Combination therapy for treating cirrhosis with portal hypertension

Abstract

Disclosed is a composition comprising a therapeutically effective amount of zipotentan and dapagliflozin for use in a method of treating liver cirrhosis in a subject in need thereof.

Description

Technical Field

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

[0002] Cirrhosis is the end-stage result of chronic liver damage or chronic liver disease, which can be characterized by advanced fibrosis. Common causes of cirrhosis include viral hepatitis (hepatitis B and C), alcoholic liver disease, and non-alcoholic steatohepatitis (NASH), while less common causes of cirrhosis include autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, hemochromatosis, biliary atresia, alpha-1 antitrypsin deficiency, and cystic fibrosis-related cirrhosis, and Wilson's disease (Romanelli et al., 2016). Cirrhosis can be compensated, in which no clinical complications that affect the outcome occur (i.e., decompensated events, such as variceal bleeding, ascites, hepatorenal syndrome or acute kidney injury, hepatic encephalopathy, hepatocellular carcinoma), or decompensated, in which the patient suffers from at least one clinical complication. In decompensated patients, the liver's ability to perform important metabolic, synthetic, and storage functions is reduced (Tsochatzis et al., 2014). Cirrhosis can be a serious condition that causes significant morbidity, resource-intensive complications, hepatocellular carcinoma, and, in the absence of liver transplantation, death. The 2017 Global Burden of Disease Study reported more than 1.32 million cirrhosis-related deaths worldwide, accounting for 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 in the liver microcirculation associated with fibrosis and increased vascular tone (Iwakiri, 2014). As portal hypertension develops, arterial vasodilation occurs, which leads to activation of the RAAS and sympathetic nervous system and results in increased blood flow to the portal circulation (Iwakiri, 2014). Ultimately, a hyperdynamic circulatory syndrome may develop, leading to further development of portal hypertension and further increase in collateral and varicose bleeding, hepatic encephalopathy, and / or ascites formation (Poordad, 2015).

[0004] Patients with cirrhosis who present with clinically significant features of portal hypertension are at significant risk for decompensation and mortality, yet medical treatment options are limited. Standard treatment for patients with chronic liver disease focuses on treating the underlying cause of liver disease, such as alcohol abstinence, antiviral agents for viral hepatitis, and treatment of the underlying metabolic disease in NASH. Although some viruses can now be eradicated, disease-modifying therapies are generally considered to have only a marginal impact on outcomes in patients with cirrhosis and portal hypertension, given the ongoing presence of fatty liver disease (Gunarathne et al., 2020). Other treatments may include the use of nonselective beta-blockers, diuretics, and vasoactive agents (Gunarathne et al., 2020). In patients who develop variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) intervention may be used to reduce portal hypertension (García-Pagán et al., 2020). However, none of the above guidelines and interventions can be used to effectively treat patients with cirrhosis who present with features of portal hypertension. Summary of the invention

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

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

[0007] In some embodiments, the subject has at least one of the following diseases: 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's Child-Pugh score is equal to or greater than 5. In some embodiments, the subject's Child-Pugh score is equal to or greater than 7. In some embodiments, the subject's Child-Pugh score is equal to or greater than 10. In some embodiments, the subject's Child-Pugh score is not measured.

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

[0010] In some embodiments, the subject does not experience a decompensation event. In some embodiments, the subject experiences a decompensation event.

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

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

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

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

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

[0018] In some embodiments, the composition is an oral dosage form comprising zilpotentan 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 one to three times per day. In some embodiments, the composition is administered to the subject once per day.

[0020] In some embodiments, the composition is applied to the subject at least once to three times a day for at least 3 weeks. In some embodiments, the composition is applied to the subject at least once to three times a day for at least 6 weeks. In some embodiments, the composition is applied to the subject at least once to three times a day for at least 12 weeks. In some embodiments, the composition is applied to the subject at least once to three times a day for at least 16 weeks. In some embodiments, according to the needs of the subject, the composition is applied to the subject at least once to three times a day for at least 16 weeks (32 weeks, 64 weeks, 1 year, 5 years or longer) of the extended time period.

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

[0022] In some embodiments, after the composition is administered to a subject, the subject's hepatic venous pressure gradient (HVPG) is reduced to less than or equal to 12 mmHg relative to the subject's baseline HVPG. In some embodiments, after the composition is administered to a subject, the subject's HVPG is less than or equal to 10 mmHg. In some embodiments, after the composition is administered to a subject, the subject's HVPG is less than or equal to 8 mmHg. In some embodiments, after the composition is administered to a subject, the subject's HVPG is reduced to less than or equal to 5 mmHg.

[0023] In some embodiments, after the composition is administered to a subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to a subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to a subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to a subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to a subject, the subject's HVPG is reduced by at least 2.5 mmHg.

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

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

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

[0027] In some embodiments, cirrhosis is caused by viral hepatitis (eg, hepatitis B or hepatitis C), alcoholic liver disease, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or a combination of these diseases.

