Methods and compositions for improving motor function

Abstract

Various methods and compositions for treating patients with single ventricle heart disease (SVHD), including patients with a Fontan circulation who have undergone the Fontan procedure (Fontan patients), to improve exercise function, particularly to improve exercise function at peak or max VO2 in the sub-super Fontan population, i.e., a subgroup of Fontan patients with a baseline peak or max VO2 less than 80% (<80%) of predicted, and to improve exercise function at ventilatory anaerobic threshold ("VAT") in both the super Fontan population, i.e., Fontan patients with a baseline peak or max VO2 greater than 80% (>80%) of predicted, and the sub-super Fontan population.

Description

[Technical field]

[0001] Opinions on government interests This work was funded, at least in part, by grants from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. Major grant support was from NHLBI grants U24 HL135691 and / or U01 HL068270 to New England Research Institutes, Inc. and grants to the Pediatric Heart Network clinical sites (UG1 HL135685, UG1 HL135680, UG1 HL135683, UG1 HL135689, UG1 HL135682, UG1 HL135665, UG1 HL135646, UG1 HL135678, UG1 HL135666). The government may have certain rights in the data and inventions disclosed herein.

[0002] Related Applications This provisional application claims priority from Provisional Application No. 63 / 291,858, filed December 20, 2021. Related provisional applications include Provisional Application No. 62 / 905,350, filed September 24, 2019, Provisional Application No. 62 / 936,497, filed November 16, 2019, and Provisional Application No. 63 / 023,070, filed May 11, 2020.

[0003] A method of improving exercise function in patients with single ventricle heart disease ("SVHD"), including SVHD patients with Fontan physiology (Fontan patients), in particular improving exercise function at peak or max VO2 in the sub-super Fontan population, i.e., a subgroup of Fontan patients with a baseline peak or max VO2 less than 80% (<80%) of predicted, and improving exercise function at ventilatory anaerobic threshold ("VAT") in both the super Fontan population, i.e., Fontan patients with a baseline peak or max VO2 greater than 80% (>80%) of predicted, and the sub-super Fontan population. [Background technology]

[0004] The heart is a muscular organ that pumps blood through the blood vessels of the circulatory system. In humans, the heart is located between the lungs and the rib cage and is divided into a left and right side. A normal human heart has four chambers: the left atrium and left ventricle on the left side, and the right atrium and right ventricle on the right side. Oxygen-poor blood ("blue blood") enters the right side through the right atrium, and newly oxygenated blood ("red blood") exits the left side through the left ventricle. The heart has four valves: the tricuspid valve, the pulmonary valve, the mitral valve, and the aortic valve. These valves prevent blood from flowing backwards within the heart and allow blood to flow forward to the lungs and the body.

[0005] The human heart beats (expands and contracts) about 100,000 times per day, pumping 5 to 6 quarts of blood per minute, or about 2,000 gallons per day. The left ventricle, the main pumping chamber of the heart, pumps newly oxygenated blood (red blood) through the aortic valve to the body. The blood then circulates through the arteries and arterioles to all parts of the body, delivering oxygen and nutrients. As the blood circulates, it exchanges oxygen and nutrients for carbon dioxide and metabolic waste products. In this process, the blood transitions from oxygen-rich blood (red blood) to oxygen-poor blood (blue blood). The oxygen-poor blood then returns to the right atrium through the veins of the body. The blue blood enters the right atrium through the tricuspid valve into the right ventricle, where it is then pumped by the right ventricle to the lungs, exchanging carbon dioxide for oxygen. The newly oxygenated blood (red blood) now returns from the lungs to the left atrium by the pulmonary veins. Blood passes from the left atrium through the mitral valve into the left ventricle, then is pumped to the body to begin the circulation again.

[0006] Thus, the normal human cardiovascular system consists of pulmonary and systemic circulations that are connected in series and powered by the pumping of the right and left ventricles.

[0007] Gewillig M.: Congenital heart disease. THE FONTAN CIRCULATION. Heart, 91:839-846 (2005).

[0008] Single ventricle heart disease (SVHD) is a rare pediatric condition that includes a group of congenital abnormalities of the heart, each of which results in the presence of only a single functional ventricle (pumping chamber). In other words, unlike newborns born with normal hearts (four chambers and two ventricles), newborns with SVHD are born with only one functioning ventricle (one pumping chamber), i.e., a univentricular heart. The non-functioning or non-existent ventricle (pumping chamber) may be smaller than a single ventricle, such that it does not function adequately, may not exist at all, or may be configured in such a way that it cannot contribute to normal blood flow through the circulation. Examples of SVHD include hypoplastic left heart syndrome, tricuspid atresia, bi-atrioventricular left ventricular insertion, etc.

[0009] Typically, newborns with SVHD are cyanotic and blue in color because a mixture of oxygen-poor (blue blood) and oxygen-rich (red blood) blood mix together in a single ventricle. The amount of oxygen in the blood mixture leaving the heart depends largely on the type, severity, and location of the SVHD heart defect. Newborns with SVHD may be mildly cyanotic or severely cyanotic and require early intervention to meet the body's oxygen demands and survive. Unfortunately, without surgical intervention, most newborns born with SVHD do not survive.

[0010] SVHD can be considered to have two basic subtypes: in the first, the left ventricle and aorta (the main artery to the body) are underdeveloped and the heart is unable to pump blood to the body without an intervention procedure; in the second, the right ventricle and pulmonary artery (the main artery to the lungs) are underdeveloped and the heart is unable to pump blood to the lungs.

[0011] For those infants born with the first subtype, a hypoplastic left ventricle and aorta, emergency intervention is required within the first few days or weeks of life to stabilize blood flow to the body. This intervention is called the Norwood procedure (see Figure 5) and involves reconstruction of the aorta (the main artery to the body) using the pulmonary valve and pulmonary artery along with patch material. Because the Norwood procedure repurposes the pulmonary artery to supply blood to the body, it must also include the route of blood getting to the lungs. This is accomplished by including a "shunt" of blood from the aortic circulation to the pulmonary circulation. The shunt is typically a tubing graft placed between the right subclavian artery (the artery that supplies blood to the right arm) and the right pulmonary artery. The Norwood procedure allows newborns to survive infancy, but is not a permanent solution. This temporary procedure puts the single, pumping chamber of the heart under stress, forcing it to pump blood to both the body and the lungs. To relieve this stress, two further procedures are performed. The first of these, the Glenn shunt or hemi-Fontan (see Figure 6), occurs at 4-6 months of age and involves connecting the superior vena cava (the main vein in the upper body) directly to the pulmonary artery. This allows blue blood from the upper body to return to the lungs for oxygenation without the need for a ventricular pump. The last operation, the Fontan operation (see Figure 1A and Figure 7), typically occurs at 18-48 months of age and involves connecting the inferior vena cava (the main vein in the lower body) directly to the pulmonary artery. This allows blue blood from the lower body to return to the lungs for oxygenation without the need for a ventricular pump, specifically to pump blood to the lungs. After the Fontan operation, all blue blood returns to the lungs and all red blood returns from the lungs to the heart, but this is accomplished without the assistance of a ventricular pump dedicated to pumping blood through the lungs to the heart as in a normal four-chambered heart.

[0012] For those infants born with the second subtype, a hypodeveloped right ventricle and pulmonary artery, emergency neonatal intervention is often not required. This group of babies requires close monitoring to determine whether there is too little blood flow to the lungs, too much blood flow to the lungs, or the right amount of blood flow to allow for growth and development. If there is too little blood flow to the lungs, a shunt is often placed, similar to that done as part of the Norwood procedure. If there is too much blood flow to the lungs, a restrictor may be placed around the pulmonary artery to reduce blood flow to the lungs and prevent the progression of congestive heart failure. If there is adequate blood flow to the lungs, infants born with a hypodeveloped right ventricle and pulmonary artery may experience the early months of their lives without the need for surgical intervention. Whether too little, too much, or just the right amount of blood is going to the lungs, infants born with this type of SVHD still require a Glenn shunt or hemifontan shunt at 4 to 6 months of age, and a Fontan shunt at 18 to 48 months of age, to take strain off the heart and separate blue blood from red blood.

[0013] After the Fontan operation, the subtype of single ventricle heart disease is less important because all patients are left with the same physiology: (i) passive blood flow from the inferior and superior vena cava directly to the lungs, bypassing the heart, and (ii) a single ventricle to pump blood to the body. This "Fontan circulation" has enabled many thousands of patients to survive for the last 40-50 years, but it is far from normal. In the absence of a ventricular pump to push blood to the lungs and back to the heart, the Fontan circulation must rely on pressure generated in the veins of the body to accomplish this task. This results in a very elevated "blood pressure" in the veins, which also limits the flow rate that can circulate through the body at a given time. This is called reduced cardiac output.

[0014] Over time, the combination of elevated venous pressure and reduced cardiac output leads to a predictable series of long-term complications, ultimately resulting in greatly reduced survival. Complications associated with the Fontan circulation include damage to the kidneys and liver, overload of the lymphatic circulation leading to loss of proteins in the lungs or gastrointestinal tract, bleeding and coagulation disorders including risk of stroke, and progressive impairment of the heart's own pumping ability.

[0015] The ability to exercise is used in many forms of cardiac disease as a marker of circulatory health. For individuals with Fontan circulation, exercise is an important measure of health as well and a good predictor of outcome. Exercise capacity is often preserved in individuals with Fontan circulation during childhood, but typically begins to decline during adolescence and early adulthood. This deterioration correlates with increased prevalence of heart failure symptoms, hospitalizations, and mortality, often due to complications of the Fontan circulation itself. In some cases, heart transplantation may still be a therapeutic option, but it carries its own set of risks, and individuals with Fontan circulation are often not candidates for heart transplantation due to chronic progressive dysfunction of many organ systems.

[0016] Despite this long-standing and very serious congenital heart disease, to date, no drug therapies have been approved by the U.S. Food and Drug Administration (FDA) or any other comparable agency worldwide for the treatment of SVHD patients, including Fontan patients. Thus, there is a real need and demand for new drug therapies for SVHD patients, including Fontan patients, that avoid or delay disease progression and the need for heart transplantation, with the goal of increasing the longevity of SVHD patients, including Fontan patients, associated with complications of SVHD and the Fontan circulation.

[0017] There is also a real need and demand for new pharmacotherapy for SVHD patients, including Fontan patients, to (i) improve myocardial performance index ("MPI"), (ii) improve single ventricular function, (iii) improve exercise capacity at ventilatory anaerobic threshold (VAT) and / or maximal aerobic capacity (VO2 max or VO2 max), (iv) improve work rate at VAT, (v) improve ventilatory equivalent of carbon dioxide (VE / VCO2) at VAT, and / or (vi) improve single ventricle cardiac function. Summary of the Invention

[0018] The present invention overcomes the above-mentioned shortcomings and disadvantages associated with current treatments of SVHD patients, including Fontan patients, through the discovery of new methods of treating SVHD patients, including Fontan patients.

[0019] Generally speaking, the methods of the present invention relate to the use of udenafil or a pharma- ceutically acceptable salt thereof to treat SVHD patients, including Fontan patients.

[0020] More specifically, the methods of the present invention include administering, preferably daily, an effective amount of udenafil or a pharma- ceutically acceptable salt thereof to SVHD patients, including Fontan patients, to improve, inter alia, the MPI and exercise capacity or function of such patients.

[0021] In general, the methods of the invention involve administering an effective amount of udenafil, or a pharma- ceutical acceptable salt thereof, daily to a patient with SVHD, including a Fontan patient, (a) Ventricular function of one functioning ventricle in SVHD patients measured by MPI; (b) Exercise capacity as measured by oxygen consumption during VAT; (c) exercise capacity as measured by oxygen consumption at maximal exertion or VO2 max; (d) VAT work rate, (e) VE / VCO2 in VAT, (f) resting diastolic blood pressure, and (g) improving resting oxygen saturation (%), either individually, collectively or in any combination thereof.

[0022] Preferably, the method of the present invention improves (a)-(g) listed above, individually, collectively, or any combination thereof. Preferably, the method of the present invention improves at least a combination of (a)-(e) listed above. Most preferably, (a)-(g) listed above, individually, collectively, or any combination thereof, are improved according to the present invention by daily administration of an effective amount of udenafil or a pharmacologic acceptable salt thereof to SVHD patients, including Fontan patients.

[0023] The improvement of single ventricle function according to the method of the present invention includes both systolic and diastolic function. These can be demonstrated by, but are not limited to, improvements in blood pool MPI, tissue Doppler MPI, cardiac output (estimated by the integral under the Doppler-derived outflow curve times the heart rate), and other measures of single ventricle cardiac function. The improvement of exercise capacity or function according to the method of the present invention includes, but is not limited to, improved exercise capacity or function at anaerobic threshold ("VAT") and / or improved exercise capacity or function at maximum exertion or maximum VO2. Also according to the present invention, when the method of the present invention is performed on SVHD patients, including Fontan patients, the power at VAT, the ventilatory equivalent of carbon dioxide (VE / VCO2) at VAT, resting diastolic blood pressure, and / or resting oxygen saturation (%) are improved.

[0024] In general, an "effective amount" is used herein to mean an amount of udenafil or a pharma- ceutically acceptable salt thereof sufficient to produce or elicit a therapeutic or pharmacological effect without causing treatment-limiting side effects.

[0025] More specifically, "effective amount" is used herein to mean an amount of udenafil or a pharma- ceutically acceptable salt thereof sufficient to produce or elicit a therapeutic or pharmacological effect in SVHD patients, including Fontan patients, without causing treatment-limiting toxicity, treatment-limiting side effects associated with inhibition of PDE6 and / or PDE11, and / or any other treatment-limiting side effects.

[0026] Examples of "effective amounts" of udenafil or a pharma- ceutically acceptable salt thereof according to the present invention include a total daily amount ranging from about 87.5 mg to about 175 mg, including but not limited to. More preferably, an "effective amount" of udenafil or a pharma-ceutically acceptable salt thereof according to the present invention includes a total daily amount ranging from about 125 mg to about 175 mg. Even more preferably, an "effective amount" of udenafil or a pharma-ceutically acceptable salt thereof according to the present invention includes oral doses including but not limited to single doses administered daily, including a single dose of about 75 mg or 87.5 mg administered once or twice daily, and a single dose of about 125 mg administered once daily.

[0027] The present invention also contemplates a method comprising administering, preferably daily, an effective amount of udenafil or a pharma- ceutically acceptable salt thereof to SVHD patients, including Fontan patients, to improve, individually, collectively, or in any combination, in particular, MPI, ventricular function, cardiac output, exercise capacity or function at VAT, exercise capacity or function at maximum exertion or VO2 max, work rate at VAT, VE / VCO2 at VAT, resting diastolic blood pressure, and resting oxygen saturation (%), without causing treatment-limiting side effects, such as visual communication or visual function, back pain, muscle pain, impaired sperm concentration or quality. In other words, the present invention contemplates the treatment, preferably daily, of SVHD patients, including Fontan patients, with an effective amount of an effective PDE5 inhibitor, preferably udenafil or a pharma-ceutically acceptable salt thereof, without causing treatment-limiting side effects associated with the inhibition of phosphodiesterase-6 ("PDE6") and / or phosphodiesterase-11 ("PDE11"). As used herein, PDE6 includes any isozymes, variants, catalytic and / or inhibitory subunits of PDE6, such as PDE6a, PDE6P, PDE6Y, PDE6R and / or PDE6C, individually, collectively or in any combination, and as used herein, PDE11 includes phosphodiesterase-11A (PDE11A) and any isozymes, variants, catalytic and / or inhibitory subunits of PDE11, such as PDE11A1, PDE11A2, PDE11A3 and / or PDE11A4, individually, collectively or in any combination.

[0028] In one embodiment, the present invention relates to a method for improving the MPI of SVHD patients, including Fontan patients.As used herein, MPI measures both systolic and diastolic function for the assessment of global cardiac function.The method includes administering to the patient an effective amount of an effective PDE5 inhibitor, preferably daily, wherein the PDE5 inhibitor is preferably udenafil or its pharmacologic acceptable salt.

[0029] With respect to MPI according to the present invention, by "improve, improving, improved or improved" it is understood herein to mean improving single ventricle function, i.e. improving the diastolic and systolic function of one functioning ventricle. In other words, one functioning ventricle exerts pressure better or more efficiently with each heartbeat. As a result, the cardiac output and the amount of blood that can circulate at a given time through the body of an SVHD patient, including a Fontan patient, treated or performed according to the methods of the present invention is increased or improved, particularly compared to an SVHD patient, including a Fontan patient, that is not treated according to the methods of the present invention. Thus, the methods of the present invention result in an improvement in MPI, or other disclosed measures of ventricular function, in SVHD patients, including Fontan patients, compared to MPI, or other disclosed measures of single ventricle function, lacking the methods of the present invention (e.g., without udenafil administration). For example, the improvement can be about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more compared to blood pool MPI lacking the methods of the invention (e.g., without daily udenafil administration), or other disclosed measures of single ventricular function.

[0030] The method comprises the step of administering to the patient, preferably daily, an effective amount of an effective PDE5 inhibitor, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutically acceptable salt thereof.

[0031] In one embodiment, the present invention relates to a method of improving the contractile function of one functioning ventricle in an SVHD patient, including a Fontan patient. The method comprises administering, preferably daily, to an SVHD patient an effective amount of an effective PDE5 inhibitor or a pharma- ceutically acceptable salt thereof, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutically acceptable salt thereof.

[0032] In one embodiment, the present invention relates to a method for improving diastolic function of one functioning ventricle in a patient with SVHD, including a Fontan patient. The method comprises administering, preferably daily, to a patient with SVHD an effective amount of an effective PDE5 inhibitor or a pharma- ceutical acceptable salt thereof, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0033] In one embodiment, the present invention relates to a method for improving the cardiac output of one functioning ventricle in an SVHD patient, including a Fontan patient. The method comprises administering, preferably daily, to an SVHD patient an effective amount of an effective PDE5 inhibitor or a pharma- ceutically acceptable salt thereof, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutically acceptable salt thereof.

[0034] In one embodiment, the present invention relates to a method for improving the pressure exerting capacity of one functioning ventricle in an SVHD patient, including a Fontan patient. The method comprises administering, preferably daily, to an SVHD patient, including a Fontan patient, an effective amount of an effective PDE5 inhibitor or a pharma- ceutical acceptable salt thereof, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0035] In another embodiment, the present invention relates to a method for improving venous pressure by reducing elevated venous pressure in SVHD patients, including Fontan patients. The method comprises administering, preferably daily, to a SVHD patient, including Fontan patients, an effective amount of an effective PDE5 inhibitor, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0036] In one embodiment, the invention relates to a method of improving the amount of blood that can circulate through the body of an SVHD patient, including a Fontan patient, at a given time. The method comprises administering, preferably daily, to an SVHD patient, including a Fontan patient, an effective amount of an effective PDE5 inhibitor or a pharma- ceutically acceptable salt thereof, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutically acceptable salt thereof.

[0037] Accordingly, the present invention relates to a method for improving global single ventricular function of one functioning ventricle in SVHD patients, including Fontan patients, comprising the step of administering, preferably daily, to an SVHD patient an effective amount of an effective PDE5 inhibitor or a pharma- ceutical acceptable salt thereof, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0038] In yet another embodiment, the present invention relates to a method for improving the resting diastolic blood pressure of SVHD patients, including Fontan patients, thereby significantly reducing the resting diastolic blood pressure of SVHD patients, including Fontan patients.The method includes administering an effective amount of an effective PDE5 inhibitor to SVHD patients, including Fontan patients, preferably daily, wherein the PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.

