Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

• the normal human heart has four chambers, a left atrium and left ventricle, the left side, and a right atrium and right ventricle, the right side.
• the oxygen-poor blood (“blue blood”) enters the right side through the right atrium and freshly oxygenated blood (“red blood”) exits the left side through the left ventricle.
• the heart has four valves, the tricuspid valve, the pulmonic valve, the mitral valve and the aortic valve. These valves prevent backflow of blood within the heart and force blood to flow to the lungs and body in a forward direction.
• a human heart beats (expands and contracts) approximately 100,000 times per day, pumping five to six quarts of blood each minute, or about 2,000 gallons per day.
• the left ventricle pumps freshly oxygenated blood (red blood) to the body through the aortic valve.
• the blood then circulates to all parts of the body through arteries and arterioles, delivering oxygen and nutrients.
• oxygen-rich blood red blood
• oxygen-poor blood blue blood
• the oxygen-poor blood then returns to the right atrium through the veins of the body.
• the blue blood passes through the tricuspid valve from the right atrium to the right ventricle, and then it is pumped to the lungs by the right ventricle to exchange carbon dioxide for oxygen.
• the now freshly oxygenated blood returns from the lungs to the left atrium via the pulmonary veins.
• the blood passes through the mitral valve from the left atrium to the left ventricle, and then is pumped to the body to start the circulation anew.
• 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.
• Gewillig M. Congenital heart disease. THE FONTAN CIRCULATION. Heart, 91:839-846 (2005).
• Single ventricle heart disease SVHD is a rare pediatric disease that includes a group of cardiac malformations, each of which results in the presence of only a single functional ventricle (pumping chamber).
• SVHD newborns are born with only one functioning ventricle (one pumping chamber), i.e., single ventricle hearts.
• the non-functioning or missing ventricle may be smaller than the single ventricle such that it does not sufficiently function, it may be absent altogether, or it may be configured in such a way as to prevent it from contributing to the normal flow of blood through the circulation.
• Examples of SVHD include hypoplastic left heart syndrome, tricuspid atresia, double inlet left ventricle, and others.
• SVHD newborns are cyanotic, blue in color, since a mixture of oxygen-poor blood (blue blood) and oxygen-rich blood (red blood) mix together in the single ventricle.
• the amount of oxygen within the blood mixture leaving the heart is very dependent upon the type, severity and location of the SVHD heart defect.
• Some SVHD newborns will be mildly cyanotic, whereas others will be severely cyanotic, requiring early intervention to meet the oxygen demands of the body to survive.
• SVHD can be thought of as having two primary subtypes.
• the left ventricle and the aorta (the main artery to the body) are under-developed and the heart is not able to pump blood to the body without an interventional procedure.
• the right ventricle and the pulmonary artery (the main artery to the lungs) are under-developed and the heart is not able to pump blood to the lungs.
• an urgent 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 operation, see FIG.5, and involves rebuilding the aorta (the main artery to the body) using the pulmonary valve and pulmonary artery along with patch material.
• the Norwood operation repurposes the pulmonary artery to supply blood to the body, it also must include a way for blood to get to the lungs. This is accomplished by the inclusion of a “shunt” of blood from the aortic circulation to the pulmonary circulation.
• This shunt is generally a tube graft that is placed between the right subclavian artery (the artery that supplies blood to the right arm) and the right pulmonary artery.
• the Norwood operation allow newborns to survive infancy, but is not a permanent solution. This temporary procedure forces the single pumping chamber of the heart to pump blood to both the body and to the lungs, putting it under stress. To relieve this stress, two additional procedures are performed.
• a restrictor may be placed around the pulmonary artery to reduce the amount of blood flow to the lungs to avoid the development of congestive heart failure. If the amount of blood flow to the lungs is appropriate, infants born with an under-developed right ventricle and pulmonary artery may go through their initial months of life without the need for a surgical intervention. Whether there is too little, too much, or an appropriate amount of blood flow to the lungs, infants born with this type of SVHD still require the Glenn shunt or hemi-Fontan at 4-6 months of age and the Fontan at 18-48 months of age to relieve the burden from the heart and to separate the blue blood from the red blood.
• the subtype of single ventricle heart disease is less important as all patients are left with a common physiology: (i) passive blood flow from the superior and inferior vena cava directly to the lungs bypassing the heart and (ii) a single ventricle that pumps blood to the body.
• this “Fontan circulation” has allowed for the survival of many thousands of patients over the last 40-50 years, it is far from normal. In the absence of a ventricular pump to push blood through 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.
• Fontan- associated liver disease is defined as abnormalities in liver structure and function resulting from the abnormal circulation created by the total cavopulmonary connection (TCPC) and not related to any other process (1).
• FALD is increasingly recognized as one of the most common complications of the TCPC (2, 3) and one which is universally present in patients with TCPC physiology (8-11).
• TCPC total cavopulmonary connection
• FIG.9 blood from the inferior and superior vena cava are routed directly to the pulmonary arteries bypassing the heart (FIG.9). In this circulation, blood is not “pumped” through the lungs but is “pushed” through by chronic elevation of the central venous pressure.
• Fontan’s elevated, non-phasic systemic venous pressure results in obligate chronic hepatic venous hypertension and congestion that is likely an important driver of hepatic fibrosis.
• activated myofibroblasts deposit excess extracellular matrix in the perisinusoidal space, a process which, if it persists, can lead to increased hepatocellular injury, progressive fibrosis, organ dysfunction, and, ultimately, to cirrhosis and hepatic failure.
• the congestion and fibrosis result in a wide spectrum of liver disease, including synthetic dysfunction, ascites, portal hypertension, cirrhosis, and hepatocellular carcinoma, and may culminate in fulminant liver failure.
• liver fibrosis is known to increase with time after TCPC and occurs in the absence of any other identifiable etiology of chronic liver disease.
• a roadblock to understanding and treating FALD is the lack of an established, noninvasive means of detecting it.
• Basic laboratory testing platelet count, AST, ALT, bilirubin, GGT, INR
• standard imaging conventional ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI)
• US conventional ultrasound
• CT computed tomography
• MRI magnetic resonance imaging
• Ultrasound shear wave elastography based on the measurement of tissue shear wave speed, provides a non-invasive measure of liver stiffness and may provide technology to monitor the congestion and early fibrosis that precedes overt FALD.
• the utility of ultrasound SWE in assessing liver fibrosis has been well-documented (9, 10) and image-guided ultrasound SWE has been used in TCPC patients to demonstrate that liver stiffness correlates with hepatic congestion (as determined by elevated central venous pressures) and hepatic fibrosis (as determined by liver biopsy) (11-13).
• MRI-elastography may be of utility as it allows sampling over a much larger region of the liver (thus, minimizing sampling error) and may potentially allow differentiation of stiffness due to fibrosis versus congestion, a feature which may be particularly useful in the evaluation of Fontan patients and in determining the best approach to targeted therapy in this population (14). Notwithstanding this long-standing very serious congenital heart disease, to date, no pharmacotherapy has been approved by the U.S. Food & Drug Administration (FDA) or any other equivalent agency through-out the world for the treatment of SVHD patients, including Fontan patients.
• FDA U.S. Food & Drug Administration
• the present invention overcomes the above-mentioned drawbacks and disadvantages associated with current treatments of patients, especially single ventricle heart disease (SVHD) patients, including SVHD patients who have undergone Fontan surgery and have Fontan physiology, who have impaired liver function as characterized by enhanced liver fibrosis (ELF) score, through the discovery of novel methods of treating such patients, especially the SVHD patients and Fontan patients, with daily administration of an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to improve their impaired liver function, maintain their impaired liver function or slow the rate of decline of impaired liver function at a level that correlates with an (ELF) score.
• SVHD single ventricle heart disease
• EEF enhanced liver fibrosis
• the methods of the present invention are directed to the use of udenafil, or a pharmaceutically acceptable salt thereof, to treat patients, especially SVHD patients and Fontan patients. More specifically, methods of the present invention comprise administering, preferably daily, to patients with impaired liver function, especially SVHD patients and Fontan patients, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to improve, amongst other things, their impaired liver function due to, amongst other things, liver fibrosis.
• methods of the present invention comprise administering, preferably daily, to a SVHD patient, including a Fontan patient, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to improve, amongst other things, their MPI and exercise capacity or performance.
• the methods of the present invention include administering daily an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient, to improve: (a) ventricular performance of the SVHD patient’s single functioning ventricle as measured by MPI; (b) exercise capacity as measured by oxygen consumption at VAT; (c) exercise capacity as measured by oxygen consumption at maximal effort or max VO 2 ; (d) work rate at VAT; (e) VE/VCO 2 at VAT; (f) diastolic blood pressure at rest; (g) impaired liver function; and (h) oxygen saturation (%) at rest, each individually, collectively or in any combination thereof.
• the methods of the present invention improve (a)-(h) listed above, including individually, collectively or in any combination thereof.
• the methods of the present invention improve at least the combination of (a)-(e) and (g) listed above.
• (a)-(h) listed above, including individually, collectively or in any combination thereof are improved in accordance with the present invention by administering daily to a SVHD patient, including a Fontan patient, an effective amount of udenafil, or a pharmaceutical acceptable salt thereof.
• Improvements in single ventricle performance in accordance with the methods of the present invention include improvements in both systolic and diastolic function.
• Improvements in exercise capacity or performance in accordance with the methods of the present invention include, but are not limited to, improvements in exercise capacity or performance at anaerobic threshold (“VAT”) and/or improvements in exercise capacity or performance at maximal effort or max VO 2 .
• VAT anaerobic threshold
• VE/VCO 2 ventilatory equivalents of carbon dioxide at VAT
• VE/VCO 2 diastolic blood pressure at rest
• impaired liver function and/or oxygen saturation (%) at rest when the methods of the present invention are practiced with regard to SVHD patients, including Fontan patients.