[0028] In some embodiments, the cirrhosis is caused by autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, hemochromatosis, Wilson's disease, biliary atresia, alpha-1 antitrypsin deficiency, and cystic fibrosis-related cirrhosis, or a combination of these diseases.

[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 a kit. In some embodiments, the kit includes: (a) an oral dosage form comprising about 0.25 mg to about 20 mg of zilpotentan 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 zilpotentan 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 of 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 a therapeutically effective amount of zilpotentan and dapagliflozin. In certain embodiments, reducing the risk of hospitalization may mean a first hospitalization or repeated hospitalization or the total number of hospitalizations. In certain embodiments, reducing the risk of hospitalization may mean reducing the risk of hospitalization due to a decompensation event.

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

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

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

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

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

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

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

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

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

[0043] In certain aspects, the present disclosure relates to a method of reducing the risk of varicose bleeding and / or death in a subject in need thereof, or a method of preventing and / or delaying progression to varicose bleeding and / or death in a subject in need thereof. In some embodiments, the method comprises administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin.

[0044] In certain aspects, the present disclosure relates to a method of treating ascites in a subject in need thereof and / or preventing or reducing ascites formation in a subject in need thereof and / or delaying the progression of ascites in a subject in need thereof and / or delaying progression to ascites complications in a subject in need thereof. In some embodiments, the method comprises administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The following drawings constitute part of this specification and are included to further demonstrate exemplary embodiments of certain aspects of the present disclosure.

[0046] Figure 1 The study design of Example 1 is shown. Dapa = dapagliflozin; HVPG = hepatic venous pressure gradient; N = number of participants; Zibo = zilpotentan. DETAILED DESCRIPTION

[0047] Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art.

[0048] Throughout this application, the term "about" is used to indicate that a certain value includes the inherent error variation of the method / device for determining the value, or the variation existing among the research subjects. Generally, the term "about" is intended to cover about or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% or higher variability ("greater than" or "less than" indicated value), depending on the actual situation. In an embodiment, those skilled in the art will understand the variability level indicated by the term "about", and this is due to the context used in this article. It should also be understood that the use of the term "about" also includes the value specifically listed.

[0049] Any type of range provided herein includes all values ​​within the specified range and values ​​about the endpoints of the specified range. As used herein, "between" is a range that includes the end values ​​of the range. For example, a number between x and y explicitly includes the numbers x and y, as well as any number that falls within x and y.

[0050] The term "dose" means a compound or medicament of a specified amount provided in a single administration or within a specified time period. In certain embodiments, the dose can be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is required, the desired dose may require a volume that is not easily accommodated by a single injection. In such embodiments, two or more injections may be used to reach the desired dose. In certain embodiments, the dose can be administered in two or more injections to minimize injection site reactions in an individual. In other embodiments, the compound or medicament is administered by infusion or continuous infusion over an extended time period. The dose can be expressed as an hourly, daily, weekly, or monthly dosage of the medicament.

[0051] The term "therapeutic effect" refers to the ability to produce a desired effect.

[0052] The term "treat" refers to the administration of a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder or condition in the animal.

[0053] The term "cirrhosis" refers to an advanced result of liver disease in which the liver becomes visibly scarred and damaged. Scar tissue replaces healthy liver tissue, preventing the liver from working properly. As cirrhosis worsens, the liver begins to fail.

[0054] The term "subject" means any subject, particularly a mammalian subject, that needs to be treated with a combination of zilpotentan and dapagliflozin or with dapagliflozin alone. Mammalian subjects include humans or 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 over 12 years old, over 14 years old, 4 to 17 years old, over 18 years old. In some embodiments, the human subject is 18 to 80 years old.

[0055] Non-human animals include, but are not limited to, pigs, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, cows, apes, monkeys, orangutans, chimpanzees, etc. As used herein, "subjects in need thereof" refers to subjects in need of treatment, for example, subjects with cirrhosis of the liver with portal hypertension.

[0056] Zipotentan is a compound of the following formula 1:

[0057]

[0058] Zipotentan or ZD4054 has been disclosed in WO1996040681 and is a selective endothelin (ET A ) receptor antagonists, which have more BHigh level of selectivity (ET A IC 50 =13nM, at ET B Zipotentan is a 2-hydroxy-1-hydroxy-2-nitropropene antagonist that has been previously developed as an anticancer drug candidate. Although not bound by any particular mechanism of action, zilpotentan may be an antagonist of endothelin (ET-1)-mediated vasoconstriction in the portal vasculature and intrahepatic stellate cells, which may result in a reduction in portal pressure in established portal hypertension. Studies of beta-blockers in cirrhosis have established that reduction of portal hypertension improves outcome and may reduce the risk of decompensated events and possibly death. Non-selective beta-blockers reduce portal hypertension primarily by reducing blood flow in the portal vein and venous collaterals. Zipotentan may provide further benefits through its effects on hepatic vascular resistance (reduction) and improved endothelial function, and may also exhibit antifibrotic effects in the liver over the long term, which is expected to improve overall liver function. However, as a chronic monotherapy, the benefit-risk profile of zilpotentan in patients with cirrhosis may be unfavorable given that ET-1 antagonism may lead to fluid retention in some participants.