[0039] In yet another embodiment, the present invention relates to a method of improving resting oxygen saturation (%) in an SVHD patient, including a Fontan patient, comprising administering, preferably daily, an effective amount of an effective PDE5 inhibitor to an SVHD patient, including a Fontan patient, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutically acceptable salt thereof.

[0040] In yet another embodiment, the present invention relates to a method for improving motor function or capacity in a patient with SVHD, including a Fontan patient, comprising administering, preferably daily, an effective amount of an effective PDE5 inhibitor to a patient with SVHD, including a Fontan patient, wherein the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0041] In another embodiment, the present invention relates to a method for improving exercise function or exercise capacity at ventilatory anaerobic threshold ("VAT") in SVHD patients, including Fontan patients. The method of the present invention results in improved VO2 at VAT in SVHD patients, including Fontan patients, compared to VO2 at VAT in SVHD patients, including Fontan patients, who are not treated with the method of the present invention or who do not perform the method of the present invention (e.g., without daily udenafil administration according to the method of the present invention). For example, the improvement can be 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 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more compared to VO2 at VAT lacking the method of the present invention (e.g., without daily udenafil administration). The method includes administering, preferably daily, an effective amount of an effective PDE5 inhibitor to an SVHD patient, including a Fontan patient, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0042] In another embodiment, the present invention relates to a method for improving exercise function or exercise capacity at maximum exertion or maximum VO2 in SVHD patients, including Fontan patients. The method of the present invention results in an improved VO2 at maximum exertion in SVHD patients, including Fontan patients, compared to the VO2 at maximum exertion in the absence of the method of the present invention (e.g., in the absence of daily udenafil administration). For example, the improvement can be 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 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more compared to the VO2 at maximum exertion in the absence of the method of the present invention (e.g., in the absence of daily udenafil administration). The method includes administering, preferably daily, an effective amount of an effective PDE5 inhibitor to an SVHD patient, including a Fontan patient, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0043] In another embodiment, the present invention relates to a method for improving the power in the VAT of SVHD patients, including Fontan patients. The method of the present invention results in an improved power in the VAT of SVHD patients, including Fontan patients, compared to the power in the VAT lacking the method of the present invention (e.g., without daily udenafil administration). For example, the improvement can be 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 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more compared to the VO2 in the VAT lacking the method of the present invention (e.g., without daily udenafil administration). The method includes administering, preferably daily, an effective amount of an effective PDE5 inhibitor to an SVHD patient, including a Fontan patient, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0044] In another embodiment, the present invention relates to a method for improving the ventilatory equivalent of carbon dioxide ("VE / VCO2") in the VAT of SVHD patients, including Fontan patients. The methods of the present invention result in improved VE / VCO2 in the VAT of SVHD patients, including Fontan patients, compared to VE / VCO2 in the VAT lacking the methods of the present invention (e.g., in the absence of daily udenafil administration). For example, the improvement can be 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 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% or more compared to VO2 in the VAT lacking the methods of the present invention (e.g., in the absence of daily udenafil administration). The method includes administering, preferably daily, an effective amount of an effective PDE5 inhibitor to a SVHD patient, including a Fontan patient, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0045] In one embodiment, the invention relates to improved methods of treating SVHD patients, including Fontan patients who have undergone cardiac remodeling of abnormal SVHD hearts, where the daily methods of the invention result in fewer severe adverse events compared to conventional methods of treating SVHD patients, including such Fontan patients.

[0046] In another embodiment, the present invention causes few, if any, severe, moderate, or mild adverse events.The method includes administering an effective amount of an effective PDE5 inhibitor to a SVHD patient, including a Fontan patient, preferably daily, wherein the PDE5 inhibitor is preferably udenafil or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the present invention relates to an improved method of treating SVHD patients who have undergone the Fontan procedure. In one such embodiment, a Fontan patient is diagnosed with hypoplastic left heart syndrome (HLHS), but first undergoes the Norwood procedure (see, for example, FIG. 5), followed by the Hemi-Fontan procedure or the Bidirectional Glenn procedure (see, for example, FIG. 6), and then undergoes the Fontan procedure (see, for example, FIG. 1A and FIG. 7). In another such embodiment, a Fontan patient first undergoes the Hemi-Fontan procedure or the Bidirectional Glenn procedure, and then undergoes the Fontan procedure. The method includes administering an effective amount of an effective PDE5 inhibitor to a SVHD patient, including a Fontan patient, preferably daily, where the PDE5 inhibitor is preferably udenafil or a pharmacologic acceptable salt thereof.

[0048] In one embodiment, the present invention provides an improved method of treating SVHD patients, including Fontan patients, wherein the SVHD patients are selected from the group of SVHD patients consisting of atrioventricular canal defect (AV canal), bilateral atrioventricular valve left ventricular insertion (DILV), double outlet right ventricle (DORV), Ebstein anomaly, HLHS, mitral atresia (usually associated with HLHS), pure pulmonary atresia (PA / IVS), single left ventricle, tricuspid atresia, and tricuspid atresia with stenosis. The method comprises administering an effective amount of an effective PDE5 inhibitor to SVHD patients, including Fontan patients, preferably daily, wherein the PDE5 inhibitor is preferably udenafil or a pharmacologic acceptable salt thereof. In an exemplary embodiment, the method of the present invention comprises administering an effective amount of an effective PDE5 inhibitor or a pharmacologic acceptable salt thereof once a day to SVHD patients, including Fontan patients, wherein the PDE5 inhibitor is preferably udenafil or a pharmacologic acceptable salt thereof.

[0049] In another embodiment, the methods of the invention comprise administering an effective amount of an effective PDE5 inhibitor or a pharma- ceutical acceptable salt thereof to an SVHD patient, including a Fontan patient, twice daily, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0050] In another embodiment, the methods of the invention comprise administering an effective amount of an effective PDE5 inhibitor or a pharma- ceutical acceptable salt thereof to an SVHD patient, including a Fontan patient, three or more times daily, where the PDE5 inhibitor is preferably udenafil or a pharma- ceutical acceptable salt thereof.

[0051] In another embodiment, SVHD patients, including Fontan patients, are pediatric patients, ages 2 to about 18. Treatment of adult patients is also encompassed by the methods of the invention.

[0052] In yet another embodiment, the present invention relates to an improved method of treating SVHD patients, including Fontan patients, which method shows improved compliance of SVHD patients, including Fontan patients, with a dosing schedule of udenafil or a pharma- ceutically acceptable salt thereof, compared to SVHD patients, including Fontan patients, prescribed a non-udenafil drug.

[0053] Finally, in yet another embodiment, the methods of the present invention can result in a unique and distinctive pharmacokinetic profile, which has a C of between 300 and 700 ng / ml, more specifically, a C of about 500 ng / ml. max , between 1 and 1.6 hours, more specifically a T of about 1.3 hours max , between 2550 and 4150 ng·hr / ml or more, specifically, an AUC of approximately 3350 ng·hr / ml t , and between 5110 and 8290 ng·hr / ml or more, specifically an AUC of approximately 6701 ng·hr / ml 0-24 may include.

[0054] It is understood that the present invention contemplates udenafil drug products that are therapeutically equivalent to the udenafil drug products of the present invention. In other words, the present invention contemplates udenafil drug products that are (i) therapeutically equivalent, (ii) bioequivalent, (iii) interchangeable, and (iv) have effective bioavailability in carrying out or implementing the objectives of the present invention when administered to SVHD patients, including Fontan patients, according to the methods of the present invention.

[0055] Thus, according to one embodiment of the present invention, the present invention contemplates drug formulations having a 90% confidence interval (90% CI) for the pharmacokinetic profile with a mean ratio in the range of between about 0.8 and about 1.25. In another embodiment according to the present invention, the present invention contemplates exchangeable udenafil drug formulations having a 90% confidence interval (90% CI) for the pharmacokinetic profile with a mean ratio in the range of between about 0.8 and about 1.2. The present invention thus contemplates the pharmacokinetic profiles, e.g., their C max , T max The present invention contemplates SVHD patients, including Fontan patients, treated with or undergoing the methods of the present invention, having udenafil plasma concentrations that can vary by up to about 45% (i.e., -20 to +25%) of the CUC and AUC. More preferably, the present invention provides pharmacokinetic profiles, e.g., their CUC and AUC. max , T max , AUC t and AUC 0-24 The present invention contemplates SVHD patients, including Fontan patients, treated with or undergoing the methods of the invention, having udenafil plasma concentrations that can vary by up to about 40% (i.e., -20 to +20%) of the normal range. By way of example, the present invention provides an udenafil pharmacokinetic profile: (a) C of about -20 to about +25% at about 500 ng / ml max Udenafil C at a plasma concentration of about -20 to about +20% of, more preferably, about 500 ng / ml max Plasma concentration, (b) T of about -20% to about +25% for about 1.3 hours max More preferably, about -20 to about +20% of udenafil T for 1.3 hours.max , (c) AUC of approximately -20 to +25% at approximately 3350 ng·hr / ml t , and more preferably about -20 to about +20% of the udenafil AUC of about 3350 ng hr / ml. t , and (d) AUC of approximately -20 to +25% of approximately 6701 ng·hr / ml 0-24 , and more preferably about -20 to about +20% of the udenafil AUC of about 6701 ng hr / ml. 0-24 Contemplated are SVHD patients, including Fontan patients, who have, individually, collectively, or in any combination, the following to be treated or undergo the methods of the invention:

[0056] Thus, the present invention contemplates a bioequivalent and interchangeable udenafil drug product for use according to the methods of the present invention. Further, the present invention contemplates the above-mentioned C-terminal urinary incontinence in SVHD patients, including Fontan patients, when administered to SVHD patients, including Fontan patients, according to the methods of the present invention. max , T max , AUC t and / or AUC 0-24 This article examines udenafil drug products that cause side effects.

[0057] Methods of the present invention include, but are not limited to, the following. 1. A method of treating a single ventricle heart disease (SVHD) patient having one functioning ventricle and post-Fontan physiology (Fontan patient) and in need of treatment to improve the Fontan patient's exercise capacity as measured by oxygen consumption at maximal exertion or peak VO2, wherein the Fontan patient has a baseline peak or max VO2 that is less than 80% (<80%) of predicted and the Fontan exercise capacity is adversely affected by the decline in the Fontan patient's cardiac function post-Fontan procedure, the method comprising: 2. A method comprising: administering an effective amount of udenafil, or a pharma- ceutical acceptable salt thereof, to a Fontan patient daily to improve the Fontan patient's exercise capacity as measured by oxygen consumption at maximal exertion or peak VO2.

[0058] 2. The method of claim 1, wherein the effective amount is a total daily dosage of udenafil or a pharma- ceutically acceptable salt thereof in an amount between about 125 mg and 175 mg.

[0059] 3. The method of claim 1, wherein the effective daily amount is a total daily dosage of udenafil or a pharma- ceutically acceptable salt in an amount of about 175 mg.

[0060] 4. The method of claim 3, wherein the total daily dosage consists of two individual doses of udenafil or a pharma- ceutically acceptable salt thereof, each of which is about 87 mg of udenafil or a pharma- ceutically acceptable salt thereof.

[0061] 5. The method of claim 4, wherein each said individual dose is an oral solid dosage form.

[0062] 6. The method of claim 5, wherein the udenafil or a pharma- ceutically acceptable salt thereof is in an oral solid or semi-solid dosage form selected from the group consisting of a tablet, capsule, gel, liquid, dispersion, pill, powder, and suspension.

[0063] 7. The method of claim 1, wherein the udenafil or a pharma- ceutically acceptable salt thereof is in an oral solid dosage form.

[0064] 8. The method of claim 7, wherein the oral solid dosage form is an oral solid or semi-solid dosage form selected from the group consisting of a tablet, a capsule, a gel, a liquid, a dispersion, a pill, a powder, and a suspension.

[0065] 9. The method of claim 1, wherein the Fontan patient is at least 12 years of age.

[0066] 10. Fontan patients (a) Ventricular function of one functioning ventricle in Fontan patients as measured by the Myocardial Performance Index (MPI); (b) exercise capacity as measured by oxygen consumption at ventilatory anaerobic threshold (VAT); (c) the work rate at VAT, and (e) further improving VE / VCO2 in VAT, alone or in any combination, according to claim 1.

[0067] 11. A method of treating a single ventricle heart disease (SVHD) patient having one functioning ventricle and post-Fontan physiology (super-Fontan patient) and in need of treatment to improve the exercise capacity of the super-Fontan patient as measured by oxygen consumption at maximal exertion or peak VO2, wherein the super-Fontan patient has a baseline peak or max VO2 that is greater than 80% (≧80%) of predicted, and the exercise capacity of the super-Fontan patient is adversely affected by the decline in cardiac function of the super-Fontan patient after the Fontan procedure, the method comprising: 2. A method comprising: administering an effective amount of udenafil or a pharmacologic acceptable salt thereof to a Super Fontan patient daily to improve exercise capacity in the Super Fontan patient as measured by oxygen consumption at ventilatory anaerobic threshold (VAT).

[0068] 12. The method of claim 11, wherein the effective amount is a total daily dosage of udenafil or a pharma- ceutically acceptable salt thereof in an amount between about 125 mg and 175 mg.

[0069] 13. The method of claim 11, wherein the effective amount is a total daily dosage of udenafil or a pharma- ceutically acceptable salt thereof in an amount of about 175 mg.

[0070] 14. The method of claim 13, wherein the total daily dosage consists of two individual doses of udenafil or a pharma- ceutically acceptable salt thereof, each of which is about 87 mg of udenafil or a pharma- ceutically acceptable salt thereof.

[0071] 15. The method of claim 14, wherein each such individual dose is an oral solid dosage form.

[0072] 16. The method according to claim 15, wherein the udenafil or a pharma- ceutically acceptable salt thereof is in an oral solid or semi-solid dosage form selected from the group consisting of a tablet, capsule, gel, liquid, dispersion, pill, powder, and suspension.

[0073] 17. The method of claim 11, wherein the udenafil or a pharma- ceutically acceptable salt thereof is in an oral solid dosage form.

[0074] 18. The method of claim 17, wherein the oral solid dosage form is an oral solid or semi-solid dosage form selected from the group consisting of a tablet, a capsule, a gel, a liquid, a dispersion, a pill, a powder, and a suspension.

[0075] 19. The method of claim 11, wherein the Super Fontan patient is at least 12 years of age.

[0076] 20. Super Fontan Patients (a) Ventricular function of one functioning ventricle in Super Fontan patients as measured by the Myocardial Performance Index (MPI); (b) the work rate at VAT, and (d) further improving VE / VCO2 in VAT, alone or in any combination, according to claim 11.

[0077] It should be further understood that the above summary of the invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The foregoing description further sets forth illustrative embodiments and provides an explanation of the invention as claimed. In several places throughout the specification, guidance is provided by way of examples, which examples can be used in various combinations. In each instance, the examples serve only as a representative group and should not be construed as exclusive examples.

[0078] The foregoing and other objects, advantages, and features of the present invention, as well as the manner in which they are carried out, will become readily apparent to those skilled in the art from the following brief description of the drawings, detailed description, and examples which illustrate embodiments. [Brief description of the drawings]

[0079] [Figure 1-1] FIG. 1A is a schematic diagram of exemplary Fontan physiology. [Figure 1-2] Figure 1B is the screening process (participant randomization and treatment) used for the Fontan Udenafil Exercise Longitudinal (FUEL) trial described in Examples 1-2. Peak VO2 (VO2 max) indicates oxygen consumption during peak exercise. RER indicates respiratory exchange ratio. [Figure 2-1] FIG. 2A demonstrates the differences in mean peak or maximum VO2 change from baseline to week 26 and the standard deviation for each treatment arm. [Figure 2-2] FIG. 2B demonstrates the percentage of subjects (y-axis) who demonstrated an improvement in peak VO2 above the reference percentage (x-axis). [Figure 3-1] FIG. 3A demonstrates the differences in mean VO2 change during VAT from baseline to week 26 and standard deviation for each treatment arm. [Figure 3-2] FIG. 3B demonstrates the percentage of subjects (y-axis) who demonstrated an improvement in VO2 during VAT above the reference percentage (x-axis). [Figure 4-1] FIG. 4A demonstrates the differences in the change in mean power during VAT from baseline to week 26 and the standard deviation for each treatment arm. [Figure 4-2] FIG. 4B demonstrates the percentage of subjects (y-axis) who demonstrated an improvement in power output (x-axis) above the reference percentage. [Diagram 5] FIG. 5 is a schematic diagram of an exemplary Norwood procedure (stage 1) of a reconstructed SVHD heart presenting with Hypoplastic Left Heart Syndrome (HLHS). [Figure 6]FIG. 6 is a schematic diagram of an exemplary Bidirectional Glenn Procedure (Stage 2) of a reconstructed SVHD heart presenting with Hypoplastic Left Heart Syndrome (HLHS). [Figure 7] FIG. 7 is a schematic diagram of an exemplary Fontan procedure (stage 3) for a remodeled SVHD heart presenting with Hypoplastic Left Heart Syndrome (HLHS). [Figure 8] Figure 8 shows cumulative incidence plots of primary and secondary outcomes stratified by change in peak oxygen consumption (Cunningham 2017). [Figure 9] Figure 9 shows CPET performance when stratified by the subsequent primary clinical outcome of death or transplant (Cunningham, 2017). [Figure 10] FIG. 10 shows the prognostic value of serial CPET studies in Fontan subjects. [Figure 11] FIG. 11 shows improvement in peak VO2 by treatment group. ITT analysis of the FUEL trial. [Figure 12] Figure 12 shows improvement in peak VO2 by treatment group. Analysis of the subpopulation of Fontan subjects with baseline predicted peak VO2 less than 80%. [Figure 13] Figure 13 shows improvement in peak VO2 by treatment group. Analysis of SuperFontan, a subpopulation of Fontan subjects with greater than 80% predicted peak VO2 at baseline. [Figure 14] FIG. 14 shows percent change in peak VO2 by treatment group and FUEL analysis. [Figure 15] Figure 15 shows annual change in peak VO2 by treatment group. Analysis of the subpopulation of Fontan subjects with baseline predicted peak VO2 less than 80%. [Figure 16] FIG. 16 shows the change in peak VO2 after exercise training. [Figure 17] FIG. 17 shows improvement in VO2 during VAT by treatment group in the FUEL ITT analysis. [Figure 18] FIG. 18 shows percent change in VO2 during VAT by treatment group in the FUEL ITT analysis. [Figure 19] Figure 19 shows the mean change from baseline in peak or maximum VO2 (mL / min) in FUEL and FUEL OLE. Placebo = FUEL trial results for participants randomized to placebo. No udenafil = FUEL OLE results for participants randomized to placebo in the FUEL trial and newly enrolled participants in FUEL OLE patients. Udenafil = FUEL and FUEL OLE results for those randomized to udenafil in the FUEL trial and continued on to FUEL OLE. [Figure 20] FIG. 20 shows the effect of the FUEL trial on "Super Fontan" subjects on statistical endpoints. [Figure 21] FIG. 21 shows the effects of the FUEL trial on all secondary endpoints. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] I. Fontan Physiology Fontan physiology is the ultimate palliation for those classes of congenital heart defects that share the common feature of a functional single ventricle. They include defects that result in a hypoplastic (dysfunctional) left or right ventricle. Usually, through a series of two or three operations, the systemic and pulmonary circulations are separated, largely eliminating the mixing of oxygenated and deoxygenated blood caused by congenital heart defects. This is accomplished by directly attaching the superior and inferior vena cava to the pulmonary artery, i.e., total cavopulmonary artery connection. This results in Fontan physiology, which functions as follows: (1) A single systemic ventricle pumps oxygenated blood (red blood) from the arteries to the body's systemic arterial vascular bed, (2) systemic venous blood (blue blood) then returns by the vena cava, and the blue blood flows passively through the pulmonary vascular bed for oxygen uptake in the lungs without the assistance of a subpulmonary ventricle to oxygenate the blue blood, (3) where the oxygenated blood (red blood) then returns to the functioning single systemic ventricular pump via a normal systemic functioning atrium, and the red blood-blue blood circulation cycle is repeated. This anatomical structure is illustrated in Figure 1A and Figure 7.

