Combination therapy for the treatment of liver cirrhosis with portal hypertension

Abstract

1. A composition comprising therapeutically effective amounts of zibotentan and dapagliflozin for use in a method of treating cirrhosis in a subject in need thereof.

Description

[Technical Field]

[0001] The present disclosure provides methods and compositions for treating cirrhosis in a subject in need thereof, particularly compositions comprising therapeutically effective amounts of zibotentan and dapagliflozin, and methods of administering the compositions. [Background technology]

[0002] Cirrhosis is the end-stage result of chronic liver injury or disease and can be characterized by advanced fibrosis. Common causes of cirrhosis include viral hepatitis (hepatitis B and hepatitis C), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), while less common causes include autoimmune hepatitis, primary sclerosing cholangitis, primary cholangitis, hemochromatosis, biliary atresia, α1-antitrypsin deficiency, cystic fibrosis-associated cirrhosis, and Wilson's disease (Romanelli et al., 2016). Cirrhosis can be considered compensated if the patient has not developed a clinical complication that impacts outcome (i.e., a decompensation event, such as variceal bleeding, ascites, hepatorenal syndrome or acute kidney injury, hepatic encephalopathy, or hepatocellular carcinoma), or if the patient has decompensated and has at least one clinical complication. In decompensated patients, the liver has a diminished ability to perform vital metabolic, synthetic, and storage functions (Tsochatzis et al., 2014). Cirrhosis can be a severe condition resulting in significant morbidity, resource-intensive complications, hepatocellular carcinoma, and death in the absence of liver transplantation. The 2017 Global Burden of Disease Study reported over 1.32 million cirrhosis-related deaths worldwide, representing approximately 2.4% of all deaths worldwide (GBD 2017 Cirrhosis Collaborators, 2020).

[0003] Portal hypertension is a common feature of chronic liver disease. The primary cause of portal hypertension in cirrhosis is increased intrahepatic vascular resistance due to structural changes associated with fibrosis and increased vascular tone in the hepatic microcirculation (Iwakiri, 2014). When portal hypertension develops, arterial vasodilation occurs, resulting in activation of the RAAS and sympathetic nervous system, increasing blood flow to the portal circulation (Iwakiri, 2014). Ultimately, a hyperactive circulatory syndrome develops, which can lead to portal hypertension, the formation of collateral vessels, and further variceal bleeding, hepatic encephalopathy, and / or ascites (Poordad, 2015).

[0004] Patients with cirrhosis characterized by clinically significant portal hypertension are at significant risk for decompensation and death but have limited pharmacological treatment options. Standard treatment for patients with chronic liver disease focuses on addressing the underlying cause of liver disease, such as alcohol abstinence, antiviral medications for viral hepatitis, and treatment of the underlying metabolic disorder in NASH. Given the continued emergence of fatty liver disease, disease-modifying therapies are generally expected to have only a modest impact on outcomes in patients with cirrhosis and portal hypertension, although some viruses may now be eradicated (Gunarathne et al., 2020). Other treatments may include the use of nonselective beta-blockers, diuretics, and vasoactive agents (Gunarathne et al., 2020). In patients developing variceal bleeding, intervention with a transjugular intrahepatic portosystemic shunt (TIPS) can be used to reduce portal hypertension (Garcia-Pagan et al., 2020). However, none of the above guidelines and interventions can be used to effectively treat cirrhotic patients with features of portal hypertension. Summary of the Invention

[0005] The present disclosure provides a method for treating cirrhosis in a subject in need thereof. In some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the subject has portal hypertension.

[0006] In some embodiments, the subject has a hepatic venous pressure gradient (HVPG) greater than 5 mmHg. In some embodiments, the subject has a HVPG greater than 7.5 mmHg. In some embodiments, the subject has a HVPG greater than 10 mmHg. In some embodiments, the subject has a HVPG greater than 12 mmHg.

[0007] In some embodiments, the subject has at least one of esophageal varices, splenomegaly, variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, recurrent hepatic encephalopathy, lower extremity swelling, coagulopathy, pulmonary complications, and portosystemic shunt.

[0008] In some embodiments, the subject has a Child-Pugh classification of 5 or greater. In some embodiments, the subject has a Child-Pugh classification of 7 or greater. In some embodiments, the subject has a Child-Pugh classification of 10 or greater. In some embodiments, the Child-Pugh classification is not measured in the subject.

[0009] In some embodiments, the subject has a Model for End-Stage Liver Disease (MELD) score of 5 or greater. In some embodiments, the subject has a MELD score of 10 or greater. In some embodiments, the subject has a MELD score of 20 or greater. In some embodiments, the subject has a MELD score of 25 or greater. In some embodiments, the MELD score is not measured in the subject.

[0010] In some embodiments, the subject does not have a decompensation event. In some embodiments, the subject has a decompensation event.

[0011] In some embodiments, the composition contains about 0.1 mg to about 240 mg of zibotentan. In some embodiments, the composition contains about 0.2 mg to about 50 mg of zibotentan. In some embodiments, the composition contains about 0.5 mg to about 20 mg of zibotentan. In some embodiments, the composition contains about 1 mg to about 10 mg of zibotentan.

[0012] In some embodiments, the composition comprises about 1 mg of zibotentan. In some embodiments, the composition comprises about 2.5 mg of zibotentan. In some embodiments, the composition comprises about 5 mg of zibotentan.

[0013] In some embodiments, the composition comprises about 0.1 mg to about 100 mg of dapagliflozin. In some embodiments, the composition comprises about 0.25 mg to about 50 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg to about 10 mg of dapagliflozin.

[0014] In some embodiments, the composition comprises about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 10 mg of dapagliflozin.

[0015] In some embodiments, the composition comprises about 1 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg of zibotentan and about 10 mg of dapagliflozin.

[0016] In some embodiments, the composition comprises about 2.5 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of zibotentan and about 10 mg of dapagliflozin.

[0017] In some embodiments, the composition comprises about 5 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of zibotentan and about 10 mg of dapagliflozin.

[0018] In some embodiments, the composition is an oral dosage form comprising zibotentan and dapagliflozin. In some embodiments, the oral dosage form is a capsule or a tablet.

[0019] In some embodiments, the composition is administered to the subject 1 to 3 times daily. In some embodiments, the composition is administered to the subject once daily.

[0020] In some embodiments, the composition is administered to a subject at least 1-3 times daily for at least 3 weeks. In some embodiments, the composition is administered to a subject at least 1-3 times daily for at least 6 weeks. In some embodiments, the composition is administered to a subject at least 1-3 times daily for at least 12 weeks. In some embodiments, the composition is administered to a subject at least 1-3 times daily for at least 16 weeks. In some embodiments, the composition is administered to a subject at least 1-3 times daily for an extended period of more than 16 weeks (32 weeks, 64 weeks, 1 year, 5 years or more), depending on the needs of the subject(s).

[0021] In some embodiments, the subject has a hepatic venous pressure gradient (HVPG) response, and the HVPG is reduced by at least 10-40% after administering the composition to the subject compared to the subject's baseline HVPG. In some embodiments, the HVPG is reduced by at least 10% after administering the composition to the subject compared to the subject's baseline HVPG. In some embodiments, the subject's HVPG is reduced by at least 15% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 20% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 25% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 30% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 35% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 40% after administering the composition to the subject.

[0022] In some embodiments, the subject has a decrease in hepatic venous pressure gradient (HVPG) to 12 mmHg or less after administering the composition to the subject, compared to the subject's baseline HVPG. In some embodiments, the subject's HVPG is 10 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is 8 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is decreased to 5 mmHg or less after administering the composition to the subject.

[0023] In some embodiments, the subject's HVPG is reduced by at least 1.0 mmHg after administration of the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.5 mmHg after administration of the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.0 mmHg after administration of the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.5 mmHg after administration of the composition to the subject.

[0024] In some embodiments, the subject has one or more of the following outcomes after administration of the composition to the subject: (i) at least a 5% reduction in body weight; (ii) at least a 5% reduction in body water content; (iii) at least a 5% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 130; (v) a reduction in diastolic blood pressure to less than 90; and (vi) at least a 5% reduction in cumulative use of additional loop diuretic equivalents.

[0025] In some embodiments, the subject has one or more of the following outcomes after administration of the composition to the subject: (i) at least a 10% reduction in body weight; (ii) at least a 10% reduction in body water content; (iii) at least a 10% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 120; (v) a reduction in diastolic blood pressure to less than 80; and (vi) at least a 10% reduction in cumulative use of additional loop diuretic equivalents.

[0026] In some embodiments, the subject has one or more of the following outcomes after administration of the composition to the subject: (i) at least a 15% reduction in body weight; (ii) at least a 15% reduction in body water content; (iii) at least a 15% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 110; (v) a reduction in diastolic blood pressure to less than 70; and (vi) at least a 15% reduction in cumulative use of additional loop diuretic equivalents.

[0027] In some embodiments, the cirrhosis results from viral hepatitis (e.g., hepatitis B or hepatitis C), alcoholic liver disease, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or a combination thereof.

[0028] In some embodiments, the cirrhosis is due to cirrhosis associated with autoimmune hepatitis, primary sclerosing cholangitis, primary cholangitis, hemochromatosis, Wilson's disease, biliary atresia, alpha 1-antitrypsin deficiency, and cystic fibrosis, or a combination thereof.

[0029] In some embodiments, the subject is a human subject. In some embodiments, the human subject is between 18 and 80 years old.

[0030] In certain aspects, the present disclosure relates to kits. In some embodiments, the kits include (a) an oral dosage form comprising about 0.25 mg to about 20 mg of zibotentan and a pharmaceutically acceptable excipient, and (b) an oral dosage form comprising about 0.5 mg to about 40 mg of dapagliflozin and a pharmaceutically acceptable excipient.

[0031] In certain aspects, the present disclosure relates to a kit. In some embodiments, the kit includes (a) an oral dosage form comprising about 2.5 mg of zibotentan and a pharmaceutically acceptable excipient, and (b) an oral dosage form comprising about 5 mg of dapagliflozin and a pharmaceutically acceptable excipient.

[0032] In certain aspects, the present disclosure relates to a method for reducing the risk of hospitalization, transjugular intrahepatic portosystemic shunt, and / or transplantation in a subject in need thereof. In some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In certain embodiments, reducing the risk of hospitalization can refer to initial or repeat hospitalization or the total number of hospitalizations. In certain embodiments, reducing the risk of hospitalization can refer to reducing the risk of hospitalization due to a decompensation event.

[0033] In certain aspects, the present disclosure relates to a method of reducing fluid overload associated with cirrhosis in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0034] In certain aspects, the present disclosure relates to a method of reducing the risk of all-cause mortality associated with cirrhosis in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0035] In certain aspects, the present disclosure relates to a method of reducing hepatic portal vein pressure in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0036] In certain aspects, the present disclosure relates to a method for reducing Child-Pugh classification and / or reducing the progression of Child-Pugh classification in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0037] In certain aspects, the present disclosure relates to a method of reducing a MELD score and / or reducing the progression of a MELD score in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0038] In certain aspects, the present disclosure relates to methods of treating cirrhosis or preventing and / or slowing the progression of cirrhosis in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0039] In certain aspects, the present disclosure relates to a method of treating cirrhosis associated with portal hypertension or preventing and / or slowing the progression of cirrhosis associated with portal hypertension in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0040] In certain aspects, the present disclosure relates to a method of treating cirrhosis with clinically significant portal hypertension or preventing and / or slowing the progression of cirrhosis with clinically significant portal hypertension in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0041] In certain aspects, the present disclosure relates to methods of reducing the risk of cirrhosis decompensation or preventing and / or delaying progression to a cirrhosis decompensation event in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0042] In certain aspects, the present disclosure relates to methods for reducing the risk of, and / or preventing and / or delaying progression to, a liver-related decompensation event or death in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0043] In certain aspects, the present disclosure relates to methods for reducing the risk of, or preventing and / or delaying progression to, variceal bleeding and / or mortality in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

[0044] In certain aspects, the present disclosure relates to methods of treating ascites, and / or preventing or reducing the formation of ascites, and / or slowing the progression of ascites, and / or slowing the progression of ascites to complications, in a subject in need thereof, hi some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. [Brief explanation of the drawings]

[0045] The following drawings form part of the present specification and are included to further demonstrate illustrative embodiments of certain aspects of the present disclosure. [Figure 1] The study design of Example 1 is shown. Dapa = dapagliflozin; HVPG = hepatic venous pressure gradient; N = number of participants; Zibo = zibotentan. DETAILED DESCRIPTION OF THE INVENTION

[0046] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings that are commonly understood by those skilled in the art.

