USE OF INHALED NITRIC OXIDE FOR THE TREATMENT OF PULMONARY HYPERTENSION ASSOCIATED WITH LUNG DISEASE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No.

62/552,022 filed on August 30, 2017 and U.S. Provisional Application Serial No. 62/611,325 filed December 28, 2017, which are incorporated by reference herein in their entirety.

TECHNICAL FIELD

[0002] Principles and embodiments of the present invention generally relate to the field of inhaled nitric oxide delivery.

BACKGROUND

[0003] Inhaled nitric oxide (iNO) has been well established as an effective vasodilator for use in pediatric pulmonary hypertension such as persistent pulmonary hypertension of the newborn (PPHN). It has been proposed that iNO could be an effective vasodilator for the treatment of various types of pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH) (WHO Group I), PH associated with left heart disease (WHO Group 2), PH associated with lung disease and/or chronic hypoxemia (WHO Group 3), chronic thromboembolic pulmonary hypertension (WHO Group 4) or PH with unclear multifactorial mechanisms (WHO Group 5).

[0004] Accordingly, there is a need for new therapies that utilize iNO for the treatment of PH associated with lung disease.

SUMMARY

[0005] Various aspects of the present invention pertain to dosing regimens of iNO for the treatment of PH associated with lung disease.

[0006] One aspect of the present invention pertains to a method of improving oxygen saturation in a patient with PH and a ventilation-perfusion (V/Q) mismatch.

[0007] Another aspect of the present invention pertains to a method of improving oxygen saturation in a patient with PH associated with lung disease. [0008] Another aspect of the present invention pertains to a method of treating PH in a patient with a V/Q mismatch.

[0009] Another aspect of the present invention pertains to a method of treating PH associated with lung disease.

[0010] Another aspect of the present invention pertains to a method of treating PH by improving oxygen saturation.

[0011] In one or more embodiments, the patient is administered an effective amount of iNO at a dose of about 5 to about 70 micrograms NO per kilogram ideal body weight per hour (mcg/kg IBW/hr). In one or more embodiments, the effective amount of iNO is in the range of about 5 to about 60 mcg/kg IBW/hr, such as about 20 to about 40 mcg/kg IBW/hr.

[0012] In one or more embodiments, the iNO is administered to the patient during the first half of inspiration.

[0013] In one or more embodiments, the patient is administered an effective amount of iNO in combination with an effective amount of long-term oxygen therapy (LTOT).

[0014] In one or more embodiments, the iNO is administered for a certain minimum treatment time, such as 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 12, about 18 or about 24 months.

[0015] In one or more embodiments, the iNO is administered for a certain amount of time each day, such as at least 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 16, about 18 or about 24 hours a day.

[0016] In one or more embodiments, the patient has a low, intermediate, or high probability of PH.

[0017] In one or more embodiments, the patient has PH associated with lung disease and/or chronic hypoxemia (WHO Group 3).

[0018] In one or more embodiments, the patient has WHO Group 3 PH associated with interstitial lung disease (PH-ILD).

[0019] In one or more embodiments, the patient has WHO Group 3 PH associated with idiopathic pulmonary fibrosis (PH-IPF).

[0020] In one or more embodiments, the patient has WHO Group 3 PH associated with chronic obstructive pulmonary disease (PH-COPD). [0021] In one or more embodiments, the patient has PH associated with pulmonary edema from high altitude sickness.

[0022] In one or more embodiments, the patient has a V/Q mismatch.

[0023] In one or more embodiments, a plurality of pulses of a gas comprising NO is administered to the patient over a plurality of breaths.

[0024] In one or more embodiments, the gas comprising NO is not administered to the patient in at least one breath of the plurality of breaths.

[0025] In one or more embodiments, the maximum time period between successive pulses of the gas comprising NO does not exceed about 30, about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds.

[0026] In one or more embodiments, the maximum number of consecutive skipped breaths does not exceed three, two or one breaths.

[0027] In one or more embodiments, the average time period between successive pulses of the gas comprising NO does not exceed about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds.

[0028] In one or more embodiments, the average time period between successive pulses of the gas comprising NO does not exceed about 3, about 2.5, about 2, about 1.5 or about 1 breaths.

[0029] In one or more embodiments, 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 700, about 750, about 800, about 850, about 900, about 950 or about 1,000 pulses of the gas comprising NO is administered to the patient every hour.

[0030] In one or more embodiments, the administration of iNO provides an increase in

Sp02 nadir during exercise after 4 weeks of iNO administration, such as at least about 1, about 2, about 3, about 4, about 5 or about 6. [0031] In one or more embodiments, the administration of iNO provides an increase in

Sp02 average during exercise after 4 weeks of iNO administration, such as at least about 1, about 2, about 3, about 4, about 5 or about 6.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The patent or application file contains at least one drawing executed in color.

Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0033] Further features of the present invention will become apparent from the following written description and the accompanying figures, in which:

[0034] FIG. 1 shows the treatment visit schedule for Part 2a of a three-part clinical trial evaluating the use of iNO;

[0035] FIG. 2 shows the treatment visit schedule for Part 2b of a three-part clinical trial evaluating the use of iNO;

[0036] FIG. 3 shows the treatment visit dose titration details for Part 3a of a three-part clinical trial evaluating the use of iNO;

[0037] FIG. 4 shows the treatment visit schedule for Part 3b of a three-part clinical trial evaluating the use of iNO;

[0038] FIG. 5 shows the regional vasodilation in the lungs of a first PH-IPF patient receiving an iNO dose of 75 mcg/kg IBW/hr;

[0039] FIG. 6 shows the regional vasodilation in the lungs of a second PH-IPF patient receiving an iNO dose of 75 mcg/kg IBW/hr;

[0040] FIG. 7 shows the regional vasodilation in the lungs of a third PH-IPF patient receiving an iNO dose of 30 mcg/kg IBW/hr;

[0041] FIG. 8 shows the regional vasodilation in the lungs of a fourth PH-IPF patient receiving an iNO dose of 30 mcg/kg IBW/hr;

[0042] FIG. 9 shows the ventilation vs vasodilation for PH-COPD patients during an acute iNO assessment;

[0043] FIG. 10 shows the change in six-minute walk distance (6MWD) in PH-COPD subjects at baseline and during chronic iNO therapy;

[0044] FIG. 11 shows systolic pulmonary artery pressure (sPAP) in PH-COPD subjects at baseline, during chronic iNO therapy and after discontinuation of chronic iNO therapy; and [0045] FIG. 12 shows TAPSE in PH-COPD patients at baseline, during chronic iNO therapy and after discontinuation of chronic iNO therapy.

DETAILED DESCRIPTION

[0046] Before describing several exemplary embodiments of the invention, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or being carried out in various ways.

[0047] It has surprisingly been discovered that long-term iNO therapy at doses below

75 mcg/kg IBW/hr provides improved oxygen saturation in patients with PH associated with lung disease. Previously, a clinical study had demonstrated that an iNO dose of 75 mcg/kg IBW/hr was effective for the treatment of pulmonary arterial hypertension (PAH), whereas the same study found an iNO dose 25 mcg/kg IBW/hr was inefficacious. Accordingly, various aspects of the present invention pertain to the use of iNO doses below 75 mcg/kg IBW/hr for the treatment of PH and/or improving oxygenation in patients with lung disease and/or a V/Q mismatch.

[0048] Maintenance and/or improvements in oxygen saturation can be assessed by many measurements. Oxygen saturation is an indication of how much hemoglobin in the blood is bound to oxygen, and is typically provided as a percentage of oxyhemoglobin to the total hemoglobin. Sp02 is an indication of oxygen saturation in the peripheral capillaries. Exemplary methods to measure Sp02 include, but are not limited to, pulse oximetry. Other parameters can also be used to assess oxygenation, such as arterial oxygen saturation (Sa02) and/or partial pressure of oxygen in arterial blood (Pa02). Oxygen desaturation refers to a drop in oxygen saturation, such as a drop in oxygen saturation after the patient performs a test assessing exercise capacity.

[0049] Oxygen saturation can be measured before, during or after tests that assess exercise capacity. One approach to assess exercise capacity is the six-minute walk test, which provides the 6MWD. Other measurements that can be used to assess exercise capacity include, but are not limited to, shuttle walk test, activity level, forced exercise, maximal exercise test, treadmill, bicycle and cardiopulmonary exercise test.

[0050] Accordingly, in one or more embodiments, the iNO therapy maintains or improves one or more parameters related to oxygen saturation. In some embodiments, maintenance of a parameter corresponds to no change in that parameter over a certain time period. In some embodiments, if a parameter is expected to worsen in an untreated patient over time (e.g. oxygen saturation is expected to decrease in untreated PH patients), then maintenance of a parameter also includes a clinical worsening of the parameter that is a smaller magnitude than the clinical worsening that is expected for an untreated patient.

[0051] In one or more embodiments, the iNO therapy maintains or increases oxygen saturation (e.g. Sp02) over a certain time period, such as after administering iNO for 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 or 24 months or at least 1, 2, 3, 4 or 5 years.

[0052] In one or more embodiments, the patient's oxygen saturation does not change during iNO therapy, even though the oxygen saturation is expected to decrease in an untreated patient. In other embodiments, a patient's oxygen saturation is increased over a certain time period. Exemplary increases in oxygen saturation include increases of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 5, about 6, about 7, about 8, about 9 or about 10.

[0053] In one or more embodiments, the oxygen saturation is provided as an average oxygen saturation during the exercises test, such as an Sp02 average during the 6MWT. In one or more embodiments, the oxygen saturation is provided as a minimum oxygen saturation during the exercises test, such as an Sp02 nadir during the 6MWT. The oxygen saturation can be monitored continuously or at certain intervals, such as every minute, every 30 seconds, every 15 seconds, every second, etc.

[0054] In one or more embodiments, 4 weeks of iNO therapy provides an average increase in Sp02 during exercise in a group of patients of at least about 1. In various embodiments, the average increase in Sp02 during exercise in the group of patients after 4 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5 or about 6.

[0055] In one or more embodiments, 4 weeks of iNO therapy provides an average increase in Sp02 nadir during exercise in a group of patients of at least about 1. In various embodiments, the average increase in Sp02 nadir during exercise in the group of patients after 4 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5 or about 6.

[0056] In one or more embodiments, 4 weeks of iNO therapy provides an average increase in Sp02 average during exercise in a group of patients of at least about 1. In various embodiments, the average increase in Sp02 average during exercise in the group of patients after 4 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5 or about 6.

