated to the highest dose of 125 mcg / kg per protocol. All eight patients demonstrated declines in mPAP and PVR across doses of iNO from iNO30 to iNO125, as determined by a blinded core lab. Group median mPAP baseline was 37.2 mmHg, declining 6-10% across doses from iNO30 to iNO125. Group median PVR baseline was 329 dynes*sec*cm-5, with a median decline of 20% (-54% to +22%) at the iNO45 dose. Dose escalation to the iNO125 dose resulted in a median decline 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.

[0086]

[0088] Hemodynamic changes were determined for absolute change (shown in Figures 2A-2D) and percent change (shown in Figures 2E-2H) from baseline in PVR, mPAP, CO, and PCWP. Analyses shown show change from baseline (box plots show median, IQR, and min / max). Statistical analysis based on Wilcoxon log-rank test was evaluated between baseline and each dose, and between each dose and each preceding dose, with no correction for multiplicity. All eight subjects showed reductions in mPAP and PVR across the dose range, with the iNO30 dose achieving statistical significance for mPAP compared to baseline, and the iNO125 dose achieving statistical significance for PVR compared to both baseline and the preceding iNO75 dose. CO and PCWP remained stable across all doses, and iNO was well tolerated across all doses. Median mPAP reductions ranged from 6.3% to 10.6%, with an IQR range of 10% to 15.8%. The reduction in mPAP was statistically significant (p<0.05) at the iNO30 dose, but due to the small data set, the remaining doses did not reach statistically significant levels for change from baseline or the preceding dose. Cardiac output values ​​remained stable across all doses and did not change significantly with any dose of iNO.

[0087]

[0089] The median reduction in PVR was 7.0% to 28.7% (IQR 10.6% to 37.7%). Given the overlap in interquartile ranges between doses, and due to small sample sizes, no dose was judged to be clearly superior, but the iNO125 dose showed a statistically significant reduction in PVR compared to baseline (p<0.05), as did the preceding iNO75 dose.

[0088]

[0090] While preferred embodiments of the present disclosure have been shown and described herein, such 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 employed in practicing the present disclosure.

Claims

1. 1. A method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need of such treatment, the method comprising administering inhaled nitric oxide (iNO) to the patient.

2. 1. A method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, comprising administering to said patient inhaled nitric oxide (iNO), said iNO comprising: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating when to administer a dose of nitric oxide; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

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

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

5. 3. The method of claim 1 or 2, wherein the treatment further comprises reducing pulmonary vascular resistance (PVR) and / or reducing mean pulmonary artery pressure (mPAP) compared to baseline levels.

6. 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 by at least about 20%, compared to baseline levels.

7. 6. The method of claim 5, 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 by at least about 10%, compared to baseline levels.

8. The method described in claim 1 or 2, wherein the treatment further comprises maintaining resting cardiac output (CO) and / or maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

9. 3. The method of claim 1 or 2, wherein delivery of the dose of iNO occurs within the first third of the total inspiration time, the first two-thirds of the total inspiration time, or the first half of the total inspiration time.

10. 3. The method of claim 1 or 2, wherein delivery of at least 50 percent of the dose of iNO occurs within the first third of the total inhalation time, delivery of at least 90 percent of the dose of iNO occurs within the first two-thirds of the total inhalation time, and / or delivery of at least 70 percent of the dose of iNO occurs within the first half of the total inhalation time.

11. 3. The method of claim 1 or 2, wherein the nitric oxide is delivered in a series of pulses over a period of time.

12. 3. The method of claim 1 or 2, wherein the pulmonary hypertension is selected from WHO Group I, WHO Group II, WHO Group III, WHO Group IV, and WHO Group V pulmonary hypertension, optionally WHO Group V pulmonary hypertension.

13. 3. The method of claim 1 or 2, wherein the patient is receiving long-term oxygen therapy (LTOT).

14. 3. The method of claim 1 or 2, 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. 15. The method of claim 14, wherein the dose of iNO is selected from 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. 3. The method of claim 1 or 2, wherein the dose of iNO is about 45 mcg / kg IBW / hr.

17. 3. The method of claim 1 or 2, wherein the dose of iNO is about 125 mcg / kg IBW / hr.

18. 1. A method for reducing pulmonary vascular resistance (PVR) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, the method comprising administering to said patient inhaled nitric oxide (iNO), wherein said nitric oxide comprises: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating when to administer a dose of nitric oxide; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

19. 1. A method for reducing mean pulmonary artery pressure (mPAP) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, the method comprising administering to said patient inhaled nitric oxide (iNO), wherein said nitric oxide: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating when to administer a dose of nitric oxide; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

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

21. 20. The method of claim 18 or 19, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, the slope algorithm detecting a breath when the rate of pressure drop reaches a predetermined threshold.

22. 20. The method of claim 18 or 19, 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 by at least about 20%, compared to baseline levels.

23. 20. The method of claim 19, 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 by at least about 10%, compared to baseline levels.

24. 20. The method of claim 18 or 19, further comprising maintaining resting cardiac output (CO) and / or maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

25. 20. The method of claim 18 or 19, wherein delivery of the dose of iNO is delivered within the first one-third of the total inspiration time, the first two-thirds of the total inspiration time, or the first one-half of the total inspiration time.