[0047] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the method / device being used to determine the value or the variation that exists between study subjects. Typically, the term "about" is meant to encompass less than or equal to about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% variation (either "greater than" or "less than" the stated value), depending on the context. In embodiments, one of ordinary skill in the art will understand the level of variability implied by the term "about" depending on the context in which it is used herein. It should also be understood that use of the term "about" includes specifically recited values.

[0048] The ranges provided herein are of any type and include all values within the specified ranges described, as well as the values associated with the endpoints of the specified ranges. As used herein, "between" refers to a range that includes the ends of the range. For example, a number between x and y explicitly includes the numbers x and y, as well as any number between x and y.

[0049] The term "dosage" refers to a specified amount of a compound or pharmaceutical agent provided in a single administration or over a specified period of time. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments where subcutaneous administration is desired, the desired dose may require a volume not easily accommodated by a single injection. In such embodiments, two or more injections can be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reactions in individuals. In other embodiments, a compound or pharmaceutical agent is administered by infusion over an extended period of time or continuously. A dose may be described as the amount of pharmaceutical agent per hour, day, week, or month.

[0050] The term "efficacy" refers to the ability to produce a desired effect.

[0051] The term "treat" or "treatment" refers to the administration of a compound or pharmaceutical composition to an animal to bring about an alteration or improvement of a disease, disorder, or condition in the animal.

[0052] The term "cirrhosis" refers to the late stage of liver disease, in which the liver becomes significantly scarred and damaged. The scar tissue replaces healthy liver tissue and prevents the liver from functioning normally. As cirrhosis worsens, the liver begins to fail.

[0053] The term "subject" refers to any subject, particularly a mammalian subject, in need of treatment with a combination of zibotentan and dapagliflozin, or treatment with dapagliflozin alone. Mammalian subjects include humans and non-human animals. In some embodiments, the term "subject" refers to a human subject. In some embodiments, the term "subject" refers to a female subject. In some embodiments, the term "subject" refers to a male subject. In some embodiments, the human subject is 12 years of age or older, 14 years of age or older, 4 to 17 years of age or older, or 18 years of age or older. In some embodiments, the human subject is 18 to 80 years of age.

[0054] Non-human animals include, but are not limited to, pigs, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, bears, bovines, apes, monkeys, orangutans, chimpanzees, etc. As used herein, "subject in need thereof" refers to a subject in whom treatment is desirable, for example, a subject with cirrhosis associated with portal hypertension.

[0055] Zibotentan is a compound of formula 1 below.

[0056] [ka] Zibotentan, or ZD4054, is disclosed in WO 1996040681 and is described in ET B A selective endothelin (ET) with a high level of selectivity for A ) receptor antagonist (ET A I C 50 ET = 13nM, up to 50mM B(Morris et al., "Specific inhibition of the endothelin A receptor with ZD4054: clinical and preclinical evidence," Br J Cancer, 2005, 92(12):2148-2152), was previously developed as a potential anticancer drug. Without being bound by any specific mechanism of action, zibotentan may be an antagonist of endothelin (ET-1)-mediated vasoconstriction in the portal vasculature and hepatic stellate cells, which may result in a reduction in portal pressure in established portal hypertension. Studies of beta-blockers in cirrhosis have established that reduced portal hypertension can improve outcomes and reduce the risk of decompensation events and possibly death. Nonselective beta-blockers reduce portal hypertension primarily by reducing blood flow in the portal vein and venous collaterals. Zibotentan may provide further benefit through its effect on hepatic vascular resistance (reduction), improve endothelial function, and, in the long term, may also exhibit antifibrotic effects in the liver, which are expected to improve overall liver function. However, as a chronic monotherapy, the benefit:risk profile of zibotentan in cirrhosis may be unfavorable in some participants, given that ET-1 antagonism may cause fluid retention.

[0057] Dapagliflozin is a compound of formula 2.

[0058] [ka] Dapagliflozin is a potent, selective, orally active inhibitor of sodium-glucose cotransporter 2 (SGLT2) and is effective in treating IC 50=3.75 nM. Dapagliflozin was initially developed to improve glycemic control in patients with diabetes mellitus and provides cardiorenal benefits to patients with and without type 2 diabetes mellitus (T2DM). Dapagliflozin has also been used to treat certain types of heart failure and chronic kidney disease. SGLT2 inhibition blocks glucose and sodium reabsorption in the proximal tubules of the kidney, resulting in osmotic diuresis without subsequent hyponatremia or hyperkalemia, while counteracting the effects of renin-angiotensin-aldosterone system activation.

[0059] In some embodiments, at least one compound is selected from compounds of Formula 2. In some embodiments, at least one compound is in the form of a pharmaceutically acceptable solvate, mixed solvate, or complex. In some embodiments, at least one compound is in a non-crystalline solid form (e.g., an amorphous form). In some embodiments, at least one compound is in a crystalline solid form.

[0060] In some embodiments, at least one compound is in the form of an (S)-propylene glycol ((S)-PG) solvate, having the structure shown below:

[0061] [ka]

[0062] In some embodiments, at least one compound is in the form of a crystalline S-PG solvate. Methods for preparing (S)-PG solvates of dapagliflozin, including crystalline S-PG solvates, are provided in U.S. Patent No. 7,919,598.

[0063] In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compounds of Formula 2 and prodrugs thereof, alone or in combination with at least one other therapeutic agent.

[0064] The mechanisms of action of zibotentan and dapagliflozin are different. Without being bound by any particular theory, in some embodiments, zibotentan blocks changes in intrahepatic resistance (including portal and sinusoidal vasoconstriction) caused by endothelin-1, reducing vascular stiffness, improving endothelial function, and reducing liver inflammation, potentially reducing fibrosis in the long term. Separately, in some embodiments, dapagliflozin can have beneficial effects on metabolic dysfunction, reducing hepatocellular injury and sodium and water overload, potentially normalizing blood volume while avoiding hyponatremia and hyperkalemia. The reduced need for diuretics may also potentially reduce the risk of other complications, such as acute kidney injury or encephalopathy.

[0065] In some embodiments, the subject has portal hypertension. The term "portal hypertension" refers to abnormally elevated portal vein pressure - blood pressure in the portal vein and its branches, which drain most of the intestine to the liver. In some embodiments, portal hypertension is defined as a hepatic venous pressure gradient (HVPG) greater than 5 mmHg. In some embodiments, HVPG greater than 10 mmHg is defined as clinically significant. In subjects with cirrhosis, HVPG refers to portal vein pressure. In some embodiments, the subject has an HVPG greater than 4 mmHg, 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, or 12 mmHg. In some embodiments, the subject has an HVPG greater than 5 mmHg. In some embodiments, the subject has an HVPG greater than 7.5 mmHg. In some embodiments, the subject has an HVPG greater than 10 mmHg. In some embodiments, the subject has an HVPG greater than 12 mmHg.

[0066] In some embodiments, HVPG is measured either directly or indirectly by methods known to those skilled in the art. In some embodiments, HVPG is measured directly, for example, by direct catheterization of the portal vein, e.g., Myers JD, Taylor WJ, "An estimation of portal venous pressure by occlusive catheterization of a hepatic venule," J Clin Invest, 30 (1951), pp. 662-663. In some embodiments, HVPG is measured indirectly, for example, by compressing (occluding) the hepatic vein using a balloon catheter. See, e.g., Groszmann RJ, Glickman MC, Blei AT, Storer E., Conn HO, "Wedged and free hepatic venous pressure measured with a balloon catheter," Gastroenterology, 76 (1979), pp. 253-258.

[0067] In some embodiments, HVPG is a clinical measurement of the pressure gradient between obstructed hepatic venous pressure (WHVP) and free hepatic venous pressure (FHPV), and is therefore an estimate of the pressure gradient between the portal vein and the inferior vena cava. HVPG greater than 5 mmHg defines portal hypertension, and a measurement greater than 10 mmHg is called clinically significant portal hypertension. At levels greater than 12 mmHg, the risk of variceal bleeding may further increase.

[0068] In some embodiments, when blood flow in the hepatic vein is stopped by an inflated balloon, the proximal static column of blood transmits pressure from the preceding transmitted vascular region (hepatic sinusoids) to the catheter. Therefore, WHVP reflects hepatic sinusoidal pressure, not portal vein pressure itself. In a normal liver, occlusion pressure is slightly lower than portal vein pressure due to pressure equilibration through interconnected sinusoids, but this difference is not clinically significant. In cirrhosis, the static column generated by balloon inflation cannot be decompressed at the sinusoidal level due to the destruction of normal intersinusoidal communication. Therefore, HVPG (WHVP-FHVP) provides an accurate estimate of portal vein pressure in cirrhosis.

[0069] In some embodiments, HVPG is not measured directly or indirectly, but is determined by observing the characteristics consistent with portal hypertension in the subject.In some embodiments, the subject has clinically significant portal hypertension (CSPH).In some embodiments, the term "portal hypertension characteristics" includes the subject having compensated cirrhosis associated with CSPH, such as the signs and symptoms of esophageal varices, portosystemic shunt, splenomegaly and low platelet count, or the subject has decompensated events, including variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, and recurrent hepatic encephalopathy.

[0070] In some embodiments, the subject has a decompensation event. In some embodiments, a "decompensation event" can include ascites, hepatic encephalopathy, hepatorenal syndrome, acute kidney injury, or variceal bleeding. In some embodiments, the subject exhibits one or more decompensation events, such as esophageal varices, variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, recurrent hepatic encephalopathy, jaundice, or pulmonary complications (including their onset, worsening, and / or complications). In some embodiments, the subject does not have a decompensation event. In some embodiments, the "Child-Pugh Classification" is used to assess the prognosis of chronic liver disease, primarily cirrhosis. The "Child-Pugh Classification" was originally used to predict intraoperative mortality, but is now used to determine prognosis, the required intensity of treatment, and the need for liver transplantation. See, for example, Andrea Tsoris; Clinton A. Marlar, "Use of the Child-Pugh Score in Liver Disease," [Updated 2022 Mar 18]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; (2022): Available at https: / / www.ncbi.nlm.nih.gov / books / NBK542308 / (Accessed June 29, 2022). Chronic liver disease can be classified into Child-Pugh classes A-C, with class A having a Child-Pugh score of 5-6, class B having a Child-Pugh score of 7-9, and class C having a Child-Pugh score of 10-15. The higher the Child-Pugh score, the higher the mortality risk.

[0071] In some embodiments, the subject has a Child-Pugh classification of 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more. In some embodiments, the subject has a Child-Pugh classification of 5 or more. In some embodiments, the subject has a Child-Pugh classification of 7 or more. In some embodiments, the subject has a Child-Pugh classification of 10 or more. In some embodiments, the Child-Pugh classification is not measured in the subject.

[0072] In some embodiments, the term "Model for End-Stage Liver Disease (MELD) score" is used to evaluate liver disease. MELD is a prognostic scoring system based on laboratory parameters used to predict 3-month mortality due to liver disease. See, for example, Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31(4):864-871, and Biggins SW, Kim WR, Terrault NA, et al. Evidence-Based Incorporation of Serum Sodium Concentration Into MELD. Gastroenterology. 2006;130(6):1652-1660. In some embodiments, the MELD score can include the addition of serum sodium to the MELD score, i.e., MELD-Na. See, e.g., Ruf AE, et al., "Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone," Liver Transpl. 2005 Mar;11(3):336-43. MELD scores range from 6 to 40, with higher scores associated with higher 3-month liver disease-related mortality.