[0059] Dapagliflozin is a compound of formula 2:

[0060]

[0061] Dapagliflozin is a potent, selective and orally active sodium-glucose cotransporter 2 (SGLT2) inhibitor. 50 =3.75nM. Dapagliflozin was originally developed to improve glycemic control in diabetic patients and provides cardiorenal benefits to patients with and without type 2 diabetes (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 kidneys, leading to osmotic diuresis without subsequent hyponatremia or hyperkalemia, while counteracting the effects of renin-angiotensin-aldosterone system activation.

[0062] In some embodiments, at least one compound is selected from the 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 the form of a non-crystalline solid (e.g., an amorphous form). In some embodiments, at least one compound is in the form of a crystalline solid.

[0063] In some embodiments, at least one compound is in the form of (S)-propylene glycol ((S)-PG) solvate, which has the structure shown below:

[0064]

[0065] 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 US Pat. No. 7,919,598.

[0066] 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 compounds of Formula 2 and prodrugs thereof, alone or in combination with at least one other therapeutic agent.

[0067] The mechanisms of action of zilpotentan and dapagliflozin are different. Although not bound by any particular theory, in some embodiments, zilpotentan can block changes in intrahepatic resistance driven by endothelin 1 (including elements of portal vein and hepatic sinusoidal vasoconstriction), reduce vascular stiffness, improve endothelial function, reduce liver inflammation, and in the long run, potentially reduce fibrosis. Separately, in some embodiments, dapagliflozin can have a beneficial effect on metabolic dysfunction, reduce hepatocellular damage and sodium and water overload, and potentially normalize blood volume while avoiding hyponatremia and hyperkalemia. Reducing the need for diuretics can also reduce the risk of potential acute kidney injury or other complications (such as encephalopathy).

[0068] In some embodiments, the subject suffers from portal hypertension. The term "portal hypertension" refers to portal pressure in the portal vein and its branches-abnormally elevated blood pressure, which flows from most of the intestine to the liver. In some embodiments, portal hypertension is defined as a hepatic venous pressure gradient (HVPG) greater than 5mmHg. In some embodiments, when HVPG is greater than 10mmHg, it is defined as clinically significant. In subjects with cirrhosis, HVPG represents portal pressure. In some embodiments, the subject's HVPG is greater than 4mmHg, 5mmHg, 6mmHg, 7mmHg, 8mmHg, 9mmHg, 10mmHg, 11mmHg or 12mmHg. In some embodiments, the subject's HVPG is greater than 5mmHg. In some embodiments, the subject's HVPG is greater than 7.5mmHg. In some embodiments, the subject's HVPG is greater than 10mmHg. In some embodiments, the subject's HVPG is greater than 12mmHg.

[0069] In some embodiments, HVPG is measured directly or indirectly by methods known to those skilled in the art. In some embodiments, HVPG is measured directly, for example, by direct portal vein catheterization, such as Myers JD, Taylor W.J., "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 wedging (blocking) the hepatic vein with a balloon catheter. See, for example, Groszmann RJ, Glickman M.C., Blei AT, Storer E., Conn HO, "Wedged and free hepatic venous pressure measured with a balloon catheter," Gastroenterology, 76 (1979), pp. 253-258.

[0070] In some embodiments, HVPG is the pressure gradient between the clinically measured hepatic vein wedge pressure (WHVP) and the hepatic vein free pressure (FHPV), and is therefore an estimate of the pressure gradient between the portal vein and the inferior vena cava. HVPG>5mmHg defines portal hypertension, and if the measurement exceeds 10mmHg, it is called clinically significant portal hypertension. At levels above 12mmHg, the risk of variceal bleeding may increase further.

[0071] In some embodiments, when blood flow in the hepatic vein is blocked by the inflated balloon, the proximal static blood column transmits pressure from the previously connected vascular region (hepatic sinusoids) to the catheter. Therefore, WHVP reflects the hepatic sinusoidal pressure rather than the portal vein pressure itself. In the normal liver, the wedge pressure is slightly lower than the portal vein pressure due to pressure balance through the interconnected hepatic sinusoids, although this difference is not clinically significant. In cirrhosis, the static blood column generated by balloon inflation cannot decompress at the level of the hepatic sinusoids due to the interruption of the normal intersinusoidal communication; therefore, HVPG (WHVP-FHVP) gives an accurate estimate of portal vein pressure in cirrhosis.

[0072] In some embodiments, HVPG is not measured directly or indirectly, but is determined by observing features consistent with portal hypertension in the subject. In some embodiments, the subject suffers from clinically significant portal hypertension (CSPH). In some embodiments, the term "features of portal hypertension" includes those signs and symptoms of a subject with compensated cirrhosis associated with CSPH, such as esophageal varices, portosystemic shunts, splenomegaly, and low platelet counts, or the subject has experienced a decompensated event, including variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, recurrent hepatic encephalopathy.