[0081] The Fontan procedure, which creates a total cavopulmonary shunt, separates the systemic and pulmonary circulations and eliminates both hypoxemia and ventricular volume overload.

[0082] However, after the Fontan procedure, there is no ventricular pump to push blue blood into the pulmonary artery. Instead, blue blood returns to the lungs by passive flow in the systemic veins. The primary physiological effect of this type of relaxation is therefore that pulmonary blue blood flow is entirely dependent on the pressure gradient from the systemic venous bed to the atrium. Normal circulatory flow in the pulmonary vascular bed is increased by the increased pressure generated by the right ventricle. In healthy adolescents, this results in an increase in pulmonary arterial pressure of approximately 20-25 mmHg at rest, which can be doubled with exercise. In Fontan physiology, there is no subpulmonary ventricle, and therefore no increase in pressure as blue blood enters the pulmonary artery. At rest, the pressure gradient across the pulmonary vascular bed is fairly small. The ability to increase this pressure gradient with exercise is extremely limited by the body's ability to tolerate increasingly elevated central venous pressures.

[0083] As a result of its overall reliance on passive reduction of venous pressure to manipulate pulmonary blood flow, Fontan physiology is extremely sensitive to changes in pulmonary vascular resistance. Even increases that are within the normal range of pulmonary resistance in normal physiology have deleterious effects on Fontan physiology. The use of udenafil offers a unique potential treatment for this class of mitigated congenital heart defects. Unlike other uses of PDE-5 inhibitors, this treatment lowers pulmonary vascular resistance in a population without elevated pulmonary vascular resistance or pulmonary vascular pressure. This is a distinctly different use of this class of agent compared to (i) patients with structurally normal heart and pulmonary vascular disease, such as pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD), (ii) patients with heart failure, such as congestive heart disease, or (iii) the very rare patients with congenital heart disease and associated pulmonary vascular disease mitigated by biventricular repair (and thus with a subpulmonary ventricle).

[0084] II. Clinical Measures Appropriate for Fontan Patients For children born with a functional single ventricle or single ventricle congenital heart disease, the Fontan procedure is the current standard of care. Although the Fontan procedure is palliative rather than curative and has greatly increased survival in pediatric subjects with functional single ventricle heart disease, the procedure also results in a series of side effects and complications that can be debilitating to the patient, such as arrhythmias, ventricular dysfunction, and the unusual clinical syndromes of protein-losing enteropathy (PLE) and plastic bronchitis, as well as hepatic and renal complications.

[0085] In certain embodiments, the disclosed invention relates to improving or inhibiting the decline of certain clinically relevant physiological measures indicative of patient health following the Fontan procedure, including, but not limited to, exercise testing, vascular function testing, and echocardiographic assessment of ventricular function.

[0086] III. Exercise Testing Exercise testing may include assessment of VO2 values ​​during maximal exertion or at the ventilatory anaerobic threshold (VAT). VO2 max, or maximum oxygen consumption, refers to the maximum amount of oxygen an individual can utilize during intense exercise. This measurement is generally considered to be a reliable indicator of cardiovascular fitness and aerobic endurance. The more oxygen a person can use during high levels of exercise, the more energy he or she can generate. This test has become the standard for cardiopulmonary fitness because for prolonged (aerobic) exercise, muscles need oxygen, blood needs to carry oxygen to the muscles, and the heart needs to pump a sufficient amount of blood to meet the demands of aerobic exercise.

[0087] VO2 is often measured by placing a mask on the subject and measuring the volume of air inhaled and exhaled and the gas concentrations. This measurement is often used in both clinical settings and research and is considered the most accurate. Tests generally involve either exercising on a treadmill or riding a bicycle ergometer at increasing intensity to fatigue and are designed to take readings at the subject's maximal exertion and / or the subject's anaerobic threshold.

[0088] SVHD patients, including SVHD patients who have previously undergone the Fontan procedure, generally experience a decline in VO2 measurement over time.However, when SVHD patients, including Fontan patients, are treated with the method according to the present invention, VO2 measurement (i) remains at a similar level, demonstrating no further decline in VO2 measurement, or (ii) improves with treatment, demonstrating an increase in VO2 and / or a decrease in the rate of decline in VO2 measurement, thus improving, each of which indicates that the treatment or method of the present invention is clinically beneficial.In some SVHD patients, treatment according to the present invention may significantly delay or reduce the decline in VO2 measurement during exercise.

[0089] In one embodiment, the present invention relates to a method for improving or maintaining the VO2 measurement of SVHD patients or subjects who have previously undergone Fontan surgery.The method of the present invention comprises administering an effective amount of an effective PDE5 inhibitor to SVHD patients, including Fontan patients, preferably daily, where the PDE5 inhibitor is preferably udenafil or its pharmacologic acceptable salt.In some embodiments of the present invention, VO2 is measured at maximal exertion, while in other embodiments, VO2 is measured at the subject's anaerobic threshold (VAT).

[0090] In some embodiments, the disclosed methods and compositions of the present invention are administered to SVHD patients, including Fontan patients, to result in no or minimal decline in exercise capacity over time. More specifically, the disclosed methods and compositions of the present invention can result in a decline in exercise capacity of less than about 40, less than about 35, less than about 30, less than about 35, less than about 20, less than about 15, less than about 10, or less than about 5% over time. The time period between the first and second measurements used to calculate the decline in exercise capacity can be, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months; 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 13, about 14, or about 15 years, or any combination thereof, such as 1 year, 3 months; 4 years, 7 months, etc.

[0091] In some embodiments, the disclosed methods and compositions of the present invention can be administered to SVHD patients, including Fontan patients, to improve exercise capacity. More specifically, the disclosed methods and compositions of the present invention can improve VO2 at maximal exertion by 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more. Alternatively, the disclosed methods and compositions of the present invention can improve VO2 at ventilatory anaerobic threshold (VAT) by 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more in SVHD patients, including Fontan patients.

[0092] IV. Vascular Function Tests Endothelial dysfunction is an important outcome for assessing vascular health in interventional studies. It is now well established that endothelial dysfunction is positively associated with traditional cardiovascular disease (CVD) risk factors and independently predicts cardiovascular events over a 1- to 6-year interval.

[0093] Pulse amplitude tonometry (PAT), an FDA-approved method for assessing vascular function, is increasingly being used as a surrogate measure of endothelium-dependent dilation and flow-mediated vasodilation (FMD) in response to reactive hyperemia. PAT devices record digital pulse wave amplitude (PWA) using fingertip plethysmography. PWA can be measured continuously during three phases: a quiet baseline period, a 5-minute forearm occlusion, and reactive hyperemia, after which the blood pressure cuff is removed. Unlike FMD, PAT testing does not depend on highly skilled experts, and post-test analysis is largely automated. Most importantly, at least one longitudinal study has shown that PAT measurements of endothelial function predict CVD events over a 6-year follow-up period. These significant advantages may make PAT testing suitable for clinical practice if prognostic significance and reliability can be demonstrated.

[0094] SVHD patients, including SVHD patients who have previously undergone the Fontan procedure, typically experience a decline in vascular function over time. Treatment of SVHD patients, including Fontan patients, that improves or prevents further decline in vascular function in SVHD patients, including Fontan patients, indicates that treatment is clinically beneficial and may improve the quality of life or prevent the decline in cardiovascular function in SVHD patients, including Fontan patients.

[0095] In one embodiment, the present invention relates to a method for improving or maintaining vascular function in SVHD patients, including SVHD patients who have previously undergone Fontan surgery.The method comprises administering an effective amount of an effective PDE5 inhibitor to SVHD patients, including Fontan patients, preferably daily, wherein the PDE5 inhibitor is preferably udenafil or its pharmacologic acceptable salt.In some embodiments, vascular function is measured using PAT index.

[0096] In some embodiments, the disclosed methods and compositions of the present invention are administered to SVHD patients, including Fontan patients, resulting in no or minimal decline in vascular function over time. Vascular function can be measured using any conventionally known technique, including but not limited to pulse amplitude tonometry measurements, natural logarithm of reactive hyperemia index, reactive hyperemia index, Framingham (RHI), area under the curve to max-occlusion / control, average to max-occlusion / control, and other known EndoPAT indices. In some embodiments of the present invention, vascular function is measured using the PAT index. More specifically, the disclosed methods and compositions of the present invention can result in a decline in vascular function of less than about 40, less than about 35, less than about 30, less than about 35, less than about 20, less than about 15, less than about 10, or less than about 5% over time. The period of time between the first and second measurements used to calculate the decline in vascular function can be, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months; 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 13, about 14, or about 15 years, or any combination thereof, e.g., 1 year, 3 months; 4 years, 7 months, etc.

[0097] In some embodiments, the disclosed methods and compositions of the present invention may be administered to SVHD patients, including Fontan patients, to result in improved vascular function. Vascular function may be measured using any conventionally known technique, including, but not limited to, pulse amplitude tonometry measurements, natural logarithm of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the curve to max-occlusion / control, average to max-occlusion / control, and other known EndoPAT indices. In some embodiments of the present invention, vascular function is measured using a PAT index. More specifically, the disclosed methods and compositions may result in about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% or more improvement in one or more measurements of vascular function, including, but not limited to, pulse amplitude tonometry measurements, natural logarithm of reactive hyperemia index, reactive hyperemia index, Framingham RHI, area under the curve to max-occlusion / control, average to max-occlusion / control, and other known EndoPAT indices.

[0098] V. Echocardiographic Assessment of Ventricular Function Ventricular function and cardiac contractility are important measurements that can reveal impairments in cardiovascular health before overt heart failure is present. Ventricular function can be assessed using echocardiography and quantified by the myocardial performance index, or MPI, which is a combined measure of systolic and diastolic function.

[0099] Specifically, MPI is defined as the sum of the isovolumic contraction time and the isovolumic relaxation time divided by the ejection time.

[0100] Various versions of MPI are known in the art, and each version of MPI can be used to evaluate ventricular function. For example, MPI index can include, but is not limited to, blood pool MPI and tissue Doppler MPI. MPI can be measured by using pulsed wave tissue Doppler echocardiography (TDE). To calculate MPI using TDE, the isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and ejection time (ET) of a single functioning ventricle are measured. Then, IVCT and IVRT are summed and the sum is divided by ET to determine MPI.

[0101] Patients who have previously undergone the Fontan procedure typically experience a decline in ventricular function over time. Treating a patient so that their ventricular function is maintained, shows minimal decline over time, or increases indicates that the treatment is clinically beneficial and may improve the patient's quality of life or prevent a decline in cardiovascular function.

[0102] In one embodiment, the present invention relates to a method for maintaining, minimally decreasing, or increasing ventricular function in subjects who have previously undergone Fontan surgery.The method of the present invention comprises administering to the patient an effective amount of an effective PDE5 inhibitor, preferably daily, wherein the PDE5 inhibitor is preferably udenafil or its pharmacologic acceptable salt.In some embodiments of the present invention, ventricular function is measured using myocardial performance index (MPI).In some embodiments, the MPI can be blood pool MPI, while in other embodiments, the MPI can be tissue Doppler MPI.

[0103] In some embodiments, the disclosed methods and compositions of the invention can be administered to Fontan patients to result in no or minimal decline in ventricular function over time. Ventricular function can be measured using any conventionally known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, mean isovolumic contraction and relaxation, and other known ventricular performance indices. More specifically, the disclosed methods and compositions of the invention can result in a decline in ventricular function of less than about 40, less than about 35, less than about 30, less than about 35, less than about 20, less than about 15, less than about 10, or less than about 5% over time. The period of time between the first and second measurements used to calculate the decline in ventricular performance can be, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months; 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 13, about 14, or about 15 years, or any combination thereof, e.g., 1 year, 3 months; 4 years, 7 months, etc.

[0104] In some embodiments, the disclosed methods and compositions of the present invention can be administered to SVHD patients, including Fontan patients, to improve ventricular function over time. Ventricular function can be measured using any conventionally known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, average isovolumic contraction and relaxation, and other known ventricular performance indices. For example, the disclosed methods and compositions of the present invention can improve ventricular function by about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% or more, as measured by any known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue Doppler MPI, average isovolumic contraction and relaxation, and other known ventricular performance indices.

[0105] VI. Methods of the Invention The disclosed method of the invention relates to improving exercise and ventricular function in SVHD patients, including Fontan patients, in need of improved exercise capacity and / or ventricular function. In general, the method comprises daily administration of an effective amount of an effective PDE5 inhibitor, preferably as udenafil or a pharmacologic acceptable salt thereof, to a SVHD patient, including a Fontan patient, to: (a) Ventricular function of one functioning ventricle in SVHD patients measured by MPI; (b) Exercise capacity as measured by oxygen consumption during VAT; (c) exercise capacity as measured by oxygen consumption at maximal exertion or VO2 max; (d) VAT work rate, (e) VE / VCO2 (each separately or in any combination) at VAT; (f) resting diastolic blood pressure, and (g) Oxygen saturation at rest (%) These include improving the above individually, collectively or in any combination.

[0106] Preferably, the method of the present invention improves the above-listed (a)-(g), individually, collectively, or any combination thereof. More preferably, the above-listed (a)-(g), individually, collectively, or any combination thereof, are improved according to the present invention by daily administration of an effective amount of udenafil or a pharma- ceutically acceptable salt thereof to a SVHD patient, including a Fontan patient.

[0107] As discussed above, as used herein, an effective PDE5 inhibitor inhibits the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels that supply blood to various tissues.

[0108] As discussed above, as used herein, MPI is a measure of ventricular systolic and diastolic function determined by focal echocardiography, as well as a marker of prognosis and progression of various cardiac diseases. This value is defined as the sum of isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) divided by ejection time (ET) and can be calculated for a single ventricle. Changes in myocardial performance index are determined by velocities obtained from blood pool Doppler assessment of the inflow and outflow tracts of a single functioning ventricle. In other words, MPI is a measure of global systolic and diastolic time intervals to assess global cardiac dysfunction and ventricular function. Moreover, since MPI is a Doppler index, it is independent of ventricular geometry and can be applied to either left or right ventricular function depending on which ventricle is the single functioning ventricle in SVHD patients.

[0109] More specifically, the method involves daily administration of an effective amount of an effective PDE5 inhibitor or a pharma- ceutical acceptable salt thereof, preferably udenafil or a pharma- ceutical acceptable salt thereof, to provide one or more of the above improvements without causing treatment-limiting side effects, including, but not limited to, blindness or reduced vision due to inhibition of photoreceptor phosphodiesterase enzyme (PDE6), back pain and / or muscle pain due to inhibition of PDE11, e.g., 11A1 (PDE11A1), and / or reduced sperm concentration due to inhibition of PDE11, e.g., 11A3 (PDE11A3). Kayik, G. et al.: Investigation of PDE5 / PDE6 and PDE5 / PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development. Journal of Enzyme Inhibition and Medicinal Chemistry, 32(1):311-330 (2017); Pomara G. and Morelli G.: Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality. Int J Impot Res, 17:385-386 (2005), and Huang SA and Lie, JD: Phosphodiesterase-5 (PDE5) Inhibitors. In the Management of Erectile Dysfunction. Pharmacy and Therapeutics, 38(7):407-419 (July 2013).

[0110] Quite uniquely and surprisingly, the methods of the present invention increase and / or maximize the ventilatory anaerobic threshold (VAT) and oxygen consumption at maximal exertion or max VO2, improving exercise capacity, and increase and / or maximize work rate at VAT and VE / VCO2 at VAT in SVHD patients, including Fontan patients.

[0111] Also, very uniquely and surprisingly, the method of the present invention improves the MPI of SVHD patients, i.e. Fontan patients. In other words, the method of the present invention improves both the systolic and diastolic function of one functioning ventricle as well as global cardiac function. In other words, the method of the present invention improves the filling and emptying characteristics, i.e., the ability to exert pressure, of one functioning ventricle as well as the overall ability of the remodeled abnormal SVHD heart of SVHD patients, including Fontan patients, to pump newly oxygenated blood to the body for the needs of peripheral tissues.

[0112] The clinical value of MPI improvement is demonstrated by statistically significant improvements in MPI in SVHD patients, particularly Fontan patients, treated with the methods of the invention compared to SVHD patients treated with placebo, i.e., Fontan patients, during the FUEL trial.

[0113] The clinical value of improved MPI is also evidenced by improved single ventricular function as measured by isovolumic contraction time, isovolumic relaxation time, and ejection time using TDE, as discussed above.

[0114] By "isovolumic contraction time" (IVCT) is intended herein to mean the single ventricle event occurring early in systole, during which the single ventricle contracts without volume change (isovolumically). During this period of the cardiac cycle, the pressing event takes place, but all heart valves are closed.

[0115] By "isovolumic relaxation time" (IVRT) is intended herein to mean the interval duration of a cardiac cycle, i.e., a cycle of relaxation under pressure, related from the second heart sound caused by valve closure to the onset of filling of a single functioning ventricle following valve opening. IVRT may be indicative of diastolic dysfunction of a single functioning ventricle.

[0116] By "ejection time" (ET) is intended herein to mean the univentricular ejection time (UVET) of the reconstructed abnormal heart determined by the opening and closing of the valve, during which the pressure difference across the valve is measured.

[0117] By "stroke volume" herein is intended to mean the amount of freshly oxygenated blood that one functioning ventricle can pump into the circulatory system with one contraction.

[0118] By "cardiac output" herein is intended to mean the volume of blood that one functioning ventricle of an SVHD patient, including a Fontan patient, can pump into the circulatory system in one minute. 1 Stroke volume and heart rate determine cardiac output. ( 1 A normal adult has an average cardiac output of about 4.7 liters (5 quarts) of blood per minute.

[0119] While each of the improvements in the treatment of SVHD patients, including Fontan patients, according to the methods of the invention is individually unique and surprising, the combination of improvements in the treatment of SVHD patients, including Fontan patients, is particularly unique and surprising.

[0120] In another embodiment, it was surprising that the method of the present invention showed improved results when udenafil was administered, compared to previous very limited studies using non-udenafil PDE5 inhibitors, such as sildenafil or tadalafil.In yet another embodiment, it was surprising that the method of the present invention showed fewer and / or less severe side effects when udenafil was administered, compared to other previous treatments using non-udenafil PDE5 inhibitors, such as sildenafil or tadalafil.

[0121] In some embodiments, the Fontan patient can be an adult human, while in other embodiments, the Fontan patient can be an adolescent human. In some embodiments, the Fontan patient can be between about 12 and about 19 years of age, while in other embodiments, the Fontan patient can be between about 12 and 18 years of age. In yet other embodiments, the Fontan patient can be between about 12 and about 16 years of age. In yet other embodiments, the Fontan patient can be between about 6 years of age and adult. In one embodiment, the Fontan patient can be under 18 years of age.