[0073] In some embodiments, the subject has a MELD score of 10 or greater, 15 or greater, 20 or greater, 25 or greater, 30 or greater, 35 or greater, or 40 or greater. In some embodiments, the subject has a MELD score of 10 or greater. In some embodiments, the subject has a MELD score of 20 or greater. In some embodiments, the subject has a MELD score of 25 or greater. In some embodiments, the MELD score is not measured in the subject. In some embodiments, the subject has clinical or radiological features of clinically significant portal hypertension. Such features may include, but are not limited to, BAVENO VII criteria, including esophageal varices, side branch imaging, liver stiffness greater than 25 kPa, or liver stiffness greater than 20 kPa and a 150×10 9 Decompensation events include the presence of a platelet count less than 1 / L, and / or a history of a decompensation event. See, e.g., Franchis et al., Baveno VII - Renewing consensus in portal hypertension. Journal of Hepatology. 2022;76:959-974. In some embodiments, the previously compensated subject has a first decompensation event, wherein the first decompensation event is selected from variceal bleeding, hepatic encephalopathy, and / or ascites. In some embodiments, the subject is already decompensated and has a further decompensation event selected from: a) the development of a second portal hypertension-driven decompensation event (ascites, variceal bleeding, or hepatic encephalopathy) and / or jaundice; b) recurrent variceal bleeding, recurrent ascites (requiring 3 or more large-volume paracentesis procedures within one year), recurrent encephalopathy, spontaneous bacterial peritonitis and / or hepatorenal syndrome and / or acute kidney injury; c) in subjects presenting with only hemorrhage, the development of ascites, encephalopathy, or jaundice occurs after recovery from the hemorrhage, but not if these events occur around the time of hemorrhage. See Franchis at 967. In some embodiments, the subject has cirrhosis with features of portal hypertension. In some embodiments, the subject has cirrhosis with features of clinically significant portal hypertension. In some embodiments, the subject has compensated cirrhosis, and in some cases, the subject has decompensated cirrhosis.

[0074] In some embodiments, an effective or therapeutically effective amount of zibotentan and dapagliflozin can be administered to a subject. The term "effective amount" or "therapeutically effective amount" refers to an amount of a specified compound sufficient to achieve a desired physiological result in an individual in need of the compound. The effective amount may vary between individuals depending on the health and condition of the individual being treated, the taxonomic group of the individual being treated, the formulation of the composition, an assessment of the individual's condition, and other relevant factors.

[0075] In some embodiments, the composition may contain various amounts of zibotentan. In some embodiments, the composition contains a therapeutically effective amount of zibotentan. In some embodiments, the composition contains about 0.1 mg to about 240 mg of zibotentan. In some embodiments, the composition contains about 0.2 mg to about 50 mg of zibotentan. In some embodiments, the composition contains about 0.5 mg to about 20 mg of zibotentan. In some embodiments, the composition contains about 1 mg to about 10 mg of zibotentan. In some embodiments, the composition contains about 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 30 mg, 60 mg, 120 mg, or 240 mg of zibotentan. In some embodiments, the composition contains about 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, or 10 mg of zibotentan. In some embodiments, the composition contains about 1 mg of zibotentan. In some embodiments, the composition contains about 2.5 mg of zibotentan. In some embodiments, the composition contains about 5 mg of zibotentan.

[0076] In some embodiments, the composition can include various amounts of dapagliflozin. In some embodiments, the composition includes a therapeutically effective amount of dapagliflozin. In some embodiments, the composition includes about 0.1 mg to about 100 mg of dapagliflozin. In some embodiments, the composition includes about 0.25 mg to about 50 mg of dapagliflozin. In some embodiments, the composition includes about 1 mg to about 10 mg of dapagliflozin.

[0077] In some embodiments, the composition comprises about 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 10 mg of dapagliflozin.

[0078] In some embodiments, the composition comprises therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the composition comprises about 0.2 mg to about 25 mg of zibotentan and about 0.5 mg to about 25 mg of dapagliflozin. In some embodiments, the composition comprises about 0.2 mg to about 25 mg of zibotentan and about 1.25 mg to about 20 mg of dapagliflozin. In some embodiments, the composition comprises about 0.2 mg to about 25 mg of zibotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0079] In some embodiments, the composition comprises about 0.5 mg to about 10 mg of zibotentan and about 0.5 mg to about 25 mg of dapagliflozin. In some embodiments, the composition comprises about 0.5 mg to about 10 mg of zibotentan and about 1.25 mg to about 20 mg of dapagliflozin. In some embodiments, the composition comprises about 0.5 mg to about 10 mg of zibotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0080] In some embodiments, the composition comprises about 1 mg to about 5 mg of zibotentan and about 0.5 mg to about 25 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg to about 5 mg of zibotentan and about 1.25 mg to about 20 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg to about 5 mg of zibotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0081] In some embodiments, the composition comprises about 0.2 mg, about 0.5 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of zibotentan and about 0.5 mg, about 1 mg, about 1.25 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of dapagliflozin.

[0082] In some embodiments, the composition comprises about 1 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg of zibotentan and about 10 mg of dapagliflozin.

[0083] In some embodiments, the composition comprises about 2.5 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of zibotentan and about 10 mg of dapagliflozin.

[0084] In some embodiments, the composition comprises about 5 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of zibotentan and about 10 mg of dapagliflozin.

[0085] In some embodiments, the ratio of zibotentan to dapagliflozin can be fixed in the composition, for example, when the composition is manufactured to provide multiple fixed dosage forms. For example, in some embodiments, the composition is in an amount that forms more than 1, more than 10, or more than 1000 dosage forms (e.g., capsules or tablets). In some embodiments, one of skill in the art will understand that any of the amounts listed above for a "composition" can also apply to a single "dosage form." Thus, for example, a disclosure that "the composition comprises about 5 mg of zibotentan and about 2.5 mg of dapagliflozin" includes a single dosage form comprising about 5 mg of zibotentan and about 2.5 mg of dapagliflozin.

[0086] In some embodiments, the weight ratio of zibotentan to dapagliflozin in the composition is about 1:50 to about 10:1, about 1:20 to about 4:1, or about 1:10 to about 2:1. In some embodiments, the weight ratio of zibotentan to dapagliflozin in the composition is about 1:2.5, about 1:5, or about 1:10. In some embodiments, the weight ratio of zibotentan to dapagliflozin in the composition is about 1:1 to about 1:2, or about 1:4. In some embodiments, the weight ratio of zibotentan to dapagliflozin in the composition is about 2:1, about 1:1, or about 1:2.

[0087] The term "administration" or "administering" refers to a route of introducing a compound or composition provided herein into an individual to perform its intended function. Examples of routes of administration that may be used include, but are not limited to, oral administration or parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion. In some embodiments, the route of administration is oral administration. In some embodiments, the methods described herein are carried out orally, for example, via an oral dosage form. In some embodiments, the oral dosage form therefrom is a capsule or tablet.

[0088] As used herein, a dosage form or unit dose refers to a pharmaceutical preparation in a form marketed for use, dispensed into a specific dosage, with a specific mixture of active ingredients and inactive ingredients (excipients) in a specific configuration (e.g., capsule shell). Because different medical conditions may warrant different routes of administration, various dosage forms may exist for a single specific drug. Dosage forms may include, for example, oral dosage forms, ophthalmic dosage forms, inhalation, injection, parenteral, topical, or suppository dosage forms. Oral dosage forms may include, for example, pills in the form of tablets or capsules, syrups, specialty tablets such as buccal, sublingual, or orally disintegrating tablets, thin films, liquids, or suspensions, powders, liquids, or solid crystals, natural or herbal plants, seeds, or certain foods, pastes, or oral films.

[0089] In some embodiments, zibotentan is in an oral dosage form. In some embodiments, the zibotentan oral dosage form is a capsule or tablet. In some embodiments, dapagliflozin is in an oral dosage form. In some embodiments, the dapagliflozin oral dosage form is a capsule or tablet. In some embodiments, the composition, i.e., a composition comprising zibotentan and dapagliflozin, is in an oral dosage form. In some embodiments, the zibotentan / dapagliflozin oral dosage form is a capsule or tablet. In some embodiments, the zibotentan / dapagliflozin oral dosage form is a capsule.

[0090] In some embodiments, the composition is administered to the subject 1 to 3 times daily. In some embodiments, the composition is administered to the subject twice daily. In some embodiments, the composition is administered to the subject once daily.

[0091] As used herein, the term "daily" refers to a 24-hour period. For example, in some embodiments, the compositions of the present disclosure can be administered in the morning, evening, or midday. In some embodiments, the compositions of the present disclosure can be administered after ingesting food (e.g., after a meal) or before ingesting food (e.g., before a meal, i.e., in a fasted state). The frequency of administration of the composition can be determined by one of skill in the art. In some embodiments, the compositions of the present disclosure can be administered at 8-hour, 12-hour, or 24-hour intervals. In some embodiments, the compositions are administered daily, twice daily, or three times daily. In some embodiments, the compositions are administered weekly, twice weekly, or three times weekly. In some embodiments, the compositions are administered monthly, twice monthly, or three times monthly. In some embodiments, the compositions are administered no more than once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every seven weeks. In some embodiments, the compositions are administered "as needed," for example, when symptoms associated with cirrhosis decompensation occur, until symptoms are alleviated.

[0092] In some embodiments, the composition is administered to a subject once to three times daily for at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, or more. In certain embodiments, the composition is administered to a subject once daily for 3 weeks, or 6 weeks, or 12 weeks, or 16 weeks, or 18 weeks, or more. In some embodiments, the composition is administered to a subject at least 1 to 3 times daily for an extended period of more than 16 weeks (32 weeks, 64 weeks, 1 year, 5 years or more), depending on the needs of the subject(s).

[0093] In some embodiments, the present disclosure provides a method of reducing portal vein pressure in a subject. In some embodiments, the reduction in portal vein pressure in a subject is determined by any of the methods described herein (e.g., a reduction in HVPG) using any of the methods and compositions described herein.

[0094] In some embodiments, the subject has a hepatic venous pressure gradient (HVPG) response, and the HVPG is reduced by at least 10% compared to the subject's baseline HVPG after administering the composition to the subject once to three times daily for six weeks. In some embodiments, baseline HVPG refers to the subject's HVPG immediately prior to administration of the composition. Thus, for a subject with an elevated HVPG of 10 mmHg, the phrase "at least a 10% reduction in HVPG after administration of a composition to the subject" would indicate a reduction of at least 1 mmHg (i.e., 10% of 10 mmHg) in the subject after administration of a composition described herein. In some embodiments, the subject's HVPG is reduced by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% after administration of the composition to the subject. In some embodiments, the subject's HVPG is reduced by about 10% to about 50%, about 20% to about 40%, or about 20% to about 30% after administration of the composition to the subject.

[0095] In some embodiments, the subject's HPVPG decreases by 1 mmHg to 8 mmHg, 1 mmHg to 7 mmHg, 1 mmHg to 6 mmHg, 2 mmHg to 5 mmHg, or 3 mmHg to 4 mmHg after administering the composition to the subject. In some embodiments, the subject's HPVPG decreases by less than about 5 mmHg, less than 6 mmHg, less than 7 mmHg, or less than 8 mmHg after administering the composition to the subject. In some embodiments, the HVPG measurement is performed after administering the composition to the subject 1 to 3 times daily for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or more. In some embodiments, the HVPG measurement is performed after administering the composition to the subject 1 to 3 times daily for 6 weeks. In some embodiments, the HVPG measurement is performed after administering the composition to the subject once daily for 6 weeks or more.

[0096] In some embodiments, the HVPG endpoint can also be determined according to HVPG measurements in mmHg. In some embodiments, the subject has a decrease in HVPG, where the HVPG is 12 mmHg or less relative to the subject's baseline HVPG after administering the composition to the subject. In some embodiments, the subject's HVPG response is 11 mmHg, 10 mmHg, 9 mmHg, 8 mmHg, 7 mmHg, 6 mmHg, or 5 mmHg or less after administering the composition to the subject. In some embodiments, the HVPG measurement is performed after administering the composition to the subject once to three times daily for six weeks.