[0073] In some embodiments, a decompensation event occurs in the subject. In some embodiments, a "decompensation event" may include ascites, hepatic encephalopathy, hepatorenal syndrome, acute kidney injury or variceal bleeding. In some embodiments, the subject exhibits one or more decompensation events (including its onset, deterioration and / or complications), such as esophageal varices, variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, recurrent hepatic encephalopathy, jaundice or pulmonary complications. In some embodiments, no decompensation event occurs in the subject. In some embodiments, the "Child-Pugh score" is used to assess the prognosis of chronic liver disease (mainly cirrhosis). Although the "Child-Pugh score" was originally used to predict mortality during surgery, it is now used to determine prognosis, as well as the required intensity of treatment and the necessity of liver transplantation. See, e.g., Andrea Tsoris; Clinton A. Marlar, “Use of the Child Pugh Score in Liver Disease,” [updated March 18, 2022]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; (2022), accessed at: https: / / www.ncbi.nlm.nih.gov / books / NBK542308 / , accessed June 29, 2022. Chronic liver disease can be classified as Child-Pugh A to C, where the Child-Pugh score for A is 5-6, the Child-Pugh score for B is 7-9, and the Child-Pugh score for C is 10-15. The higher the Child-Pugh score, the higher the mortality rate.

[0074] In some embodiments, the subject has a Child-Pugh score of 5 or greater, 6 or greater, 7 or greater, 8 or greater, 9 or greater, or 10 or greater. In some embodiments, the subject has a Child-Pugh score of 5 or greater. In some embodiments, the subject has a Child-Pugh score of 7 or greater. In some embodiments, the subject has a Child-Pugh score of 10 or greater. In some embodiments, the subject's Child-Pugh score is not measured.

[0075] In some embodiments, the term "Model for End-Stage Liver Disease (MELD) score" is used to assess liver disease. The term MELD is a prognostic scoring system based on laboratory parameters for predicting 3-month mortality due to liver disease. See, e.g., Malinchoc M, Kamath PS, Gordon FD, et al., A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic hunts. Hepatology. 2000; 31(4):864-871, and Biggins SW, Kim WR, Terrault NA, et al., Evidence-Based Incorporation of Serum Sodium Concentration IntoMELD. Gastroenterology. 2006; 130(6):1652-1660. In some embodiments, the MELD score can include adding a serum sodium value (i.e., MELD-Na) to the MELD score. See, e.g., Ruf AE et al., "Addition of serumsodium 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; the higher the score, the higher the 3-month mortality associated with liver disease.

[0076] 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 subject's MELD score is not measured. In some embodiments, the subject has clinical or radiographic features of clinically significant portal hypertension. Such features may include the BAVENO VII criteria and include, but are not limited to, the presence of esophageal varices, collateral imaging, liver stiffness>25 kPa, or liver stiffness>20 kPa and platelet count<150×10 9 / L, and / or history of decompensation events. See, for example, Franchis et al., Baveno VII-Renewing consensus in portalhypertension.Journal of Hepatology.2022; 76: 959-974. In some aspects, the first decompensation event occurs in previously compensated subjects, wherein the first decompensation event is selected from variceal bleeding, hepatic encephalopathy and / or ascites. In some aspects, the subject has decompensated and other decompensation events selected from the following occur: a) a second decompensation event (ascites, variceal bleeding or hepatic encephalopathy) and / or jaundice caused by portal hypertension occurs; b) recurrent variceal bleeding, recurrent ascites (requiring ≥3 large-volume punctures within 1 year), recurrent encephalopathy, spontaneous bacterial peritonitis and / or hepatorenal syndrome and / or acute kidney injury occur; c) in subjects who only show bleeding, ascites, encephalopathy or jaundice occur after bleeding recovery, but if these events occur approximately at the time of bleeding, then not. 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. In some cases, the subject has decompensated cirrhosis.

[0077] In some embodiments, an effective amount or therapeutically effective amount of zilpotentan and dapagliflozin can be administered to a subject. The term "effective amount" or "therapeutically effective amount" means an amount of the compound sufficient to achieve a desired physiological result in an individual in need of a given compound. The effective amount may vary from individual to individual, depending on the health and physical condition of the individual to be treated, the classification group of the individual to be treated, the formulation of the composition, the assessment of the individual's medical condition, and other relevant factors.

[0078] In some embodiments, the composition may include various amounts of zilpotentan. In some embodiments, the composition includes a therapeutically effective amount of zilpotentan. In some embodiments, the composition includes about 0.1 mg to about 240 mg of zilpotentan. In some embodiments, the composition includes about 0.2 mg to about 50 mg of zilpotentan. In some embodiments, the composition includes about 0.5 mg to about 20 mg of zilpotentan. In some embodiments, the composition includes about 1 mg to about 10 mg of zilpotentan. In some embodiments, the composition includes 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 zilpotentan. In some embodiments, the composition comprises 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 zilpotentan. In some embodiments, the composition comprises about 1 mg of zilpotentan. In some embodiments, the composition comprises about 2.5 mg of zilpotentan. In some embodiments, the composition comprises about 5 mg of zilpotentan.