• effective amount is used herein to mean an amount of udenafil, or a pharmaceutically acceptable salt thereof, that is sufficient to elicit or induce a therapeutic, clinical or pharmacologic effect without causing treatment-limiting side effects.
• an “effective amount” is used herein to mean an amount of udenafil, or a pharmaceutically acceptable salt thereof, that is sufficient to elicit or induce a therapeutic, clinical or pharmacologic effect in a SVHD patient, including a Fontan patient, 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.
• An example of an “effective amount” of udenafil, or a pharmaceutically acceptable salt thereof, in accordance with the present invention includes a total daily amount in a range that includes, but is not limited to, from about 87.5 mg to about 175 mg.
• an “effective amount” of udenafil, or a pharmaceutically acceptable salt thereof, in accordance with the present invention includes a total daily amount in a range from about 125 mg to about 175 mg. Even more preferably, an “effective amount” of udenafil, or a pharmaceutically acceptable salt thereof, in accordance with the present invention includes an oral dosage amount that includes, but is not limited to, a single dosage amount administered daily, including a single dosage amount of about 75 mg or 87.5 mg administered once or twice a day and a single dosage amount of about 125 mg, 175 mg or a range of about 125 mg to about 175 mg administered once daily.
• the present invention also contemplates methods which comprise administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to a SVHD patient, including a Fontan patient, for improving, amongst other things, MPI, ventricular performance, cardiac output, exercise capacity or performance at VAT, exercise capacity or performance at maximal effort or VO 2 max, work rate at VAT, VE/VCO 2 at VAT, impaired liver function, especially impaired fibrotic liver function, and diastolic blood pressure at rest and oxygen saturation (%) at rest, individually, collectively or in any combination, without causing treatment-limiting side effects, for example, interference with visual transduction or function, back pain, myalgia, sperm concentration or quality.
• a Fontan patient for improving, amongst other things, MPI, ventricular performance, cardiac output, exercise capacity or performance at VAT, exercise capacity or performance at maximal effort or VO 2 max, work rate at VAT, VE/VCO 2 at VAT, impaired liver function, especially impaired fibrotic liver function, and dia
• the present invention contemplates treatments, preferably daily, of a SVHD patient, including a Fontan patient, with an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, without causing treatment limiting side effects associated with inhibition of phosphodiesterase-6 (“PDE6”) and/or phosphodiesterase-11 (“PDE11”).
• a SVHD patient including a Fontan patient
• PDE6 phosphodiesterase-6
• PDE11 phosphodiesterase-11
• PDE6 includes any isoenzyme, variant, catalytic subunit and/or inhibitory subunit of PDE6, such as PDE6 ⁇ , PDE6 ⁇ , PDE6 ⁇ , PDE6R and/or PDE6C, individually, collectively, or in any combination
• PDE11 includes phosphodiesterase-11A (PDE11A) and any isoenzyme, variant, catalytic subunit and or inhibitory subunit of PDE11, such as PDE11A, including PDE11A1, PED11A2, PDE11A3 and/or PDE11A4, individually, collectively, or in any combination.
• the present invention is directed to a method of improving the MPI in a SVHD patient, including a Fontan patient.
• MPI measures both systolic and diastolic function for the assessment of global heart function.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof.
• improve, improving, improvement in or improved with respect to MPI in accordance with the present invention, it means herein to improve single ventricle performance, i.e., to improve the diastolic and systolic function of the single functioning ventricle. In other words, the single functioning ventricle squeezes better or more efficiently per heartbeat.
• the cardiac output and the amount of blood flow that can circulate in a given amount of time throughout the body of the SVHD patients, including Fontan patients, who practice or who are treated in accordance with the methods of the present invention are increased or improved, especially as compared to SVHD patients, including Fontan patients, who are not treated in accordance with the methods of the present invention.
• the methods of the present invention result in MPI, or other disclosed measures of ventricular performance, improvement in a SVHD patient, including a Fontan patient, as compared to MPI, or other disclosed measures of single ventricular performance in the absence of the methods of the present invention (e.g., in the absence of udenafil administration).
• 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 greater as compared to blood pool MPI, or other disclosed measures of single ventricular performance in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof.
• the present invention is directed to a method of improving systolic function of the single functioning ventricle of a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof.
• the present invention is directed to a method of improving diastolic function of the single functioning ventricle of a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof.
• the present invention is directed to a method of improving cardiac output of the single functioning ventricle of a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof.
• the present invention is directed to a method of improving the ability of the single functioning ventricle in a SVHD patient, including a Fontan patient to squeeze.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to a SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving the venous pressure by decreasing the elevation in venous pressure in a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving the amount of blood flow that can circulate through the body of the SVHD patient, including a Fontan patient, in a given amount of time.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving global single ventricular performance of the single functioning ventricle in a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient.
• the present invention is directed to a method of improving diastolic blood pressure at rest in a SVHD patient, including a Fontan patient, whereby the SVHD patient’s, including the Fontan patient’s, diastolic blood pressure at rest is significantly lowered.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving oxygen saturation (%) at rest in a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving exercise performance or capacity in a SVHD patient, including a Fontan patient.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving exercise performance or capacity at the ventilatory anaerobic threshold (“VAT”) in a SVHD patient, including a Fontan patient.
• VAT ventilatory anaerobic threshold
• the methods of the present invention result in improved VO 2 at VAT in SVHD patient, including the Fontan patient, as compared to VO 2 at VAT in SVHD patients, including Fontan patients, who are not treated with or do not practice the methods of the present invention (e.g., in the absence of daily udenafil administration in accordance with the methods of the present invention).
• 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 greater as compared to VO 2 at VAT in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving exercise performance or capacity at maximal effort or max VO 2 in a SVHD patient, including a Fontan patient.
• the methods of the present invention result in improved VO 2 at the SVHD patient’s, including the Fontan patient’s, maximal effort, as compared to VO 2 at maximal effort in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• 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 greater, as compared to VO 2 at maximal effort in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of udenafil or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving work rate at VAT in a SVHD patient, including a Fontan patient.
• the methods of the present invention result in improved work rate at the SVHD patient’s, including the Fontan patient’s, VAT, as compared to the work rate at VAT in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• 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 greater, as compared to VO 2 at VAT in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving ventilatory equivalents of carbon dioxide at the VAT (“VE/VCO 2 ”) at VAT in a SVHD patient, including a Fontan patient.
• the methods of the present invention result in improved VE/VCO 2 at the SVHD patient’s, including the Fontan patient’s, VAT, as compared to the VE/VCO 2 at VAT in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• 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 greater, as compared to VO 2 at VAT in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to a method of improving impaired liver function in a SVHD patient, including a Fontan patient or at least 12 months and, preferably, 18 months.
• the methods of the present invention result in improved impaired liver function as characterized by an ELF score for the SVHD patient, including the Fontan patient’s, VAT, as compared to impaired liver function in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• 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%, about 30% , about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% greater, as compared to liver impaired function in the absence of the methods of the present invention (e.g., in the absence of daily udenafil administration).
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to a patient with impaired fibrotic liver function, especially an SVHD patient, including a Fontan patient, with impaired fibrotic liver function.
• the present invention is directed to improved methods for treating a SVHD patient, including a Fontan patient, who has undergone heart reconstruction of the abnormal SVHD heart, wherein the daily methods of the present invention result in fewer or less severe adverse events, as compared to conventional methods of treating such a SVHD patient, including a Fontan patient.
• the methods of the present invention result in few, if any, serious adverse events, moderate adverse events, or mild adverse events.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to improved methods for treating a SVHD patient who has undergone a Fontan procedure.
• the Fontan patient is diagnosed with hypoplastic left heart syndrome (HLHS), but first had a Norwood procedure, see, e.g., FIG.5, followed by a Hemi-Fontan or Bi-directional Glenn procedure, see, e.g., FIG.6, before undergoing the Fontan procedure, see, e.g., FIG.1A and FIG.7.
• HLHS hypoplastic left heart syndrome
• the Fontan patient first had a Hemi-Fontan or Bi-directional Glenn procedure before undergoing the Fontan procedure.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the present invention is directed to improved methods for treating a SVHD patient, including a Fontan patient, wherein the SVHD is selected from a group of SVHDs consisting of patients having an atrioventricular canal defect (AV Canal), a double inlet left ventricle (DILV), a double outlet right ventricle (DORV), Ebstein’s anomaly, HLHS, mitral valve atresia (usually associated with HLHS), pulmonary atresia with intact ventricular septum (PA/IVS), a single left ventricle, tricuspid valve atresia and tricuspid valve atresia with stenosis.
• AV Canal atrioventricular canal defect
• DILV double inlet left ventricle
• DORV double outlet right ventricle
• Ebstein’s anomaly HLHS
• mitral valve atresia usually associated with HLHS
• PA/IVS pulmonary atresia with intact ventricular septum
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient.
• the methods of the present invention comprise administering an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, once a day to a SVHD patient, including a Fontan patient.
• the methods of the present invention comprise administering an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, twice a day to a SVHD patient, including a Fontan patient.
• the methods of the present invention comprise administering an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, three or more times a day to a SVHD patient, including a Fontan patient.
• a SVHD patient including a Fontan patient
• the SVHD patient, including a Fontan patient is a pediatric patient of about 2 to about 18 years of age. Treatment of adult patients are also encompassed by the methods of the invention.
• the present invention is directed to improved methods for treating a SVHD patient, including a Fontan patient, wherein the methods of the present invention show an improvement in the SVHD patient’s, including Fontan patient’s, compliance with a dosing schedule of udenafil or a pharmaceutically acceptable salt thereof, as compared to SVHD patients, including Fontan patients, prescribed a non-udenafil drug.
• the methods of the present invention may result in a unique characteristic pharmacokinetic profile.