[0097] In some embodiments, the effect of administering the composition can also be evaluated using secondary endpoints. In some embodiments, the subject has one or more of the following outcomes after administering the composition to the subject: (i) a reduction in body weight of at least 5%; (ii) a reduction in total body water of at least 5%; (iii) a reduction in body fat of at least 5%; (iv) a reduction in systolic blood pressure to less than 130; (v) a reduction in diastolic blood pressure to less than 90; and (vi) a reduction in cumulative use of additional loop diuretic equivalents of at least 5%.

[0098] In some embodiments, the subject has one or more of the following outcomes after administration of the composition to the subject: (i) at least a 10% reduction in body weight; (ii) at least a 10% reduction in body water content; (iii) at least a 10% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 120; (v) a reduction in diastolic blood pressure to less than 80; and (vi) at least a 10% reduction in cumulative use of additional loop diuretic equivalents.

[0099] In some embodiments, the subject has one or more of the following outcomes after administration of the composition to the subject: (i) at least a 15% reduction in body weight; (ii) at least a 15% reduction in body water content; (iii) at least a 15% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 110; (v) a reduction in diastolic blood pressure to less than 70; and (vi) at least a 15% reduction in cumulative use of additional loop diuretic equivalents.

[0100] In some embodiments, the method of treating cirrhosis can be continued until one or more of the secondary endpoints is met.

[0101] In some embodiments, the subject has at least a 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% reduction in body weight after administering the composition to the subject one to three times daily for six weeks.

[0102] In some embodiments, the subject has at least a 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% reduction in body water content after administering the composition to the subject one to three times daily for six weeks.

[0103] In some embodiments, the subject has at least a 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% reduction in body fat mass after administering the composition to the subject one to three times daily for six weeks.

[0104] In some embodiments, the subject's systolic blood pressure is reduced to less than 140, less than 135, less than 130, less than 125, or less than 120 after administering the composition to the subject one to three times daily for six weeks.

[0105] In some embodiments, the subject's diastolic blood pressure is reduced to less than 90, less than 88, less than 86, less than 84, less than 82, or less than 80 after administering the composition to the subject one to three times daily for six weeks.

[0106] In some embodiments, the subject experiences a reduction in cumulative use of additional loop diuretic equivalents by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% after administering the composition to the subject one to three times daily for six weeks.

[0107] The methods described herein are for the treatment of cirrhosis. Cirrhosis can be caused by diseases (e.g., viral infections) or conditions (e.g., chronic alcoholism, obesity, etc.) that cause scar tissue to form in the liver, impairing its function. In some embodiments, the cirrhosis is caused by viral hepatitis, alcoholic liver disease, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or a combination thereof. In some embodiments, the cirrhosis is caused by autoimmune hepatitis, primary sclerosing cholangitis, primary cholangitis, hemochromatosis, Wilson's disease, biliary atresia, alpha 1-antitrypsin deficiency, and cirrhosis associated with cystic fibrosis, or a combination thereof. A "subject in need" of treatment can include any subject with cirrhosis, regardless of the cause of the cirrhosis. Furthermore, in some embodiments, a "subject in need" of treatment can include any subject with cirrhosis, even if the subject has not exhibited a decompensation event.

[0108] In certain embodiments, in addition to the methods for treating cirrhosis described herein, subjects can also be treated with additional standard of care (SoC) therapies. Here, the term "standard of care" refers to the diagnostic and treatment process that a clinician follows for a particular type of patient, disease, or clinical situation. In some embodiments, standard of care for cirrhosis can include, for example, a low-sodium diet and medication (e.g., beta-blockers such as carvedilol) to reduce portal vein pressure, diuretics such as spironolactone or furosemide to prevent fluid buildup in the body, drainage or surgery to relieve pressure if the subject experiences severe fluid buildup, antibiotic treatment, or other treatments associated with cirrhosis. In some embodiments, the methods of the present disclosure further include (i) administration of an additional active agent; (ii) administration of a low-sodium diet; or (iii) a combination thereof.

[0109] In certain aspects, the present disclosure provides oral dosage forms comprising zibotentan and dapagliflozin. The present disclosure provides that a combination of therapeutically effective amounts of zibotentan and dapagliflozin, for example when taken orally together in the same dosage form, can be useful for treating liver cirrhosis. In some embodiments, the oral dosage form comprises: (i) about 0.25 mg to about 20 mg of zibotentan; (ii) about 0.5 mg to about 40 mg of dapagliflozin; and (iii) a pharmaceutically acceptable excipient.

[0110] In some embodiments, the oral dosage form comprises about 0.5 mg to about 10 mg of zibotentan and about 1 mg to about 20 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 1.0 mg to about 5 mg of zibotentan and about 2.5 mg to about 10 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg to about 5 mg of zibotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0111] In some embodiments, the oral dosage form comprises about 1 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 1 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the single oral dosage form comprises about 1 mg of zibotentan and about 10 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg of zibotentan and about 2.5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg of zibotentan and about 10 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 5 mg of zibotentan and about 5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 5 mg of zibotentan and about 10 mg of dapagliflozin.

[0112] In some embodiments, the present disclosure provides kits comprising the compositions and / or dosage forms described herein for use in the methods described herein. In some embodiments, the kit comprises (a) an oral dosage form comprising about 0.25 mg to about 20 mg of zibotentan and a pharmaceutically acceptable excipient, and (b) an oral dosage form comprising about 0.5 mg to about 40 mg of dapagliflozin and a pharmaceutically acceptable excipient. In some embodiments, the kit comprises (a) a plurality of dosage forms comprising zibotentan, wherein each individual oral dosage form of zibotentan comprises about 0.25 mg to about 20 mg of zibotentan and a pharmaceutically acceptable excipient, and (b) a plurality of dosage forms comprising dapagliflozin, wherein each oral dosage form of dapagliflozin comprises about 0.5 mg to about 40 mg of dapagliflozin and a pharmaceutically acceptable excipient.

[0113] In some embodiments, the kit comprises (a) an oral dosage form comprising about 2.5 mg of zibotentan and a pharmaceutically acceptable excipient, and (b) an oral dosage form comprising about 5 mg of dapagliflozin and a pharmaceutically acceptable excipient. In some embodiments, the kit comprises (a) a plurality of dosage forms comprising zibotentan, wherein each individual oral dosage form of zibotentan comprises about 2.5 mg of zibotentan and a pharmaceutically acceptable excipient, and (b) a plurality of dosage forms comprising dapagliflozin, wherein each oral dosage form of dapagliflozin comprises about 5 mg of dapagliflozin and a pharmaceutically acceptable excipient.

[0114] In some embodiments, the kit includes 1 to 31 dosage forms comprising a zibotentan dosage form and 1 to 31 dosage forms comprising dapagliflozin. In some embodiments, the kit includes (a) a number of dosage forms comprising zibotentan sufficient to treat a subject for 1 week, 1 month, 2 months, or 3 months, and (b) a number of dosage forms comprising dapagliflozin sufficient to treat a subject for 1 week, 1 month, 2 months, or 3 months. In some embodiments, the kit includes instructions for administering the dosage forms found in the kit. In some embodiments, the kit includes packaging for transport and storage of the oral dosage forms. In some embodiments, the packaging separates the zibotentan dosage form from the dapagliflozin dosage form.

[0115] In certain aspects, the present disclosure relates to methods for reducing portal vein pressure in a subject in need thereof. In some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering to the subject a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the HVPG is reduced by at least 20% after administration of the composition to the subject. In some embodiments, the HVPG of the subject is reduced by at least 25% after administration of the composition to the subject. In some embodiments, the HVPG of the subject is reduced by at least 30% after administration of the composition to the subject. In some embodiments, the HVPG of the subject is reduced by at least 35% after administration of the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 40% after administering the composition to the subject. In some embodiments, the subject has a reduction in hepatic venous pressure gradient (HVPG) to 12 mmHg or less after administering the composition to the subject, compared to the subject's baseline HVPG. In some embodiments, the subject's HVPG is 10 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is 8 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced to 5 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.0 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.5 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.0 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.5 mmHg after administering the composition to the subject.

[0116] In certain aspects, the present disclosure relates to methods for reducing a subject's Child-Pugh score in need thereof to a score lower than the subject's Child-Pugh score prior to administration. In some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the Child-Pugh score is reduced by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, or more. In at least one embodiment, the Child-Pugh score is reduced by at least 5 points or more. In at least one embodiment, the subject's Child-Pugh classification is reduced to a class of differing severity (e.g., Class B reduced to Class A after administration of the composition to the subject, or Class C reduced to Class B after administration of the composition to the subject).

[0117] In certain aspects, the present disclosure relates to methods for reducing the MELD score of a subject in need thereof to a score lower than the subject's MELD score prior to administration. In some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the MELD score is reduced by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, or more. In at least one embodiment, the MELD score is reduced by at least 5 points, or at least 10 points, or at least 15 points, or at least 20 points or more.

[0118] In certain aspects, the present disclosure relates to a method of treating cirrhosis in a subject in need thereof, the method comprising administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the cirrhosis can be compensated or decompensated. In some aspects, the subject can be compensated or decompensated. A decompensated subject can be either stable or unstable, having recently suffered recurrent decompensation, e.g., within the last 1 to 3 months.

[0119] In certain aspects, the present disclosure relates to a method of treating portal hypertension in a subject with cirrhosis in need thereof, the method comprising administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the method reduces the subject's HVPG by at least 20% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 25% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 30% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 35% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 40% after administering the composition to the subject. In some embodiments, the subject has a reduction in hepatic venous pressure gradient (HVPG) to 12 mmHg or less after administering the composition to the subject, compared to the subject's baseline HVPG. In some embodiments, the subject's HVPG is 10 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is 8 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced to 5 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.0 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.5 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.0 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.5 mmHg after administering the composition to the subject.

[0120] In certain aspects, the present disclosure relates to a method of treating clinically significant portal hypertension in a subject with cirrhosis in need thereof, the method comprising administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the method reduces the subject's HVPG by at least 20% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 25% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 30% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 35% after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 40% after administering the composition to the subject. In some embodiments, the subject has a reduction in hepatic venous pressure gradient (HVPG) to 12 mmHg or less after administering the composition to the subject, compared to the subject's baseline HVPG. In some embodiments, the subject's HVPG is 10 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is 8 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced to 5 mmHg or less after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.0 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 1.5 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.0 mmHg after administering the composition to the subject. In some embodiments, the subject's HVPG is reduced by at least 2.5 mmHg after administering the composition to the subject.

[0121] In certain aspects, the disclosure relates to methods for reducing the risk of variceal bleeding and / or mortality, or preventing and / or delaying the progression of variceal bleeding and / or mortality, comprising administering to a subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin.

[0122] In certain aspects, the present disclosure provides methods for reducing the risk of cirrhosis decompensation or preventing and / or delaying the progression of cirrhosis decompensation and death in a subject in need thereof, comprising administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the method reduces the risk of developing new variceal bleeding, worsening hepatic encephalopathy, or worsening ascites.

[0123] In certain aspects, the present disclosure relates to methods of treating ascites, and / or preventing or reducing the formation of ascites, and / or delaying the progression of ascites, preventing complications of ascites (e.g., bacterial peritonitis, hepatic pleural effusion, or refractory ascites), and / or reducing the amount of ascites in a subject in need thereof. In some embodiments, the method comprises administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin. In some embodiments, the method prevents the development of Grade 1 ascites. In some embodiments, the method delays or prevents the progression of ascites from grade 1 to grade 2 or from grade 2 to grade 3. In some embodiments, the method reduces the severity of ascites, for example, from grade 3 to grade 2, or from grade 2 to grade 1, or from grade 1 to the absence of ascites. "Grade 1" ascites is understood to mean mild ascites, detectable only by imaging or ultrasound. "Grade 2" ascites is understood to mean moderate ascites, manifested by moderate, symmetric abdominal distension. "Grade 3" ascites is understood to mean bulky or macroscopic ascites distinguished by significant abdominal distension.