26. 20. The method of claim 18 or 19, wherein delivery of at least 50 percent of the dose of iNO occurs within the first third of the total inspiration time, delivery of at least 90 percent of the dose of iNO occurs within the first two-thirds of the total inspiration time, and / or delivery of at least 70 percent of the dose of iNO occurs within the first half of the total inspiration time.

27. 20. The method of claim 18 or 19, wherein the nitric oxide is delivered in a series of pulses over a period of time.

28. 20. The method of claim 18 or 19, wherein the pulmonary hypertension is selected from WHO Group I, WHO Group II, WHO Group III, WHO Group IV, and WHO Group V pulmonary hypertension, optionally WHO Group V pulmonary hypertension.

29. 20. The method of claim 18 or 19, wherein the patient is receiving long-term oxygen therapy (LTOT).

30. 20. The method of claim 18 or 19, 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. 31. The method of claim 30, wherein the dose of iNO is selected from 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. 20. The method of claim 18 or 19, wherein the dose of iNO is about 45 mcg / kg IBW / hr.

33. 20. The method of claim 18 or 19, wherein the dose of iNO is about 125 mcg / kg IBW / hr.

34. 20. The method of claim 1, 2, 18 or 19, wherein the patient is at low risk, intermediate risk, or high risk of having and / or developing pulmonary hypertension (PH).

35. 20. The method of claim 1, 2, 18 or 19, further comprising preventing a decline in, maintaining or improving one or more activity levels of the patient.

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

37. 1. A method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, comprising administering to said patient inhaled nitric oxide (iNO), said iNO comprising: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating the timing of administration of nitric oxide at a dose of about 45 mcg / kg IBW / hr; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

38. 1. A method for treating pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, comprising administering to said patient inhaled nitric oxide (iNO), said iNO comprising: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating the timing of administration of nitric oxide at a dose of about 125 mcg / kg IBW / hr; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

39. 1. A method for reducing pulmonary vascular resistance (PVR) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, the method comprising administering to said patient inhaled nitric oxide (iNO), wherein said nitric oxide comprises: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating the timing of administration of nitric oxide at a dose of about 45 mcg / kg IBW / hr; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

40. 1. A method for reducing pulmonary vascular resistance (PVR) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, the method comprising administering to said patient inhaled nitric oxide (iNO), wherein said nitric oxide comprises: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating the timing of administration of nitric oxide at a dose of about 125 mcg / kg IBW / hr; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

41. 1. A method for reducing mean pulmonary artery pressure (mPAP) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, the method comprising administering to said patient inhaled nitric oxide (iNO), wherein said nitric oxide: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating the timing of administration of nitric oxide at a dose of about 45 mcg / kg IBW / hr; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

42. 1. A method for reducing mean pulmonary artery pressure (mPAP) in a patient having or at risk of having pulmonary hypertension associated with sarcoidosis (PH-SARC) in a patient in need thereof, the method comprising administering to said patient inhaled nitric oxide (iNO), wherein said nitric oxide: a. detecting a breathing pattern in the patient, including a total inspiration time of a single breath; b. correlating said breathing pattern with an algorithm for calculating the timing of administration of nitric oxide at a dose of about 125 mcg / kg IBW / hr; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; A method in which the drug is delivered in a pulsed manner by

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

44. 43. The method of any one of claims 37 to 42, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, the slope algorithm detecting a breath when the rate of pressure drop reaches a predetermined threshold level.

45. 41. The method of claim 39 or 40, 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 by at least about 20%, compared to baseline levels.

46. 43. The method of claim 41 or 42, 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 by at least about 10%, compared to baseline levels.

47. 43. The method of any one of claims 37 to 42, further comprising maintaining resting cardiac output (CO) and / or maintaining pulmonary capillary wedge pressure (PCWP) compared to baseline levels.

48. 43. The method of any one of claims 37 to 42, wherein delivery of the dose of iNO is delivered within the first one-third of the total inspiration time, the first two-thirds of the total inspiration time, or the first one-half of the total inspiration time.

49. 43. The method of any one of claims 37 to 42, wherein delivery of at least 50 percent of the dose of iNO occurs within the first third of the total inhalation time, delivery of at least 90 percent of the dose of iNO occurs within the first two-thirds of the total inhalation time, and / or delivery of at least 70 percent of the dose of iNO occurs within the first half of the total inhalation time.

50. 43. The method of any one of claims 37 to 42, wherein the nitric oxide is delivered in a series of pulses over a period of time.

51. 43. The method of any one of claims 37 to 42, wherein the pulmonary hypertension is selected from WHO Group I, WHO Group II, WHO Group III, WHO Group IV, and WHO Group V pulmonary hypertension, optionally WHO Group V pulmonary hypertension.

52. 43. The method of any one of claims 37 to 42, wherein the patient is receiving long-term oxygen therapy (LTOT).

53. 43. The method of any one of claims 37 to 42, wherein the patient is at low risk, intermediate risk, or high risk of having and / or developing pulmonary hypertension (PH).

54. 43. The method of any one of claims 37 to 42, further comprising preventing a decline in, maintaining, or improving one or more activity levels of the patient.

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

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