• the pharmacokinetic profile can comprises a C max between 300 and 700 ng/ml, or more specifically, about 500 ng/ml; a T max between 1 and 1.6 hr, or more specifically, about 1.3 hr; an AUC t between 2550 and 4150 ng •hr/ml or more, specifically about 3350 ng •hr/ml; and an AUC 0-24 between 5110 and 8290 ng •hr/ml or more, specifically about 6701 ng •hr/ml.
• the methods of the present invention include methods of treating a patient, including SVHD and Fontan patients, having impaired liver function characterized by an elevated enhanced liver fibrosis (ELF) score for improving or maintaining the function of the impaired liver by reducing the elevated ELF score, wherein the ELF score is characterized by three biomarker components that together form an extracellular matrix (ECM) marker set comprising (i) a tissue inhibitor of metalloproteinases 1 (TIMP-1), (ii) amino-terminal propeptide of type III procollagen (PIIINP) and (iii) hyaluronic acid (HA), wherein the ELF score correlates to liver function, wherein an ELF score above 11.3 characterizes liver cirrhosis, wherein an ELF score from 9.9 to 11.3 characterizes severe fibrosis, wherein an ELF score from 7.7 to 9.9 characterizes moderate fibrosis, wherein an ELF score below 7.7 characterizes no or weak fibrosis, and wherein the patient is in need
• the patients’ impaired, fibrotic livers are improved in their function as reflected in the ELF scores by one, two or even three levels of decreased fibrosis as described above.
• patients whose ELF scores initially categorize the liver as cirrhotic upon treatment in accordance with the present invention, may improve to either severe fibrosis or moderate fibrosis or even weak or no fibrosis as indicated by the ELF scores.
• the patients’ impaired fibrotic livers which are maintained against further fibrosis, for example, those patients’ livers which are maintained in a fibrosis-free or mild fibrosis state, as measured according to the ELF score, without progressing to moderate liver fibrosis or severe liver fibrosis or cirrhosis, are maintained at the less fibrotic state for at least one year, more preferably, for at least 18 months.
• patients having moderate liver fibrosis, as indicated by the ELF score is maintained at that level and do not progress to severe fibrosis or cirrhosis, as indicated by the ELF score, for at least one year, preferably for at least 18 months.
• patients having severe fibrosis are maintained without progressing to cirrhosis, as indicated by the ELF score, for at least one year, preferably for at least 18 months.
• the patients’ impaired fibrotic livers which impaired liver function is improved, for example, those patients’ impaired livers which are in a sclerosis state are improved to a severe fibrotic, a moderate fibrotic, and/or a mild fibrotic or a fibrosis-free state, as measured according to the ELF score, are maintained at the less fibrotic state for at least one year, more preferably, for at least 18 months.
• the present invention comprises methods for improving Fontan-associated liver disease (FALD).
• FALD is defined as abnormalities in liver structure and function resulting from the abnormal circulation created by the total cavopulmonary connection (TCPC) and not related to any other process .
• liver fibrosis As part of the injury response, activated myofibroblasts deposit excess extracellular matrix in the perisinusoidal space, a process which, if it persists, can lead to increased hepatocellular injury, progressive fibrosis, organ dysfunction, and, ultimately, to cirrhosis and hepatic failure.
• the congestion and fibrosis result in a wide spectrum of liver disease, including synthetic dysfunction, ascites, portal hypertension, cirrhosis, and hepatocellular carcinoma, and may culminate in fulminant liver failure.
• the severity of liver fibrosis is known to increase with time after TCPC and occurs in the absence of any other identifiable etiology of chronic liver disease.
• a depiction showing aspects of FALD and some biomarkers associated therewith is shown in FIG.9.
• a roadblock to understanding and treating FALD is the lack of an established, noninvasive means of detecting it.
• Basic laboratory testing platelet count, AST, ALT, bilirubin, GGT, INR
• standard imaging conventional ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI)
• US conventional ultrasound
• CT computed tomography
• MRI magnetic resonance imaging
• Percutaneous core needle liver biopsy while the current standard of care, is not an ideal surveillance tool as the core sample may falsely under- or over-estimate the degree of fibrosis given the significant heterogeneity that often exists.
• Liver biopsy is also invasive and carries a small but real risk of bleeding, particularly in patients who require anti-coagulation.
• Ultrasound shear wave elastography SWE
• SWE ultrasound shear wave elastography
• Hepatic stiffness in the bidirectional cavopulmonary circulation The Liver Adult-Pediatric-Congenital-Heart-Disease Dysfunction Study group. J Thorac Cardiovasc Surg 2016 Mar;151(3):678-84; Melero-Ferrer JL, Osa- Saez A, Buendia-Fuentes F, Ballesta-Cunat A, Flors L, Rodriguez-Serrano M, Calvillo-Batlles P, Arnau-Vives MA, Palencia-Perez MA, Rueda-Soriano J. Fontan Circulation in Infant Patients: Acoustic Radiation Force Impulse Elastography as a Useful Tool for Liver Assessment.
• MRI-elastography may be of even greater utility as it allows sampling over a much larger region of the liver (thus, minimizing sampling error) and may potentially allow differentiation of stiffness due to fibrosis versus congestion, a feature which may be particularly useful in the evaluation of Fontan patients and in determining the best approach to targeted therapy in this population.
• the FUEL Study Extension Trial was an NHLBI-sponsored study that assessed the efficacy of safety and efficacy of udenafil, a phosphodiesterase-5 inhibitor (PDE-5i) that causes relaxation and decongestion of the pulmonary and systemic venous vasculature, to improve Fontan cardiac function, peripheral endothelial function, and exercise performance in adolescents who have undergone TCPC.
• PDE-5i phosphodiesterase-5 inhibitor
• Ultrasound SWE uses one or more acoustic radiation force impulses (ARFI) or “push pulses” to generate shear waves in the tissue of interest. These shear waves can be tracked and their speed measured, with increasing tissue stiffness associated with increasing tissue shear wave speed. Shear wave speed can be mathematically converted to both shear and Young’s moduli (in kPa), mechanical properties related to tissue rigidity and elasticity.
• ARFI acoustic radiation force impulses
• Shear wave speed can be mathematically converted to both shear and Young’s moduli (in kPa), mechanical properties related to tissue rigidity and elasticity.
• MR elastography uses a vibrating passive driver or “paddle” placed on the abdominal wall over the liver in order to generate in vivo shear waves. These shear waves can be tracked using an MRI modified phase contrast pulse sequence. Shear wave data is then used to generate color parameteric maps (elastograms) of liver stiffness that allow quantitative assessment (Figure 4).
• elastograms color parameteric maps of liver stiffness that allow quantitative assessment
• Patients with long Fontan duration >20 years post-op
• the study provided evidence that elevated liver stiffness in Fontan patients is likely due to both fibrosis and congestion.
• increased liver stiffness can be secondary to hepatic congestion and/or hepatic fibrosis.
• Circulating biomarkers previously demonstrated to be associated with congestive heart failure or tissue fibrosis may help to determine the primary driver of liver stiffness in a particular patient and help to monitor the response to targeted therapy.
• patients with increased liver stiffness due to hepatic congestion may have increased biomarkers of heart failure (e.g., BNP, NT- proBNP).
• Patients in whom fibrosis significantly contributes to increased liver stiffness may well have elevation in biomarkers associated with liver fibrosis (e.g., ELF panel, miR-138, miR-143, or galectin-3).
• biomarkers associated with liver fibrosis e.g., ELF panel, miR-138, miR-143, or galectin-3.
• the relative contribution of congestion or fibrosis (as determined by biomarker profiles) to the observed level of liver stiffness may correlate with which therapeutic strategies are likely to be successful in a particular patient. Therefore, in this aim, we sought to determine which circulating biomarkers correlate with measures of liver stiffness and which correlate with a change in liver stiffness with udenafil treatment.
• the U+ cohort from FUEL will allow us to determine if potential benefits of udenafil therapy sustained over time by comparing measurements after 6 (baseline entry into our study) and 18 months of therapy (after 1-year of our study).
• the Enhanced Liver Fibrosis (ELF) scores were based on the serum levels of hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase-1 (TIMP-1). Testing was performed by the FUEL-OLE Central Laboratory using the serum samples.
• present invention contemplates udenafil drug products that are therapeutically equivalent to the udenafil drug products of the present invention.
• the present invention contemplates udenafil drug products that (i) are therapeutically equivalent, (ii) are bioequivalent, (iii) are interchangeable, and (iv) have bio availabilities that, when administered to a SVHD patient, including a Fontan patient in accordance with the methods of the present invention, are effective in carrying out or performing the objectives of the present invention.
• the present invention contemplates drug formulations that have a 90% confidence interval (90% CI) for a pharmacokinetic profile wherein the ratio of the means lies within the range of between about 0.8 and about 1.25.
• the present invention contemplates interchangeable udenafil drug formulations that have a 90% confidence interval (90% CI) for a pharmacokinetic profile wherein the ratio of the means lies within the range of between about 0.8 and about 1.2.
• the present invention therefore contemplates SVHD patients, including Fontan patients, who are treated with or practice the methods of the present invention, having a udenafil plasma concentration that can vary by up to about 45% (i.e.
• the present invention contemplates SVHD patients, including Fontan patients, who are treated with or practice the methods of the present invention, having a udenafil plasma concentration that can vary by up to about 40% (i.e. -20 to +20%) of a pharmacokinetic profile, such as their C max , T max , AUC t and AUC 0-24 .