[0124] In certain aspects, the present disclosure provides methods for reducing the combined time to variceal bleeding, encephalopathy, worsening or complications of ascites (e.g., bacterial peritonitis, hepatic pleural effusion, or refractory ascites), and all-cause mortality in a subject in need thereof, the method comprising administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., a capsule or tablet) comprising about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin.

[0125] The term "preventing" refers to halting the onset, development, or progression of a disease, disorder, or condition for a period ranging from minutes to indefinitely. Delaying refers to forestalling the onset, development, or progression of a disease, disorder, or condition for a period ranging from minutes to indefinitely. The terms "reducing" or "reducing" mean to reduce to a smaller degree, size, amount, or number. Thus, "reducing the risk of cirrhosis decompensation" includes reducing the incidence and / or magnitude of cirrhosis decompensation.

[0126] In any of the above methods, the reduction or prevention or treatment may be absolute or may be relative to placebo or standard of care or monotherapy (i.e., dapagliflozin monotherapy or zibotentan monotherapy). Standard statistical considerations apply (e.g., relative risk ratio, hazard ratio, odds ratio, etc.).

[0127] Disclosed herein is a method of treating a subject with cirrhosis having signs of clinically significant portal hypertension, with or without decompensation, comprising: a) determining the concentrations of multiple clinicopathological markers in a subject; b) providing the determined values of the plurality of subject clinicopathological markers to a machine learning model; c) receiving a prediction from the machine learning model whether the patient has a likelihood of progression to the condition; and d) if the subject exhibits a likelihood of progression to the condition, administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin; Includes:

[0128] In the methods disclosed above, the clinicopathological markers can be one or more of demographic values (age, sex, race or ethnicity), comorbidity values (diabetic status or obesity), vital sign values (body mass index, blood pressure, or heart rate), blood test values, or disease progression values. Further, the markers can include, but are not limited to, esophageal varices, splenomegaly, low platelet count, liver stiffness above 25 kPa or above 20 kPa + 150 x 10 9 The clinical history of decompensated or compensated cirrhosis with features of clinically significant portal hypertension, including a platelet count less than 0.05, may include a history of decompensated or compensated cirrhosis with features of portal hypertension, including a platelet count less than 0.05, and a history of decompensated or compensated cirrhosis with features of portal hypertension. In the above methods, treatment may be initiated in subjects with compensated cirrhosis with features of portal hypertension and / or in subjects with decompensated cirrhosis, with or without a recent decompensation event (e.g., within the past 2-3 months).

[0129] All references cited herein, including patents, patent applications, articles, textbooks, etc., and the references cited therein, to the extent they are not already cited, are incorporated herein by reference in their entirety.

[0130] Example 1: Fixed-dose study of zibotentan and dapagliflozin This two-part (Parts A and B) randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study will evaluate the efficacy, safety, and tolerability of zibotentan in combination with dapagliflozin and dapagliflozin monotherapy versus placebo in participants with cirrhosis with portal hypertension features. Specifically, Part A will evaluate the efficacy, safety, and tolerability of 2.5 mg zibotentan in combination with 10 mg dapagliflozin versus placebo in participants with Child-Pugh A cirrhosis with portal hypertension features and no history of decompensation events. At the conclusion of Part A, the safety profile will be determined to be acceptable. Part B will investigate the efficacy, safety, and tolerability of 1 mg, 2.5 mg, or 5 mg zibotentan in combination with 10 mg dapagliflozin and 10 mg dapagliflozin monotherapy versus placebo in participants with cirrhosis with portal hypertension features. Part B includes a broader range of Child-Pugh A and Child-Pugh B cirrhosis participants, including those with more severe disease, a history of decompensation events, or current ascites.

[0131] 1. Overall design of the embodiment FIG. 1 shows the study design for the study outlined in Example 1.

[0132] 1.1 Term Part A1 is a parallel-group, two-arm study blinded to participants, investigators, and sponsors. Part B is a parallel-group, five-arm study blinded to participants, investigators, and sponsors. Parts A and B each include a screening period, a treatment period, and a follow-up period.

[0133] The screening period lasts up to 6 weeks and involves confirming participant eligibility and collecting baseline data on vital signs, clinical chemistry, hematology, and urinalysis; and ECHO / cardiac MRI (Part B only). Data will be collected in two periods (Visit 1 and Visit 2). At Visit 2, eligibility criteria will be assessed, safety laboratory data will be re-verified, and participants will be provided with digital medical devices and daily home weight measurements starting before the randomization visit. At Visit 2, baseline HVPG recordings will be performed, and the quality of the HVPG recordings will be assessed by a central HVPG reader. Only participants with HVPG quality sufficiently good to accurately determine their HVPG will then be randomized.

[0134] The treatment period is 6 weeks in Part A and 16 weeks in Part B. During the treatment period, data will be collected from participants five times (Part A) or eight times (Part B). At Visit 3 (Day 1), participants will be randomized and receive their first dose of study intervention. At each data collection time during the treatment period (except for the days of HVPG and VCTE / Fibroscan assessments, if visit procedures are separated on different days), participants will receive their daily dose at the study center and provide pre-dose blood samples and other laboratory samples for PK analysis before taking the study intervention. At Part A Visit 6 (or Visit 7) and Part B Visit 8 (or Visit 9), participants will provide pre-dose and post-dose blood samples for PK analysis over approximately 5 hours.

[0135] The follow-up period will be 2 weeks. Participants will not receive the study intervention during this period and will return for follow-up assessment approximately 2 weeks after the last dose of study intervention.

[0136] The study intervention is standard of care plus a once-daily dose of the assigned study intervention (oral capsules and tablets) during the treatment period (6 weeks for Part A and 16 weeks for Part B). The total study duration for participants (including screening and follow-up periods) is approximately 13 weeks for Part A and 24 weeks for Part B.

[0137] Table 1 shows the schedule of Part A activities.

[0138] [Table 1-1]

[0139] [Table 1-2] a Visits can occur up to three different days apart. b Participants must fast for at least 8 hours before study intervention administration until HVPG and VCTE / Fibroscan assessments are performed. Participants may drink water up to 1 hour before and 2 hours after study intervention administration and after completion of HVPG and VCTE / Fibroscan testing. If participants are taking nonselective beta-blockers to reduce HVPG, they should not take the morning dose and should take it after HVPG and Fibroscan assessments. c A simple physical examination. d Results must be available prior to the baseline visit. e The assessment should be made at least 3 hours after administration of the study intervention. Note that randomization should not occur before the initial HVPG record at the study center has been reviewed and concluded to be of good quality. If the evaluation of the HVPG record concludes that it is not of sufficiently good quality, the study participant will not be randomized. f Unless otherwise specified, this is done before administration of medication. g PK samples at early termination visits only. If no medication is administered, samples will be taken at any time during the study center visit with the exact date and time recorded. h Samples for PK profiling collected over a 5-hour period at the study center. Sample collection times: pre-dose, 0.5-1.0, 1.5-2.0, 2.5-3.0, 3.5-4.0, 4.5-5.5 hours post-dose; exact times must be documented. i If the PK profile is not possible at Visit 6, it may be performed at Visit 7. On the day selected for the PK profile, the study intervention must be administered at the study center to allow for scheduled PK sampling. j Participants should abstain from using nicotine-containing products the night before and during their visit. k If an SAE occurs within 48 hours after the last dose, a PK sample will be taken if possible. The exact time of the last dose and blood draw will be recorded. l HDL, total cholesterol and triglycerides. m Note that randomization should not occur before the first HVPG records at the study center have been reviewed by the central reader. n When participants can receive the study intervention at home, it will be done at the study center, with the exception of the HVPG assessment and VCTE / Fibroscan assessment visits, where visit procedures will be separated into different days (however, if the PK profile is performed at the visit, the study intervention intake will be done at the study center). o If medication is administered at the study center, a pre-dose sample will be taken; if the study intervention is administered at home, a post-dose sample may alternatively be taken at any time during the visit (recording both the exact administration and the time of sample collection). p VCTE / Fibroscan may be performed on separate days (Days 5–1) and assessed ≥3 hours after study intervention administration. VCTE / Fibroscan assessment of spleen stiffness should only be performed if it is technically feasible to complete accurate spleen stiffness measurements and is at the discretion of the study center investigator. q An ECG evaluation is performed during the HVPG procedure. Abbreviations: AUDIT = Alcohol Use Disorder Identification Test; BMI = Body Mass Index; ECG = Electrocardiogram; ECHO = Echocardiogram; eGFR = Estimated Glomerular Filtration Rate; FSH = Follicle-Stimulating Hormone; h = Time; HbA1c = Hemoglobin A1c; HVPG = Hepatic Venous Pressure Gradient; IRT = Interactive Response Technique; MELD = Model for End-Stage Liver Disease; MRI = Magnetic Resonance Imaging; PK = Pharmacokinetics; RTSM = Randomized and Study Supply Management; SAE = Serious Adverse Event; VCTE = Vibration Controlled Transient Elastography.

[0140] Table 2 shows the schedule of Part B activities.

[0141] [Table 2-1]

[0142] [Table 2-2]

[0143] [Table 2-3] a Visits can occur up to three different days apart. b Participants must fast for at least 8 hours before study intervention administration until HVPG and VCTE / Fibroscan assessments are performed. Participants may drink water up to 1 hour before and 2 hours after study intervention administration and after completion of HVPG and VCTE / Fibroscan testing. If participants are taking nonselective beta-blockers to reduce HVPG, they should not take the morning dose and should take it after HVPG and Fibroscan assessments. c A simple physical examination. d Results must be available prior to the baseline visit. eThe assessment should be made at least 3 hours after administration of the study intervention. Note that randomization should not occur before the initial HVPG record at the study center has been reviewed and concluded to be of good quality. If the evaluation of the HVPG record concludes that it is not of sufficiently good quality, the study participant will not be randomized. f Unless otherwise specified, this is done before administration of medication. g Only if historical data for the last 12 months is not available. h PK samples at early termination visits only. If no medication is administered, samples will be taken at any time during the study center visit with the exact date and time recorded. i Samples for PK profiling collected over a 5-hour period at the study center. Sample collection times: pre-dose, 0.5-1.0, 1.5-2.0, 2.5-3.0, 3.5-4.0, 4.5-5.5 hours post-dose; exact times must be documented. j If the PK profile is not possible at Visit 8, it may be performed at Visit 9. On the day selected for the PK profile, the study intervention must be administered at the study center to allow for scheduled PK sampling. k Two bottles of the study intervention to be dispensed. l Participants should abstain from using nicotine-containing products the night before and during their visit. m If an SAE occurs within 48 hours after the last dose, a PK sample will be taken if possible. The exact time of the last dose and blood draw will be recorded. n HDL, total cholesterol and triglycerides. o Note that randomization should not occur before the first HVPG record at the study center has been reviewed by the central reader. pIntake of the study intervention will occur at the study center, except for the HVPG assessment (Visit 7) and VCTE / Fibroscan assessment (Visits 7 and 10) visits, when participants will be able to administer the study intervention at home; visit procedures will be separated into different days (however, if PK profiling is performed at the visit, intake of the study intervention will occur at the study center). q If medication is administered at the study center, a pre-dose sample will be taken; if the study intervention is administered at home, a post-dose sample may alternatively be taken at any time during the visit (recording both the exact administration and the time of sample collection). r VCTE / Fibroscan may be performed on a separate day (Day 5–Day 1) and assessed 3 or more hours after study intervention administration. VCTE / Fibroscan assessment of spleen stiffness should only be performed if it is technically feasible to complete accurate spleen stiffness measurements and is at the discretion of the study center investigator. s An ECG evaluation is performed during the HVPG procedure. Abbreviations: AUDIT = Alcohol Use Disorder Identification Test; BMI = Body Mass Index; ECG = Electrocardiogram; ECHO = Echocardiogram; eGFR = Estimated Glomerular Filtration Rate; FSH = Follicle-Stimulating Hormone; h = Time; HbA1c = Hemoglobin A1c; HVPG = Hepatic Venous Pressure Gradient; IRT = Interactive Response Technique; MELD = Model for End-Stage Liver Disease; MRI = Magnetic Resonance Imaging; PK = Pharmacokinetics; RTSM = Randomized and Study Supply Management; SAE = Serious Adverse Event; VCTE = Vibration Controlled Transient Elastography.