[0057] One or more embodiments of the present invention also relate to maintaining and/or improving right ventricular (RV) function using long-term iNO therapy. Maintenance and/or improvements in RV function can be assessed by many echocardiographic measurements. One such quantitative approach to assess RV function is the measurement of the tricuspid annular plane systolic excursion (TAPSE). The TAPSE estimates RV systolic function by measuring the level of systolic excursion of the lateral tricuspid valve annulus towards the apex. An excellent correlation between the TAPSE and RV ejection fraction as assessed by radionuclide angiography has previously been established and the approach appears reproducible and proven to be a strong predictor of prognosis in heart failure. [Reference: Heart. 2006 Apr; 92(Suppl 1): Ϊ19-Ϊ26.]

[0058] Other echocardiographic measurements that may be used to assess maintenance and/or improvements in RV function include, but are not limited to, RV fractional area change (RVFAC), sPAP, tricuspid annular systolic velocity (TASV), and Tei index.

[0059] Accordingly, in one or more embodiments, the iNO therapy maintains or improves one or more of the following parameters: TAPSE, RVFAC, sPAP, tricuspid annular motion, TAPSE, TASV, and Tei index. In some embodiments, maintenance of a parameter corresponds to no change in that parameter over a certain time period. In some embodiments, if a parameter is expected to worsen in an untreated patient over time (e.g. TAPSE is expected to decrease in untreated PH patients), then maintenance of a parameter also includes a clinical worsening of the parameter that is a smaller magnitude than the clinical worsening that is expected for an untreated patient.

[0060] In one or more embodiments, the iNO therapy maintains or increases TAPSE over a certain time period, such as after administering iNO for 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 days 1, 2, 3, 4, 5, 6, 7 or 8 weeks or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 or 24 months or at least 1, 2, 3, 4 or 5 years.

[0061] In one or more embodiments, the patient's TAPSE does not change during iNO therapy, even though the TAPSE is expected to decrease in an untreated patient. In other embodiments, a patient's TAPSE is increased over a certain time period. Exemplary increases in TAPSE include increases of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 mm. Exemplary increases in TAPSE can also be expressed in percentages, such as increases of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65 or about 70%.

[0062] In one or more embodiments, 1 week of iNO therapy provides an average increase in TAPSE in a group of patients of at least 1 mm. In various embodiments, the average increase in TAPSE in the group of patients after 1 week of iNO therapy is at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 mm.

[0063] In one or more embodiments, 1 week of iNO therapy provides an average increase in TAPSE in a group of patients of at least 5%. In various embodiments, the average increase in TAPSE in the group of patients after 1 week of iNO therapy is at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65 or about 70%.

[0064] In one or more embodiments, 2 weeks of iNO therapy provides an average increase in TAPSE in a group of patients of at least 1 mm. In various embodiments, the average increase in TAPSE in the group of patients after 2 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 mm.

[0065] In one or more embodiments, 2 weeks of iNO therapy provides an average increase in TAPSE in a group of patients of at least 5%. In various embodiments, the average increase in TAPSE in the group of patients after 2 weeks of iNO therapy is at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65 or about 70%.

[0066] In one or more embodiments, 4 weeks of iNO therapy provides an average increase in TAPSE in a group of patients of at least 1 mm. In various embodiments, the average increase in TAPSE in the group of patients after 4 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 mm.

[0067] In one or more embodiments, 4 weeks of iNO therapy provides an average increase in TAPSE in a group of patients of at least 5%. In various embodiments, the average increase in TAPSE in the group of patients after 4 weeks of iNO therapy is at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65 or about 70%.

[0068] Moreover, due to the interdependencies of RV function and left ventricular

(LV) function, improving RV function can also improve LV function. Thus, iNO therapy can also be used to maintain and/or improve LV function in a patient. [0069] Maintenance and/or improvements in LV function can be assessed by many echocardiography measurements. Echocardiographic measurements that may be used to assess maintenance and/or improvements in LV function include, but are not limited to, LVEF, LV size, and LV early diastolic relaxation velocity.

[0070] Accordingly, in one or more embodiments, the iNO therapy maintains or improves one or more of the following parameters: LVEF, LV size, and LV early diastolic relaxation velocity. As described above, in some embodiments, maintenance of a parameter corresponds to no change in that parameter over a certain time period. In some embodiments, if a parameter is expected to worsen in an untreated patient over time, then maintenance of a parameter also includes a clinical worsening of the parameter that is a smaller magnitude than the clinical worsening that is expected for an untreated patient.

[0071] In one or more embodiments, the patient or group of patients are diagnosed with

PH. The patient(s) can be diagnosed by a cardiologist, pulmonologist or other physician according to suitable criteria using techniques such as echocardiography, right heart catheterization (RHC), etc. Examples of such criteria include, but are not limited to, patients that have a mean pulmonary arterial pressure (mPAP) at rest of at least 25 mm Hg, or a tricuspid regurgitation velocity greater than 2.9 m/s, or other combinations of factors as determined by an appropriate physician. The World Health Organization (WHO) has defined five categories of PH: PAH (WHO Group 1); PH associated with left heart disease (WHO Group 2), PH associated with lung disease and/or chronic hypoxemia (WHO Group 3), chronic thromboembolic pulmonary hypertension (WHO Group 4) or PH with unclear multifactorial mechanisms (WHO Group 5).