• the present invention contemplates SVHD patients, including Fontan patients, who are treated with or practice the methods of the present invention, having a udenafil pharmacokinetic profile: (a) C max plasma concentration of about -20 to about +25% of about 500 ng/ml, and more preferably a udenafil C max plasma concentration of about -20 to about +20% of about 500 ng/ml; (b) T max of about -20 to about +25% of about 1.3 hr, and more preferably a udenafil T max of about -20 to about +20% of 1.3 hr; (c) AUC t of about -20 to about +25% of about 3350 ng •hr/ml, and more preferably a udenafil AUC t of about -20 to about +20% of about 3350 ng •hr/ml; and (d) AUC 0-24 of about -20 to about +25% of about 6701 ng •hr/ml,
• the present invention contemplates bioequivalent and interchangeable udenafil drug products for use in accordance with the methods of the present invention.
• the present invention contemplates udenafil drug products that produce the above referenced C max , T max , AUC t and/or AUC 0-24 in SVHD patients, including Fontan patients, when administered to SVHD patients, including Fontan patients, in accordance with the methods of the present invention.
• C max , T max , AUC t and/or AUC 0-24 in SVHD patients, including Fontan patients, when administered to SVHD patients, including Fontan patients, in accordance with the methods of the present invention.
• FIG.1A is a schematic drawing of an exemplary Fontan physiology.
• FIG.1B is a screening process (Randomization and Treatment of the Participants) used for the Fontan Udenafil Exercise Longitudinal (FUEL) Trial as described in the Examples 1-2.
• Peak VO 2 (VO 2 max) denotes oxygen consumption at peak exercise.
• RER denotes respiratory exchange ratio.
• FIG.2A demonstrates the difference in the change in mean peak or max VO 2 from Baseline to Week 26 along with the standard deviation for each treatment arm.
• FIG.2B demonstrates the percentage of subjects (y axis) who demonstrated improvement in peak VO 2 by the reference percentage or greater (x axis).
• FIG.3A demonstrates the difference in the change in mean VO 2 at VAT from Baseline to Week 26 along with the standard deviation for each treatment arm.
• FIG.3B demonstrates the percentage of subjects (y axis) who demonstrated improvement in VO 2 at VAT by the reference percentage or greater (x axis).
• FIG.4A demonstrates the difference in the change in mean work rate at VAT from Baseline to Week 26 along with the standard deviation for each treatment arm.
• FIG.4B demonstrates the percentage of subjects (y axis) who demonstrated improvement in work rate by the reference percentage or greater (x axis).
• FIG.5 is a schematic drawing of an exemplary Norwood procedure (Stage 1) of a reconstructed SVHD heart with Hypoplastic Left Heart Syndrome (HLHS).
• FIG.6 is a schematic drawing of an exemplary Bidirectional Glenn procedure (Stage 2) of a reconstructed SVHD heart with Hypoplastic Left Heart Syndrome (HLHS).
• FIG.7 is a schematic drawing of an exemplary Fontan procedure (Stage 3), an Extracardiac Fenestrated Fontan procedure, of a reconstructed SVHD heart with Hypoplastic Left Heart Syndrome (HLHS).
• FIGS.8A and 8B depicts Chart 1A (FIG.8A) and Chart 1B (FIG.8B) which are scatterplots showing the percent change in ELF score compared to the baseline score for all subjects that had both a measurable baseline value and a measurable 52 week value.
• FIG.9 is a schematic drawing showing aspects of FALD and some biomarkers associated therewith.
• Fontan Physiology The Fontan physiology is the definitive palliation for those classes of congenital heart defects that share the common feature of a functional single ventricle and cannot support biventricular circulation. They include defects that result in hypoplastic (malfunctioning) left or right ventricles.
• the systemic and pulmonary circulations are separated to significantly eliminate the mixing of oxygenated and un-oxygenated blood caused by the congenital heart defects. This is accomplished by directly attaching the superior and inferior vena cavae to the pulmonary arteries, i.e., the total cavopulmonary connection.
• the Fontan operation which creates a total cavopulmonary connection, an alternative to atriopulmonary connection, separates the systemic and pulmonary circuits by connecting them in parallel and eliminates both hypoxemia and ventricular volume overload.
• total cavopulmonary connections are used to divert systemic venous return directly into the pulmonary vascular bed, providing more “effective” pulmonary blood flow and reducing the volume load on the single functioning ventricle.
• the Fontan procedure is palliative, rather than curative, and while it has greatly increased the survival of pediatric subjects with functional single ventricle heart disease, the procedure also results in a series of side effects and complications that can lead to attrition of patients, with complications such as arrhythmias, ventricular dysfunction, and unusual clinical syndromes of protein-losing enteropathy (PLE) and plastic bronchitis, as well as hepatic complications, including impaired liver function resulting from, e.g., fibrogenesis, and kidney complications.
• the disclosed present invention relates to improving or preventing the decline of specific clinically relevant physiological measurements that are indicative of a patient’s health following a Fontan procedure.
• Exercise testing can include assessment of VO 2 values during maximal effort or at the ventilator anaerobic threshold (VAT).
• VAT ventilator anaerobic threshold
• VO 2 max or maximal oxygen consumption, refers to the maximum amount of oxygen that an individual can utilize during intense exercise. This measurement is generally considered a reliable indicator of cardiovascular fitness and aerobic endurance. The more oxygen a person can use during high level exercise, the more energy that person can produce. This test has been the standard for cardiorespiratory fitness because muscles need oxygen for prolonged (aerobic) exercise; blood carries oxygen to the muscles and the heart must pump adequate amounts of blood to meet the demands of aerobic exercise.
• VO 2 is often measured by putting a mask on a subject, and measuring the volume and gas concentrations of inhaled and expired air. This measurement is often used in both clinical settings and research and is considered the most accurate. Testing commonly involves either exercising on a treadmill or riding a cycle ergometer at increasing intensity until exhaustion, and is designed to provide readings at a maximal effort of the subject and/or at the subject’s anaerobic threshold. SVHD patients, including SVHD patients that have previously undergone a Fontan procedure, will generally see a decline in VO 2 measurements over time.
• the VO 2 measurement (i) is maintained at a similar level, demonstrating that there has been no further decline in VO 2 measurement, or (ii) improved with therapy, demonstrating that there has been an increase in VO 2 , and/or the rate of decline in VO 2 measurement is reduced, thus, improved, each indicating that the treatments or methods of the present invention are clinically beneficial .
• treatment in accordance with the present invention may significantly slow or decrease the decline in VO 2 measured during exercise.
• the present invention is directed to a method of improving or maintaining VO 2 measurements of a SVHD patient or a subject who has previously had a Fontan procedure.
• the method of the present invention comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to a SVHD patient, including a Fontan patient.
• VO 2 is measured at maximal effort, while in other embodiments, VO 2 is measured at the subject’s anaerobic threshold (VAT).
• the disclosed methods and compositions of the present invention are administered to a SVHD patient, including a Fontan patient, and result in no decrease, or a minimal decrease, in exercise capacity over time.
• the disclosed methods and compositions of the present invention may result in a decrease 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 a first and second measurement used to calculate the decrease in exercise capacity can be, for example, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months; about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, or about 15 years, or any combination thereof, e.g., 1 year, 3 months; 4 years, 7 months, etc.
• the disclosed methods and compositions of the present invention may be administered to a SVHD patient, including a Fontan patient, and result in an improvement of exercise capacity. More specifically, the disclosed methods and compositions of the present invention may result in a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more improvement in VO 2 at maximal effort. Alternatively, the disclosed methods and compositions of the present invention may result in a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more improvement in VO 2 at the SVHD patient’s, including the Fontan patient’s, ventilatory anaerobic threshold (VAT). IV.
• VAT ventilatory anaerobic threshold
• vascular endothelial dysfunction is an important outcome for assessing vascular health in intervention studies. It is now well established that vascular endothelial dysfunction is positively associated with traditional cardiovascular disease (CVD) risk factors, and independently predicts cardiovascular events over intervals of 1 to 6 years.
• Pulse amplitude tonometry (PAT), a FDA-approved method for assessing vascular function, is increasingly being used as an alternative measure of endothelium-dependent dilation in response to reactive hyperemia and flow-mediated dilation (FMD).
• the PAT device records digital pulse wave amplitude (PWA) using fingertip plethysmography. PWA can be measured continuously during three phases: a quiet baseline period, 5-min forearm occlusion, and reactive hyperemia following cuff release.
• Treating a SVHD patient, including a Fontan patient, that improves or prevents further decline in vascular function of a SVHD patient, including a Fontan patient, would indicate that the treatment is clinically beneficial and may improve the SVHD patient’s, including the Fontan patient’s, quality of life or prevent decline in cardiovascular function.
• the present invention is directed to a method of improving or maintaining vascular function of SVHD patients, including SVHD patients that have previously undergone a Fontan procedure.
• the method comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to a SVHD patient, including a Fontan patient.
• vascular function is measured using a PAT index.
• the disclosed methods and compositions of the present invention are administered to a SVHD patient, including a Fontan patient, and result in no decrease, or a minimal decrease, in vascular function over time.
• Vascular function can be measured using any conventional known technique, including but not limited to pulse amplitude tonometry measurements, the natural log of reactive hyperemia index, Reactive Hyperemia Index, Framingham (RHI), area under the curve to max-occlusion/control, average up to max- occlusion/control, and other known EndoPAT indices.
• vascular function is measured using a PAT index.
• the disclosed methods and compositions of the present invention may result in a decrease 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 time period between a first and second measurement used to calculate the decrease in vascular function can be, for example, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11, or about 12 months; about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, or about 15 years, or any combination thereof, e.g., 1 year, 3 months; 4 years, 7 months, etc.
• the disclosed methods and compositions of the present invention may be administered to a SVHD patient, including a Fontan patient and result in an improvement of vascular function.
• Vascular function can be measured using any conventional known technique, including but not limited to pulse amplitude tonometry measurements, the natural log of reactive hyperemia index, Reactive Hyperemia Index, Framingham RHI, area under the curve to max- occlusion/control, average up to max-occlusion/control, and other known EndoPAT indices.