[0144] 1.2 Participants. In Part A, approximately 30 participants with good baseline HVPG will be randomized into two treatment arms of 15 participants per arm. With an estimated 20% early treatment discontinuation, this will allow for 12 evaluable participants per arm with evaluable HVPG measurements at baseline and Week 6 (primary endpoint).

[0145] In Part B, approximately 110 participants with good baseline HVPG will be randomized into five treatment arms of 22 participants per arm. With an estimated 20% early treatment discontinuation, this will allow for 18 evaluable participants per arm with evaluable HVPG measurements at baseline and Week 6 (primary endpoint).

[0146] 1.3 Intervention group and duration. In Part A, participants who meet the eligibility criteria and agree to participate will be randomized to one of two treatment groups (15 participants per group):

[0147] Treatment arm 1: placebo-matched zibotentan capsules + placebo-matched dapagliflozin tablets.

[0148] Treatment group 2: zibotentan capsules 2.5 mg + dapagliflozin tablets 10 mg.

[0149] The study intervention will be a once-daily dose of the assigned study intervention (oral capsules and tablets) for 6 weeks in addition to standard of care. The total study duration for participants in Part A will be approximately 14 weeks (including screening and follow-up periods).

[0150] In Part B, participants who meet the eligibility criteria and agree to participate will be randomized to one of five treatment groups (22 participants per group):

[0151] Treatment arm 1: placebo-matched zibotentan capsules + placebo-matched dapagliflozin tablets.

[0152] Treatment group 2: matched placebo zibotentan capsules + dapagliflozin tablets 10 mg.

[0153] Treatment group 3: zibotentan capsule 1 mg + dapagliflozin tablet 10 mg.

[0154] Treatment group 4: zibotentan capsules 2.5 mg + dapagliflozin tablets 10 mg.

[0155] Treatment group 5: zibotentan capsules 5 mg + dapagliflozin tablets 10 mg.

[0156] A staggered randomization scheme will be applied in Part B. Eligible participants will be randomized equally to treatment groups 1 to 4, with 22 participants per treatment group (approximately 88 participants in total).

[0157] In some embodiments, participants in Part B are stratified by the presence of clinically detectable (Grade 2) ascites at the time of randomization to ensure approximate balance between treatment arms within each subpopulation.

[0158] The study intervention will be standard of care plus a once-daily dose of the assigned study intervention (oral capsules and tablets) for 16 weeks. The total study duration for Part B participants will be approximately 24 weeks (including screening and follow-up periods).

[0159] Eligibility criteria for Part A participants: (a) Clinical and / or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa. (b) MELD score <15. (c) Child-Pugh classification ≤6. (d) No clinically evident ascites (e) No evidence of worsening liver function within the last month prior to dosing as determined by the investigator or usual medical practitioner (e.g., no clinically significant changes in signs, symptoms, or laboratory parameters of liver disease status). (f) HVPG recording of good quality as judged by a central reader.

[0160] Eligibility Criteria for Part B Participants: (a) Clinical and / or histological diagnosis of cirrhosis with features of portal hypertension. (b) MELD score <15. (c) Child-Pugh classification <10. (d) At screening, no ascites or ascites up to grade 2 without any change in diuretic treatment within the last month before the first dose, no paracentesis within the last month or planned paracentesis in the next 4 months. (e) No evidence of worsening liver function within the last month prior to dosing as determined by the investigator or usual medical practitioner (e.g., no clinically significant changes in signs, symptoms, or laboratory parameters of liver disease status). (f) HVPG recording of good quality as judged by a central reader.

[0161] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply: Medical condition (all participants) 1. Evidence of clinically significant disease that, in the opinion of the investigator, makes the participant undesirable from participating in the study. 2. Cirrhosis caused by chronic cholestatic liver disease. 3. ALT or AST ≥ 150 U / L and / or total bilirubin ≥ 3 × ULN. 4. Any history of hepatocellular carcinoma. 5. Any history of portal vein thrombosis. 6. Liver transplant or anticipated liver transplant within 6 months of screening. 7. History of TIPS or planned TIPS within 6 months of study enrollment. 8. Positive alcohol breath test or screening for drugs of abuse (excluding drugs prescribed by the participant's regular physician) at the time of screening. 9. A history of continued or significant alcohol use that would be expected to interfere with proper compliance with study procedures. 10. Active treatment for HCV within the past year or HBV antiviral therapy for less than one year. 11. Active urinary tract or genital infection 12. Uncontrolled diabetes mellitus (HbA1c >8% or >64mmol / mol in the last month). 13. Participants with T1DM. 14. Kidney transplant or chronic renal replacement therapy or short-term dialysis within the past 6 months. 15. eGFR<60mL / min / 1.73m 2 (eGFRcr[AS]). 16. Acute coronary syndrome event within 3 months prior to screening. 17. Orthostatic hypotension or hypotension (systolic blood pressure <95mmHg or diastolic blood pressure <60mmHg). 18. Participants treated with strong CYP3A4 inhibitors or strong or moderate CYP3A4 inducers within 14 days (21 days St. John's Wort) of study intervention administration (Table 7); this includes grapefruit and grapefruit juice if consumed more frequently than occasionally or in larger amounts. 19. History or ongoing allergy / hypersensitivity to SGLT2i (e.g., dapagliflozin, empagliflozin), zibotentan, or drugs with a similar chemical structure to zibotentan will be determined by the investigator. 20. Clinically significant chronic disease or disorder (e.g., cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical disorder) that may, in the investigator's judgment, put the participant at risk, e.g., primary reason for possible substitution of the participant's condition, in the investigator's judgment: a. Anemia is defined as a hemoglobin (Hb) level <100 g / L or <10 g / dL. b. Wernicke's encephalopathy or Korsakoff's syndrome. c. History of HIV. 21. Any of the following regarding COVID-19: a. Symptoms of COVID-19 infection or recent positive test within 14 days prior to study enrollment. b. Participants were hospitalized with COVID-19 infection within the past 3 months requiring in-hospital medical care (e.g., oxygen therapy, mechanical ventilation, intensive care unit admission). 22. Acute liver injury caused by drug toxicity or infection.

[0162] Medical Conditions (Part A only) 1. INR>1.5. 2. Albumin serum / plasma level ≤35g / L. 3. Platelet count <75 × 10 9 / L. 4. History of ascites 5. History of hepatic hydrothorax 6. History of portopulmonary syndrome 7. History of hepatic encephalopathy 8. History of variceal bleeding 9. History of acute kidney injury 10. History of heart failure, including high-output heart failure (e.g., due to hyperthyroidism or Paget's disease)

[0163] Medical Conditions (Part B only) 1. INR>1.7. 2. Albumin serum / plasma level ≤28g / L. 3. Platelet count <50× / 10 9 L. 4. Acute kidney injury within 3 months of screening. 5. History of West Haven grade 2 or greater encephalopathy. 6. History of variceal bleeding within 6 months prior to screening. 7. NYHA functional heart failure class III or IV, or unstable heart failure requiring hospitalization for optimization of heart failure treatment and not yet stabilized on heart failure treatment within 6 months prior to screening. 8. Heart failure primarily due to cardiomyopathy requiring certain other treatments: e.g., cardiomyopathy due to pericardial disease, cardiomyopathy associated with amyloidosis or other infiltrative diseases, cardiomyopathy associated with congenital heart disease, primary hypertrophic cardiomyopathy, cardiomyopathy associated with toxic or infectious conditions (i.e., chemotherapy, infectious myocarditis, septic cardiomyopathy). 9. High-output heart failure (e.g., due to hyperthyroidism or Paget's disease). 10. Heart failure due to primary valvular heart disease / insufficiency, severe functional mitral or tricuspid valve insufficiency, or planned heart valve repair / replacement

[0164] 1.4 Statistical methods. For Part A, the primary efficacy endpoint is the absolute change in HVPG at Week 6, and changes will be analyzed using ANCOVA with baseline values used as covariates for the comparison between the zibotentan / dapagliflozin group and the placebo group. In some embodiments, the mean absolute change in HVPG at Week 6 for the zibotentan / dapagliflozin group compared to the placebo group will differ by 2 mmHg or more, with a typical standard deviation (SD) of the HVPG difference being 2.5 mmHg or less (Bai et al., 2021). Under these circumstances, 12 HVPG-evaluable participants per group will provide 80% power to detect a difference at Week 6, with a type I error of 15% (one-sided). With an estimated 20% early treatment discontinuation, Part A will randomize a total of 30 participants (15 per group).

[0165] For Part B, the primary efficacy endpoint is HVPG response, with responders defined as a 20% or greater decrease in HVPG from baseline at Week 6 or a 12 mmHg or less decrease in HVPG. HVPG response at Week 6 will be analyzed using the Cochran Mantel-Haenszel test, accounting for stratification factors. Pairwise comparisons will be performed comparing zibotentan and dapagliflozin in combination with placebo. With a one-sided type I error of 5%, 18 HVPG-evaluable participants per group in Part B will provide 80% power to detect a difference at Week 6 between a 9% placebo HVPG response rate and a 45% zibotentan / dapagliflozin response rate, assuming zibotentan / dapagliflozin efficacy is similar to that of nonselective beta-blockers. Due to an estimated 20% early treatment discontinuation, Part B will randomize 22 participants in each of the five treatment groups to have 90 participants (18 participants per treatment group) with evaluable HVPG measurements at baseline and week 6. Thus, a maximum of 110 participants will be randomized in the study.

[0166] Changes in body weight, total body water, total body fat, cumulative dose of loop diuretic equivalents, and blood pressure in Parts A and B are analyzed using a mixed model repeated measures (MMRM) methodology. The analytical model includes fixed categorical effects for stratification factors, treatment, visit, and treatment-visit interactions, and continuous covariates for baseline measurements. In some embodiments, the model also includes cohort (by randomization) as a covariate for randomization adjustment. An unstructured covariance structure is used for within-participant error.

[0167] Previous Phase III programs in oncology have used 10 mg of zibotentan, and extensive safety data are available for this dose. Based on the zibotentan liver dysfunction study (Tomkinson et al., 2011), exposure is expected to be 1.45-fold higher in participants with moderate liver impairment compared to healthy control participants. Example 1 includes participants with mild or moderate liver impairment and normal or mild renal impairment (MELD score <15 and eGFR >60 mL / min / 1.73 m2), with dosage adjusted as described below.

[0168] Part A is designed to provide proof of concept. Participants with less severe disease, defined as Child-Pugh A and no history of decompensation events, will receive 2.5 mg zibotentan in combination with 10 mg dapagliflozin or placebo. After the combination is determined to be safe in these participants, Part B will begin, which also includes participants with Child-Pugh B, a history of decompensation events, or ascites. In Part B, only two dose levels of zibotentan will initially be tested in combination with dapagliflozin: 1 mg and 2.5 mg, conservatively representing 1 / 10 and 1 / 4 of the zibotentan dose in previous oncology programs. After evaluating the two lower dose levels for safety and tolerability, a cohort of 5 mg zibotentan in combination with 10 mg dapagliflozin will be enrolled. This is intended to evaluate the potential benefit of the 5 mg dose while increasing the dose range fivefold and protecting subjects enrolled in the study with a staggered design.

[0169] Dapagliflozin 10 mg has been widely investigated as monotherapy. Compared to healthy participants, higher dapagliflozin exposure is expected in participants with renal and / or hepatic impairment; however, given dapagliflozin's safety and tolerability profile, dose adjustments are not necessary. Dapagliflozin 10 mg once-daily did not yield any inherent safety or tolerability signals in participants with renal impairment in both chronic kidney disease (≥25 mL / min / 1.73 m2; DAPA-CKD Outcomes Study) and heart failure populations (DAPA HF Outcomes Study). Doses of up to 100 mg dapagliflozin for 14 days have been shown to be tolerable in healthy volunteers. Therefore, dapagliflozin 10 mg once-daily has also been selected for a planned clinical program in cirrhosis with portal hypertension (dapagliflozin investigational drug).