[0122] VII. Dosage and Formulation The structure of udenafil is shown below:

[0123] [ka]

[0124] In some embodiments, udenafil or a pharma- ceutically acceptable salt thereof can be administered at a total daily dose of about 0.01 to about 150 mg / kg, hi other embodiments, udenafil or a pharma- ceutically acceptable salt thereof can be administered at a total daily dose of about 0.01 mg / kg to about 30 mg / kg.In another embodiment, udenafil or a pharma- ceutically acceptable salt thereof is administered in an amount of about 2.5 mg to about 275 mg, e.g., about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 10 ... mg, approx. 47.5 mg, approx. 50 mg, approx. 52.5 mg, approx. 55 mg, approx. 57.5 mg, approx. 60 mg, approx. 62.5 mg, approx. 65 mg, approx. 67.5 mg, approx. 70 mg, approx. g, about 90mg, about 92.5mg, about 95mg, about 97.5mg, about 100mg, about 102.5mg, about 105mg, about 107.5mg, about 110mg, about 112.5mg, about 115mg, about 117.5mg, about 120mg, about 122.5mg, about 125mg, about 127 .5mg, about 130mg, about 132.5mg, about 135mg, about 137.5mg, about 140mg, about 142.5mg, about 145mg, about 147.5mg, about 150mg, about 152.5mg, about 155mg, about 157.5mg, about 160mg, about 162.5mg, about 16 5mg, about 167.5g, about 170mg, about 172.5mg, about 175mg, about 180mg, about 182.5mg, about 185mg, about 187.5mg, about 190mg, about 192.5mg, about 195mg, about 197.5mg, about 200mg, about 202.5mg, about 205mg , about 207.5 mg, about 210 mg, about 212.5 mg, about 215 mg, about 217.5 mg, about 220 mg, about 222.5 mg, about 225 mg, about 227.5 mg, about 230 mg, about 232.5 mg, about 235 mg, about 237.5 mg, about 240 mg, about 242.5 mg, about 245 mg, about 247.5 mg, about 250 mg, about 252.5 mg, about 255 mg, about 257.5 mg, about 260 mg, about 262.5 mg, about 265 mg, about 267.5 mg, about 270 mg, about 272.5 mg or about 275 mg.In yet another embodiment, udenafil or a pharma- ceutically acceptable salt thereof is administered in a dose range of about 5 mg to about 275 mg, e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, or about 40 mg, so long as any such individual total daily dose does not cause treatment-limiting toxicities or treatment-limiting side effects to such an extent that the total daily dose would not be approved for marketing. g, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 87.5 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 275 mg.

[0125] In yet another embodiment, udenafil or a pharma- ceutically acceptable salt thereof can be administered in a total daily dose of about 25 mg to about 700 mg, e.g., about 25 mg, about 37.5 mg, about 50 mg, about 75 mg, about 87.5 mg, 125 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, or about 700 mg, so long as any such individual total daily dose does not cause treatment-limiting toxicities or treatment-limiting side effects to such an extent that the total daily dose is not marketed.

[0126] In further embodiments, udenafil or a pharma- ceutically acceptable salt thereof can be administered at a total daily dose of about 37.5 mg, about 75 mg, about 87.5 mg, 125 mg, or about 175 mg. In further embodiments, udenafil or a pharma- ceutically acceptable salt thereof can be administered at a total daily dose range of about 37.5 mg to about 175 mg, preferably at a total daily dose range of 75 mg to about 175 mg, more preferably at a total daily dose range of about 87.5 mg to about 175 mg, and most preferably at a total daily dose range of 125 mg to about 175 mg. In a preferred embodiment, udenafil or a pharma- ceutically acceptable salt thereof can be administered to a Fontan patient at any dose or any total daily dose, so long as any selected individual dose or any selected individual daily dose does not cause treatment-limiting toxicities or treatment-limiting side effects to such an extent that the total daily dose is not marketed.

[0127] Thus, the present invention contemplates the administration of udenafil or a pharma- ceutically acceptable salt thereof to SVHD patients, including Fontan patients, at any dose, any total daily dose, any treatment regimen, and any dosage form, so long as any such dose, total daily dose, treatment regimen, or dosage form, when selected, does not cause treatment-limiting toxicities or treatment-limiting side effects to an extent that would prevent it from being marketed. In particular, the present invention contemplates administration of udenafil or a pharma- ceutically acceptable salt thereof in an effective amount to SVHD patients, including Fontan patients, to improve MPI, single ventricular function, systolic and / or diastolic function, ventricular pressure exertion, cardiac output, exercise capacity or function at VAT and / or max VO2, work at VAT, VE / CO2 at VAT, diastolic blood pressure at rest, oxygen saturation (%) at rest, and / or a reduction in the rate of decline in SVHD progression, as compared to untreated SVHD patients, so long as the therapeutically effective amount does not cause treatment-limiting toxicities, treatment-limiting side effects associated with inhibition of PDE6 and / or PDE11, and / or treatment-limiting side effects to the extent that a drug product would not be approved for the market.

[0128] In one embodiment, udenafil or a pharma- ceutically acceptable salt thereof can be administered once a day.

[0129] In another embodiment, udenafil or a pharma- ceutically acceptable salt thereof can be administered once a day, or in multiple divided doses, for example, two times a day, three times a day, four or more times a day.

[0130] In yet another embodiment, udenafil or a pharma- ceutically acceptable salt thereof can be administered twice daily such that a therapeutically effective blood level is maintained for at least about 1.5 to about 24 hours of a 24-hour administration period, more specifically at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours. Thus, the present invention thereby contemplates udenafil and / or any active metabolite of udenafil, such as the active metabolite DA8164, that maintains an effective blood level for any period of a 24-hour administration period.

[0131] In some embodiments, the total daily dose of udenafil or a pharma- ceutically acceptable salt administered twice daily can be less than the total daily dose of udenafil or a pharma- ceutically acceptable salt administered once daily.

[0132] In some embodiments, the total daily dose of udenafil or its pharma- ceutically acceptable salt administered twice a day can maintain therapeutically effective blood levels for the same number of hours in a 24-hour period at a higher dose than udenafil or its pharma-ceutically acceptable salt administered once a day.In another embodiment, the total daily dose of udenafil or its pharma-ceutically acceptable salt administered twice a day can maintain therapeutically effective blood levels for a longer number of hours in a 24-hour period than udenafil or its pharma-ceutically acceptable salt administered once a day.Thus, the present invention contemplates administration of any total daily dose of udenafil or its pharma-ceutically acceptable salt administered once a day or in multiple daily divided doses, for example twice a day, three times a day, four or more times a day, to maintain therapeutically effective blood levels throughout a 24-hour period.

[0133] In one embodiment, it is surprising that administration of udenafil or a pharma- ceutically acceptable salt thereof twice a day results in fewer side effects than administration of udenafil or a pharma- ceutically acceptable salt thereof once a day.In another embodiment, it is surprising that administration of udenafil or a pharma- ceutically acceptable salt thereof twice a day can reach a therapeutically effective level of udenafil at a lower total daily dose than administration of udenafil or a pharma- ceutically acceptable salt thereof once a day.

[0134] In some embodiments, the pharma- ceutically acceptable salt of udenafil may be an acid addition salt. In one embodiment, the acid addition salt of udenafil may be an inorganic acid addition salt, such as hydrochloric acid addition salt, hydrobromic acid addition salt, sulfuric acid addition salt, or phosphoric acid addition salt. In another embodiment, the acid addition salt may be an organic acid addition salt, such as citrate, tartrate, acetate, lactate, maleate, fumarate, gluconate, methanesulfonate (mesylate), glycolate, succinate, p-toluenesulfonate (tosylate), galacturonate, embonate, glutamate, aspartate, oxalate, benzenesulfonate, camphorsulfonate, cinnamate, adipate, or cyclamate. In a particular embodiment, the pharma-ceutically acceptable salt of udenafil may be an oxalate, benzenesulfonate, camphorsulfonate, cinnamate, adipate, or cyclamate.

[0135] In some embodiments, udenafil or its pharmaceutically acceptable salt can be administered as a pharmaceutical composition.In one embodiment, the pharmaceutical composition comprising udenafil or its pharmaceutically acceptable salt can be formulated into a wide variety of oral or parenteral dosage forms for clinical application.Each dosage form can contain various disintegrants, surfactants, fillers, thickeners, binders, diluents, such as wetting agents, or other pharmaceutically acceptable excipients.

[0136] The udenafil composition can be administered in any pharma- ceutically acceptable manner, for example, intranasally, bucally, sublingually, orally, rectally, ocularly, parenterally (intravenously, intradermally, intramuscularly, subcutaneously, intravesically, intraperitoneally), pulmonary, intravaginally, locally, topically, topically after scarification, mucosally, by aerosol, or by buccal or nasal gel or spray formulations.

[0137] Furthermore, the udenafil composition can be formulated into any pharma- ceutically acceptable dosage form, such as, but not limited to, solid dosage forms, including tablets, pills, lozenges, capsules, caplets, orally disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, liquids, dispersions, suspensions, solutions, aerosols, pulmonary aerosols, nasal aerosols, and semisolids, i.e., ointments, creams, films, and gels, as well as patches, such as transdermal patches.Furthermore, the composition can be a controlled release formulation, a sustained release formulation, an immediate release formulation, a modified release formulation, or any combination thereof.

[0138] Further, the composition can be a transdermal delivery system.

[0139] In another embodiment, the pharmaceutical composition comprising udenafil or a pharma- ceutically acceptable salt thereof can be formulated into a solid dosage form for oral administration, and the solid dosage form can be a powder, granule, capsule, tablet, caplet, cachet, oral disintegration dosage form, sublingual dosage form, buccal dosage form, lozenge, or pill. In yet another embodiment, the solid dosage form can include one or more excipients, such as calcium carbonate, starch, sucrose, lactose, microcrystalline cellulose, or gelatin. Furthermore, the solid dosage form can include a lubricant, such as talc or magnesium stearate, in addition to the excipient. In some embodiments, the solid dosage form can be an immediate release formulation, or a modified release formulation. Modified release dosage forms include controlled release, sustained release, modified or sustained release, enteric release, and the like. Excipients used in modified release dosage forms are generally known to those skilled in the art.

[0140] For example, a solid carrier can be one or more substances that also act as diluents, flavoring agents, binders, preservatives, oral dosage form disintegrants, or encapsulating materials. Oral dosage forms, such as powders, granules, capsules, tablets, caplets, cachets, lozenges, or pills, preferably contain 5% to 70% udenafil. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose (e.g., lactose monohydrate), pectin, dextrin, starch (e.g., corn starch), gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, silicon dioxide (e.g., colloidal silicon dioxide), low melting wax, cocoa butter, and the like. The term "formulation" is intended to include solid, liquid, or semi-solid matrix formulations of udenafil, which may or may not contain encapsulating materials.

[0141] Liquid form preparations include solutions, suspensions, and emulsions, such as aqueous solutions or water / propylene glycol solutions. For parenteral injections, liquid preparations can be formulated in solutions in aqueous polyethylene glycol solutions. For example, aqueous solutions suitable for oral use can be prepared by dissolving udenafil in water and adding the appropriate colorings, flavorings, stabilizers, and thickeners required. In another example, aqueous suspensions suitable for oral use can be made by dispersing finely divided udenafil in water with viscous materials, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0142] Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In one embodiment, the pharmaceutical composition can be formulated into a liquid dosage form for oral administration, such as a suspension, emulsion, or syrup, and can include, in addition to udenafil, colorants, flavorings, stabilizers, buffers (e.g., buffers for adjusting pH to a desired range for intravenous use, such as salts of inorganic acids, such as phosphates, borates, and sulfates), artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. In other embodiments, the liquid dosage form can include various excipients, such as humectants, sweeteners, aromatic compounds, or preservatives, in addition to commonly used simple diluents, such as water and liquid paraffin. In certain embodiments, the composition containing udenafil or its pharma- ceutically acceptable salt can be formulated to be suitable for administration to pediatric patients.

[0143] In one embodiment, the pharmaceutical composition can be formulated into a dosage form for parenteral administration, such as a sterile aqueous solution, suspension, emulsion, or non-aqueous solution.In another embodiment, the non-aqueous solution or suspension can contain propylene glycol, polyethylene glycol, vegetable oil, such as olive oil, or injectable ester, such as ethyl oleate.Alternatively, the pharmaceutical composition can be formulated into a dosage form for rectal or vaginal administration.The base material for suppositories can be witepsol, macrogol, tween61, cocoa butter, lauric oil, or glycerin-treated gelatin.

[0144] Pharmaceuticals may require surfactants or other suitable co-solvents in the composition. Such co-solvents include polysorbates 20, 60, and 80, Pluronic® F-68, F-84, and P103, cyclodextrin, and polyoxyl 35 castor oil. Such co-solvents are typically used at levels between about 0.01% and about 2% by weight. Viscosities greater than those of simple aqueous solutions may be desirable to reduce variability during formulation dispensing, reduce physical separation of the suspension or emulsion components of the formulation, and / or otherwise improve the formulation. Such viscosity-forming agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the above. Such agents are typically used at levels between about 0.01% and about 2% by weight.

[0145] The pharmaceutical product is preferably in unit dosage form. In such form, the preparation is further divided into unit doses containing an appropriate amount of udenafil or any of its acceptable pharmaceutical salts. The unit dosage form can be a packaged preparation, such as a sachet, where the package contains a discrete amount of the preparation, such as a packet of tablets, caplets, capsules, oral disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, caplet, pill, oral disintegrating dosage form, sublingual dosage form, buccal dosage form, cachet, or lozenge itself, or any of the appropriate number of these in packaged form.

[0146] The pharmaceutical compositions may include components to provide immediate, sustained, extended, or modified release, convenience, and / or comfort. Such components include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices.

[0147] In further embodiments, the pharmaceutical composition comprising udenafil or a pharma- ceutically acceptable salt thereof can be formulated as an orally disintegrating, sublingual, or buccal dosage form. Such dosage forms include sublingual tablet or solution compositions administered under the tongue, and buccal tablets placed between the cheek and gums.

[0148] The pharmaceutical preparation can be prepared by further including a coating agent, such as a light-shielding agent capable of generating free radicals by UV light, a metal oxide, such as titanium oxide as described above, and a free radical scavenger, such as an organic acid, such as benzoic acid. In addition, the coating agent can further include an enteric coating layer including a water-soluble polymer (e.g., hypromellose or hydroxypropyl cellulose), polyethylene glycol, triethyl citrate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, zein, sodium alginate, and mannitol, and / or an enteric coating aqueous solution including, for example, ethyl cellulose, medium chain triglyceride oleic acid, sodium alginate, and stearic acid, but is not limited thereto.

[0149] In yet further embodiments, the pharmaceutical composition comprising udenafil or a pharma- ceutically acceptable salt thereof can be formulated as a nasal dosage form.Such dosage forms of the present invention include solutions, suspensions, emulsions, and gel compositions for nasal delivery.

[0150] In one embodiment, pharmaceutical composition can be formulated into liquid dosage form for oral administration, such as solution, suspension, emulsion or syrup.In other embodiments, liquid dosage form can contain various excipients, such as moisturizer, sweetener, aromatic compound or preservative, in addition to commonly used simple diluent, such as water and liquid paraffin.In certain embodiments, the composition containing udenafil or its pharmaceutically acceptable salt can be formulated to be suitable for administration to pediatric patients.

[0151] The dosage of the pharmaceutical composition may vary depending on the patient's body weight, age, sex, frequency and mode of administration, excretion rate, and severity of the disease.

[0152] VIII. Exercise Testing Exercise testing may include assessment of VO2 values ​​during maximal exertion or at ventilatory anaerobic threshold ("VAT"). VO2 max ("peak VO2"), or maximum ("peak") oxygen consumption, refers to the maximum amount of oxygen an individual can utilize during intense exercise. This measurement is generally considered to be a reliable indicator of cardiovascular fitness and aerobic endurance. In theory, the more oxygen a person can use during exercise, the more energy he or she can generate. This test is often used for cardiopulmonary fitness because for prolonged (aerobic) exercise, muscles need oxygen, blood needs to carry oxygen to muscles, and the heart needs to pump enough blood to meet the demands of aerobic exercise. However, while peak VO2 may be useful as a surrogate for many cardiovascular disease states, it may not be as relevant as an endpoint after the Fontan procedure. In this unique physiology, central venous pressure, rather than right ventricular contraction (pumping), is the fundamental driver of pulmonary blood flow and therefore cardiac output.Gewillig M and Goldberg DJ. Failure of the fontan circulation. Heart Fail Clin. 10(1):105-116 (Jan 2014); Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail. 10(12): e004515 (Sept. 2017); Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La Gerche A and Gorenflo M. The Fontan circulation controls: who cardiac output? Interact Cardiovasc Thorac Surg. 10(3):428-433 (Mar 2010); and Goldberg DJ, Avitabile CM, McBride MG and Paridon SM. Exercise capacity in the Fontan circulation. Cardiol Young. 23(6):824-830 (Dec 2013). As cardiac output demands increase with exertion, central venous pressure in the Fontan circulation must rise to meet that demand but eventually reaches a critical upper limit beyond which it cannot rise any further.Navaratnam D, Fitzsimmons S, Grocott M, Rossiter HB, Emmanuel Y, Diller GP, Gordon-Walker T, Jack S, Sheron N, Pappachan J, Pratap JN, Vettukattil JJ and Veldtman G. Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation. Am J Cardiol. 117(10):1667-1671 (May 15, 2016). At submaximal exertion, the increase in central venous pressure does not reach this physiological upper limit, and therefore outcomes at this level of exercise may be more sensitive to pharmacological manipulation of the pulmonary vasculature.

[0153] VO2 is often measured by placing a mask on the subject and measuring the volume of air inhaled and exhaled and the gas concentrations. This measurement is often used in both clinical settings and research and is considered the most accurate. Tests generally involve either exercising on a treadmill or riding a bicycle ergometer at increasing intensity to fatigue and are designed to take readings at the subject's maximal exertion and / or the subject's anaerobic threshold.

[0154] Patients who have previously undergone the Fontan procedure typically experience a decline in VO2 measurements over time. Treating a patient with the methods disclosed herein such that the patient's VO2 measurements remain at a similar level, either demonstrating no further decline in VO2 function or improving with treatment, indicates that the treatment is clinically beneficial and may improve cardiovascular function or inhibit or slow the rate of decline in cardiovascular function.

[0155] IX. Myocardial Performance Index (MPI) Generally speaking, MPI (also called Doppler-derived index or Tei Index) is a measure of ventricular systolic and diastolic function determined by focal echocardiography. It evaluates cardiac function by combining systolic and diastolic time intervals. More specifically, MPI can be used to evaluate ventricular function, which is given a numerical value using cardiac time intervals. This numerical value is equal to the sum of isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) divided by the ejection time (ET) and can be determined for either the left or right ventricle. Pellett, AA, et al.: The Tei Index: Methodology and Disease. State Values. Echocardiography: A Jrnl. of CV Ultrasound & Allied Tech. 21(7):669-672 (2004); and Ulugay, A., Tatli E.: Myocardial performance index. Anadolu Kardiyol Derg. 8(2):143-8 (April, 2008), both of which are incorporated herein by reference in their entirety. In the FUEL study, the MPI measured the function of a single functioning ventricle. Thus, the MPI resulting from the FUEL study was determined by velocities obtained from blood pool Doppler assessment of the inflow and outflow tracts of a single functioning ventricle. In other words, the MPI for the FUEL study was determined by measuring cardiac time intervals using pulsed wave Doppler velocity spectra of the ventricular inflow and outflow of a single functioning ventricle.