[0072] Examples of WHO Group 3 patients include PH-COPD patients and those with interstitial lung disease (ILD) such as PH-IPF patients. Other examples of WHO Group 3 patients include those with combined pulmonary fibrosis and emphysema (CPFE), chronic high altitude exposure, or other lung diseases such as sleep disordered breathing or developmental diseases. COPD, ILD and other lung diseases can be diagnosed according to any suitable factor or combination of factors, such as those set forth in the guidelines of the American Thoracic Society. One exemplary set of criteria for diagnosing COPD is the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria. In at least one embodiment, the patient has PH-COPD. In at least one embodiment, the patient has PH and ILD, such as a patient with PH-IPF. In at least one embodiment, the patient has PH associated with pulmonary edema from high altitude sickness.

[0073] In one or more embodiments, the patient has a V/Q mismatch.

[0074] In one or more embodiments, the patient or group of patients has a low, intermediate, or high probability of PH as determined by echocardiography or other suitable technique. One exemplary set of criteria for evaluating the probability of PH is set forth in the 2015 ESC/ERS Guidelines for Diagnosis and Treatment of Pulmonary Hypertension. In at least one embodiment, the patient has a low echocardiographic probability of PH. In at least one embodiment, the patient has an intermediate echocardiographic probability of PH. In at least one embodiment, the patient has a high echocardiographic probability of PH.

[0075] In one or more embodiments, the patient has been placed on a lung transplant waiting list, and the iNO therapy is used to maintain or improve RV and/or LV function before the lung transplant. In other embodiments, the patient has already received a lung transplant.

[0076] Patients in need of a lung transplant are evaluated and receive a lung allocation score (LAS), which estimates the severity of each candidates' illness and his or her chance of success following a lung transplant. Those with a higher LAS receive a higher priority for a lung offer when a compatible lung becomes available. Improving or maintaining cardiac function (e.g. RV and/or LV function) improves the likelihood that a patient will survive long enough to receive a lung transplant. Moreover, improving or maintaining cardiac function (e.g. RV and/or LV function) improves a patient's prognosis following lung transplant. Accordingly, in one or more embodiments, iNO therapy can be provided to patients on a lung transplant list, particularly patients on a lung transplant list that have PH. Also, in one or more embodiments, iNO therapy may influence one or more factors used to determine the patient's LAS, and thus the iNO therapy may change the patient's LAS.

[0077] The iNO may be administered continuously, or by a series of pulses, or any other suitable technique for delivering iNO to a patient's lungs. Exemplary devices for the administration of iNO are described in U.S. Pat. No. 5,558,083; U.S. Pat. No. 7,523,752; U.S. Pat. No. 8,757, 148; U.S. Pat. No. 8,770,199; U.S. Pat. No. 8,893,717; U.S. Pat. No. 8,944,051 ; U.S. Pat. App. Pub. No. 2013/0239963; U.S. Pat. App. Pub. No. 2014/0000596; and U.S. Pat. App. Pub. No. 2016/0106949, the disclosures of which are hereby incorporated by reference in their entireties. [0078] In one or more embodiments, iNO is administered by a NO delivery device utilizing cylinders containing NO and a carrier gas such as nitrogen (N ₂ ). Exemplary NO cylinder concentrations include, but are not limited to, concentrations in the range of about 100 ppm to about 15,000 ppm, such as about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1,000, about 1,500, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000 or about 15,000 ppm. In one or more embodiments, the NO cylinder concentration is about 4,880 ppm.

[0079] In one or more embodiments, the NO is generated bedside or at the point of administration. For example, various chemical reactions can be used to generate NO, such as reacting N ₂ and oxygen (0 ₂ ) in the presence of an electrode, or reacting nitrogen dioxide (N0 ₂ ) with a reducing agent.

[0080] In one or more embodiments, the iNO is administered as a series of pulses. The iNO may have a specific pulse volume, such as about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.5, about 2, about 3, about 4 or about 5 mL. The pulse volume may be the same from one breath to the next, or the pulse volume may vary according to the patient's breathing rate and/or the amount of iNO already delivered to the patient.

[0081] In one or more embodiments, the effective amount of iNO is in the range of about 5 to about 70 mcg/kg IBW/hr. A patient's ideal body weight correlates with the patient's estimated lung size, and is a function of the patient's sex and height. In various embodiments, the dose of iNO is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65 or about 70 mcg/kg IBW/hr.

[0082] In one or more embodiments, a constant dose of iNO is delivered to the patient in each breath, such as a constant dose in nmol/breath, ng/breath or mL/breath. Exemplary doses include about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1,000 or about 1,500 nmol NO per breath.

[0083] In one or more embodiments, the iNO is administered continuously at a constant concentration. For example, the iNO may be administered at a constant concentration of about 1 ppm to about 100 ppm. In various embodiments, the dose of iNO is about 1, about 2, about 3, about 4, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100 ppm.

[0084] In one or more embodiments, a desired quantity of gas is administered to the patient over a plurality of breaths in a way that is independent of the patient's respiratory pattern. For example, a patient's iNO dose may be prescribed in terms of mcg/kg IBW/hr, such that a desired amount is delivered to the patient every hour regardless of the patient's respiratory pattern or breathing rate. The NO delivery device may have an input such as a dial, display, touchscreen or other user interface to receive the patient's prescription. An amount of NO per breath (e.g. nmol NO, ng NO, mL of gas comprising NO, etc.) can be calculated based on the patient's current respiratory pattern, and that amount of NO can be delivered to the patient in the next breath or for several breaths. The NO delivery device may monitor the patient's respiratory pattern or breathing rate (or changes in the respiratory pattern or breathing rate) and re-calculate and/or otherwise adjust the amount of NO-containing gas that is delivered on the current breath or on subsequent breaths. The NO delivery device can have a control system with appropriate software and/or hardware (e.g. flow sensors, pressure sensors, processors, memory, etc.) for monitoring the breath, calculating or otherwise determining the amount of NO to be delivered, and be in communication with other components of the NO delivery device (e.g. flow sensors, pressure sensors, valves, gas conduits, etc.) for delivering the gas comprising NO. The amount of NO per breath can be calculated and/or adjusted after every breath or can be calculated and/or adjusted at certain intervals such as every minute, every 10 minutes, every 10 breaths, every 100 breaths, etc.