[0170] 2. Study intervention administered. 2.1 Study intervention. All participants will receive one capsule (zibotentan or matching placebo) and one tablet (dapagliflozin or matching placebo) at each dose, as shown in Table 3 below.

[0171] [Table 3] GMP = Good Manufacturing Practice; HDPE = High Density Polyethylene; IMP = Investigational New Drug; NA = Not Applicable; NIMP = Non-Investigational New Drug.

[0172] 3. Evaluation 3.1 Effectiveness evaluation 3.1.1 Primary variable: hepatic venous pressure gradient HVPG assessments will be conducted at the time points specified in Tables 1 and 2. On the day of HVPG assessment, participants must fast and avoid nicotine-containing products until the HVPG assessment is performed. If participants are taking nonselective beta-blockers, the dose should be taken immediately after the HVPG assessment, not in the morning before the HVPG assessment. The HVPG assessment should not be performed earlier than 3 hours after the administration of the study intervention. Therefore, the timing of the HVPG assessment at Visit 7 and the intake of the study intervention will be carefully planned. The baseline recording will be reviewed by a central reader and found to be of sufficiently good quality before participants can be randomized. A sufficiently good HVPG recording is the result of a recording that meets all requirements of the experiment. While not completely satisfactory, an acceptable tracking that can be used to derive HVPG data still allows for more important information to be derived from several (if not all) measurements of WHVP, FHVP, and HVPG, and will provide consistent results even if the tracking has artifacts or if some ancillary measurements are missing (i.e., right atrial pressure, inferior vena cava pressure).

[0173] A balloon catheter is introduced into the hepatic vein via a transjugular approach under ultrasound / fluoroscopy guidance. Light sedation is provided for the participant's comfort. Midazolam is the preferred drug for sedation as it does not affect HVPG. Note that zibotentan results in a 20% increase in midazolam exposure, but this is unlikely to be clinically relevant to standard midazolam administration. Once the catheter is in situ within the hepatic vein, an initial free venous pressure measurement is taken, followed by a wedge pressure measurement. HVPG is calculated from these two values. HVPG measurements are performed three times.

[0174] 3.1.2 Secondary variables 3.1.2.1 Electronic scale measurement of weight. Body weight will be measured at each study visit. Additionally, participants will weigh themselves daily in the morning using a provided digital device.

[0175] 3.1.2.2 Bioimpedance spectroscopy. To monitor body fluid volume, bioimpedance spectroscopy (BIS) is performed at the time points specified in the SoA (Tables 1 and 2). This noninvasive procedure uses skin electrodes to pass a low-level alternating current through the body and measures the impedance to this current flow. Tissues such as fat and bone act as insulators, while electrolyte fluids conduct current; as fluid volume increases, the impedance to the current decreases (i.e., the change in impedance is inversely proportional to the volume of extracellular fluid in the body). At low frequencies, cell membranes are nonconductive, and current passes only through the extracellular fluid; however, at high frequencies, current passes through the cell membrane in addition to the extracellular and intracellular fluids.

[0176] 3.1.3 Search variables 3.1.3.1 Vibration controlled transient elastography (VCTE). VCTE will be performed in the fasting state and at least 3 hours after administration of the study intervention at the time points specified in Tables 1 and 2. If participants are taking nonselective beta-blockers, the dose will be taken immediately after the VCTE assessment, not in the morning before the VCTE. A Fibroscan device will be used, which allows for the measurement of splenic stiffness. Splenic stiffness will be collected as an exploratory endpoint to determine its potential as a surrogate for changes in the hepatoportal pressure gradient. Measurements will preferably be performed by the same examiner in all cases.

[0177] VCTE / Fibroscan assessment of splenic stiffness will only be performed if it is technically feasible to complete an accurate measurement of splenic stiffness.

[0178] 3.1.3.2 Serum analysis of creatinine and cystatin C (eGRF). Participants' eGFR will be calculated according to the 2021 CKD EPI equation, hereafter referred to as eGFR1, based on serum creatinine concentration alone (Inker et al., 2021) for eligibility and safety purposes. Additionally, eGFR for exploratory evaluations will be calculated based on both serum creatinine and serum cystatin C concentrations (Inker et al., 2021), hereafter referred to as eGFR2.

[0179] Estimated GFR using serum creatinine alone or together with serum cystatin C is calculated as follows: eGFR1=142×Min(Scr / κ,1) -0.241(女性の場合) / 0.302(男性の場合) ×Maximum(Scr / κ,1) -1.200 ×0.994 年齢 ×1.012 [for women] eGFR2=135×Min(Scr / κ,1) -0.219(女性の場合) / 0.144(男性の場合) ×Maximum(Scr / κ,1) -0.544 ×Min(Scys / 0.8,1) -0.323 ×Maximum (Scys / 0.8,1) -0.778 ×0.996 年齢 ×0.963 [for women] where S cr = Serum creatinine (mg / dL) S cys = Serum cystatin C (mg / L) κ = 0.7 (female) and 0.9 (male). Min = minimum value of Scr / κ or 1 Max = maximum value of Scr / κ or 1

[0180] 3.1.3.3 Laboratory Evaluation for Exploratory Analysis Blood and urine samples will be collected as indicated in the SoA (Tables 1 and 2) to measure levels of the following biomarkers for analysis of exploratory variables: Plasma / serum AST, ALT, FIB 4 are derived from safety variables (Part B only). The MELD score (MELD = 3.78 × ln [serum bilirubin (mg / dL)] + 11.2 × ln [INR] + 9.57 × ln [serum creatinine (mg / dL)] + 6.43) will be calculated at each visit. Plasma / serum potassium, sodium, creatinine, cystatin C, uric acid, serum osmolality, BUN, BNP, NTproBNP, HbA1c, hematocrit, hemoglobin, ET1, ELDP, CTproET1, and copeptin are non-fasting plasma biomarkers of SoA. Fasting plasma / serum glucose, fasting insulin, and fasting beta-hydroxybutyrate are fasting plasma biomarkers in SoA. Total cholesterol, triglycerides, and HDL-cholesterol are additional fasting plasma biomarkers in SoA. Spot urine tests for potassium, sodium, and creatinine, as well as urea, uric acid, osmolality, glucose, and albumin will be measured at visits specified in the SoA. eGFr will be calculated at each visit.

[0181] The Child-Pugh classification is calculated as seen in Table 5.

[0182] [Table 4]

[0183] 3.2.1 Vital signs Vital signs will be collected on the timeline specified in the SoA (Tables 1 and 2), including supine and upright blood pressure, pulse, and temperature.

[0184] Prior to blood collection for laboratory testing with participants resting in a supine position using fully automated equipment, assess routine blood pressure, pulse, and temperature as outlined in the SoA (Table 1 and Table 2). Manual techniques are used only if automated equipment is not available.

[0185] All participants were also equipped with a home blood pressure monitor to be used if the participant suffered from symptoms suggestive of low blood pressure or orthostatic hypotension.

[0186] Before vital sign measurements in the supine position, participants were allowed to rest for at least 5 minutes in a quiet setting without distractions (e.g., television, cell phone), and a physical examination consisting of one pulse, one temperature, and three blood pressure measurements (three consecutive blood pressure measurements recorded at least 1 minute apart) was performed. The average of the three blood pressure measurements was recorded on the eCRF. Also, after 2–5 minutes in an upright position, an orthostatic blood pressure measurement was recorded. These assessments were preferably performed in the morning. If orthostatic hypotension was observed during the study, it was reported as an AESI, including symptoms related to the orthostatic vital sign measurements, if any.

[0187] There will be real-time safety monitoring of weight online data from a home-based monitoring device by study physicians, who will alert the respective investigators if any significant weight gain (>2 kg per week) occurs.

[0188] 3.2.2 Electrocardiogram After participants have rested in the supine position for at least 10 minutes, a single 12-lead ECG will be performed at the visit outlined in the SoA (Tables 1 and 2).

[0189] Throughout the study, any clinically relevant new finding or worsening of an existing finding on the ECG (any parameter or abnormal finding on follow-up) will be considered an AE and will be recorded on the AE CRF form.

[0190] 3.2.3 Clinical Safety Laboratory Evaluation Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis for safety analyses will be collected at the visits indicated in Tables 1 and 2. Laboratory evaluations for exploratory analyses are presented above.

[0191] The following laboratory safety variables are measured as seen in Table 5:

[0192] [Table 5]

[0193] 3.2 Pharmacokinetics Plasma samples will be collected to measure zibotentan and dapagliflozin concentrations as specified in the SoA (Tables 1 and 2).

[0194] Samples may be collected at additional time points during the study if required and agreed upon between the investigator and sponsor for safety reasons, e.g., SAE. The timing of sample collection may be modified during the course of the study (e.g., to obtain data closer to the time of peak or trough matrix concentration) to ensure adequate monitoring.

[0195] Samples for determining drug concentrations in plasma are assayed using an appropriately validated bioanalytical method. Contaminant sample reproducibility analyses, if any, are performed in parallel with the test sample bioanalysis.

[0196] 3.3 Pharmacodynamics Plasma / serum parameters will be measured during the study for evaluation of exploratory endpoints. Parameters will be measured from blood samples collected for safety that will be analyzed at a central core laboratory. Blood samples will be collected as described in the SoA (Tables 1 and 2) and analyzed by the central laboratory.

[0197] 3.4 Study Endpoints Study endpoints are summarized in Tables 4 and 5. The primary efficacy objective for Part A is the absolute change in HVPG from baseline to week 6 in participants treated with 2.5 mg zibotentan in combination with 10 mg dapagliflozin compared to placebo. The primary efficacy objective for Part B is the proportion of participants treated with 1, 2.5, or 5 mg zibotentan in combination with 10 mg dapagliflozin and 10 mg dapagliflozin monotherapy achieving a 20% or greater reduction in HVPG or a 12 mmHg or less reduction in HVPG compared to placebo. Secondary objectives for both Parts A and B include the rate of change in HVPG, as well as assessments of body weight, body fat mass, and body water, cumulative dose of loop diuretic equivalents, and blood pressure.

[0198] [Table 6] a. Home balance. b. Visit balance. c. 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg ethacrynic acid. Abbreviations: AE = adverse event; AESI = adverse event of special interest; AKI = acute kidney injury; DAE = discontinuation due to adverse event; ECG = electrocardiogram; GI = genital tract infection; HVPG = hepatic venous pressure gradient; SAE = serious adverse event; UTI = urinary tract infection. d. VCTE / Fibroscan assessment of spleen stiffness should only be performed if it is technically feasible to complete an accurate measurement of spleen stiffness and is at the discretion of the testing center investigator. Abbreviations: AE = adverse event; AESI = adverse event of particular interest; AKI = acute kidney injury; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CTproET-1 = C-terminal pro-endothelin-1; DAE = discontinuation due to adverse event; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; FIB-4 = fibrosis-4; GI = genital tract infection; HbA1c = hemoglobin A1c; HE = hepatic encephalopathy; HVPG = hepatic venous pressure gradient; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; UTI = urinary tract infection; VCTE = vibration-controlled transient elastography.