[0079] In some embodiments, the composition may 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.

[0080] 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.

[0081] In some embodiments, the composition comprises a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the composition comprises about 0.2 mg to about 25 mg zilpotentan and about 0.5 mg to about 25 mg dapagliflozin. In some embodiments, the composition comprises about 0.2 mg to about 25 mg zilpotentan and about 1.25 mg to about 20 mg dapagliflozin. In some embodiments, the composition comprises about 0.2 mg to about 25 mg zilpotentan and about 2.5 mg to about 10 mg dapagliflozin.

[0082] In some embodiments, the composition comprises about 0.5 mg to about 10 mg of zilpotentan 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 zilpotentan 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 zilpotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0083] In some embodiments, the composition comprises about 1 mg to about 5 mg of zilpotentan 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 zilpotentan 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 zilpotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0084] 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, about 10 mg of zilpotentan 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.

[0085] In some embodiments, the composition comprises about 1 mg of zilpotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg of zilpotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 1 mg of zilpotentan and about 10 mg of dapagliflozin.

[0086] In some embodiments, the composition comprises about 2.5 mg of zilpotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of zilpotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 2.5 mg of zilpotentan and about 10 mg of dapagliflozin.

[0087] In some embodiments, the composition comprises about 5 mg of zilpotentan and about 2.5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of zilpotentan and about 5 mg of dapagliflozin. In some embodiments, the composition comprises about 5 mg of zilpotentan and about 10 mg of dapagliflozin.

[0088] In some embodiments, the ratio of zilpotentan and dapagliflozin in the composition can be fixed, for example, when the composition is produced to provide a plurality of fixed dosage forms. For example, in some embodiments, the composition is present in an amount to form more than 1, more than 10, or more than 1000 dosage forms (e.g., capsules or tablets). In some embodiments, one skilled in the art will appreciate that any amount listed above for a "composition" can be applied to a single "dosage form." Thus, for example, the disclosure "the composition comprises about 5 mg zilpotentan and about 2.5 mg dapagliflozin" includes a single dosage form comprising about 5 mg zilpotentan and about 2.5 mg dapagliflozin.

[0089] In some embodiments, the weight ratio between zilpotentan and 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 between zilpotentan and dapagliflozin in the composition is about 1:2.5, about 1:5, or about 1:10. In some embodiments, the weight ratio between zilpotentan and dapagliflozin in the composition is about 1:1 to about 1:2, or about 1:4. In some embodiments, the weight ratio between zilpotentan and dapagliflozin in the composition is about 2:1, about 1:1, or about 1:2.

[0090] The term "administering" refers to the introduction of a compound or composition provided herein into an individual to achieve its intended function. Examples of routes of administration that can 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 via oral administration (e.g., oral dosage forms). In some embodiments, the oral dosage form is a capsule or tablet.

[0091] As used herein, a dosage form or unit dose is a drug product that exists in the form in which it is sold, has a specific mixture of active ingredients and inactive ingredients (excipients), has a specific structure (such as a capsule shell) and is distributed into a specific dose. There may be various dosage forms for a single specific drug, because different medical conditions may require different routes of administration. The dosage form may include, for example, an oral dosage form, an ophthalmic dosage form, an inhalation dosage form, an injection dosage form, a parenteral dosage form, a topical dosage form or a suppository. The oral dosage form may include, for example, pills in the form of tablets or capsules, syrups, special tablets (such as buccal tablets, sublingual tablets or orally disintegrating tablets), films, liquid solutions or suspensions, powders or liquid or solid crystals, natural or herbal plants, seeds, or various foods, pastes or buccal films.

[0092] In some embodiments, zilpotentan is an oral dosage form. In some embodiments, the oral dosage form of zilpotentan is a capsule or tablet. In some embodiments, dapagliflozin is an oral dosage form. In some embodiments, the oral dosage form of dapagliflozin is a capsule or tablet. In some embodiments, the composition (i.e., a composition comprising zilpotentan and dapagliflozin) is an oral dosage form. In some embodiments, the oral dosage form of zilpotentan / dapagliflozin is a capsule or tablet. In some embodiments, the oral dosage form of zilpotentan / dapagliflozin is a capsule.

[0093] In some embodiments, the composition is administered to the subject once to three times a day. In some embodiments, the composition is administered to the subject twice a day. In some embodiments, the composition is administered to the subject once a day.

[0094] As used herein, the term "daily" refers to a 24-hour cycle. For example, in some embodiments, the composition of the present disclosure can be applied in the morning, evening or at noon. In some embodiments, the composition of the present disclosure can be applied after eating (for example, after a meal) or before eating (for example, before a meal, i.e., under fasting conditions). The frequency of administration of the composition can be determined by a person of ordinary skill in the art. In some embodiments, the composition of the present disclosure can be applied at 8-hour intervals, 12-hour intervals or 24-hour intervals. In some embodiments, the composition is applied once a day, twice a day or three times a day. In some embodiments, the composition is applied once a week, twice a week or three times a week. In some embodiments, the composition is applied once a month, twice a month or three times a month. In some embodiments, the composition is applied no more than once a week, no more than once every two weeks, no more than once every three weeks, no more than once every four weeks, no more than once every five weeks, no more than once every six weeks or no more than once every seven weeks. In some embodiments, the composition is applied "as needed", for example, when even symptoms associated with decompensation of cirrhosis occur, until symptoms are alleviated.