[0085] In one or more embodiments, the iNO is not delivered to the patient every breath and at least one breath is skipped during the iNO therapy. The time period between individual pulses of gas comprising NO can vary or can be constant. In various embodiments, a maximum time period between pulses, a maximum average time period between pulses and/or a minimum pulse frequency may be provided.

[0086] Various situations can result in iNO being skipped in a particular breath. For example, an intermittent dosing regimen may be utilized in which the iNO is administered every n ^th breath, with n being greater than 1. In various embodiments, n is about 1.01, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10. When n is not a whole number (e.g. 1.1 or 2.5), n can represent an average over multiple breaths. As an example, administering iNO every 2.5 breaths indicates that iNO is administered an average of 2 breaths out of every 5 breaths (i.e. 5/2 = 2.5). Similarly, administering iNO every 1.1 breaths indicates that iNO is administered an average of 10 breaths out of every 11 breaths (i.e. 11/10 = 1.1). Similar calculations can be performed for other intermittent dosing regimens where iNO is administered every n ^th breath, with n being greater than 1.

[0087] In one or more embodiments, an intermittent dosing regimen may be utilized in which predetermined breaths are skipped. The skipping of predetermined breaths can be based on predetermined patterns such as skipping every other breath, skipping every third breath, skipping two consecutive breaths and delivering on the third breath, etc. The predetermined pattern can include delivering gas comprising NO on every n ^th breath, such as having n be greater than 1, for example about 1.01, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10.

[0088] In one or more embodiments, one or more breaths is skipped in a certain time period. For example, 1, 2, 3, 4, 5, etc. breaths may be skipped every hour, every 30 minutes, every 15 minutes, every 10 minutes, every minute, every 30 seconds, etc. In some embodiments, as little as one breath is skipped during the entire iNO therapy. In other embodiments, multiple breaths are skipped during iNO therapy.

[0089] In one or more embodiments, an intermittent dosing regimen may be utilized in which random breaths are skipped. The random breath skipping can be determined according to a random number generator and/or can be based on current clinical conditions such as the patient's respiratory pattern, the patient's breathing rate, the amount of iNO that has been delivered to the patient, the patient's iNO prescription, etc., and/or can be based on settings for the NO delivery device such as a minimum pulse volume.

[0090] In one or more embodiments, the NO delivery device may have a minimum quantity of gas that can be delivered in a breath, such as a minimum pulse volume. This minimum quantity of gas can be set by the user or can be a minimum threshold value set by the specifications of the NO delivery device. In one or more embodiments, when the quantity of gas comprising NO to be delivered to the patient in a particular breath is less than the minimum quantity of gas per breath (e.g. minimum pulse volume), administration of the gas is skipped for that breath. In one or more embodiments, when the breath is skipped, a new quantity of gas per breath is calculated and/or the quantity of gas is carried over and is added to the amount of gas to be delivered in one or more subsequent breaths.

[0091] In addition to the exemplary situations described above, other situations that can result in one or more breaths being skipped during iNO therapy are also encompassed by the present disclosure. Such situations include, but are not limited to, skipped breaths or a pause in iNO therapy due to: changing or switching the drug cylinder or cartridge; NO delivery device purging; engagement with other devices or delivery systems such as LTOT, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BPAP), etc.; NO delivery device alarm conditions such as apnea, empty drug cylinder/cartridge, empty battery, etc.; or NO delivery device fault condition(s).

[0092] In one or more embodiments, there is a maximum time period between successive pulses of the gas comprising NO. For example, the time period between successive pulses may vary or may be constant, but an upper limit may be provided that prevents too long of a period between successive pulses of gas. In exemplary embodiments, the maximum time period between successive pulses of gas comprises NO does not exceed about 30, about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds.

[0093] In one or more embodiments, the maximum time period between successive pulses of the gas comprising NO is provided as a maximum number of breaths. In exemplary embodiments, the maximum number of consecutive skipped breaths does not exceed four, three, two or one breaths.

[0094] In one or more embodiments, the average time period between successive pulses of the gas comprising NO does not exceed a certain time period, such as not exceeding about 30, about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds. Again, the time period between individual pulses can vary or can be the same.

[0095] In one or more embodiments, the average number of consecutive skipped breaths does not exceed about 3, about 2.5, about 2, about 1.5, about 1 or about 0.5 breaths.

[0096] In one or more embodiments, the frequency of pulse administration is provided as a number of pulses in a given time period, such as pulses per hour. For example, in one or more embodiments the patient is administered 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 700, about 750, about 800, about 850, about 900, about 950 or about 1,000 pulses of the gas comprising NO per hour.