[0199] [Table 7-1]

[0200] [Table 7-2] a. Home balance. b. Visit balance. c. 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg ethacrynic acid. t VCTE / Fibroscan assessment of splenic stiffness should only be performed if it is technically feasible to complete an accurate splenic stiffness measurement and is at the discretion of the study center investigator. u AKI is defined as any of the following: an increase in s-creatinine of 0.3 mg / dL (26.5 μmol / L) within 48 hours, or an increase in s-creatinine to 1.5 times baseline, known or presumed to have occurred within the previous 7 days (or the last available outpatient s-creatinine value within 3 months is used as the baseline value); or a urine output of <0.5 mL / kg / h for 6 hours. v Clinical grading of ascites: Grade 1: Mild ascites, detectable only by imaging / ultrasound. Grade 2: Moderate ascites manifested by moderate symmetric abdominal distension. Grade 3: Massive or gross ascites causing significant abdominal distension. West Haven Standards for HE: No HE. Minimal HE: No clinical evidence of psychiatric changes, psychometric or neuropsychological changes on tests exploring psychomotor speed / executive function or neurophysiological changes. Grade 1: Minimal lack of awareness, euphoria or anxiety, shortened attention span, impaired addition or subtraction, altered sleep rhythm. Grade 2: lethargy or apathy, disorientation to time, obvious personality change, inappropriate behavior, schizophrenia, asterixis. Grade 3: Somnolence to semi-consciousness, drowsiness, unresponsive to stimuli, confusion, gross disorientation, bizarre behavior. Grade 4: Coma. Abbreviations: AE = adverse event; AESI = adverse event of special interest; AKI = acute kidney injury; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CTproET-1 = C-terminal pro-endothelin-1; DAE = discontinuation due to adverse event; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ELDP = endothelin-like domain peptide; ET-1 = endothelin-1; FIB-4 = fibrosis-4; GI = genital tract infection; HbA1c = hemoglobin A1c; HE = hepatic encephalopathy; HVPG = hepatic venous pressure gradient; MELD = model for end-stage liver disease; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; UTI = urinary tract infection; VCTE = vibration-controlled transient elastography.

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Claims

1. 1. A method of treating cirrhosis in a subject in need thereof, comprising administering to the subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

2. 10. The method of claim 1, wherein the subject has characteristics of portal hypertension.

3. 3. The method of claim 1 or 2, wherein the subject has a hepatic venous pressure gradient (HVPG) greater than 5 mmHg.

4. The method of any one of claims 1 to 3, wherein the subject has an HVPG greater than 7.5 mmHg.

5. The method of any one of claims 1 to 4, wherein the subject has an HVPG greater than 10 mmHg.

6. 6. The method of any one of claims 1 to 5, wherein the subject has at least one of esophageal varices, splenomegaly, variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, recurrent hepatic encephalopathy, lower extremity swelling, coagulopathy, pulmonary complications, and portosystemic shunt.

7. The method of any one of claims 1 to 6, wherein the subject has a Child-Pugh classification of 5 or greater.

8. The method of any one of claims 1 to 7, wherein the subject has a Child-Pugh classification of 7 or greater.

9. The method of any one of claims 1 to 8, wherein the subject has a Child-Pugh classification of 10 or greater.

10. 10. The method of any one of claims 1 to 9, wherein the subject has a Model for End-Stage Liver Disease (MELD) score of 5 or greater.

11. The method of any one of claims 1 to 10, wherein the subject has a MELD score of 10 or greater.

12. The method of any one of claims 1 to 11, wherein the subject has a MELD score of 20 or greater.

13. The method of any one of claims 1 to 12, wherein the subject is free of a decompensation event.

14. The method of any one of claims 1 to 12, wherein the subject has a decompensation event.

15. The method of any one of claims 1 to 14, wherein the composition comprises from about 0.1 mg to about 240 mg of zibotentan.

16. The method of any one of claims 1 to 15, wherein the composition comprises about 0.2 mg to about 50 mg of zibotentan.

17. The method of any one of claims 1 to 16, wherein the composition comprises about 0.5 mg to about 20 mg of zibotentan.

18. The method of any one of claims 1 to 17, wherein the composition comprises about 1 mg to about 10 mg of zibotentan.

19. The method of any one of claims 1 to 18, wherein the composition comprises about 1 mg of zibotentan.

20. The method of any one of claims 1 to 18, wherein the composition comprises about 2.5 mg of zibotentan.

21. The method of any one of claims 1 to 18, wherein the composition comprises about 5 mg of zibotentan.

22. 22. The method of any one of claims 1 to 21, wherein the composition comprises from about 0.1 mg to about 100 mg of dapagliflozin.

23. 23. The method of any one of claims 1 to 22, wherein the composition comprises from about 0.25 mg to about 50 mg of dapagliflozin.

24. 24. The method of any one of claims 1 to 23, wherein the composition comprises from about 1 mg to about 10 mg of dapagliflozin.

25. The method of any one of claims 1 to 24, wherein the composition comprises about 2.5 mg of dapagliflozin.

26. The method of any one of claims 1 to 24, wherein the composition comprises about 5 mg of dapagliflozin.

27. 25. The method of any one of claims 1 to 24, wherein the composition comprises about 10 mg of dapagliflozin.

28. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 1 mg of zibotentan and about 2.5 mg of dapagliflozin.

29. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 1 mg of zibotentan and about 5 mg of dapagliflozin.

30. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 2.5 mg of zibotentan and about 2.5 mg of dapagliflozin.

31. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 2.5 mg of zibotentan and about 5 mg of dapagliflozin.

32. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 2.5 mg of zibotentan and about 10 mg of dapagliflozin.

33. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 5 mg of zibotentan and about 5 mg of dapagliflozin.

34. 15. The method of any one of claims 1 to 14, wherein the composition comprises about 5 mg of zibotentan and about 10 mg of dapagliflozin.

35. The method according to any one of claims 1 to 34, wherein the zibotentan is in an oral dosage form.

36. 36. The method of claim 35, wherein the oral dosage form is a capsule.

37. The method according to any one of claims 1 to 36, wherein the dapagliflozin is in an oral dosage form.

38. 38. The method of claim 37, wherein the oral dosage form is a tablet.

39. The method of any one of claims 1 to 34, wherein the composition is in an oral dosage form.

40. 40. The method of claim 39, wherein the oral dosage form is a capsule or a tablet.

41. 41. The method of any one of claims 1 to 40, wherein the composition is administered to the subject from 1 to 3 times daily.

42. 42. The method of claim 41, wherein the composition is administered to the subject once daily.

43. 43. The method of any one of claims 1-42, wherein the composition is administered to the subject at least once to three times daily for at least three weeks.

44. 43. The method of any one of claims 1-42, wherein the composition is administered to the subject at least 1 to 3 times daily for at least 6 weeks.

45. 43. The method of any one of claims 1-42, wherein the composition is administered to the subject at least 1 to 3 times daily for at least 12 weeks.

46. 43. The method of any one of claims 1-42, wherein the composition is administered to the subject at least 1 to 3 times daily for at least 16 weeks.

47. the subject has a hepatic venous pressure gradient (HVPG) response; the HVPG is reduced by at least 10% compared to the subject's baseline HVPG after administration of the composition to the subject; 47. The method of any one of claims 1 to 46.

48. 48. The method of claim 47, wherein the HVPG in the subject is reduced by at least 20% after administration of the composition to the subject.

49. 49. The method of claim 48, wherein the HVPG in the subject is reduced by at least 25% after administration of the composition to the subject.

50. 50. The method of claim 49, wherein the HVPG in the subject is reduced by at least 40% after administration of the composition to the subject.

51. the subject has a hepatic venous pressure gradient (HVPG) response; the HVPG is 12 mmHg or less relative to the subject's baseline HVPG after administration of the composition to the subject; 51. The method of any one of claims 1 to 50.

52. 52. The method of claim 51, wherein after administration of the composition to the subject, the HVPG of the subject is 10 mmHg or less.

53. 53. The method of claim 52, wherein after administration of the composition to the subject, the HVPG of the subject is 8 mmHg or less.

54. 54. The method of claim 53, wherein after administration of the composition to the subject, the HVPG of the subject is 5 mmHg or less.

55. The subject experiences one of the following outcomes after administering the composition to the subject: (i) a loss of at least 5% of body weight; (ii) at least a 5% decrease in body water content; (iii) at least a 5% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 130; (v) a decrease in diastolic blood pressure to less than 90; and (vi) at least a 5% reduction in cumulative use of additional loop diuretic equivalents 55. The method of any one of claims 1 to 54, comprising one or more of:

56. The subject, after administering the composition to the subject, experiences one of the following outcomes: (i) a loss of at least 10% of body weight; (ii) at least a 10% decrease in body water content; (iii) at least a 10% reduction in body fat mass; (iv) a decrease in systolic blood pressure to less than 120; (v) a reduction in diastolic blood pressure to less than 80; and (vi) at least a 10% reduction in cumulative use of additional loop diuretic equivalents 56. The method of claim 55, comprising one or more of:

57. The subject, after administering the composition to the subject, experiences one of the following outcomes: (i) a loss of at least 15% of body weight; (ii) at least a 15% reduction in body water content; (iii) at least a 15% reduction in body fat mass; (iv) a reduction in systolic blood pressure to less than 110; (v) a reduction in diastolic blood pressure to less than 70; and (vi) at least a 15% reduction in cumulative use of additional loop diuretic equivalents 57. The method of claim 56, comprising one or more of:

58. 58. The method of any one of claims 1 to 57, wherein the cirrhosis is caused by viral hepatitis, alcoholic liver disease, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or a combination thereof.

59. 58. The method of any one of claims 1 to 57, wherein the cirrhosis is caused by cirrhosis associated with autoimmune hepatitis, primary sclerosing cholangitis, primary cholangitis, hemochromatosis, Wilson's disease, biliary atresia, alpha 1-antitrypsin deficiency, and cystic fibrosis, or a combination thereof.

60. 60. The method of any one of claims 1 to 59, wherein the subject is a human subject.

61. 61. The method of claim 60, wherein the human subject is between 18 and 80 years old.

62. 1. An oral dosage form comprising: a. about 0.25 mg to about 20 mg of zibotentan; b. about 0.5 mg to about 40 mg of dapagliflozin; and c. Pharmaceutically acceptable excipients 10. An oral dosage form comprising:

63. 63. The oral dosage form of claim 62, comprising from about 0.5 mg to about 10 mg of zibotentan and from about 1 mg to about 20 mg of dapagliflozin.

64. 64. The oral dosage form of claim 63, comprising from about 1 mg to about 5 mg of zibotentan and from about 2.5 mg to about 10 mg of dapagliflozin.

65. 65. The oral dosage form of claim 64, comprising about 1 mg of zibotentan and about 2.5 mg of dapagliflozin.

66. 65. The oral dosage form of claim 64, comprising about 1 mg of zibotentan and about 5 mg of dapagliflozin.

67. 65. The oral dosage form of claim 64, comprising about 2.5 mg of zibotentan and about 2.5 mg of dapagliflozin.

68. 65. The oral dosage form of claim 64, comprising about 2.5 mg of zibotentan and about 5 mg of dapagliflozin.

69. 65. The oral dosage form of claim 64, comprising about 2.5 mg of zibotentan and about 10 mg of dapagliflozin.

70. 65. The oral dosage form of claim 64, comprising about 5 mg of zibotentan and about 5 mg of dapagliflozin.

71. 65. The oral dosage form of claim 64, comprising about 5 mg of zibotentan and about 10 mg of dapagliflozin.

72. A kit comprising: a. an oral dosage form comprising about 0.25 mg to about 20 mg of zibotentan and a pharmaceutically acceptable excipient; and b. An oral dosage form comprising about 0.5 mg to about 40 mg of dapagliflozin and a pharmaceutically acceptable excipient. Includes a kit.

73. A kit comprising: a. an oral dosage form comprising about 2.5 mg of zibotentan and a pharmaceutically acceptable excipient; and b. An oral dosage form comprising about 5 mg of dapagliflozin and a pharmaceutically acceptable excipient. Includes a kit.

74. 1. A method for reducing the risk of, or preventing and / or slowing the progression of, variceal bleeding and / or mortality in a subject in need thereof, comprising administering to said subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

75. 75. The method of claim 74, wherein the composition comprises about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan.

76. 75. The method of claim 74, wherein the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin.

77. A method for reducing the risk of liver cirrhosis decompensation or preventing and / or delaying the progression of liver cirrhosis decompensation in a subject in need thereof, comprising administering to said subject a composition comprising therapeutically effective amounts of zibotentan and dapagliflozin.

78. 78. The method of claim 77, wherein the composition comprises about 0.25 mg to about 20 mg of dapagliflozin and about 0.5 mg to about 10 mg of zibotentan.

79. 79. The method of claim 78, wherein the composition comprises about 1 mg, 2.5 mg, or 5 mg of zibotentan and about 2.5 mg, 5 mg, or 10 mg of dapagliflozin.

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