[0156] X. Echocardiogram Examination Echocardiograms were performed by sonographers specially trained in this protocol. The primary outcome of interest was MPI using Doppler-derived measures of inflow and outflow duration. Inflow into the main ventricle and outflow through the main semilunar valves were measured and used to calculate MPI using standard formulas. Tei C, Ling LH, Hodge DO, et al.: New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function-a study in normals and dilated cardiomyopathy. J Cardiol, 26(6):357-66 (1995); and Pellet AA et al.: The Tei Index: Methodology and Disease State Values. Echocardiography: A Jrnl Of CV Ultrasound & Allied Tech, 21(7):669-672 (2004). Additional tissue Doppler images were obtained and used to calculate tissue Doppler-based MPI as previously described. Harada K, Tamura M, Toyono M et al.: Comparison of the right ventricular Tei index by tissue Doppler imaging to that obtained by pulsed Doppler in children without heart disease. Am J Cardiol, 90(5):566-9 (2002). Whenever possible, measurements were taken three times, and the average period was used for calculation.

[0157] XI. Super-Fontan patients with baseline predicted maximum or peak VO2% ≥ 80% and subgroup Fontan patients with baseline predicted maximum or peak VO2% < 80% The FUEL trial in Example 1 below did not exclude Fontan patients based on the upper limit of aerobic exercise capacity (peak or max VO2). This trial design led to the enrollment of a substantial number of participants (20% of the analyzable ITT cohort) with baseline peak VO2 of 80% or more, subjects with normal or near-normal exercise capacity. Only recently has this subgroup of super Fontan patients been formally recognized academically, and they have been called "high functioners" or "super Fontan" (Powell 2020 and Weinreb 2020). At the time of the design of the FUEL trial, the existence of these Fontan high functioners or super Fontan patients was not fully appreciated. Furthermore, the physiological explanation for their unique limitations to exercise was not fully understood. Thus, treatment with pulmonary artery vasodilators may not increase the already high pulmonary vascular reserve in these Fontan subjects (i.e., adequate vasodilatory state at baseline). Thus, the inclusion of this subgroup of high functioners may serve to dilute the measurable clinical impact of pulmonary vasodilators on peak VO2 in the entire ITT cohort.The following findings support this assertion and the conclusion of efficacy of udenafil in patients with SVHD mitigated to the Fontan circulation:1. Despite the inclusion of high Fontan functioners, the overall ITT results still surprisingly demonstrated near statistical significance in clinical improvement and effect of udenafil on peak VO2 (p=0.092 when peak VO2 is expressed as ml / kg / min and p=0.071 when peak VO2 is expressed as ml / min).

[0158] Baseline predicted peak or maximum VO2% influenced treatment response. See Figure 2. A strong response is evident only for Fontan patients in the udenafil group with baseline predicted maximum or peak VO2% less than 80%. For patients with baseline peak VO2 greater than 80%, there appears to be little response during peak or maximum VO2 exercise. Note that the placebo group response is negligible across all baseline strata. This concentration of udenafil drug effects in those with low function surprisingly provides a great opportunity for pharmacological improvement of peak or maximum exercise capacity in Fontan patients who are at high risk for adverse clinical events.

[0159] Excluding the high-functioning Fontan subgroup (peak VO2 ≥ 80% of predicted) results in a cohort with clinically and statistically significant improvement in peak VO2 for udenafil drug (p = 0.023 when peak VO2 is expressed as ml / kg / min and p = 0.030 when expressed as ml / min). This Fontan subgroup represents the majority of subjects enrolled in the FUEL trial (80% of the analyzable ITT cohort) and is the subgroup most at risk for short-term adverse clinical outcomes (Table 1). These findings are strongly supported by information that was not available at the time the FUEL trial was planned. Improving pulmonary vasodilation in patients with normal pulmonary vasodilator reserve is simply not feasible, and including such patients in the FUEL trial would have diluted the treatment effect.

[0160] Of note, VO2 during VAT was associated with clinically and statistically significant improvements in the entire ITT cohort (p=0.012) and in the Fontan subgroup excluding high-functioning Fontan subjects (p=0.022). This finding provides mechanistic insight and confirmation into the efficacy of udenafil in the Fontan circulation: pulmonary artery vasodilator treatment can alter (delay) the transition from aerobic to anaerobic metabolism, but may not further improve peak exercise capacity in super-Fontan patients for reasons detailed above.

[0161] Over time, even well-functioning Fontan subjects deteriorate, with peak or maximum VO2 declining into the abnormal range. Thus, although treatment with pulmonary vasodilator therapy may not necessarily improve peak or maximum VO2 in normal or near-normal (high functioning) individuals, it is reasonable to assume that such treatment could slow or attenuate the inevitable decline in peak VO2 noted in natural history studies of all Fontan patients.

[0162] The present method can be further understood by the following non-limiting examples.

[0163] [Example 1] The Fontan Udenafil Exercise Longitudinal (FUEL) trial The FUEL trial was conducted at 30 centers worldwide. It was a phase 3, randomized, double-blind, placebo-controlled trial of udenafil in adolescents with SVHD undergoing Fontan palliation. (Funded by Mezzion Pharma Co. Ltd. and conducted by the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network; ClinicalTrials.gov number NCT02741115.)

[0164] The primary objective was to determine the effect of udenafil on exercise capacity in adolescents with Fontan physiology over a 6-month period. The primary outcome was the change in oxygen consumption at peak exercise (maximal or peak VO2) from baseline to the 26-week visit. Secondary exercise outcomes included changes in additional measures at maximal exertion, as well as changes in measures of submaximal exercise at the ventilatory anaerobic threshold (VAT). Primary outcomes for clinical secondary objectives included changes in myocardial performance index (MPI), an echocardiography-derived measure of systolic and diastolic ventricular function, changes in log-transformed reactive hyperemia index (lnRHI), a PAT-derived measure of peripheral vascular function, and changes in log-transformed serum BNP levels. Safety was monitored via adverse event reports collected according to a prespecified protocol of study coordinator outreach, as well as ad hoc patient and family communication with members of the study team at each site.

[0165] Trial Group Individuals between 12 and 18 years of age (inclusive) who had undergone the Fontan procedure, had not been treated with a PDE5 inhibitor, weighed 40 kg or more, and met the minimum height requirement for cycle ergometry (132 cm or more) were eligible for enrollment. To isolate the effect of udenafil on exercise performance, patients with severe ventricular dysfunction, severe atrioventricular regurgitation, or whose previous clinical exercise test had peak oxygen consumption less than 50% of predicted for their age and sex were excluded. A complete list of inclusion and exclusion criteria is provided in Table 1.

[0166] [Table 1]

[0167] More specifically, the FUEL trial was designed to evaluate 26-week changes in exercise capacity in patients randomized to udenafil versus placebo. At the time of study conception, it was accepted that Fontan patients with very limited exercise capacity (baseline peak or max VO2 less than 50% of predicted) would be excluded from the trial. The rationale for this exclusion was based on (1) safety, and (2) the understanding that this subset population was unlikely to yield valid cardiopulmonary maximal exercise test data. During the design of the FUEL trial, no consideration was given to an upper limit of predicted peak VO2, nor the possibility of excluding patients with high exercise capacity at baseline, since the range of these uniquely high exercisers had not been identified or evaluated.

[0168] Importantly, the situation has changed since the FUEL trial and its protocol design. New information emerged after the initiation and unblinding of the FUEL trial. In particular, four publications emerged that acknowledged the existence of a subset of Fontan patients with high exercise capacity (Cordina 2018, Powell, 2019, Weinreb, 2020, and Goldberg, 2021). Cordina et al. showed that 14 / 133 (11%) Fontan patients had an exercise capacity of greater than 80% predicted peak VO2. Similarly, Powell identified 22 / 112 (25%) Fontan patients with high exercise capacity, defined as greater than 80% predicted peak VO2. In hindsight, the “high functioners” should have been excluded from the FUEL trial, at least with respect to the peak or max VO2 testing, because such Fontan patients with high exercise capacity at baseline would not likely benefit from a treatment assessed by peak cardiopulmonary exercise function. Such high Fontan function does not represent the typical Fontan population. Analysis of a subset of the ITT population excluding Fontan "high functioners," otherwise analyzed per protocol, gives statistically significant results for the primary peak or maximum VO2 endpoint (p=0.023) and clinical relevance.

[0169] Randomization and study procedures Enrolled participants were randomly assigned to udenafil or placebo in a 1:1 ratio using permuted blocks and stratified by ventricular morphology (left vs. right ventricle or mixed). Randomization assignment was generated by a web-based algorithm after confirmation of trial eligibility and compliance.

[0170] Baseline clinical trials completed before drug initiation included blood sampling to measure brain-type natriuretic peptide (BNP) levels, cardiopulmonary exercise testing (CPET) using a standardized cycle ergometer ramp protocol, standardized echocardiograms, and assessment of peripheral vascular function using peripheral arterial tonometry (PAT) measured by finger cuff (EndoPAT; Itamar Medical, Israel). Participants who achieved maximal effort, defined as a respiratory exchange ratio (RER) ≥ 1.10 at peak exercise during CPET, were eligible for randomization and study drug initiation. Participants who did not achieve maximal effort were given a subsequent opportunity to repeat the exercise test within 2 weeks of the first attempt. Clinical trials after study completion included repeated measurements of serum BNP, CPET, echocardiograms, and PAT.

[0171] statistical analysis A sample size of 200 participants per treatment group was selected to allow for 90% power to detect a 10% mean treatment difference in the change in VO2 max from baseline to the 26-week study with a type I error of 0.05. The following assumptions were made: baseline standard deviation of 7.235 ml / kg / min, correlation between VO2 max measures of 0.33, dropout and study non-completion rates of 10%, and failure to reach maximal effort in the 26-week exercise study of 15% of participants. These assumptions were based on historical data and reflected a conservative approach to assessing within-participant correlations and failure to reach maximal effort.

[0172] The primary analysis used an intention-to-treat population to assess differences in the change in the primary outcome between treatment arms. Analysis of covariance (ANCOVA) was used to assess this difference, with ventricular morphology (left single vs. right single or mixed) and treatment group as fixed factors and baseline max VO2 as a continuous covariate. For those without data at the 26-week visit, this value was imputed as equal to the baseline value (no change). Secondary analyses included participants who successfully completed the protocol and had measurable values ​​for each secondary endpoint. Secondary outcomes with continuous data points were analyzed in the manner described for the primary outcomes. To assess the generalizability of findings in ventilatory anaerobic threshold, demographic and clinical characteristics were compared between participants with unpaired VO2 in the VAT data and the remainder of the cohort.

[0173] Trial Results Between July 2016 and May 2018, 1376 patients were screened at 30 sites (Figure 1B). Of these, 200 were randomly assigned to udenafil and 200 to placebo. At randomization, the mean age was 15.5 years, the mean height was 163.6 cm, and the mean weight was 58.1 kg. Sixty percent of participants were male, and 81% described their racial identity as white. Those in the placebo group were taller compared with those in the udenafil group, but other baseline characteristics were similar between groups.

[0174] Primary purpose – movement measurement Maximal exercise data (VO2 max) were available for all participants at baseline and for 379 participants (189 in the udenafil group, 190 in the placebo group) at week 26 of the study.

[0175] Reasons for absence of data at the 26-week study included patient dropout or errors in data capture (n=14) and participants' inability to generate an RER of 1.10 or greater (n=7). No differences were observed between the udenafil and placebo groups in change from baseline to the 26-week study in resting heart rate, respiratory rate, or systolic blood pressure. There was a small but statistically significant increase in resting oxygen saturation and a statistically significant decrease in diastolic blood pressure in the udenafil group.

[0176] Resting data and exercise performance results are provided in Table 2.

[0177] [Table 2]

[0178] Analysis of resting diastolic blood pressure demonstrated a statistically significant change (a decrease indicates improvement) in diastolic blood pressure in the udenafil group (-2.9 decrease, improvement) compared to the placebo group (+0.2 increase, no improvement) (p=0.003).

[0179] Analysis of oxygen saturation (%) at rest demonstrated a statistically significant change (an increase indicates improvement) in oxygen saturation (%) in the udenafil group (increase of +0.5, improvement) compared to the placebo group (decrease of -0.3, no improvement) (=0.002).

[0180] Analysis at maximal exercise demonstrated an increase of 44 mL / min (2.8%) in VO2max in the udenafil group compared to a decrease of 3.7 mL / min (-0.2%) in the placebo group, although the difference did not reach statistical significance (p=0.071).

[0181] Additionally, metabolic data to calculate VO2 during VAT were available for 317 participants; 170 in the udenafil group and 181 in the placebo group, as shown in Table 2 above. No differences were noted in baseline demographic or clinical characteristics of this subgroup compared to the larger cohort. For those with paired VO2 during VAT data, a statistically significant improvement of 30 mL / min (1.92%) was noted in the udenafil group compared to a decrease of 8 mL / min (-0.7%) in the placebo group (p=0.023). The ventilatory equivalent of carbon dioxide (VE / VCO2) measured during VAT was significantly reduced (improved ventilatory efficiency) by 0.8 (2.1%) in the udenafil group compared to 0.05 (0.2%) in the placebo group (p=0.011), while the power output was significantly improved by 3.5 watts (5.5%) in the udenafil group compared to 0.31 watts (0.78%) in the placebo group (p=0.029). Thus, treatment of Fontan patients with 87.5 mg twice daily demonstrated statistically significant improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.

[0182] Secondary Objective Measurement Paired echocardiographic data for MPI measurements were available for 250 participants (63%); 122 in the udenafil group and 128 in the placebo group. Table 3. A statistically significant change (decrease indicates improvement) was observed in MPI in the udenafil-treated group (-0.02 decrease, improvement) compared with the placebo group (+0.01 increase, no improvement) (p=0.028).

[0183] Paired PAT-derived vascular function data were available for 328 participants (81%); 163 in the udenafil group and 165 in the placebo group. There was no significant improvement in lnRHI in both the udenafil and placebo groups (0.07 vs. 0.05, p=0.59). Paired measurements of serum BNP levels were available for 378 participants (95%); 187 in the udenafil group and 191 in the placebo group. Changes in log serum BNP levels were not significant between groups (p=0.18). Paired echocardiographic data, paired PAT-derived vascular function data, and paired measurements of serum BNP levels are provided in Table 3.

[0184] [Table 3]

[0185] [Table 4]

[0186] Safety and Tolerability

[0187] [Table 5]

[0188] Udenafil and placebo were well tolerated by study participants. There were no deaths in the study cohort. A total of 24 participants (6%); 14 in the udenafil group and 10 in the placebo group experienced serious adverse events. There were three events in the udenafil group and two in the placebo group that were considered to have a possible, probable, or definite relationship to the study drug. Those occurring in the udenafil group included unilateral retinal arterial and venous thrombosis, transient lower limb diplegia, and transient dyspnea. Frequent nonserious adverse events considered to have a possible, probable, or definite relationship to the study drug that occurred in at least 5% of participants in either treatment group are provided in Table 4. Headache, facial flushing, abdominal pain, epistaxis, and erections (male participants) were more common in the udenafil group. All other adverse events occurred with similar frequency between groups.

[0189] [Example 2] Additional FUEL Trial Results The following example further describes the above-mentioned FUEL trial, referenced in Goldberg, DJ, et al.: Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial. Circulation, 141(8):141:641-651 (2020), which is hereby incorporated by reference in its entirety.

[0190] The Fontan procedure creates a total cavopulmonary anastomosis, a circulation that emphasizes the importance of pulmonary vascular resistance. Over time, this circulation leads to impaired cardiovascular efficiency that is associated with decreased exercise performance.

[0191] Rigorous clinical trials to improve physiology and guide pharmacotherapy are lacking.

[0192] The FUEL trial was a 30-center phase III clinical trial. Participants were randomly assigned in a 1:1 ratio to receive udenafil, 87.5 mg twice daily, or placebo. The primary outcome was between-group difference in change in oxygen consumption during peak exercise. Secondary outcomes included between-group differences in change in submaximal exercise at ventilatory anaerobic threshold (VAT), myocardial performance index (MPI), natural logarithm of reactive hyperemia index (lnRHI), and serum brain-type natriuretic peptide (BNP).

[0193] Between 2017 and 2019, 400 participants with Fontan physiology were randomized at 30 clinical sites in North America and South Korea. The mean age at randomization was 15.5 ± 2 years; 60% of participants were male, and 81% were white. All 400 subjects were included in the primary analysis, and 21 participants with missing data were imputed at the 26-week endpoint (11 randomized to udenafil and 10 to placebo). Among randomized participants, peak oxygen consumption increased by 44 ± 245 mL / min (2.8%) in the udenafil group and decreased by 3.7 ± 228 mL / min (-0.2%) in the placebo group (p = 0.071). Analysis during VAT demonstrated statistically significant improvements in oxygen consumption (+33 ± 185 (3.2%) vs. -9 ± 193 (-0.9%) mL / min, p = 0.012), carbon dioxide ventilatory equivalent (-0.8 vs. -0.06, p = 0.014), and power (+3.8 vs. +0.34 watts, p = 0.021) in the udenafil vs. placebo groups. Analysis of MPI also demonstrated statistically significant improvements in the udenafil-treated group compared to the group taking placebo over the same period (p = 0.028). No differences were observed in lnRHI, or changes in serum BNP levels.

[0194] In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was associated with improvement in peak exercise oxygen consumption (p=0.071), and statistically significant improvements in (i) multiple measures of exercise performance at ventilatory anaerobic threshold (VAT), (ii) MPI, (iii) resting diastolic blood pressure, and (iv) resting oxygen saturation (%).

[0195] The FUEL trial was funded by Mezzion Pharma Co. Ltd. and conducted by the National Heart, Lung and Blood Institute-funded Pediatric Heart Network, ClinicalTrials.gov number NCT02741115, which is hereby incorporated by reference in its entirety.

[0196] Clinical Perspective New Aspects Circulation reports the results of the Fontan-Udenafil Exercise Longitudinal (FUEL) trial, the largest medical intervention trial in congenital heart disease. Goldberg DJ et al.: Results of the FUEL Trial. Circulation, 141(8):141:641- 651 (2020)

[0197] Circulation errata to Goldberg DJ et al.: Results of the FUEL Trial. Circulation, 141(8):141:641-651 (2020) describes the corrected MPI results of the FUEL trial, as incorporated in Example 4.

[0198] Treatment with udenafil did not result in a statistically significant increase in peak oxygen consumption, but it did result in a significant increase in peak oxygen consumption.

[0199] Treatment with udenafil resulted in statistically significant improvements in measures of exercise performance at ventilatory anaerobic threshold (VAT), work rate at VAT, ventilatory equivalent of carbon dioxide at VAT (VE / VCO2), MPI, resting diastolic blood pressure, and resting oxygen saturation.

[0200] Udenafil was well tolerated by FUEL trial subjects, with side effects limited to those already known to be associated with phosphodiesterase type 5 inhibitors.

[0201] Clinical Implications Udenafil is the first medication to be evaluated in a large Phase III clinical trial to demonstrate a quantifiable benefit on measures of exercise capacity in adolescents following Fontan palliation.

[0202] These findings suggest that treatment with udenafil may improve physiology, exercise capacity, power, VE / VCO2, MPI, cardiac output, squeezing performance, the amount of fluid that can circulate through the body in a given time, resting diastolic blood pressure and / or oxygen saturation, and performance of a single functioning ventricle in a cohort of patients with total cavopulmonary artery bypass.

[0203] Ongoing surveillance is needed to determine the effect of chronic treatment with udenafil on the long-term clinical course of survivors with single ventricle congenital heart disease.

[0204] Children born with single ventricle congenital heart disease (SVHD) require a series of staged surgical interventions to reconstruct their defective heart and ensure long-term survival. The Fontan operation is the final planned palliative procedure in this series of staged surgical interventions to reconstruct the heart and separate the systemic and pulmonary circulations by creating a bicaval-pulmonary anastomosis. Fontan F and Baudet E. Surgical repair of tricuspid atresia. Thorax. 26(3):240-248 (May 1971); and Kreutzer G, Galindez E, Bono H, De Palma C and Laura JP. An operation for the correction of tricuspid atresia. The Journal of thoracic and cardiovascular surgery. 66(4):613-621 (Oct 1973).