[0097] Shorter durations may also be used, and these pulse frequencies can likewise be expressed in terms of pulses per minute or other time period. In one or more embodiments, the patient is administered at least about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9 about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9 about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9 about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9 about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 16, about 17, about 18, about 19 or about 20 pulses per minute.

[0098] In one or more embodiments, the iNO is administered for a certain amount of time each day. For example, the iNO may be administered for at least about 1 hour a day. In various embodiments, the iNO is administered for at least 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 16, about 18 or about 24 hours a day.

[0099] In one or more embodiments, the iNO is administered for a certain treatment time. For example, the iNO may be administered for at least 2 days. In various embodiments, the iNO is administered for at least 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, or 1, 2, 3, 4 or 5 years.

[00100] In one or more embodiments, the patient is also receiving long-term oxygen therapy (LTOT). In various embodiments, the LTOT is administered for at least 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 16, about 18 or about 24 hours a day. In various embodiments, the LTOT is administered at a dose of about 0.5 L/min to about 10 L/min, such as about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10 L/min. The LTOT may be administered continuously or via pulses. EXAMPLES

Example 1 - Effect of iNQ Therapy on Vasodilation and Hemodynamics in Patients with PH- IPF

Study Design

[00101] This study was an exploratory, three-part, clinical study to assess the effect of pulsed iNO on functional pulmonary imaging parameters in subjects with PH-COPD on LTOT (Part 1) PH-IPF on LTOT (Part 2 and Part 3) (IK-7002-COPD-006; NCT02267655). The objective of this exploratory study was to examine the utility of high resolution computed tomography (HRCT) to measure changes in functional respiratory imaging parameters as a function of short term iNO administration using a pulsed NO delivery device in subjects with PH-IPF (Part 2 and Part 3) on LTOT. The primary endpoint in this exploratory study is the change from baseline in lobar blood volume at total lung capacity (TLC) after dosing with pulsed iNO (Part 1), iNO or Placebo (Part 2a) and after 4 weeks iNO treatment (Part 3b) as measured by HRCT.

[00102] The secondary endpoints of Part 2a (acute; placebo vs. iNO 75 mcg/kg IBW/hr) were change in Borg CRIO leg fatigue and dyspnea scale, changes in breathing questionnaire and changes in right ventricular and left ventricular function.

[00103] The secondary endpoints of Part 2b (chronic dosing) were change in 6MWT with Borg CRIO leg fatigue and dyspnea scale and Sp02, at the beginning and end of the 6MWT and symptoms evaluated using a questionnaire with after 4 weeks use of iNO at a dose of 75 mcg/kg IBW/hr and 2 weeks post discontinuation of iNO.

[00104] The secondary endpoints of Part 3b (chronic dosing) were change in 6MWT with Borg CRIO leg fatigue and dyspnea scale and Sp02, at the beginning and end of the 6MWT and symptoms evaluated using a questionnaire after 4 weeks use of iNO at a dose of 30 mcg/kg IBW/hr.

[00105] The safety endpoints in this study were:

1. Incidence and severity of treatment emergent adverse events (AEs), including those related to device deficiency;

2. Incidence of MetHb levels > 7.0%;

3. New symptoms that may be due to rebound PH associated with a temporal acute withdrawal of investigational study drug (i.e., symptoms occurring within 20 minutes of acute withdrawal and including those associated with investigational medical device malfunction or failure): systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, near-syncope, syncope, ventricular fibrillation, and/or cardiac arrest;

4. New or worsening symptoms of left heart failure or pulmonary edema; and

5. Any decrease in systemic oxygenation measured by oxygen saturation of arterial blood by pulse oximetry (Sp02), i.e., hypoxia or oxygen saturation decrease, deemed by the Investigator to be clinically significant.

[00106] This was an exploratory clinical study to evaluated the utility of HRCT to measure the pharmacodynamic effects of short term pulsed administration of iNO using a pulsed NO delivery device in subjects with PH-IPF (Part 2 and Part 3) on LTOT.

[00107] In Part 2b and Part 3b change in 6MWT with Borg CR10 leg fatigue and dyspnea scale and Sp02, at the beginning and end of the 6MWT, and a symptoms questionnaire were used to assess the effects of long term pulsed iNO administered using a pulsed NO delivery device in subjects with PH associated with IPF on LTOT.

[00108] In Part 2 of the study the subjects needed to have severe PH, therefore PH in

Part 2 was defined as sPAP > 50 mm Hg by 2-D echocardiogram. In Part 3 PH was defined as sPAP > 35 mm Hg by echocardiogram (Part 3).

[00109] The initial protocol intended that 4 subjects would be enrolled in Part 2. However during the conduct of Part 2 of the trial, after enrollment of 2 subjects, it was noticed that the two IPF patients included both suffered from a sudden increase in PAP after discontinuation with the use of iNO at a dose of 75 mcg/kg IBW/hr. It was decided to temporarily stop recruitment. One of the 2 subjects completed 4 weeks of chronic use in Part 2b.

[00110] In the amendment a total of 2 subjects participated in Part 3. The dose in Part

3 was lower than in Part 2 and each subject was titrated to the optimum dose as determined by the investigator. The dose of iNO was lowered to prevent the sudden swings in PAP. The dose was monitored with a RHC in place. The investigator found that both the next 2 subjects could titrate to iNO at a dose of 30 mcg/kg IBW/hr safely. This dose was used in these 2 subjects in Part 3.