[0095] In some embodiments, the composition is applied to the subject once to three times a day, and continues 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 longer. In certain embodiments, the composition is applied to the subject once a day, and continues for 3 weeks, 6 weeks, 12 weeks, 16 weeks, 18 weeks or longer. In some embodiments, according to the needs of the subject, the composition is applied to the subject at least once to three times a day, and continues for an extended period of more than 16 weeks (32 weeks, 64 weeks, 1 year, 5 years or longer).

[0096] In some embodiments, the present disclosure provides a method for 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 and compositions described herein, by any of the methods described herein (e.g., HVPG reduction).

[0097] In some embodiments, the subject has a hepatic venous pressure gradient (HVPG) response; and after the composition is applied to the subject once to three times a day for 6 weeks, the HVPG is reduced by at least 10% relative to the baseline HVPG of the subject. In some embodiments, baseline HVPG refers to the HVPG of the subject before the composition is applied. Therefore, for a subject whose HVPG rises to 10 mmHg, the phrase "after the composition is applied to the subject, the HVPG is reduced by at least 10%" will mean that after the composition described herein is applied, the HVPG of the subject is reduced by at least 1 mmHg (i.e., 10% of 10 mmHg). In some embodiments, after the composition is applied to the subject, the HVPG of the subject is reduced by at least 15%, 20%, 25%, 30%, 35% or 40%. In some embodiments, after the composition is applied to the subject, the HVPG of the subject is reduced by about 10% to about 50%, about 20% to about 40%, or about 20% to about 30%.

[0098] In some embodiments, after the composition is applied to a subject, the subject's HPVG decreases by 1mmHg to 8mmHg, 1mmHg to 7mmHg, 1mmHg to 6mmHg, 2mmHg to 5mmHg, or 3mmHg to 4mmHg. In some embodiments, after the composition is applied to a subject, the subject's HVPG decreases to about less than 5mmHg, less than 6mmHg, less than 7mmHg, or less than 8mmHg. In some embodiments, HVPG measurements are performed after the composition is applied to a subject once to three times a day for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or longer. In some embodiments, HVPG measurements are performed after the composition is applied to a subject once to three times a day for 6 weeks or longer. In some embodiments, HVPG measurements are performed after the composition is applied to a subject once a day for 6 weeks or longer.

[0099] In some embodiments, the HVPG endpoint can also be determined according to the HVPG measurement results (in mmHg). In some embodiments, the HVPG of the subject is reduced; and after the composition is applied to the subject, the HVPG is less than or equal to 12 mmHg relative to the baseline HVPG of the subject. In some embodiments, the HVPG response of the subject is less than or equal to 11 mmHg, 10 mmHg, 9 mmHg, 8 mmHg, 7 mmHg, 6 mmHg or 5 mmHg after the composition is applied to the subject. In some embodiments, the HVPG measurement is performed after the composition is applied to the subject once to three times a day for 6 weeks or more.

[0100] In some embodiments, the effect of administering the composition can also be evaluated using secondary target endpoints. In some embodiments, the subject has one or more of the following results after the composition is administered to the subject: (i) weight loss of at least 5%; (ii) body water volume reduction of at least 5%; (iii) body fat volume reduction of at least 5%; (iv) systolic blood pressure reduction to less than 130; (v) diastolic blood pressure reduction to less than 90; and (vi) cumulative additional loop diuretic equivalents reduction of at least 5%.

[0101] In some embodiments, the subject has one or more of the following results after the composition is administered to the subject: (i) a decrease in body weight of at least 10%; (ii) a decrease in body water mass of at least 10%; (iii) a decrease in body fat mass of at least 10%; (iv) a decrease in systolic blood pressure to less than 120; (v) a decrease in diastolic blood pressure to less than 80; and (vi) a decrease in the cumulative use of additional loop diuretic equivalents of at least 10%.

[0102] In some embodiments, the subject has one or more of the following results after the composition is administered to the subject: (i) a decrease in body weight of at least 15%; (ii) a decrease in body water mass of at least 15%; (iii) a decrease in body fat mass of at least 15%; (iv) a decrease in systolic blood pressure to less than 110; (v) a decrease in diastolic blood pressure to less than 70; and (vi) a decrease in the cumulative use of additional loop diuretic equivalents of at least 15%.

[0103] In some embodiments, these methods of treating cirrhosis can be continued until one or more secondary objective endpoints are achieved.

[0104] In some embodiments, after the composition is administered to the subject once to three times a day for 6 weeks, the subject's body weight is reduced by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or 30%.