• vascular function is measured using a PAT index.
• the disclosed methods and compositions may result in about a 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 measurement, the natural log of reactive hyperemia index, Reactive Hyperemia Index, Framingham RHI, area under the curve to max-occlusion/control, average up to max- occlusion/control, and other known EndoPAT indices.
• V. Echocardiographic Assessment of Ventricular Performance Ventricular performance and cardiac contractility are important measurements that can reveal impairment of cardiovascular health before overt heart failure is present.
• MPI myocardial performance index
• MPI is an index that combines systolic and diastolic function. Specifically, MPI is defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time.
• MPI indices may include, but are not limited to, blood pool MPI and tissue Doppler MPI. MPI can be measured by using pulsed-wave tissue Doppler echocardiography (TDE).
• isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT) and ejection time (ET) of the functioning single ventricle are measured.
• MPI is then determined by adding together the IVCT and the IVRT and dividing the sum by ET.
• Patients that have previously undergone a Fontan procedure will generally see a decline in ventricular performance over time. Treating a patient such that the patient’s ventricular performance is maintained, exhibits minimal decrease over time, or increases indicates that the treatment is clinically beneficial and may improve patient quality of life or prevent decline in cardiovascular function.
• the present invention is directed to a method of maintaining, producing a minimal decrease in, or increasing ventricular performance of a subject who has previously had a Fontan procedure.
• the method of the present invention comprises administering, preferably daily, an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the patient.
• ventricular performance is measured using a myocardial performance index (MPI).
• MPI myocardial performance index
• the MPI may be a blood pool MPI, while in other embodiments the MPI may be a tissue Doppler MPI.
• the disclosed methods and compositions of the present invention may be administered to a Fontan patient and result in minimal or no decrease in ventricular performance over time.
• Ventricular performance can be measured using any conventional known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue doppler MPI, average isovolumetric contraction and relaxation, and other known ventricular performance indices. More specifically, the disclosed methods and compositions of the present invention may result in a decrease in ventricular performance 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.
• MPI myocardial performance index
• blood pool MPI blood pool MPI
• tissue doppler MPI tissue doppler MPI
• average isovolumetric contraction and relaxation and other known ventricular performance indices. More specifically, the disclosed methods and compositions of the present invention may result in a decrease in ventricular performance 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 a first and second measurement used to calculate the decrease in ventricular performance can be, for example, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months; about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, or about 15 years, or any combination thereof, e.g., 1 year, 3 months; 4 years, 7 months, etc.
• the disclosed methods and compositions of the present invention may be administered to a SVHD patient, including a Fontan patient, and result in an improvement of ventricular performance over time.
• Ventricular performance can be measured using any conventional known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue doppler MPI, average isovolumetric contraction and relaxation, and other known ventricular performance indices.
• MPI myocardial performance index
• blood pool MPI blood pool MPI
• tissue doppler MPI tissue doppler MPI
• average isovolumetric contraction and relaxation and other known ventricular performance indices.
• the disclosed methods and compositions of the present invention may result in about a 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 ventricular performance, as measured by any known technique, including but not limited to myocardial performance index (MPI), blood pool MPI, tissue doppler MPI, average isovolumetric contraction and relaxation, and other known ventricular performance indices.
• MPI myocardial performance index
• blood pool MPI blood pool MPI
• tissue doppler MPI tissue doppler MPI
• average isovolumetric contraction and relaxation and other known ventricular performance indices.
• the methods include administering daily an effective amount of udenafil, or a pharmaceutically acceptable salt thereof, to the SVHD patient, including a Fontan patient, to improve: (a) ventricular performance of the SVHD patient’s single functioning ventricle as measured by MPI; (b) exercise capacity as measured by oxygen consumption at VAT; (c) exercise capacity as measured by oxygen consumption at maximal effort or max VO 2 ; (d) work rate at VAT; (e) VE/VCO 2 at VAT, each individually or in any combination; (f) diastolic blood pressure at rest; (g) impaired liver function; and (h) oxygen saturation (%) at rest, each individually, collectively or in any combination.
• the methods of the present invention improve (a)-(h) listed above, including individually, collectively or in any combination thereof. More preferably, (a)-(h) listed above, including individually, collectively or in any combination thereof, is improved in accordance with the present invention by administering daily to a SVHD patient, including a Fontan patient, an effective amount of udenafil or a pharmaceutical acceptable sat thereof. As discussed above and used herein, udenafil, or a pharmaceutically acceptable salt thereof, effectively 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.
• PDE5 cGMP-specific phosphodiesterase type 5
• MPI is a measure of ventricular systolic and diastolic function and a prognostic and progression marker for various heart diseases, as determined by a focused echocardiogram. This numeric value is defined as the sum of isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) divided by ejection time (ET) and can be calculated for a single ventricle. The change in the myocardial performance index is determined by velocities obtained from blood pool Doppler assessment of the inflow and outflow tract of the single functioning ventricle.
• MPI is a measure of global systolic and diastolic time intervals to assess global cardiac dysfunction and ventricular performance.
• the MPI is a Doppler index, it is independent of ventricular geometry and can be applied to either left and right ventricular function, depending upon which ventricle is the single functioning ventricle in the SVHD patients. More specifically, the methods include administering daily an effective amount of an effective PDE5 inhibitor or a pharmaceutically acceptable salt thereof, preferably udenafil or a pharmaceutically acceptable salt thereof, to effect one or more of the above improvements without causing treatment- limiting side effects including, but not limited to, blindness or loss of vision via inhibition of photoreceptor phosphodiesterase enzyme (PDE6), back pain and/or myalgia via inhibition of PDE11, such as 11A1 (PDE11A1) and/or decrease in sperm concentration via inhibition of PDE11, such 11A3 (PDE11A3).
• PDE6 photoreceptor phosphodiesterase enzyme
• PDE11A1 11A1
• PDE11A3 decrease in sperm concentration via inhibition of PDE11
• the methods of the present invention increase and/or maximize oxygen consumption at the ventilatory anaerobic threshold (VAT) and at maximum effort or max VO 2 to improve exercise capacity, and increase and/or maximize work rate at VAT and VE/VCO 2 at VAT in SVHD patients, including Fontan patients.
• VAT ventilatory anaerobic threshold
• the methods of the present invention improve impaired liver function, as characterized by the ELF score.
• the methods of the present invention improve, stabilize/maintain, prevent and/or reduce the rate of decline of impaired liver function, that correlates with an ELF score, for at least 12 months and preferably 18 months.
• the methods of the present invention improve, stabilize/maintain, prevent and/or reduce the rate of decline of fibrotic impaired liver function, transform a fibrotic liver into a less fibrotic liver, maintain fibrotic liver condition, and/or reverse fibrotic liver condition and function in patients who have fibrotic livers, as characterized by an ELF score, for at least 12 months, preferably 18 months, especially in patients having single ventricle heart disease (SVHD), who have undergone Fontan surgery and have Fontan physiology. Also, quite uniquely and surprisingly, the methods of the present invention improve the MPI of the SVHD patients, namely, the Fontan patients.
• SVHD single ventricle heart disease
• the methods of the present invention improve both systolic and diastolic function of the single functioning ventricle and the global heart function.
• the methods of the present invention improve the filling and emptying characteristics, i.e., the squeezing ability of the single functioning ventricle and the overall ability of the reconstructed abnormal SVHD heart of the SVHD patients, including the Fontan patients, to pump the freshly oxygenated blood to the body for peripheral tissue needs.
• the clinical value of the MPI improvement is evidenced by the statistically significant improvement in the MPI in those SVHD patients, and in particular the Fontan patients, who were treated with the methods of the present invention, as compared to those SVHD patients, namely the Fontan patients, who were treated with placebo during the FUEL Trial.
• the clinical value of the MPI improvement is also evidenced by the improvement of the single ventricular performance as measured by the isovolumic contraction time, isovolumic relaxation time and ejection time using TDE, as discussed above.
• isovolumetric contraction time IVCT
• IVRT isovolumic relaxation time
• ejection time it is meant herein to mean the single ventricular ejection time (UVET) of the reconstructed abnormal heart determined by the opening and closing of the valve during which the pressure differences across the valve are measured.
• stroke volume it is meant herein to mean the amount of freshly oxygenated blood that the single functioning ventricle can pump out into the circulatory system in one contraction.
• cardiac output it is meant herein to mean the amount of blood the single functioning ventricle in an SVHD patient, including a Fontan patient, can pump through the circulatory system in one minute.
• a normal adult has a cardiac output on average of about 4.7 liters (5 quarts) of blood per minute.
• the stroke volume and the heart rate determine cardiac output.
• the methods of the invention show improved results when udenafil, or a pharmaceutically acceptable salt thereof, is administered as compared to prior very limited studies using a non- udenafil PDE5 inhibitor, such as sildenafil or tadalafil.
• a non-udenafil PDE5 inhibitor such as sildenafil or tadalafil.
• the methods of the invention show fewer side effects, and/or less severe side effects when udenafil, or a pharmaceutically acceptable salt thereof, is administered, as compared to other prior treatments using a non-udenafil PDE5 inhibitor, such as sildenafil or tadalafil.
• the Fontan patient can be an adult human, whereas 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 old, whereas in other embodiments, the Fontan patient can between about 12 and 18 years old. In yet other embodiments, the Fontan patient can be from about 12 to about 16 years old. In yet other embodiments, the Fontan patient can be from about 6 years old to adult. In one embodiment, the Fontan patient can be less than 18 years old. VII. Doses and Dosage Forms The structure of udenafil is shown below:
• udenafil or a pharmaceutically acceptable salt thereof can be administered at total daily dosage amounts of about 0.01 to about 150 mg/kg. In another embodiment, the udenafil or a pharmaceutically acceptable salt thereof can be administered at total daily doses of about 0.01 mg/kg up to about 30 mg/kg.