[00111] The 2 subjects enrolled in Part 2 were randomly assigned for Part 2a to 1 of 2 sequences to receive iNO utilizing the NO cylinder concentration (4,880 ppm) at a dose of 75 mcg/kg IBW/hr or placebo set at a dose of 75 mcg/kg IBW/hr. FIG. 1 shows the treatment visit schedule for Part 2a.

[00112] One patient from Part 2a entered into Part 2b. During Part 2b patient receive iNO utilizing NO cylinder concentration (4,880 ppm) at a dose of 75 mcg/kg IBW/hr during 4 weeks for at least 12 hours/day. The treatment visit schedule for Part 2b is summarized in FIG. 2.

[00113] The 2 subjects enrolled in Part 3a each received three different doses of iNO utilizing NO cylinder concentration (4,880 ppm) at a dose of 5 mcg/kg IBW/hr, 10 mcg/kg IBW/hr and 30 mcg/kg IBW/hr, all with LTOT. For each dose, the change in PAP pressure and the change in cardiac output was evaluated by RHC. The investigator could decide after each dose to continue with the following dose or not. FIG. 3 shows the treatment visit dose titration details for Part 3 a.

[00114] The 2 patients from Part 3a entered Part 3b. During Part 3b, patients received iNO utilizing NO cylinder concentration (4,880 ppm) at a dose of 30 mcg/kg IBW/hr. One subject did not tolerate the device and discontinued treatment after 2 weeks. FIG. 4 shows the treatment visit schedule for Part 3b.

[00115] The study population consisted of subjects > 40 years, < 80 years, with a confirmed diagnosis of IPF (Part 2 and Part 3) who are receiving LTOT and have PH. A total of 4 subjects were enrolled.

[00116] The study had the following inclusion criteria for Part 2 and Part 3:

1. Patients will have a diagnosis of IPF as determined by a responsible and experienced Respiratory physician and based on;

i. HRCT: usual interstitial pneumonia

ii. FVC: 50-90% of predicted FVC

2. PH defined as sPAP > 50 mm Hg by echocardiogram (Part 2) and sPAP

> 35 mm Hg by echocardiogram or right heart catheterization (Part 3). If in Part 3a Screening Visit and Treatment Visit are performed on the same day documented results by echocardiogram or RHC from within 12 months prior to the Screening Visit should be available to evaluate eligibility.

3. Age > 40 years

4. Receiving LTOT for > 3 months 5. Females of childbearing potential must have a negative pre-treatment urine pregnancy test

6. Signed informed consent prior to the initiation of any study mandated procedures or assessments

7. BMI < 35 (Part 3 only)

[00117] The study had the following key exclusion criteria for Part 2 and Part 3.

Subjects who meet any of the following criteria were not eligible for enrollment:

1. Patients with a current IPF exacerbation or exacerbation within the past 30 days.

2. Clinically significant valvular heart disease that may contribute to PH, including mild or greater aortic valvular disease (aortic stenosis or regurgitation) and/or moderate or greater mitral valve disease (mitral stenosis or regurgitation), or status post mitral valve replacement

3. Use within 30 days of screening or current use of approved specific PH medications (ERA or PDE-5 inhibitor, or oral, inhaled, subcutaneous, or intravenous prostacyclin or a prostacyclin analog)

4. Use of investigational drugs or devices within 30 days prior to enrollment into the study

5. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study

Results

[00118] As can be seen from the above description, patients with PH-IPF were put on acute and chronic treatment with iNO. During the chronic phase, the vasodilation and the hemodynamics were assessed. During the chronic phase, the focus was exercise capacity. Oxygen saturation during exercise was evaluated both at baseline as well as after 4 weeks of chronic treatment with iNO. Both the acute and chronic phases evaluated iNO doses of 30 and 75 mcg/kg IBW/hr.

[00119] Table 1 below shows the acute effect of iNO on blood vessel volume as well as sPAP. Table 1; Changes in Blood Vessel Volume and sPAP in PH-IPF Subjects

[00120] As can be seen from Table 1, the increase in blood vessel volume is much higher for the iNO dose of 75 mcg/kg IBW/hr dose compared to the iNO dose of 30 mcg/kg IBW/hr. However, the effect on sPAP is similar or skewed towards the lower iNO dose of 30 mcg/kg IBW/hr.

[00121] Assessment of the regional vasodilation provides greater insight into the effect of iNO doses of 30 mcg/kg IBW/hr versus 75 mcg/kg IBW/hr. As seen in FIGS. 5 and 6, there is little to no targeted vasodilation for the iNO dose of 75 mcg/kg IBW/hr (Patients 1 & 2) where essentially the whole lung is green. However, as shown in FIGS. 7 and 8, there is a clear targeting of the drug for the lower iNO dose of 30 mcg/kg IBW/hr (Patients 3 & 4), where only portions of the lung are green and others remain unchanged (grey) or show some reduction in blood flow (red/orange). This correlates to the overall vasodilation being 14.2-34.2% for the iNO dose of 75mcg/kg IBW/hr and a more modest 2.8-10.1% for the lower iNO dose of 30 mcg/kg IBW/hr.

Table 2: SpQ2 Nadir and SpQ2 Average in PH-IPF Subjects

[00122] As can be seen from Table 2, there is a much larger improvement in the Sp02

Nadir with the iNO dose of 30 mcg/kg IBW/hr compared to the iNO dose of 75 mcg/kg IBW/hr. In addition, the average Sp02 actually decreases for the iNO dose of 75 mcg/kg IBW/hr, while the average Sp02 increases for the iNO dose of 30 mcg/kg IBW/hr. These results are consistent with the non-targeted vasodilation seen for the iNO dose of 75 mcg/kg IBW/hr that results in the inability to maintain V/Q matching and thereby oxygen saturation levels during exercise.