[0105] In some embodiments, after the composition is administered to the subject once to three times daily for 6 weeks, the subject's body water volume is reduced by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or 30%.

[0106] In some embodiments, after the composition is administered to the subject once to three times daily for 6 weeks, the subject's body fat mass is reduced by at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, 20%, 25% or 30%.

[0107] In some embodiments, after administering the composition to the subject one to three times daily for 6 weeks, the subject's systolic blood pressure is reduced to below 140, below 135, below 130, below 125, or below 120.

[0108] In some embodiments, after administering the composition to the subject one to three times daily for 6 weeks, the subject's diastolic blood pressure is reduced to below 90, below 88, below 86, below 84, below 82, or below 80.

[0109] In some embodiments, after the composition is administered to the subject once to three times daily for 6 weeks, the subject's cumulative additional loop diuretic equivalent usage is reduced by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or 30%.

[0110] Methods described herein are used to treat liver cirrhosis. Liver cirrhosis can be caused by disease (e.g., viral infection) or illness (e.g., chronic alcoholism, obesity, etc.), thereby forming scar tissue on the liver, making it difficult for the liver to function. In some embodiments, liver cirrhosis is caused by viral hepatitis, alcoholic liver disease, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or a combination of these. In some embodiments, liver cirrhosis is caused by autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, hemochromatosis, Wilson's disease, biliary atresia, alpha-1 antitrypsin deficiency and cystic fibrosis-related liver cirrhosis or a combination of these. "Subjects needing treatment" may include any subject suffering from liver cirrhosis, regardless of the cause of liver cirrhosis. In addition, in some embodiments, "subjects needing treatment" may include any subject suffering from liver cirrhosis, even if the subject does not show a decompensation event.

[0111] In certain embodiments, in addition to the methods for treating cirrhosis described herein, subjects may also be treated with additional standard of care (SoC) therapies. Here, the term "standard of care" means the diagnosis and treatment process that clinicians should follow for a particular type of patient, disease, or clinical situation. In some embodiments, the standard of care for cirrhosis may include, for example, a low sodium diet and medication (e.g., beta blockers, such as carvedilol) to reduce portal blood pressure, and diuretics such as spironolactone or furosemide to prevent fluid accumulation in the body, drainage of fluid or surgery to relieve pressure when the subject experiences severe fluid accumulation, treatment with antibiotics, or other treatments associated with cirrhosis. In some embodiments, the method of the present disclosure also includes: (i) administering an additional agent; (ii) administering a low sodium diet; or (iii) a combination of these.

[0112] In certain aspects, the present disclosure provides an oral dosage form comprising zilpotentan and dapagliflozin. The present disclosure provides a combination of zilpotentan and dapagliflozin in therapeutically effective amounts, which, when taken orally together, for example in the same dosage form, can be used to treat liver cirrhosis. In some embodiments, the oral dosage form comprises: (i) about 0.25 mg to about 20 mg zilpotentan; (ii) about 0.5 mg to about 40 mg dapagliflozin; and (iii) a pharmaceutically acceptable excipient.

[0113] In some embodiments, the oral dosage form comprises about 0.5 mg to about 10 mg of zilpotentan 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 zilpotentan 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 zilpotentan and about 2.5 mg to about 10 mg of dapagliflozin.

[0114] In some embodiments, the oral dosage form comprises about 1 mg of zilpotentan and about 2.5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 1 mg of zilpotentan and about 5 mg of dapagliflozin. In some embodiments, the single oral dosage form comprises about 1 mg of zilpotentan and about 10 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg of zilpotentan and about 2.5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg of zilpotentan and about 5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 2.5 mg of zilpotentan and about 10 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 5 mg of zilpotentan and about 5 mg of dapagliflozin. In some embodiments, the oral dosage form comprises about 5 mg of zilpotentan and about 10 mg of dapagliflozin.

[0115] In some embodiments, the present disclosure provides a kit comprising a composition and / or dosage form described herein, which is used 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 zilpotentan 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 zilpotentan and a pharmaceutically acceptable excipient, wherein each individual oral dosage form of zilpotentan comprises about 0.25 mg to about 20 mg of zilpotentan; and (b) a plurality of dosage forms comprising dapagliflozin and a pharmaceutically acceptable excipient, wherein each oral dosage form of dapagliflozin comprises about 0.5 mg to about 40 mg of dapagliflozin.

[0116] In some embodiments, the kit comprises: (a) an oral dosage form comprising about 2.5 mg of zilpotentan 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 zilpotentan and a pharmaceutically acceptable excipient, wherein each individual oral dosage form of zilpotentan comprises about 2.5 mg of zilpotentan; and (b) a plurality of dosage forms comprising dapagliflozin and a pharmaceutically acceptable excipient, wherein each oral dosage form of dapagliflozin comprises about 5 mg of dapagliflozin.