• udenafil or a pharmaceutically acceptable salt thereof can be administered in a dosage amount of from about 2.5 mg to about 275 mg, such as 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 47.5 mg, about 50 mg, about 52.5 mg, about 55 mg, about 57.5 mg, about 60 mg, about 62.5 mg, about 65 mg, about 67.5 mg, about 70 mg, about 72.5 mg, about 75 mg, about 77.5 mg, about 80 mg, about 82.5 mg, about 85 mg, about 87.5 mg, about 90 mg, about 92.5 mg, about 95 mg, about 97.5 mg, about 100 mg, about 102.5 mg, about 105 mg, about 107.5 mg, about 110 mg, about 112.5 mg, about 115 mg, bout 117.5 mg, about 120 mg, about
• udenafil or a pharmaceutically acceptable salt thereof can be administered at total daily doses of from about 5 mg to about 275 mg, such as 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, about 35 mg, 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, including from about 125 mg to about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 275 mg, so long as any such individual total daily dose does not cause treatment-limiting toxicity or treatment-limiting side effects to the extent that the total daily dose would not be approved for market.
• udenafil or a pharmaceutically acceptable salt thereof can be administered in total daily doses of from about 25 mg to about 700 mg, such as 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 toxicity or treatment-limiting side effects to the extent that the total daily dose would not be approved for market.
• udenafil or a pharmaceutically 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.
• udenafil or a pharmaceutically acceptable salt thereof can be administered at a total daily dose range of from about 37.5 mg to about 175 mg, preferably, a total daily dose range of from 75 mg to about 175 mg, more preferably, a total daily dose range of from about 87.5 mg to about 175 mg and, most preferably, a total daily dose range of from 125 mg to about 175 mg.
• udenafil or any pharmaceutically acceptable salt thereof can be administered to a Fontan patient in any effective dosage amount or in any effective total daily dose, so long as any selected individual dosage amount or any selected individual total daily dose does not cause treatment-limiting toxicity or treatment-limiting side effects to the extent that the total daily dose would not be approved for market.
• the present invention contemplates administration of udenafil or a pharmaceutically acceptable salt thereof to SVHD patients, including Fontan patients, at any dosage amount, at any total daily dose, at any treatment regimen and in any dosage form, so long as when any such dosage amount, total daily dose, treatment regimen or dosage form is selected, it does not cause treatment-limiting toxicity or treatment-limiting side effects to the extent that such would not be approved for market.
• the present invention contemplates administration of udenafil or a pharmaceutically acceptable salt thereof in an effective amount to SVHD patients, including Fontan patients to improve MPI, single ventricular performance, systolic and/or diastolic function, ventricular squeeze capability, cardiac output, exercise capacity or performance at VAT and/or max VO 2 , work rate at VAT, VE/CO2 at VAT, diastolic blood pressure at rest, oxygen saturation (%) at rest and/or decrease the rate of decline of progression of SVHD, as compared to untreated SVHD patients, so long as the therapeutically effective amount does not cause treatment-limiting toxicity, treatment limiting side effects associated with inhibition of PDE6 and/or PDE11, and/or treatment-limiting side effects to the extent that the drug product would not be approved for market or requires discontinued use.
• the present invention also contemplates the administration of udenafil or a pharmaceutically acceptable salt thereof, preferably orally, in an effective amount to SVHD patients, including Fontan patients to improve impaired fibrotic liver function, as characterized by an ELF score for at least 12 months and preferably for at least 18 months, as compared to untreated patients including SVHD patients, so long as the therapeutically effective amount does not cause treatment-limiting toxicity, treatment limiting side effects associated with inhibition of PDE6 and/or PDE11, and/or treatment- limiting side effects to the extent that the drug product would not be approved for market or requires discontinued use.
• the udenafil or a pharmaceutically acceptable salt thereof can be administered once a day.
• the udenafil or a pharmaceutically acceptable salt thereof can be administered once daily or in divided multiple dosages, such as twice a day, three times a day, four times a day or more.
• the udenafil or a pharmaceutically acceptable salt thereof can be administered twice a day such that therapeutically effective blood levels are maintained for at least about 1.5 hours to about 24 hours, more particularly at least about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours of a 24 hour dosing period.
• the present invention therefore contemplates udenafil and/or any udenafil active metabolite, such as DA8164 active metabolite, maintaining an effective blood level for any period of time within a 24 hour dosing period.
• the total daily dosage amount of udenafil or a pharmaceutically acceptable salt administered twice a day can be less than the total daily dosage amount of udenafil or a pharmaceutically acceptable salt thereof administered once a day.
• the total daily dosage amount of udenafil or a pharmaceutically acceptable salt thereof administered twice a day can maintain therapeutically effective blood levels for the same number of hours in a 24 hour period as a higher dosage of udenafil or a pharmaceutically acceptable salt thereof when administered once a day.
• the total daily dosage amount of udenafil or a pharmaceutically acceptable salt thereof administered twice a day can maintain therapeutically effective blood levels for a higher number of hours in a 24 hour period as the same dosage of udenafil or a pharmaceutically acceptable salt thereof when administered once a day.
• the present invention contemplates administration of any total daily dosage amount of udenafil or any acceptable salt thereof once daily or in divided doses multiple times a day, such as twice daily, three times daily, four times daily or more, to maintain therapeutically effective blood levels throughout a 24 hour period.
• twice a day udenafil or a pharmaceutically acceptable salt thereof results in fewer side effects than the administration of once a day udenafil or a pharmaceutically acceptable salt thereof.
• twice a day administration of udenafil or a pharmaceutically acceptable salt thereof can achieve therapeutically effective levels of udenafil at a lower total daily dosage than a once a day administration.
• the pharmaceutically acceptable salt of udenafil can be an acid addition salt.
• the acid addition salt of udenafil can be an inorganic acid addition salt such as, hydrochloric, hydrobromic, sulfuric, or phosphoric acid addition salt.
• the acid addition salt can be an organic acid addition salt such as citrate, tartarate, acetate, lactate, maleate, fumarate, gluconate, methanesulfonate (mesylate), glycolate, succinate, p-toluenesulfonate (tosylate), galacturonate, embonate, glutamate, aspartate, oxalate, benzensulfonate, camphorsulfonate, cinnamate, adipate, or cyclamate.
• organic acid addition salt such as citrate, tartarate, acetate, lactate, maleate, fumarate, gluconate, methanesulfonate (mesylate), glycolate, succinate, p-toluenesulfonate (tosylate), galacturonate, embonate, glutamate, aspartate, oxalate, benzensulfonate, camphorsulfonate, cinnamate,
• the pharmaceutically acceptable salt of udenafil can be an oxalate, benzensulfonate, camphorsulfonate, cinnamate, adipate, or cyclamate salt.
• the udenafil or a pharmaceutically acceptable salt thereof can be administered as a pharmaceutical composition.
• the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated in a wide variety of oral or parenteral dosage forms on clinical application. Each of the dosage forms can contain various disintegrating agents, surfactants, fillers, thickeners, binders, diluents such as wetting agents or other pharmaceutically acceptable excipients.
• the udenafil composition can be administered using any pharmaceutically acceptable method, such as intranasal, buccal, sublingual, oral, rectal, ocular, parenteral (intravenously, intradermally, intramuscularly, subcutaneously, intracisternally, intraperitoneally), pulmonary, intravaginal, locally administered, topically administered, topically administered after scarification, mucosally administered, via an aerosol, or via a buccal or nasal gel or spray formulation.
• any pharmaceutically acceptable method such as intranasal, buccal, sublingual, oral, rectal, ocular, parenteral (intravenously, intradermally, intramuscularly, subcutaneously, intracisternally, intraperitoneally), pulmonary, intravaginal, locally administered, topically administered, topically administered after scarification, mucosally administered, via an aerosol, or via a buccal or nasal gel or spray formulation.
• the udenafil composition can be formulated into any pharmaceutically acceptable dosage form, such as a solid dosage form, including but not limited to a tablet, pill, lozenge, capsule, caplet, orally-disintegrating dosage form, sublingual dosage form, buccal dosage form, liquid, liquid dispersion, liquid suspension, solution, aerosol, pulmonary aerosol, nasal aerosol and semi-solid, namely, ointment, cream, thin film, and gel, and patches such as transdermal patches.
• the composition may be a controlled release formulation, sustained release formulation, immediate release formulation, modified release formulation or any combination thereof.
• the composition may be a transdermal delivery system.
• the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated into a solid dosage form for oral administration, and the solid dosage form can be powders, granules, capsules, tablets, caplets, caches, orally-disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, lozenges or pills.
• the solid dosage form can include one or more excipients such as calcium carbonate, starch, sucrose, lactose, microcrystalline cellulose or gelatin.
• the solid dosage form can include, in addition to the excipients, a lubricant such as talc or magnesium stearate.
• the oral dosage form can be immediate release, or a modified release form.
• Modified release dosage forms include controlled, sustained, modified or extended release, enteric release, and the like.
• the excipients used in the modified release dosage forms are commonly known to a person of ordinary skill in the art.
• a solid carrier may be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, oral dosage form disintegrating agents, or an encapsulating material.
• the oral dosage forms such as powders, granules, capsules, tablets, caplets, caches, lozenges or pills, preferably contain from 5% to 70% of the 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, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, silicon dioxide (e.g., colloidal silicon dioxide), a low melting wax, cocoa butter, and the like.
• lactose e.g., lactose monohydrate
• pectin dextrin
• starch e.g., corn starch
• gelatin tragacanth
• methylcellulose sodium carboxymethylcellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, silicon dioxide (e.g., colloidal silicon dioxide), a low melting wax, cocoa butter, and the like.
• preparation is intended to include the formulation of the udenafil solid, liquid or semi
• Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions.
• liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
• aqueous solutions suitable for oral use can be prepared by dissolving the udenafil in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
• aqueous suspensions suitable for oral use can be made by dispersing the finely divided udenafil in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
• liquid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
• liquid forms include solutions, suspensions, and emulsions.
• the pharmaceutical composition can be formulated in a liquid dosage form for oral administration, such as suspensions, emulsions or syrups, which may contain, in addition to the udenafil, colorants, flavors, stabilizers, buffers (e.g., buffers to adjust the pH to a desirable range for intravenous use such as salts of inorganic acids such as phosphate, borate, and sulfate), artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
• the liquid dosage form can include, in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as humectants, sweeteners, aromatics or preservatives.
• the composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated to be suitable for administration to a pediatric patient.
• the pharmaceutical composition can be formulated in a dosage form for parenteral administration, such as sterile aqueous solutions, suspensions, emulsions or nonaqueous solutions.
• the non-aqueous solutions or suspensions can include propyleneglycol, polyethyleneglycol, vegetable oils such as olive oil or injectable esters such as ethyl oleate.
• the pharmaceutical composition can be formulated in a dosage form for rectal or vaginal administration.
• a base for suppositories witepsol, macrogol, tween 61, cacao oil, laurin oil or glycerinated gelatin can be used.
• the pharmaceutical preparation may require a surfactant or other appropriate co-solvent in the composition.
• co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P103; cyclodextrin; and polyoxyl 35 castor oil.
• co-solvents are typically employed at a level between about 0.01 % and about 2% by weight. Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
• Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.
• the pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the udenafil or any acceptable pharmaceutical salt thereof.
• the unit dosage form can be a packaged preparation, such as a sachet, the package containing discrete quantities of preparation, such as packeted tablets, caplets, capsules, orally-disintegrating dosage forms, sublingual dosage forms, buccal dosage forms and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, caplets, pills, orally- disintegrating dosage forms, sublingual dosage forms, buccal dosage forms, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the pharmaceutical compositions may include components to provide immediate release, sustained release, extended release, modified release, convenience and/or comfort.
• Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates.
• the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated as an orally-disintegrating, sublingual or buccal dosage form.
• dosage forms comprise sublingual tablets or solution compositions that are administered under the tongue and buccal tablets that are placed between the cheek and gum.
• the pharmaceutical preparation may be prepared by further containing a coating agent for example, the light shielding agent capable of generating free radical by UV light, metal oxides such as titanium oxide and the like are described, and as the free radical scavenger, for example, organic acids such as benzoic acid and the like.
• the coating agent may further include, but not be limited to, an water-soluble polymer (e.g., hypromellose or hydroxypropyl cellulose,), an enteric coating layer containing polyethylene glycol, triethyl citrate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, zein, sodium alginate, and mannitol, and/or enteric coating aqueous solution including, for example, ethylcellulose, medium chain triglycerides, oleic acid, sodium alginate, stearic acid.
• an enteric coating layer containing polyethylene glycol, triethyl citrate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate
• the pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated as a nasal dosage form.
• dosage forms of the present invention comprise solution, suspension, emulsion, and gel compositions for nasal delivery.
• the pharmaceutical composition can be formulated in a liquid dosage form for oral administration, such as solutions, suspensions, emulsions or syrups.
• the liquid dosage form can include, in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as humectants, sweeteners, aromatics or preservatives.
• the composition comprising udenafil or a pharmaceutically acceptable salt thereof can be formulated to be suitable for administration to a pediatric patient.
• the dosage of the pharmaceutical composition can vary depending on the patient’s weight, age, gender, administration time and mode, excretion rate, and the severity of disease.
• Exercise Testing can include assessment of VO 2 values during maximal effort or at ventilator anaerobic threshold (“VAT”).
• VAT ventilator anaerobic threshold
• VO 2 max (“peak VO 2 ”), or maximal (“peak”) oxygen consumption refers to the maximum amount of oxygen that an individual can utilize during intense exercise. This measurement is generally considered a reliable indicator of cardiovascular fitness and aerobic endurance. Theoretically, the more oxygen a person can use during exercise, the more energy that person can produce.
• VO 2 is often measured by putting a mask on a subject, and measuring the volume and gas concentrations of inhaled and expired air. This measurement is often used in both clinical settings and research and has been considered the most accurate. Testing commonly involves either exercising on a treadmill or riding a cycle ergometer at increasing intensity until exhaustion, and is designed to provide readings at a maximal effort of the subject and/or at the subject’s anaerobic threshold. Patients that have previously undergone a Fontan procedure will generally see a decline in VO 2 measurements over time.
• MPI Myocardial Performance Index
• MPI is a measure of ventricular systolic and diastolic function as determined by a focused echocardiogram. It combines systolic and diastolic time intervals to assess heart function. More specifically, MPI can be used to assess ventricular performance represented by a numeric value using cardiac time intervals.
• This numeric value equals the sum of isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) divided by ejection time (ET) and can be determined for either the left or right ventricle.
• ICT isovolumetric contraction time
• IRT isovolumetric relaxation time
• E ejection time
• the MPI results from the FUEL Trial were determined by velocities obtained from blood pool Doppler assessment of the inflow and outflow tract of the functioning single ventricle.
• the FUEL Trial MPI was determined by measuring the cardiac time intervals using pulsed-wave Doppler velocity spectra of the ventricular inflow and outflow of the single functioning ventricle.
• Echocardiogram Testing Echocardiograms were performed by sonographers with specific training for this protocol. The primary outcome of interest was MPI using Doppler-based measures of inflow and outflow duration. The duration of inflow into the dominant ventricle and outflow across the dominant semilunar valve were measured and used to calculate MPI using the standard formula.
• 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 normal 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 the tissue Doppler based MPI as previously described.
• the methods of the present invention include methods of treating a patient, including SVHD and Fontan patients, having impaired liver function characterized by an elevated enhanced liver fibrosis (ELF) score for improving or maintaining the function of the impaired liver by reducing the elevated ELF score, wherein the ELF score is characterized by three biomarker components that together form an extracellular matrix (ECM) marker set comprising (i) a tissue inhibitor of metalloproteinases 1 (TIMP-1), (ii) amino-terminal propeptide of type III procollagen (PIIINP) and (iii) hyaluronic acid (HA), wherein the ELF score correlates to liver function, wherein an ELF score above 11.3 characterizes liver cirrhosis, wherein an ELF score from 9.9 to 11.3 characterizes severe fibrosis, wherein an ELF score from 7.7 to 9.9 characterizes moderate fibrosis, wherein an ELF score below 7.7 characterizes no or weak fibrosis, and wherein the patient is in need of treatment to
• the patients’ impaired, fibrotic livers are improved in their function as reflected in the ELF scores by one, two or even three levels of decreased fibrosis as described above.
• patients whose ELF scores initially categorize the liver as cirrhotic upon treatment in accordance with the present invention, may improve to either severe fibrosis or moderate fibrosis or even weak or no fibrosis as indicated by the ELF scores.
• the patients’ impaired fibrotic livers which are maintained against further fibrosis, for example, those patients’ livers which are maintained in a fibrosis-free or mild fibrosis state, as measured according to the ELF score, without progressing to moderate liver fibrosis or severe liver fibrosis or cirrhosis, are maintained at the less fibrotic state for at least one year, more preferably, for at least 18 months.
• patients having moderate liver fibrosis, as indicated by the ELF score is maintained at that level and do not progress to severe fibrosis or cirrhosis, as indicated by the ELF score, for at least one year, preferably for at least 18 months.
• patients having severe fibrosis are maintained without progressing to cirrhosis, as indicated by the ELF score, for at least one year, preferably for at least 18 months.
• the patients’ impaired fibrotic livers which impaired liver function is improved, for example, those patients’ impaired livers which are in a sclerosis state are improved to a severe fibrotic, a moderate fibrotic, and/or a mild fibrotic or a fibrosis-free state, as measured according to the ELF score, are maintained at the less fibrotic state for at least one year, more preferably, for at least 18 months.
• patients having impaired liver function at severe liver fibrosis level are converted to a level of moderate fibrosis and/or mild fibrosis or no-fibrosis state, as indicated by the ELF score, for at least one year, preferably for at least 18 months.
• patients having moderate fibrosis are converted to a mild fibrosis or fibrosis-free state, as indicated by the ELF score, for at least one year, preferably for at least 18 months.
• the results of the FALD trial showed beneficial treatment of fibrotic impaired liver patients.
• Table A shows the average change and average percent change of the Enhanced Liver Fibrosis Score (ELF) from baseline of the patients in the FUEL/FALD test.
• ELF Enhanced Liver Fibrosis Score
• the U+ cohort had been treated with udenafil for 18 months.
• the U- cohort started treatment with udenafil at the same time they started the FALD test, and thus had been treated with udenafil for only a year at the time of the one year sampling.
• EXAMPLE 1 The Fontan Udenafil Exercise Longitudinal (FUEL) Trial The FUEL Trial was conducted at 30 centers around the world. The FUEL Trial was a Phase 3, randomized, double-blind, placebo-controlled trial of udenafil in adolescents with SVHD who had undergone Fontan palliation. The primary aim was to determine the effect of udenafil on exercise capacity in adolescents with Fontan physiology over a six-month period. The primary outcome was the change in oxygen consumption at peak exercise (max or peak VO 2 ) from baseline to the 26-week visit. Secondary exercise outcomes included change in additional measures at maximal exertion, as well as change in measures of submaximal exercise at the ventilatory anaerobic threshold (VAT).
• VAT ventilatory anaerobic threshold
• the primary outcome for clinical secondary aims included change in myocardial performance index (MPI), an echocardiographically-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 level.