[0205] However, in the absence of a subpulmonary pump, the resulting Fontan circulation is characterized by passive pulmonary blood flow, chronically elevated central venous pressure, and reduced cardiac output. Gewillig M and Goldberg DJ. Failure of the fontan circulation. Heart Fail Clin. 10(1):105-116 (Jan 2014);Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail. 10(12): e004515 (Sept. 2017); Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La Gerche A and Gorenflo M. The Fontan controls circulation: who cardiac output? Interact Cardiovasc Thorac Surg. 10(3):428-433 (Mar 2010); and Goldberg DJ, Avitabile CM, McBride MG and Paridon SM. Exercise capacity in the Fontan circulation. Cardiol Young. 23(6):824-830 (Dec 2013). Fontan physiology is often well tolerated in childhood, but cardiovascular efficiency declines across adolescence and adulthood. Dennis M, Zannino D, du Plessis K, Bullock A, Disney PJS, Radford DJ, Hornung T, Grigg L, Cordina R, d'Udekem Y and Celermajer DS. Clinical Outcomes in Adolescents and Adults After the Fontan Procedure. J Am Coll Cardiol.71(9):1009-1017 (Mar 6 2018);Fernandes SM, McElhinney DB, Khairy P, Graham DA, Landzberg MJ and Rhodes J. Serial cardiopulmonary exercise testing in patients with previous Fontan surgery. Pediatr Cardiol. 31(2):175-180 (Feb 2010);Giardini A, Hager A, Pace Napoleone C and Picchio FM. Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann Thorac Surg. 85(3):818-21 (Mar 2008);Jenkins PC, Chinnock RE, Jenkins KJ, Mahle WT, Mulla N, Sharkey AM and Flanagan MF. Decreased exercise performance with age in children with hypoplastic left heart syndrome. J Pediatr. 152(4):507-512 (Apr 2008);Paridon SM, Mitchell PD, Colan SD, Williams RV, Blaufox A, Li JS, Margossian R, Mital S, Russell J, Rhodes J and Pediatric Heart Network I. A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol.52(2):99-107 (Jul 8 2008); and Atz AM, Zak V, Mahony L, Uzark K, D 'Agincourt N, Goldberg DJ, Williams RV, Breitbart RE, Colan SD, Burns KM, Margossian R, Henderson HT, Korsin R, Marino BS, Daniels K, McCrindle BW and Pediatric Heart Network I. Longitudinal Outcomes of Patients With Single Ventricle After the Fontan Procedure. J Am Coll Cardiol. 69(22):2735-2744 (Jun 6 2017). This deterioration correlates with decreased exercise capacity, overall cardiac performance, and single ventricular performance, as well as increased prevalence of heart failure symptoms, hospitalization, and mortality. Diller GP, Dimopoulos K, Okonko D, Li W, Babu-Narayan SV, Broberg CS, Johansson B, Bouzas B, Mullen MJ, Poole-Wilson PA, Francis DP and Gatzoulis MA. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation. 112(6):828-35 (Aug 9 2005);Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, Giannakoulas G, Khambadkone S, Lammers AE, Picchio FM, Gatzoulis MA and Hager A.Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J. 31(24):3073-3083 (Dec 2010);Downing TE, Allen KY, Glatz AC, Rogers LS, Ravishankar C, Rychik J, Faerber JA, Fuller S, Montenegro LM, Steven JM, Spray TL, Nicolson SC, Gaynor JW and Goldberg DJ. Long-term survival after the Fontan operation: Twenty years of experience at a single center. The Journal of thoracic and cardiovascular surgery. 154(1):243-253 e2 (Jul 2017);Khairy P, Fernandes SM, Mayer JE, Jr., Triedman JK, Walsh EP, Lock JE and Landzberg MJ. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation. 117(1):85-92 (Jan 1 2008);Pundi KN, Johnson JN, Dearani JA, Pundi KN, Li Z, Hinck CA, Dahl SH, Cannon BC, O'Leary PW, Driscoll DJ and Cetta F. 40-Year Follow-Up After the Fontan Operation: Long-Term Outcomes of 1,052 Patients. J Am Coll Cardiol.66(15):1700-1710 (Oct 13 2015);Cunningham JW, Nathan AS, Rhodes J, Shafer K, Landzberg MJ and Opotowsky AR. Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation. Am Heart J. 189:184-192 (Jul 2017);およびUdholm S, Aldweib N, Hjortdal VE and Veldtman GR. Prognostic power of cardiopulmonary exercise testing in Fontan patients: a systematic review. Open Heart. 5(1):e000812 (Jul 2018)。.

[0206] Pulmonary blood flow after the Fontan operation depends on the relationship between central venous pressure, pulmonary vascular resistance and systemic atrial pressure. This construct emphasizes the role of pulmonary vascular resistance as a modulator of pulmonary blood flow and univentricular preload, which is important for circulation efficiency. Gewillig M and Goldberg DJ. Failure of the fontan circulation. Heart Fail Clin. 10(1):105-116 (Jan 2014);Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail. 10(12): e004515 (Sept. 2017); Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La Gerche A and Gorenflo M. The Fontan controls circulation: who cardiac output? Interact Cardiovasc Thorac Surg. 10(3):428-433 (Mar 2010); and Goldberg DJ, Avitabile CM, McBride MG and Paridon SM. Exercise capacity in the Fontan circulation. Cardiol Young. 23(6):824-830 (Dec 2013). Previous reports have investigated the use of pulmonary vasodilators, including phosphodiesterase type 5 (PDE5) inhibitors, with mixed results. Agnoletti G, Gala S, Ferroni F, Bordese R, Appendini L, Pace Napoleone C and Bergamasco L.Endothelin inhibitors lower pulmonary vascular resistance and improve functional capacity in patients with Fontan circulation. The Journal of thoracic and cardiovascular surgery. 153(6): 1468-1475 (Jun 2017); Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM and Rychik J. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 123(11):1185-1193 (May 22 2011); Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sorensen KE and Sondergaard L. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo- Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation.130(23):2021-2030 (Dec 2 2014);Mori H, Park IS, Yamagishi H, Nakamura M, Ishikawa S, Takigiku K, Yasukochi S, Nakayama T, Saji T and Nakanishi T. Sildenafil reduces pulmonary vascular resistance in single ventricular physiology. Int J Cardiol. 221:122-127 (Oct 15 2016);Rhodes J, Ubeda-Tikkanen A, Clair M, Fernandes SM, Graham DA, Milliren CE, Daly KP, Mullen MP and Landzberg MJ. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 168(3):2435-2440 (Oct 3 2013);Schuering MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, Sieswerda GT, de Bruin-Bon RH, Mulder BJ and Bouma BJ. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Failure. 15(6):690-698 (June 2013); Tunks RD, Barker PC, Benjamin DK, Jr, Cohen-Wolkowiez M, Fleming GA, Laughon M, Lee JS and Hill KD. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med.15(1):28-34 (Jan 2014);Van De Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, Bogaert J, Claus P, Heidbuchel H, Gewillig M and Budts W. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 7(2):265-273 (Mar 2014);Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM and Rychik J. Impact of sildenafil on echocardiographic indices of myocardial performance after the Fontan operation. Pediatr Cardiol. 33(5):689-696 (June 2012);Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M and Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 29(13):1681-1687 (Jul 2008).

[0207] A phase I / II study of udenafil (Mezzion Pharma Co.Ltd., Seoul, Korea), a long-acting PDE5 inhibitor, has been completed in adolescents with Fontan physiology, demonstrating tolerability at all dosing regimens tested. Goldberg DJ, Zak V, Goldstein BH, Chen S, Hamstra MS, Radojewski EA, Maunsell E, Mital S, Menon SC, Schumacher KR, Payne RM, Stylianou M, Kaltman JR, deVries TM, Yeager JL, Paridon SM and Pediatric Heart Network I. Results of a phase I / II multi-center investigation of udenafil in adolescents after fontan palliation. Am Heart J. 188:42-52 (Jun 2017). The 87.5 mg twice daily dose was associated with the highest mean serum concentrations and was not associated with dose-limiting adverse events. In the Pediatric Heart Network (PHN) Fontan Udenafil Exercise Longitudinal (FUEL) trial (NCT02741115), we evaluated the effect of udenafil on exercise function and other cardiovascular and functional outcomes over a 6-month period in adolescents undergoing Fontan palliation.

[0208] method The FUEL trial was an international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil added to standard care in adolescents with SVHD undergoing Fontan palliation. The trial was supported by PHN funded by the National Heart, Lung, and Blood Institute (NHLBI) in partnership with regulatory sponsor Mezzion Pharma Co. Ltd. under Special Protocol Assessment by the Food and Drug Administration. The FUEL protocol and consent form and all subsequent amendments were approved by the DSMB, the Institutional Review Board or equivalent at each study site, and regulatory authorities in the United States, Canada, and Korea. Consent was obtained from study participants or legal guardians for those under 18 years of age. Assented were obtained from participants over 18 years of age. The trial design has been previously published. Goldberg DJ, Zak V, Goldstein BH, McCrindle BW, Menon SC, Schumacher KR, Payne RM, Rhodes J, McHugh KE, Penny DJ, Trachtenberg F, Hamstra MS, Richmond ME, Frommelt PC, Files MD, Yeager JL, Pemberton VL, Stylianou MP, Pearson GD, Paridon SM and Pediatric Heart Network I. Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. Am Heart J. 201:1-8 (Jul 2018).

[0209] Trial Group Individuals between 12 and 18 years of age (inclusive) who had undergone the Fontan procedure, had not been treated with a PDE5 inhibitor, weighed 40 kg or more, and met the minimum height requirement for cycle ergometry (132 cm or more) were eligible for enrollment. To isolate the effect of udenafil on exercise performance, patients with severe ventricular dysfunction, severe atrioventricular regurgitation, or whose previous clinical exercise test had peak oxygen consumption less than 50% of predicted for their age and sex were excluded. A complete list of inclusion and exclusion criteria is provided in Table 1 above for the study protocol.

[0210] Randomization and study procedures Enrolled participants were randomly assigned to udenafil or placebo in a 1:1 ratio in a double-blind fashion using permuted blocks and stratified by ventricular morphology (left vs. right ventricle or mixed). Randomization assignment was generated by a web-based algorithm after confirmation of trial eligibility and consent.

[0211] Baseline clinical trials completed prior to drug initiation included blood sampling to measure brain-type natriuretic peptide (BNP) levels, cardiopulmonary exercise testing (CPET) using a standardized cycle ergometer ramp protocol (previously described in children and adolescents with Fontan physiology, Sleeper LA, Anderson P, Hsu DT, Mahony L, McCrindle BW, Roth SJ, Saul JP, Williams RV, Geva T, Colan SD, Clark BJ and Pediatric Heart Network I. Design of a large cross-sectional study to facilitate future clinical trials in children with the Fontan palliation. Am Heart J. 152(3):427-433 (Sep 2006)), standardized echocardiogram, and assessment of peripheral vascular function using peripheral arterial tonometry (PAT) measured by finger cuff (EndoPAT; Itamar Medical, Israel). Participants who achieved maximal effort, defined as a respiratory exchange ratio (RER) >1.10 at peak exercise during CPET, were eligible for randomization and study drug initiation. Participants who did not achieve maximal effort were given a subsequent opportunity to repeat the exercise test within 2 weeks of the first attempt. End-of-study clinical examinations included repeated measurements of serum BNP, CPET, echocardiogram, and PAT.

[0212] Primary and Secondary Endpoints The primary objective was to determine the effect of udenafil on exercise performance in adolescents with Fontan physiology over a 6-month period. The primary outcome was the difference between groups in the change in oxygen consumption at peak exercise (peak VO2) from baseline to the 26-week visit. Secondary exercise outcomes included the difference between groups in the change in additional measures at maximal exertion, as well as the change in submaximal exercise measures at the ventilatory anaerobic threshold (VAT). All measurements of values ​​related to exercise testing were initially performed by exercise physiologists and physicians at each participating center. These were then reviewed for accuracy in a blinded fashion at each center by one of two trained reviewers in collaboration with the center's exercise team prior to completion (MGM, SMP). For both peak VO2 and VO2 at VAT, non-indexed oxygen consumption was assessed to avoid the introduction of confounds based on short-term changes in physical habits. Analyses of oxygen consumption adjusted for body weight are included in Table 5.

[0213] [Table 6]

[0214] Primary outcomes for clinical secondary objectives included between-group differences in change in myocardial performance index (MPI), an echocardiography-derived measure of systolic and diastolic ventricular function, change in log-transformed reactive hyperemia index (lnRHI), a PAT-derived measure of peripheral vascular function, and change in log-transformed serum BNP levels. Measurements of each of these secondary outcomes were performed in a core laboratory. Safety was monitored via adverse event reports collected according to a prespecified protocol of study coordinator outreach and ad hoc patient and family communication with members of the study team at each site.

[0215] statistical analysis A sample size of 200 participants per treatment group was chosen to allow for 90% power to detect a 10% mean treatment difference in the change in peak VO2 from baseline to the 26-week study with a type I error of 0.05. We assumed a baseline standard deviation of 7.235 ml / kg / min, a correlation between peak VO2 measurements of 0.33, a dropout and study non-completion rate of 10%, and 15% of participants failing to reach maximal effort at the 26-week exercise study. These assumptions were based on historical data and reflect a conservative approach to assessing within-participant correlations and failure to reach maximal effort, and analyses were performed using two-sample independent mean t-tests. The primary analysis used an intention-to-treat population to assess differences in the change in the primary outcome between treatment arms. Analysis of covariance (ANCOVA) was used to assess this difference, with ventricular morphology (left single vs. right single or mixed) and treatment group as fixed factors and baseline peak VO2 as a continuous covariate. For those without data at the 26-week visit, this value was imputed as equal to the baseline value (no change). The alpha level was set at 0.05, and two-sided tests were performed. All statistical analyses were performed using SAS statistical software 9.4 (SAS Institute, Inc., Cary, NC). Secondary analyses included participants who successfully completed the protocol and had measurable values ​​for each secondary endpoint. Secondary outcomes of continuous data points were analyzed in the manner described for the primary outcomes. To assess the generalizability of the findings in ventilatory anaerobic threshold, demographic and clinical characteristics were compared between participants with unpaired VO2 data in the VAT and those with the remainder of the cohort using Student's t-test and Fisher's exact test. Fisher's exact test was used to compare adverse events between the udenafil and placebo cohorts.

[0216] result Participants: Between July 2016 and May 2018, 1376 patients were screened at 30 sites; Figure 1B. Of these, 200 were randomly assigned to udenafil and 200 to placebo. At randomization, the mean age was 15.5 years, the mean height was 163.6 cm, and the mean weight was 58.1 kg. Sixty percent of participants were male, and 81% described their racial identity as white. Those in the placebo group were taller compared to those in the udenafil group, but other baseline characteristics were similar between groups in Table 6.

[0217] [Table 7]

[0218] Movement measurements Resting, submaximal, and maximal exercise measurements are shown in Table 2. Maximal exercise data were available for all participants at baseline and for 379 participants (189 in the udenafil group, 190 in the placebo group) at the 26-week study. Reasons for absence of data at the 26-week study included patient dropout or errors in data capture (n=14) and participants' inability to generate an RER of 1.10 or greater (n=7). There were no differences in the change from baseline to the 26-week study in resting heart rate, respiratory rate, or systolic blood pressure between the udenafil and placebo groups. Peak minute ventilation at baseline (before drug exposure) was greater in the placebo group, but there were no differences in the change in minute ventilation between the groups. There was a small but statistically significant increase in resting oxygen saturation and a small but statistically significant decrease in diastolic blood pressure in the udenafil group.

[0219] Analysis at maximal exercise demonstrated an increase of 44 mL / min (2.8%) in peak VO2 in the udenafil group compared to a decrease of 3.7 mL / min (-0.2%) in the placebo group, although the difference did not reach statistical significance; Figure 2A-2B, p=0.071. Metabolic data were available to calculate VO2 at VAT for 351 participants; 170 in the udenafil group and 181 in the placebo group. No differences were noted in demographic or clinical characteristics at baseline for this subgroup compared to the larger cohort; Table 7. For those with paired VO2 at VAT data, there was a statistically significant improvement of 29.7 mL / min (2.85%) in the udenafil group compared to a decrease of 9 mL / min (-0.8%) in the placebo group; Figure 3A-3B, p=0.023. The ventilatory equivalent of carbon dioxide (VE / VCO2) measured during VAT was significantly reduced (improved ventilatory efficiency) to 0.8 in the udenafil group compared to 0.05 in the placebo group (p = 0.0114), and at the same time the power output was significantly improved to 3.5 watts (5.2%) in the udenafil group compared to 0.31 watts (0.5%) in the placebo group (Figure 4A-4B, p = 0.029).

[0220] [Table 8]

[0221] Secondary Objectives Paired echocardiographic data for measurements of MPI were available for 250 participants (63%); 122 in the udenafil group and 128 in the placebo group. Table 3. A statistically significant change (decrease indicates improvement) was observed in MPI in the udenafil-treated group (-0.02 decrease, improvement) compared with the placebo group (+0.01 increase, no improvement) (p=0.028). Paired PAT-derived vascular function data were available for 328 participants (81%); 163 in the udenafil group and 165 in the placebo group. No significant improvement was observed in lnRHI in both the udenafil and placebo groups (0.07 vs. 0.05, p=0.59). Paired measurements of serum BNP levels were available for 378 participants (95%); 187 in the udenafil group and 191 in the placebo group. The change in log serum BNP levels did not differ between groups (p=0.18).

[0222] Safety and Tolerability Udenafil and placebo were well tolerated by study participants. There were no deaths in the study cohort. A total of 24 participants (6%); 14 in the udenafil group and 10 in the placebo group experienced serious adverse events. There were three events in the udenafil group and two in the placebo group that were considered to have a possible, probable, or definite relationship to the study drug. Those occurring in the udenafil group included unilateral retinal arterial and venous thrombosis, transient lower limb diplegia, and transient dyspnea. Frequent nonserious adverse events considered to have a possible, probable, or definite relationship to the study drug are listed in Table 4. Headache, facial flushing, abdominal pain, epistaxis, and erections (male participants) were more common in the udenafil group. No episodes of priapism were reported. All other adverse events occurred with similar frequency between groups.