[00123] The results show that in Group 3 PH, the iNO dose needs to be lower as selective vasodilation cannot be maintained with the higher iNO dose of 75 mcg/kg IBW/hr.

[00124] Table 3 below shows the TAPSE results from two PH-IPF subjects in this trial.

Subject 1 received pulsed iNO at a dose of 75 mcg/kg IBW/hr for 4 weeks, and Subject 3 received pulsed iNO at a dose of 30 mcg/kg IBW/hr for 4 weeks.

Table 3: Changes in TAPSE in PH-IPF Subjects During Chronic iNO Therapy

[00125] As can be seen from Table 3, these results show that the long-term pulsed iNO therapy increased TAPSE in both PH-IPF subjects. This increase in TAPSE indicates an improvement in RV function. However, as explained above, the iNO dose needs to be lower than 75 mcg/kg/ IBW/hr to provide selective vasodilation.

Example 2 - Effect of Long-Term iNO Therapy on RV Function in Subjects with PH-COPD

[00126] This study is an open label Phase 1 study of iNO therapy in subjects with PH-

COPD (PULSE-COPD-007; NCT03135860). The primary outcome of this study is the change in lobar blood volume at total lung capacity with iNO and the change in lobar blood volume with iNO after 4 weeks of treatment with iNO as measured by HRCT.

[00127] Subjects had a confirmed diagnosis of COPD by the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria. Subjects also had sPAP > 38 mm Hg as measured by echocardiogram, a post-bronchodilatory FEV1/FVC < 0.7 and a FEV1 < 60% predicted. All subjects were at least 40 years old and were current or former smokers with at least 10 pack- years of tobacco cigarette smoking before study entry. All subjects also had been receiving LTOT for at least 3 months for at least 10 hours per day.

[00128] The PH-COPD subjects received pulsed iNO therapy for 4 weeks for at least 12 hours/day. The iNO was administered utilizing a 4,880 ppm NO cylinder concentration.

[00129] Table 4 below shows the TAPSE results from four PH-COPD subjects in this trial. These subjects were diagnosed with PH-COPD and received 4 weeks of treatment with iNO at a dose of 30 mcg/kg IBW/hr. The results verify the increase in TAPSE which correlates to RV function.

Table 4: Changes in TAPSE in PH-COPD Subjects During Chronic iNO Therapy

[00130] As can be seen from Table 4, these results show that the long-term pulsed iNO therapy increased TAPSE in three subjects, and TAPSE did not change in the fourth subject. This increase in TAPSE indicates an improvement in RV function for the three subjects and a maintenance in RV function for the fourth subject. Overall, the average increase in TAPSE of 25% across all four subjects shows that iNO therapy improves and/or maintains RV function.

[00131] An acute assessment with iNO of nine PH-COPD subjects showed a statistically significant increase (average 4.2%) in blood vessel volume on iNO. As shown in FIG. 9, the ventilation-vasodilation correlation was significant (p=0.03), thus indicating targeted delivery to the well ventilated alveoli.

[00132] A further analysis was performed of seven PH-COPD subjects that completed 4 weeks of treatment with iNO at a dose of 30 mcg/kg IBW/hr. A summary of the baseline, acute and chronic parameters for these patients in shown in Table 5 below. The 6MWD and sPAP results are also presented in FIGS. 10 and 11, respectively. Table 5: Acute Change in Blood Vessel Volume and Chronic Changes in sPAP and

6MWD in PH-COPD Subjects

Method error during testing

[00133] iNO 30 mcg/kg/IBW resulted in a significant increase in the 6MWD (FIG. 10) and decrease in sPAP as measured by echocardiogram (FIG. 11). As shown in in FIG. 10, the change in 6MWD after 2 weeks of iNO therapy is +53.9 meters (p=0.02). Similarly, the change in 6MWD after 4 weeks of iNO therapy is +50.7 meters (p=0.04). In the literature, 27-54 meter improvements in 6MWD are considered clinically significant as measured by patient perceptions of improvement.

[00134] As shown in FIG. 11, the sPAP at baseline was 60.3 mm Hg. After 4 weeks of iNO therapy, the sPAP was 48.3 mm Hg [12.0 mm Hg drop; 19.9% drop] (p=0.02). 4 weeks after iNO therapy was discontinued, the sPAP increased to 58.0 mm Hg.

[00135] The decrease in sPAP correlated with a trend in the improvement in RV function as measure by TAPSE, as shown in FIG. 12. The baseline TAPSE was 18.8 (N=6), the TAPSE after chronic iNO therapy was 21.3 (N=7) and the TAPSE after iNO therapy was discontinued was 19.0 (N=5). These results further confirm that iNO therapy improves and/or maintains RV function.

[00136] Reference throughout this specification to "one embodiment," "certain embodiments," "various embodiments," "one or more embodiments" or "an embodiment" means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of the phrases such as "in one or more embodiments," "in certain embodiments," "in various embodiments," "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[00137] Although the disclosure herein provided a description with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made to the present disclosure without departing from the spirit and scope thereof. Thus, it is intended that the present disclosure include modifications and variations that are within the scope of the appended claims and their equivalents.