• MPI myocardial performance index
• lnRHI log- transformed reactive hyperemia index
• PAT-derived measure of peripheral vascular function a PAT-derived measure of peripheral vascular function
• Table 1 FUEL inclusion and exclusion criteria Inclusion criteria 1 Males and females with Fontan physiology 12- ⁇ 19 y of age at enrollment 2 Participant consent or parental/guardian consent with participant assent 3 Participant fluent in English, Spanish, or Korean Exclusion criteria 1 Weight ⁇ 40 kg 2 Height ⁇ 132 cm 3 Hospitalization for acute decompensated heart failure within the last 12 m 4 Current intravenous inotropic drugs 5 Undergoing evaluation for heart transplantation or listed for transplantation 6 Diagnosis of active protein-losing enteropathy or plastic bronchitis within the last 3 y, oral history of liver cirrhosis 7 Known Fontan baffle obstruction, branch pulmonary artery stenosis, or pulmonary vein stenosis resulting in a mean gradient of .>4 mm I I Ig between the regions proximal and distal to the obstruction as measured by either catheterization or echocardiography, obtained prior to screening for the trial 8 Single lung physiology with greater than flow to 1 lung 9 VO2 max less than 50$ of predicted for
• Randomization and Study Procedures Enrolled participants were assigned to udenafil or placebo in a 1:1 ratio using randomly permuted blocks and stratified by ventricular morphology (left ventricle versus right ventricle or mixed). Randomization assignments were generated by a web-based algorithm after confirmation of trial eligibility and consent.
• Baseline clinical testing completed before drug initiation included a blood draw to measure brain-type natriuretic peptide (BNP) level, a cardiopulmonary exercise test (CPET) using a standardized cycle ergometer ramp protocol, a standardized echocardiogram, and an assessment of peripheral vascular function using peripheral arterial tonometry (PAT) measured by finger cuff (EndoPAT; Itamar Medical, Israel).
• BNP brain-type natriuretic peptide
• CPET cardiopulmonary exercise test
• PAT peripheral arterial tonometry
• RER respiratory exchange ratio
• Participants who achieved maximal effort defined as 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 two weeks of the initial attempt. End-of-study clinical testing included repeat measurement of serum BNP, CPET, echocardiogram, and PAT.
• Statistical Analysis A sample size of 200 participants per arm was chosen to allow for 90% power to detect a mean treatment difference in change from baseline to 26-week testing in max VO 2 of 10% with a type 1 error of 0.05.
• the primary analysis used the intention-to-treat population to evaluate the difference in the change in the primary outcome between treatment arms. This difference was assessed with an analysis of covariance (ANCOVA) with fixed factors for ventricular morphology (single left versus single right or mixed) and treatment group, with a continuous covariate of baseline max VO 2 .
• ANCOVA covariance
• Udenafil and placebo were well tolerated by study participants. There were no deaths in the study cohort. A total of 24 participants (6%) experienced a serious adverse event; 14 in the udenafil group and 10 in the placebo group. There were 3 events in the udenafil group and 2 events in the placebo group that were thought to have a possible, probable, or definite relationship to study drug. Those that occurred in the udenafil group included unilateral retinal artery and vein thrombosis, transient lower extremity diplegia, and transient dyspnea. Frequent non-serious adverse events thought to have a possible, probable, or definite relationship to study drug that occurred in at least 5% of participants in either treatment group are provided in Table 4.
• the FUEL Trial was a Phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between group differences in changes in sub-maximal exercise at the ventilatory anaerobic threshold (VAT), the myocardial performance index (MPI), the natural log of the reactive hyperemia index (lnRHI), and serum brain-type natriuretic peptide (BNP).
• VAT ventilatory anaerobic threshold
• MPI myocardial performance index
• lnRHI the natural log of the reactive hyperemia index
• BNP serum brain-type natriuretic peptide
• Fontan operation the final planned palliative procedure in this series of staged surgical interventions to reconstruct the heart, separates the systemic and pulmonary circulations by creating a total cavopulmonary connection.
• 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).
• the resultant Fontan circulation is characterized by passive pulmonary blood flow, chronically elevated central venous pressure, and low cardiac output.
• Circulation.112(6):828-35 (Aug 92005); 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.
• 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 22014); 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.
• 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.
• the trial was supported by the National Heart, Lung, and Blood Institute (NHLBI)-funded PHN in partnership with the regulatory sponsor, Mezzion Pharma Co. Ltd., under a Special Protocol Assessment through the Food and Drug Administration.
• the FUEL protocol and consent forms and all subsequent amendments were approved by the DSMB, the institution review board or equivalent at each study center, and regulatory agencies from the United States, Canada, and the Republic of Korea. Consent was obtained from the study participant, or the legal guardian for those ⁇ 18 years of age. Assent was obtained from participants >18 years of age.
• the trial design has been published previously.
• Randomization and Study Procedures Enrolled participants were assigned to udenafil or placebo in a 1:1 ratio in a double-blind manner using randomly permuted blocks and stratified by ventricular morphology (left ventricle versus right ventricle or mixed). Randomization assignments were generated by a web-based algorithm after confirmation of trial eligibility and consent.
• Baseline clinical testing completed before drug initiation included a blood draw to measure brain-type natriuretic peptide (BNP) level, a cardiopulmonary exercise test (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.
• BNP brain-type natriuretic peptide
• CPET cardiopulmonary exercise test
• the primary aim was to determine the effect of udenafil on exercise capacity in adolescents with Fontan physiology over a six-month period.
• the primary outcome was the between group difference in the change in oxygen consumption at peak exercise (peak VO 2 ) from baseline to the 26-week visit.
• Secondary exercise outcomes included between group differences in change in additional measures at maximal exertion, as well as change in measures of submaximal exercise at the ventilatory anaerobic threshold (VAT). All measurement of values for exercise testing were initially made by the exercise physiologists and physicians at the individual participating sites. These were subsequently reviewed for accuracy in a blinded fashion at each site by one of two trained reviewers (MGM, SMP) in conjunction with the sites’ exercise teams prior to finalization.
• MGM two trained reviewers
• the primary analysis used the intention-to-treat population to evaluate the difference in the change in the primary outcome between treatment arms. This difference was assessed with an analysis of covariance (ANCOVA) with fixed factors for ventricular morphology (single left versus single right or mixed) and treatment group, with a continuous covariate of baseline peak VO 2 . 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 with two-sided testing.
• the FUEL trial was a phase III clinical trial of udenafil in children with SVHD who have undergone the Fontan operation. Although the relative improvement in peak VO 2 in the udenafil group did not reach statistical significance when compared between treatment arms, treatment with udenafil did lead to statistically significant improvements in pre-specified secondary outcome measures of sub- maximal exercise. Participants randomized to udenafil had superior gains in oxygen consumption, work rate, ventilatory efficiency at the anaerobic threshold, and the myocardial performance index. A relative improvement in the PAT-derived reactive hyperemia index was not seen. Overall, udenafil was well tolerated with few serious adverse events and side effects limited to those known to be associated with PDE5 inhibitor therapy.
• 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 12003); 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.
• 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 22014); 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.
• 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.
• the FUEL trial is the first large-scale, multi- institutional study to suggest a physiologic benefit associated with the use of a specific pulmonary vasodilator at a dose determined by phase I clinical testing in adolescents with SVHD following Fontan palliation. See further Goldberg, D. et al.: Results of the FUEL Trial. Circulation.2020 Feb 25;141:641–651; and Goldberg, D. et al.: Correction to: Results of the FUEL Trial. Circulation.2020 Jul 14;142(2):e31, each of which are incorporated herein by reference in their entireties. The challenges of living with Fontan physiology are well demonstrated by evaluations of exercise performance.
• Adolescents with Fontan physiology have diminished exercise capacity relative to healthy peers, a difference that is accentuated over time and associated with an increased rate of hospitalization and heart failure symptoms.
• Giardini A, Hager A, Pace Napoleone C and Picchio FM Natural history of exercise capacity after the Fontan operation: a longitudinal study.
• EXAMPLE 3 Formulation of Udenafil Tablet An exemplary formulation of a tablet containing 87.5 mg of the udenafil is detailed in Table 8. The udenafil formulation as reported in Table 8 was used with Fontan patients enrolled in the FUEL trial, which is discussed in Examples 1 and 2 above. Table 8: Composition of Udenafil Tablets, 87.5 mg.
• EXAMPLE 4 Udenafil effect on echocardiographic indices of myocardial performance in SVHD subjects with Fontan Palliation
• An objective of the FUEL Trial was to determine the effect of udenafil on echocardiographic measures of myocardial performance in adolescents, ages about 12 to about 18, with a functional single-ventricle physiology after Fontan surgery.
• the FUEL Trial was a randomized, double-blind, placebo-controlled, trial and was conducted in adolescents, ages about 12 to about 18, after the Fontan operation, at 30 different sites located in the United States (26), Canada (2) and South Korea (2).
• the Fontan patients were randomized to receive placebo or udenafil (87.5 mg twice daily) for 26 weeks.
• MPI myocardial performance index
• Myocardial performance is an important factor in the long-term health of those with SVHD, including those with SVHD who have undergone Fontan surgery, and improvement in this aspect of physiology complements the improvement noted in exercise performance and suggests that the benefit of treatment with udenafil may be multifactorial.
• Subjects who had a decrease in ELF score are plotted below the zero line. Subjects that had an increase in ELF score are plotted above the zero line. About 94% of the U+ cohort patients had improved ELF scores.
• In the scatterplot labeled Cohort(N) U+ (subjects treated with udenafil for 78 weeks) all but 2 of 31 subjects had a decrease (improvement) in ELF score.
• In the scatterplot labeled Cohort (N) U- (subjects treated with udenafil for 52 weeks), about 30 of 40 subjects (75%) had a decrease (Improvement) in ELF score. Overall, about 84% of the subjects had an improved ELF score.

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