[0223] Consideration The FUEL trial was a phase III clinical trial of udenafil in children with SVHD who underwent the Fontan procedure. Although the relative improvement in peak VO2 in the udenafil group did not reach statistical significance when compared between treatment arms, treatment with udenafil led to a statistically significant improvement in the prespecified secondary outcome measure, submaximal exercise. Participants randomized to udenafil had superior increases in oxygen consumption, work rate, ventilatory efficiency at anaerobic threshold, and myocardial performance index. There was no relative improvement in the PAT-derived reactive hyperemia index. Overall, udenafil was well tolerated with few serious adverse events and side effects limited to those known to be associated with PDE5 inhibitor therapy.Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM and Rychik J. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 123(11):1185-1193 (May 22 2011);Goldberg DJ, Zak V, Goldstein BH, McCrindle BW, Menon SC, Schumacher KR, Payne RM, Rhodes J, McHugh KE, Penny DJ, Trachtenberg F, Hamstra MS, Richmond ME, Frommelt PC, Files MD, Yeager JL, Pemberton VL, Stylianou MP, Pearson GD, Paridon SM and Pediatric Heart Network I. Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. Am Heart J. 201:1-8 (Jul 2018);およびChang HJ, Song S, Chang SA, Kim HK, Jung HO, Choi JH, Lee JS, Kim KH, Jeong JO, Lee JH and Kim DK. Efficacy and Safety of Udenafil for the Treatment of Pulmonary Arterial Hypertension: a Placebo-controlled, Double-blind, Phase IIb Clinical Trial. Clin Ther. 41(8):1499-1507 (Aug 2019)。

[0224] Although the Fontan operation and its refinements have led to the survival of many patients with otherwise end-stage SVHD, the circulation created by the procedure has inherent physiological defects: central venous pressure is chronically elevated and cardiac output is chronically depressed. Gewillig M and Goldberg DJ. Failure of the fontan circulation. Heart Fail Clin. 10(1):105- 116 (Jan 2014); Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail. 10(12): e004515 (Sept. 2017); and Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La Gerche A and Gorenflo M. The Fontan circulation: who cardiac controls output? Interact Cardiovasc Thorac Surg. 10(3):428-433 (Mar 2010). The fundamental limitations of cardiovascular efficiency in the Fontan circulation are many and usually include abnormalities in pulmonary vascular resistance, single ventricular diastolic function, systemic and pulmonary endothelial dysfunction, and pathological vascular remodeling. Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail. 10(12): e004515 (Sept. 2017);Averin K, Hirsch R, Seckeler MD, Whiteside W, Beekman RH, 3rd and Goldstein BH.Diagnosis of occult diastolic dysfunction late after the Fontan procedure using a rapid volume expansion technique. Heart. 102(14):1109-1114 (Jul 15 2016);Goldstein BH, Connor CE, Gooding L and Rocchini AP. Relation of systemic venous return, pulmonary vascular resistance, and diastolic dysfunction to exercise capacity in patients with single ventricle receiving fontan palliation. Am J Cardiol. 105(8):1169-1175 (Apr 15 2010);Hays BS, Baker M, Laib A, Tan W, Udholm S, Goldstein BH, Sanders SP, Opotowsky AR and Veldtman GR. Histopathological abnormalities in the central arteries and veins of Fontan subjects. Heart. 104(4):324-331 (Feb 2018);Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE and Redington AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation. 107(25):3204-3208 (Jul 1 2003);Mitchell MB, Campbell DN, Ivy D, Boucek MM, Sondheimer HM, Pietra B, Das BB and Coll JR.Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg. 128(5):693-702 (Nov 2004); and Sarkola T, Jaeggi E, Slorach C, Hui W, Bradley T and Redington AN. Assessment of vascular remodeling after the Fontan procedure using a novel very high resolution ultrasound method: arterial wall thinning and venous thickening in late follow-up. Heart Vessels. 28(1):66-75 (Jan 2013). .

[0225] Although each pathological feature of the circulation may represent a potential therapeutic target, pharmacotherapy with agents designed to reduce pulmonary vascular resistance makes intuitive sense given its broad tolerability, its efficacy for treating pulmonary hypertension, and the unique role of pulmonary vascular resistance as a modulator of cardiac output post-Fontan. Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail. 10(12): e004515 (Sept. 2017).

[0226] Previous studies with other pulmonary vasodilators in those with the Fontan circulation have been equivocal. Agnoletti G, Gala S, Ferroni F, Bordese R, Appendini L, Pace Napoleone C and Bergamasco L. Endothelin inhibitors lower pulmonary vascular resistance and improve functional capacity in patients with Fontan circulation. J Thorac Cardiovasc Surg. 153(6):1468- 1475 (Jun 2017);Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM and Rychik J. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo- controlled, crossover trial. Circulation. 123(11):1185-1193 (May 22 2011);Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sorensen KE and Sondergaard L. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study.Circulation. 130(23):2021-2030 (Dec 2 2014);Mori H, Park IS, Yamagishi H, Nakamura M, Ishikawa S, Takigiku K, Yasukochi S, Nakayama T, Saji T and Nakanishi T. Sildenafil reduces pulmonary vascular resistance in single ventricular physiology. Int J Cardiol. 221:122-127 (Oct 15 2016);Rhodes J, Ubeda-Tikkanen A, Clair M, Fernandes SM, Graham DA, Milliren CE, Daly KP, Mullen MP and Landzberg MJ. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 168(3):2435-2440 (Oct 3 2013);Schuering MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, Sieswerda GT, de Bruin-Bon RH, Mulder BJ and Bouma BJ. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Failure. 15(6):690-698 (June 2013); Tunks RD, Barker PC, Benjamin DK, Jr, Cohen-Wolkowiez M, Fleming GA, Laughon M, Lee JS and Hill KD. Sildenafil exposure and hemodynamic effect after Fontan surgery.Pediatr Crit Care Med. 15(1):28-34 (Jan 2014);Van De Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, Bogaert J, Claus P, Heidbuchel H, Gewillig M and Budts W. Sildenafil improves exercise Hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 7(2):265-273 (Mar 2014);Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM and Rychik J. Impact of sildenafil on echocardiographic indices of myocardial performance after the Fontan operation. Pediatr Cardiol. 33(5):689-696 (Jun 2012); and Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M and Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 29(13):1681-1687 (Jul 2008). Numerous small single-center studies across various classes of pulmonary vasodilators have demonstrated acute improvements after a single dose, but these sustained effects or chronic use have not been examined. Rhodes J, Ubeda-Tikkanen A, Clair M, Fernandes SM, Graham DA, Milliren CE, Daly KP, Mullen MP and Landzberg MJ.Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 168(3):2435-2440 (Oct 3 2013);Tunks RD, Barker PC, Benjamin DK, Jr, Cohen-Wolkowiez M, Fleming GA, Laughon M, Lee JS and Hill KD. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med. 15(1):28-34 (Jan 2014);Van De Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, Bogaert J, Claus P, Heidbuchel H, Gewillig M and Budts W. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 7(2):265-273 (Mar 2014); Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M and Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Your Heart J.29(13):1681-1687 (Jul 2008). After Fontan, there have been two medium-sized studies evaluating the use of endothelin receptor antagonists in adolescents and adults, but these two trials demonstrated conflicting results, and no phase I trials were performed in this cohort. Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sorensen KE and Sondergaard L. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation. 130(23):2021-2030 (Dec 2 2014); and Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, Sieswerda GT, de Bruin-Bon RH, Mulder BJ and Bouma BJ. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart fail. 15(6):690-698 (Jun 2013). Moreover, in studies suggesting a benefit, this benefit was associated with a decrease in hemoglobin levels, a side effect that likely offsets the drug's putative benefit. Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sorensen KE and Sondergaard L.Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation. 130(23):2021-2030 (Dec 2 2014). The FUEL trial is the first large-scale multicenter study to suggest physiological benefits associated with the use of a specific pulmonary vasodilator at doses determined by a phase I clinical trial in adolescents with SVHD after Fontan palliation.

[0227] The challenges of living with Fontan physiology have been well documented through assessments of exercise performance: adolescents with Fontan physiology have reduced exercise capacity compared with their healthy peers, a difference that accentuates over time and is associated with increased rates of hospitalization and heart failure symptoms. Fernandes SM, McElhinney DB, Khairy P, Graham DA, Landzberg MJ and Rhodes J. Serial cardiopulmonary exercise testing in patients with previous Fontan surgery. Pediatr Cardiol. 31(2):175-180 (Feb 2010);Giardini A, Hager A, Pace Napoleone C and Picchio FM. Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann Thorac Surg. 85(3):818-21 (Mar 2008);Jenkins PC, Chinnock RE, Jenkins KJ, Mahle WT, Mulla N, Sharkey AM and Flanagan MF. Decrease exercise performance with age in children with hypoplastic left heart syndrome. J Pediatr. 152(4):507-512 (Apr 2008);Paridon SM, Mitchell PD, Colan SD, Williams RV, Blaufox A, Li JS, Margossian R, Mital S, Russell J, Rhodes J and Pediatric Heart Network I. A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol.52(2):99-107 (Jul 8 2008);Atz AM, Zak V, Mahony L, Uzark K, D'Agincourt N, Goldberg DJ, Williams RV, Breitbart RE, Colan SD, Burns KM, Margossian R, Henderson HT, Korsin R, Marino BS, Daniels K, McCrindle BW and Pediatric Heart Network I. Longitudinal Outcomes of Patients With Single Ventricle After the Fontan Procedure. J Am Coll Cardiol. 69(22):2735-2744 (Jun 6 2017);Diller GP, Dimopoulos K, Okonko D, Li W, Babu-Narayan SV, Broberg CS, Johansson B, Bouzas B, Mullen MJ, Poole-Wilson PA, Francis DP and Gatzoulis MA. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation. 112(6):828-35 (Aug 9 2005);Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, Giannakoulas G, Khambadkone S, Lammers AE, Picchio FM, Gatzoulis MA and Hager A. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients.Eur Heart J. 31(24):3073-3083 (Dec 2010);Cunningham JW, Nathan AS, Rhodes J, Shafer K, Landzberg MJ and Opotowsky AR. Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation. Am Heart J. 189:184-192 (Jul 2017);and Udholm S, Aldweib N, Hjortdal VE and Veldtman GR. Prognostic power of cardiopulmonary exercise testing in Fontan patients: a systematic review. Open Heart. 5(1):e000812 (Jul 2018). Exercise capacity below 50% predicted for age and sex is approximately the threshold at which circulation-related morbidity becomes common, typically during the third decade but may occur earlier. Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, Giannakoulas G, Khambadkone S, Lammers AE, Picchio FM, Gatzoulis MA and Hager A. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J.31(24):3073-3083 (Dec 2010). The ability to improve exercise capacity, as a marker of improved more general circulatory function, is likely important to the long-term health of those who have had the Fontan procedure. This trial suggests that udenafil may help improve important measures of exercise capacity after pharmacological intervention in Fontan patients.

[0228] The FUEL trial was powered to detect changes in peak VO2 because it is relatively easy to measure and peak VO2 has been used in previous trials as an accepted surrogate for cardiac events. Dallaire F, Wald RM and Marelli A. The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot. Pediatr Cardiol. 38(6):1097- 1105 (Aug 2017);Mancini D, LeJemtel T and Aaronson K. Peak VO(2): a simple yet enduring standard. Circulation. 101(10):1080-1082 (Mar 2000);Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, Foldes G, Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD and Ponikowski P Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol.51(2):103-112 (Jan 15 2008); and Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E and Trial R. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 309(12):1268-1277 (Mar 27 2013). However, while peak VO2 may be a useful surrogate for many cardiovascular pathologies, it may be less relevant as an endpoint after the Fontan procedure. In this unique physiology, central venous pressure, rather than right ventricular contraction, is the primary driver of transpulmonary blood flow and therefore cardiac output. Gewillig M and Goldberg DJ. Failure of the fontan circulation. Heart Fail Clin. 10(1):105-116 (Jan 2014);Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR and Borlaug BA. Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. Circ Heart Fail.10(12): e004515 (Sept. 2017);Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, La Gerche A and Gorenflo M. The Fontan circulation: who controls cardiac output? Interact Cardiovasc Thorac Surg. 10(3):428-433 (Mar 2010);and Goldberg DJ, Avitabile CM, McBride MG and Paridon SM. Exercise capacity in the Fontan circulation. Cardiol Young. 23(6):824-830 (Dec 2013). As cardiac output demands increase with exertion, central venous pressure in the Fontan circulation must rise to meet those demands, eventually reaching a critical upper limit beyond which it cannot rise any further. Navaratnam D, Fitzsimmons S, Grocott M, Rossiter HB, Emmanuel Y, Diller GP, Gordon-Walker T, Jack S, Sheron N, Pappachan J, Pratap JN, Vettukattil JJ and Veldtman G. Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation. Am J Cardiol. 117(10):1667-1671 (May 15, 2016). At submaximal exertion, the increase in central venous pressure does not reach this physiological upper limit, and therefore outcomes at this level of exercise may be more sensitive to pharmacological manipulation of the pulmonary vasculature. This is demonstrated by the relatively higher ratios of both oxygen consumption and work rate at anaerobic threshold compared to peak exercise, and is distinct from physiology involving the subpulmonary ventricles, where changes in central venous pressure during exercise are minimal, and improvements or decreases in VO2 at VAT and peak VO2 tend to be comparable.

[0229] Despite the importance of the findings reported here, this trial has limitations. First, to minimize participant burden, the study design did not include detailed hemodynamic measurements, such as those that can be obtained with cardiac magnetic resonance imaging or invasive catheterization studies. Furthermore, evaluation of PAT outcomes did not show an advantage of udenafil over placebo. Further validation of the multiple measures provided by these studies was not performed in this initial analysis but will be the subject of future analyses. Finally, the duration of the FUEL trial precluded long-term evaluation of safety, which is being addressed by the ongoing FUEL open-label extension study.

[0230] Treatment with udenafil (87.5 mg twice daily) in addition to standard therapy was not associated with a statistically significant improvement in peak exercise oxygen consumption, but demonstrated statistically significant improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. As the first large-scale, multicenter, placebo-controlled, randomized trial to demonstrate a measurable physiological benefit for Fontan patients, the FUEL trial represents a milestone in nearly 50 years of Fontan circulation experience and serves as a model for how public-private partnerships can advance the science in congenital heart disease. Further studies are warranted to determine whether udenafil selectively benefits subpopulations within a larger cohort of patients presenting with SVHD and to evaluate the long-term tolerability and safety of the treatment.

[0231] The disclosure set forth in this Example 2 is hereby incorporated by reference in its entirety as if fully set forth herein.

[0232] [Example 3] Formulation of udenafil tablets An exemplary formulation of a tablet containing 87.5 mg of udenafil is detailed in Table 11. The udenafil formulations reported in Table 11 were used in Fontan patients enrolled in the FUEL trial discussed in Examples 1 and 2 above.

[0233] [Table 9]

[0234] [Example 4] Effect of udenafil on echocardiographic indices of myocardial performance in SVHD subjects with Fontan palliation The purpose of the FUEL trial is to determine the effect of udenafil on echocardiographic measures of myocardial performance in adolescents aged approximately 12 to approximately 18 years with functional single ventricle physiology following the Fontan procedure. The FUEL trial was a randomized, double-blind, placebo-controlled trial conducted at 30 different sites in the United States (26), Canada (2), and South Korea (2) in adolescents aged approximately 12 to approximately 18 years following the Fontan procedure. Fontan patients were randomized to receive placebo or udenafil (87.5 mg twice daily) for 26 weeks.

[0235] Each subject underwent an echocardiogram at the start and at the end of the 26th week. Paired echocardiogram data for measurements of MPI were available for 250 participants (63%); 122 in the udenafil group and 128 in the placebo group. Table 3. A statistically significant change was noted in MPI in the udenafil-treated treatment group (-0.02 decrease, improvement) compared to the placebo group (+0.01 increase, no improvement) (p=0.028). Changes in MPI were determined by velocities obtained from blood pool Doppler assessment of the inflow and outflow tracts of the single functioning dominant ventricle. All measurements were performed by echocardiography in the core laboratory at Children's Hospital of Wisconsin. Subjects treated with udenafil demonstrated a statistically significant improvement (decrease indicates improvement) in their myocardial performance index (MPI) compared to subjects taking placebo over the same period, p=0.028.

[0236] These data demonstrate an improvement in MPI in the udenafil group compared to the placebo group (-0.02 vs. +0.01, p=0.028). Myocardial performance is an important factor in the long-term health of those with SVHD, including those with SVHD who have undergone the Fontan procedure, and the improvement in this aspect of physiological function complements the improvements noted in exercise performance, suggesting that the benefits of treatment with udenafil may be multifactorial.

[0237] U.S. Patent Application No. 14 / 788,211, U.S. Patent Publication No. 2019 / 0030037, U.S. Patent No. 10,137,128, and U.S. Patent Application No. 15 / 887,523, U.S. Patent Publication No. 2018 / 0169103, U.S. Patent No. 10,653,698, Goldberg, DJ et al.: Results of the FUEL Trial. Circulation. 141:641-651 (February 25, 2020), and Goldberg, DJ et al.: Correction to: Results of the FUEL Trial. Circulation. 142:e31 (July, 14, All disclosures, including all patents, patent documents, articles, abstracts, errata, and publications referred to or cited in this specification, including the entire disclosures of ... are incorporated by reference in their entirety as if each was individually and fully incorporated and set forth herein.

[0238] In the event of a conflict with any related prior-filed application listed under "Related Applications," this specification, including definitions, shall control.

[0239] Various improvements and modifications to this invention will become apparent to those skilled in the art without departing from the scope and spirit of the invention. Illustrated embodiments and examples are provided by way of example only and are not intended to limit the scope of the invention, which is limited only by the claims set forth below.

[0240] [Example 5] This Example 5 demonstrates the efficacy of udenafil for the sub-super Fontan population with baseline peak or max VO2 less than 80% of predicted, the efficacy of secondary points of udenafil for both sub-super Fontan and super Fontan patients, the importance of VO2 at VAT in all Fontan patients, including super Fontan patients and the sub-super Fontan population with baseline peak VO2 greater than or equal to 80% of predicted, and confirmation of the FUEL OLE trial clinical benefit of treating the Fontan population with udenafil.

[0241] (a) Peak V for sub-super Fontan patients with baseline percent predicted peak VO2 less than 80% O2 The following demonstrates that the Fontan population with baseline peak VO2 <80% of predicted, representing 75% of the total enrolled population in the FUEL trial, is an appropriate population to analyze the drug effect of udenafil at peak exercise to improve exercise capacity in Fontan patients, a rare pediatric population with significant, life-threatening unmet need.

[0242] At the start of the FUEL trial, it had not yet been established in the scientific community that a subset of the Fontan population, so-called “super Fontan” patients, could reach peak exercise levels at or near normal levels for those with biventricular (normal) hearts. It was not until the FUEL trial neared completion of enrollment in June 2018 that the concept of “super Fontan,” defined as those with a peak VO2 of 80% or greater than predicted, began to emerge in the medical literature. See Cordina 2018, Powell 2019, and Weinrab 2020. The validity of this super Fontan subset, or even its existence, was essentially unknown during the clinical trial design of the FUEL trial and could not have been predicted at the time the FUEL trial was designed and presented to the FDA for review and agreement.

[0243] In parallel with the emergence of an understanding of super-Fontan patients, there has been an increased understanding of the physiological upper limit of peak exercise in the Fontan circulation. When super-Fontan patients reach their peak level of exercise, central venous pressure, the driver of cardiac output, is at a near-maximal physiological value and therefore cannot be meaningfully increased further (Goldberg 2021) and (Navaratnam 2016). This physiological upper limit of central venous pressure is thought to limit the ability to further increase peak exercise in this population. However, despite this limitation in the ability to improve peak exercise, an increase in exercise at the ventilatory anaerobic threshold ("VAT") is unexpectedly realized for super-Fontan patients, given that the ventilatory anaerobic threshold occurs below the physiological upper limit of central venous pressure.

[0244] In light of the clinical justification for this subgroup analysis presented above, the response of individual subjects to udenafil treatment depended, to some extent, on their peak or maximum exercise capacity at the time of trial entry. A fixed factor analysis of covariance for treatment group (udenafil vs. placebo) was performed for baseline peak exercise capacity subsets (subgroups of percent predicted peak VO2 below 80% vs. ≥80%; cut points defined in the Fontan Medical Literature) and the interaction of treatment group by subset. This analysis was performed for peak or maximum VO2, as well as measures of exercise at ventilatory anaerobic threshold ("VAT") and myocardial performance index (MPI). The results are shown in Table 1.

[0245] [Table 10]

[0246] ANCOVA analysis with fixed factors confirmed a significant interaction between treatment group and baseline peak exercise capacity subsets for the outcome measure of peak VO2 (p=0.037), but did not demonstrate a significant interaction between treatment group and subsets for exercise outcomes at ventilatory anaerobic threshold (all p's ≥0.58) and MPI (p=0.17). These results may be considered as confirmation that baseline peak exercise capacity significantly influences drug treatment effects for peak or max VO2, whereas baseline exercise capacity does not significantly influence drug treatment effects on other (secondary) outcome measures. Taken together, these results support the emerging understanding of Fontan physiology first published in the medical literature in 2018 and clarify the detrimental impact (e.g. diluting the trial cohort) of including Fontan patients with baseline percent predicted peak VO2 ≥80% on the primary outcome of peak or max VO2 in the FUEL trial.

[0247] (b) Evidence of clinical effectiveness In the FUEL trial, the p-value for the improvement in peak VO2, the primary outcome measure, was 0.092, a statistically minor step but still effective. Given the new scientific knowledge of Fontan physiology since the FUEL trial design (e.g., "super Fontan" and ceiling effects), and confirmation of that understanding in the above analysis, udenafil was statistically significant for sub-super Fontan patients with baseline percent predicted peak VO2 below 80%. In fact, the analysis accurately captures the population that would have been prospectively studied in the FUEL trial if there had been new medical knowledge during the trial design (e.g., with the addition of trial exclusion criteria for baseline peak VO2 above 80%). Importantly, this subgroup analysis incorporates Fontan patients with reduced peak exercise function, precisely those at high risk for short-term adverse outcomes including death, transplantation, or hospitalization for heart failure (Udholm 2018; Giardini 2007; Diller 2010; Fernandes 2011, Ohuchi 2015). It should be noted that the overall sample size for this subgroup analysis was n=301.

[0248] As shown in Table 2, subgroup analysis of those with a baseline percent predicted peak VO2 of less than 80% demonstrates a significant improvement in peak or max VO2. This improvement in peak or max VO2 is consistent with the statistically significant improvements shown for both the ITT cohort and subgroup analyses in all secondary outcome measures, including exercise at VAT and the primary outcome of ventricular function, MPI. These submaximal findings are predicted based on the novel analysis presented above, with improvements at VAT seen regardless of baseline peak exercise capacity (e.g., even when including "super Fontan" patients in the ITT cohort).

[0249] [Table 11]

[0250] While the benefit of udenafil for sub-super Fontan patients with a peak or max VO2 less than 80% of predicted at baseline was apparent, the results for super Fontan patients with a peak or max VO2 greater than or equal to 80% of predicted appeared to be negative. Indeed, the 26-week change in peak or max VO2 in this small subgroup (n=77) did not reveal a significant udenafil treatment effect (Table 1, p=0.32). The emergence of a slightly negative treatment effect of udenafil in this super Fontan subgroup was not statistically significant, in part reflecting the small sample size, and would not have been expected to become significant, even if adequately powered, since all secondary exercise measures demonstrated a positive udenafil treatment effect across the entire study population. This discussion continues in the following column in relation to Figure 6.

[0251] (c) Clinical significance of udenafil treatment effect in intention-to-treat and post-hoc subpopulation analyses of patients with baseline peak VO2 less than 80% of predicted There is recent literature relating changes in exercise function (peak VO2, mL / kg / min) to short- and mid-term risk of death and heart transplant in Fontan patients (Cunningham, 2017 and Egbe, 2017). The Cunningham and Egbe studies provide strong support that FUEL outcomes (peak VO2, mL / kg / min) are highly clinically significant, unexpected, and valid.

[0252] (1) Clinical significance: Change in peak VO2 (mL / kg / min) in the Fontan population In a 2017 study from Boston Children's Hospital, Cunningham and colleagues examined the impact of change in peak VO2 on short-term clinical outcomes in 130 adolescent and young adult Fontan patients (mean age 26.8 ± 9.4 years) in paired cardiopulmonary exercise testing (CPET) studies separated by 1.4 ± 0.5 years. When change in peak VO2 was assessed as a continuous variable, higher peak VO2 (mL / kg / min) at the second CPET was significantly associated with a reduced short-term risk of death or transplant. Notably, a 1 mL / kg / min increase in peak VO2 was associated with a HR of 0.79 (95% CI 0.68 to 0.92, p = 0.004) for death or transplant. Furthermore, for every 10% decline in peak VO2, the risk of death or transplant doubled (HR 1.96, 95% CI 1.2 to 3.1, p = 0.004). When peak VO2 was assessed as a binary outcome, as shown in Figure 8 (increased VO2 [blue series] vs. stable / decreased VO2 [red series]), any decline in peak VO2 was associated with a significantly increased short-term risk of a) death or transplant (p=0.027), b) death, transplant, or heart failure hospitalization (p=0.024), and c) a near-significant risk of death, transplant, or non-elective cardiovascular hospitalization (p=0.14).

[0253] Additionally, (Cunningham (2017) evaluated CPET performance stratified by subsequent primary clinical outcome of death or transplant. See Figure 9. Fontan survivors (grey) showed increases in % predicted peak VO2 (left) and % change in peak VO2 (right) between CPET studies, while Fontan patients (black) who subsequently met the primary clinical outcome showed declines in both exercise measures.

[0254] Egbe et al (2017) investigated the prognostic value of serial CPET examinations in young adults with a prior Fontan procedure. In this important study from the Mayo Clinic, including 145 Fontan patients with a mean age of 24 ± 3 years, the investigators evaluated CPET examinations separated by 3.8 ± 0.3 years. Adverse cardiovascular events occurred in 37% of patients during a medium-term follow-up of 8 ± 3 years. A number of risk factors for adverse cardiovascular events were considered. Figure 10 shows freedom from adverse cardiovascular events stratified by annual decline in predicted peak VO2% of ≥ 3% (blue) or < 3% (red). The only predictor of 5-year risk of adverse cardiovascular events was a decline in predicted peak VO2% of ≥ 3% per year (p = 0.03).

[0255] In the intent-to-treat (ITT) analysis of the FUEL trial without imputation of missing data, in Figure 11, 46% (n=86) of udenafil patients showed an increase in peak VO2, while only 36% (n=68) of placebo patients showed an increase in peak VO2. This difference was just short of statistical significance (p=0.075) and corresponds to a number needed to treat (NNT) of 10, which means that 10 patients would need to be treated with udenafil for one patient to experience an increase in peak VO2. Alternatively, considering the outcome data provided by the Cunningham study, NNT10 means that 10 patients would need to be treated with udenafil for one patient to show a substantial reduction in the short-term risk of death or transplant.

[0256] In a post-hoc subgroup analysis (excluding patients with a baseline peak VO2 ≥ 80% of predicted) of the FUEL trial in Figure 12, 50% (n = 75) of udenafil patients showed an increase in peak VO2, while only 38% (n = 57) of placebo patients showed an increase in peak VO2. This difference was statistically significant (p = 0.037) and corresponds to a number needed to treat (NNT) of 8.2, meaning that approximately 8 patients would need to be treated with udenafil for one patient to show an increase in peak VO2. Considering the outcome data by Cunningham et al., approximately 8 patients would need to be treated with udenafil for one patient to show a substantial reduction in the short-term risk of death or transplant.

[0257] Given the concerns expressed at the Late Cycle Meeting about the possibility of a negative udenafil treatment effect in the Super Fontan cohort, we also performed this same analysis on the post hoc subgroup of patients with a baseline peak VO2 of 80% or greater than predicted in the FUEL trial. See Figure 13. We found that a comparable low percentage of patients, 28-29% of each treatment group, showed positive changes, while a comparable high percentage of patients, 71-72% of each treatment group, showed negative changes, with no difference between treatment arms (p>0.99). These findings are consistent with the results of the ANCOVA with fixed effects analysis in which the baseline peak VO2 subgroup had a significant interaction with treatment group (e.g., high baseline exercise capacity precluded any further benefit to the drug). More importantly, it is important to recognize that in this Super Fontan subgroup, udenafil treatment does not appear to have a significant short-term effect (beneficial or detrimental) on the outcome measure of peak VO2.

[0258] We then show in Figure 14 the % change in peak VO2 over the 26-week FUEL trial for both the ITT cohort (left) and the post-hoc subgroup (excluding patients with a baseline peak VO2 ≥ 80% of predicted, right). In the ITT analysis, both groups show a negative % change in peak VO2, although to a much lesser extent in the udenafil treatment group, with no statistical difference between the groups (p = 0.072). However, in the post-hoc subgroup analysis, the mean effect on peak VO2 in the udenafil group is positive, while the placebo group still shows a deterioration. This difference is statistically significant (p = 0.037). Given the findings of the Cunningham study, our data allow us to estimate that udenafil is associated with a reduced short-term risk of death or transplant for Fontan patients in the post-hoc subgroup analysis.

[0259] Here, Figure 15 shows the annual change in predicted peak VO2% as determined by doubling the change during the 6-month FUEL trial for the ITT cohort (left) and for the post hoc subgroup (excluding patients with a baseline peak VO2 ≥ 80% of predicted, right). Converting the 6-month change in FUEL to an annualized rate facilitates direct comparison with the Fontan cohort by Egbe. In the ITT analysis, both groups show a decrease in predicted peak VO2% although only the placebo group exceeds the threshold of a 3% annual decline associated with an increased 5-year risk of adverse cardiovascular events according to Egbe et al. This difference is not statistically significant (p = 0.077). However, in the post hoc subgroup analysis, the udenafil group shows an increase in predicted peak VO2% while the placebo group still shows a decline. This difference is statistically significant (p = 0.009). Moreover, only the placebo group exceeded the threshold of a 3% annual decline that is associated with an increased 5-year risk of adverse cardiovascular events (Egbe 2017).

[0260] Finally, in the absence of existing pharmacological therapies for the treatment of SVHD patients after Fontan palliation, it is prudent to compare the treatment effect of FUEL with non-pharmacological treatment options aimed at improving exercise capacity in this population. Although there is little, physical exercise training or cardiac rehabilitation is the most reasonable non-pharmacological treatment with available evidence available for review. Recently, Scheffers et al. 2021 undertook a systematic review of 16 studies reported in 22 publications including 264 Fontan patients with a mean age range of 8.7-31 years. In this systematic review, the authors reported a significant increase in peak VO2 after training in only 9 studies (56%), with a mean increase of +1.72 ml / kg / min for studies that demonstrated benefit. Of note, this reported increase does not reflect a placebo-adjusted treatment effect, but rather is simply the mean increase in patients who underwent exercise training. However, when all studies shown in Figure 16 were included in the calculation of the change in peak VO2, the mean increase was only slightly greater than 0 ml / kg / min. Given the continued presence of equipoise surrounding physical training as a treatment for maintaining or improving motor skills in Fontan patients, the Fontan Fitness Intervention Trial (F-FIT), a randomized, multicenter, controlled study of adolescent and adult Fontan patients, is currently ongoing in Australia (Tran 2022).

[0261] This review of recent relevant Fontan literature relating changes in exercise function (peak VO2, mL / kg / min) to the short-term and mid-term risk of adverse clinical outcomes (including death and heart transplant) is relevant to the interpretation of the results of the primary analysis and post-hoc subgroup analyses of the FUEL trial. These data and analyses provide strong support that the FUEL outcomes (peak VO2, mL / kg / min) are highly clinically significant, unexpected, and plausible. Furthermore, in the absence of available pharmacological therapy indicated for treatment of the Fontan circulation, alternative therapies need to be compared. Physical training (cardiac rehabilitation) has been repeatedly tried in the Fontan population, where the benefits gained are only evident about half the time and the overall effect on peak VO2 is negligible across the entirety of the analyzed cohort. Finally, the short-term nature of these risks, including death and transplant, suggests the real-time need for effective treatment options in the Fontan population. Delays in the availability of effective treatment options each year inevitably result in the loss of a large cohort of Fontan patients, leading to ongoing risk of mortality or heart transplant.

[0262] (d) The importance of VO2 during VAT in the clinical management of the Fontan population, including super-Fontan patients Peak VO2 is an important marker of overall cardiovascular health and a predictor of adverse cardiac events, but is rarely achieved in patients' daily lives. VO2 at VAT, on the other hand, is the upper level of sustained physical activity and sets the limit at which an individual patient can perform daily physical activity. This criterion is the point at which the metabolic demands of the exercising muscles during incremental physical activity exceed the cardiovascular system's ability to maintain sufficient blood flow for oxygen delivery, thereby converting metabolism from aerobic to anaerobic metabolism. In healthy teenagers and children, this point usually occurs at approximately 55-60% of the subject's maximum VO2 and is the limit of physical activity that can be continued indefinitely. In the FUEL trial, treatment with udenafil resulted in a robust increase in VO2 at VAT compared with placebo in the entire intention-to-treat population and in the analysis of Super Fontan patients.

[0263] The clinical relevance of this finding is highly significant. Individuals rarely, if ever, function near their maximum VO2 during their daily activities. Thus, while peak VO2 is an important marker of overall cardiovascular health and a well-described predictor of adverse cardiac events, it has limited impact on how well patients feel or function in their daily lives. On the other hand, VO2 at VAT sets the limits within which an individual patient needs to function on a daily basis. These limits determine the capacity for daily activities, including work, school, and recreation. Any improvement in VO2 at VAT necessarily results in improved tolerance of these daily activities.

[0264] VO2 at VAT is a highly clinically relevant endpoint, but can be challenging to obtain. To measure VAT accurately and precisely, respiratory rate and tidal volume must be consistent. In clinical practice, erratic breathing at the onset of anaerobic metabolism precludes accurate assessment in approximately 15%-20% of exercise trials performed. This measurement difficulty is of particular concern when designing clinical trials with VO2 at VAT as an endpoint, as sample size calculations must be larger to compensate for expected data loss. Given concerns over data availability and the understanding that filling vacancies in this rare disease has been a challenge, the Pediatric Heart Network elected to use VO2 at VAT as a secondary endpoint. However, although predicted paired VAT data was available for approximately 80% of the cohort, this measure still demonstrated clinically and statistically significant responses across the entire population.

[0265] The importance of VO2 at VAT as an end point was highlighted in a 2007 report by McCrindle et al (McCrindle 2007), who examined the relationship between parent / patient view of functional health status and measures of motor function in 147 Fontan patients with a mean age of 11.6 years (range 7–18.4 years). In that cohort, the mean percent predicted peak VO2 was 67% ± 15%, which is directly comparable to function in the FUEL cohort. The authors found that greater motor function was associated with higher scores on overall health, physical function, impact of physical limitations, freedom from physical pain, general health view, and physical function summary score (p<0.05 for each). Indeed, for several important measures of functional status, including overall health, physical function, impact of physical limitations, and self-esteem, correlations with measures of motor function were stronger for percent predicted VO2 at VAT than for peak VO2. Given the clinically relevant correlations between percent predicted VO2 at VAT and overall health (R 0.45, p<0.05) and self-esteem (R 0.28, p<0.05), even modest drug effects are predicted to produce perceptible functional benefits to patients and parents. Indeed, as shown in Figure 17, there are more patients who experienced positive changes in VO2 at VAT with udenafil treatment than with placebo, although the difference was not statistically significant (p=0.311). More importantly, as shown in Figure 18, VO2 at VAT is substantially better maintained with udenafil treatment compared to placebo, both in the entire ITT cohort (p=0.026) and in the subgroup analysis excluding Super Fontan patients (p=0.052). In light of McCrindle's data, this suggests that udenafil treatment is associated with better preservation of existing functional status when compared with the inevitable decline in functional status of those not receiving treatment (e.g., placebo or Fontan natural history). These findings support the idea that udenafil-mediated improvements in VO2 at VAT, in addition to improvements in peak VO2, are associated with clinically meaningful improvements in multiple domains of functional health.

[0266] (e) Confirmation of clinical benefit in the Fontan population through the FUEL OLE (open-label extension) trial As confirmation of the benefit of udenafil demonstrated in FUEL, we evaluated the available clinical data from patients in the FUEL OLE trial. Like many extension studies, the FUEL open-label extension trial was not a placebo-controlled trial, but instead was designed to establish a longer-term safety profile of drug exposure and is an independent source of data from FUEL. Despite the inherent limitations of this extension study, FUEL OLE provides evidence supporting the efficacy of udenafil, as shown in Figure 19 below over the 18 months of FUEL and FUEL OLE. There is a continuation of benefit in those treated with udenafil in the FUEL trial, while for those not taking udenafil, there is an emerging benefit that recapitulates that observed versus placebo in the FUEL trial. In the 26-78 week OLE study, all patient groups show substantial clinical benefit from udenafil treatment.

[0267] The FUEL and FUEL OLE trials unexpectedly and surprisingly demonstrated that udenafil is safe and effective to improve exercise capacity in Fontan palliative patients at least 12 years of age. The data generated by these trials are compelling and demonstrate meaningful clinical benefit for this rare disease population, a population lacking approved pharmacological treatment options. Analysis of efficacy data from the Fontan subgroup most in need of treatment - those with lower than normal exercise capacity, i.e., baseline percent predicted peak VO2 below 80% - indicates that the drug effect of udenafil seen in this subpopulation is highly clinically relevant. Furthermore, the observed improvements in all important secondary measures of exercise function and myocardial performance index measured in the FUEL trial constitute substantial evidence of udenafil's efficacy and are believed to support the clinical benefit of udenafil treatment in the Fontan population, including super Fontan patients. This significant clinical benefit in the Fontan population demonstrates excellent and unexpected results with very low safety risks.

[0268] (2) References, each of which is incorporated herein by reference in its entirety.

[0269] [Table 12-1]

[0270] [Table 12-2]

[0271] All articles, references, patent documents and disclosures mentioned herein are hereby incorporated by reference in their entirety as if fully set forth herein.

[0272] The present disclosure has been described with reference to exemplary embodiments. Modifications and alterations will occur to others upon reading and understanding the preceding detailed description. It is intended that the present disclosure be deemed to include all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims

1. 1. A pharmaceutical composition comprising an effective amount of udenafil or a pharmaceutically acceptable salt thereof for use in improving exercise capacity as measured by (a) oxygen consumption at the ventilatory anaerobic threshold (VAT); (b) power at the VAT; and (c) VE / VCO2 at the VAT in patients with single ventricle heart disease (SVHD) and Fontan physiology after the Fontan operation (Fontan patients), The pharmaceutical composition, wherein the Fontan patient has a baseline peak or maximum VO2 that is less than (<) 80% of predicted.

2. 2. The pharmaceutical composition of claim 1, wherein the effective amount is a total daily dose of udenafil or a pharmaceutically acceptable salt thereof in an amount of about 125 mg to about 175 mg.

3. The pharmaceutical composition of claim 1, wherein the effective daily dose is a total daily dose of udenafil or a pharmaceutically acceptable salt thereof in an amount of approximately 175 mg.

4. 4. The pharmaceutical composition of claim 3, wherein the total daily dosage consists of two individual doses of udenafil or a pharmaceutically acceptable salt thereof, each individual dose being about 87.5 mg of udenafil or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, wherein each individual dose is a solid oral dosage form.

6. 6. The pharmaceutical composition of claim 5, wherein the udenafil or a pharmaceutically acceptable salt thereof is in a solid or semi-solid oral dosage form selected from the group consisting of a tablet, a capsule, a gel, a liquid, a liquid dispersion, a pill, a powder, and a suspension.

7. 2. The pharmaceutical composition of claim 1, wherein the udenafil or a pharmaceutically acceptable salt thereof is in a solid oral dosage form.

8. 8. The pharmaceutical composition of claim 7, wherein the solid oral dosage form is a solid or semi-solid oral dosage form selected from the group consisting of a tablet, a capsule, a gel, a liquid, a liquid dispersion, a pill, a powder, and a suspension.

9. 10. The pharmaceutical composition of claim 1, wherein the Fontan patient is at least 12 years old.

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