[0117] In some embodiments, the kit includes 1 to 31 dosage forms comprising zilpotentan and 1 to 31 dosage forms comprising dapagliflozin. In some embodiments, the kit includes (a) multiple dosage forms comprising zilpotentan sufficient to treat a subject for 1 week, 1 month, 2 months, or 3 months, and (b) multiple 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 present in the kit. In some embodiments, the kit includes packaging for transporting and storing these oral dosage forms. In some embodiments, the packaging separates the zilpotentan dosage form from the dapagliflozin dosage form.

[0118] In certain aspects, the present disclosure relates to a method for reducing portal vein pressure in a subject in need thereof. In some embodiments, the method includes administering a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin to the subject. In some embodiments, the method includes administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg dapagliflozin. In some embodiments, after the composition is administered to the subject, HVPG is reduced by at least 20%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 25%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 30%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 35%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 40%. In some embodiments, after the composition is administered to the subject, the subject's hepatic venous pressure gradient (HVPG) is reduced to less than or equal to 12 mmHg relative to the subject's baseline HVPG. In some embodiments, after the composition is administered to the subject, the subject's HVPG is less than or equal to 10 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is less than or equal to 8 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced to less than or equal to 5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg.

[0119] In certain aspects, the present disclosure relates to a method for reducing the Child-Pugh score of a subject in need to a Child-Pugh score lower than the Child-Pugh score of the subject before administration. In some embodiments, the method includes administering a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin to the subject. In some embodiments, the method includes administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg 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 severity of the subject's Child-Pugh score is reduced to a different category (e.g., category B is reduced to category A after administration of the composition to the subject, or category C is reduced to category B after administration of the composition to the subject).

[0120] In certain aspects, the disclosure relates to a method for reducing the MELD score of a subject in need to a MELD score lower than the subject's MELD score before administration. In some embodiments, the method includes administering a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin to the subject. In some embodiments, the method includes administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg 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 points. In at least one embodiment, the MELD score is reduced by at least 5 points, reduced by at least 10 points, reduced by at least 15 points, reduced by at least 20 points, or more.

[0121] In certain aspects, the present disclosure relates to a method for treating cirrhosis of a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg zilpotentan and about 2.5 mg, 5 mg, or 10 mg dapagliflozin. In some embodiments, cirrhosis may be compensated or decompensated. In some aspects, the subject may be compensated or decompensated. Decompensated subjects may be in a stable state or in an unstable state, in which case they have recently suffered recurrent decompensation, such as during the past 1 to 3 month period.

[0122] In certain aspects, the present disclosure relates to a method for treating portal hypertension in a cirrhotic subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg dapagliflozin. In some embodiments, the method reduces the HVPG of the subject by at least 20% after administering the composition to the subject. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 25%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 30%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 35%. In some embodiments, after the composition is administered to the subject, the HVPG of the subject is reduced by at least 40%. In some embodiments, after the composition is administered to the subject, the subject's hepatic venous pressure gradient (HVPG) is reduced to less than or equal to 12 mmHg relative to the subject's baseline HVPG. In some embodiments, after the composition is administered to the subject, the subject's HVPG is less than or equal to 10 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is less than or equal to 8 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced to less than or equal to 5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg.

[0123] In certain aspects, the present disclosure relates to a method for treating clinically significant portal hypertension in a subject with cirrhosis in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg 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, after the composition is administered to the subject, the subject's HVPG is reduced by at least 25%. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 30%. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 35%. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 40%. In some embodiments, after the composition is administered to the subject, the subject's hepatic venous pressure gradient (HVPG) is reduced to less than or equal to 12 mmHg relative to the subject's baseline HVPG. In some embodiments, after the composition is administered to the subject, the subject's HVPG is less than or equal to 10 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is less than or equal to 8 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced to less than or equal to 5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg. In some embodiments, after the composition is administered to the subject, the subject's HVPG is reduced by at least 2.5 mmHg.

[0124] In certain aspects, the present disclosure relates to a method of reducing the risk of varicose bleeding and / or death in a subject in need thereof, or preventing and / or delaying the progression of varicose bleeding and / or death in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg zilpotentan and about 2.5 mg, 5 mg, or 10 mg dapagliflozin.

[0125] In certain aspects, the present disclosure provides a method for reducing the risk of decompensated liver cirrhosis in a subject in need, or preventing and / or delaying the progression and death of decompensated liver cirrhosis in a subject in need, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg dapagliflozin. In some embodiments, the method reduces the risk of new variceal bleeding, worsening of hepatic encephalopathy or worsening of ascites.

[0126] In certain aspects, the present disclosure relates to a method for treating ascites in a subject in need and / or preventing or reducing ascites formation in a subject in need and / or delaying ascites progression in a subject in need, preventing ascites complications (e.g., bacterial peritonitis, hepatopleural effusion, or refractory ascites) in a subject in need, and / or reducing ascites volume in a subject in need. In some embodiments, the method comprises administering a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin to the subject. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg, or 5 mg zilpotentan and about 2.5 mg, 5 mg, or 10 mg dapagliflozin. In some embodiments, the method prevents the development of grade 1 ascites. In some embodiments, the method delays or prevents ascites from progressing from grade 1 to grade 2, or from grade 2 to grade 3. In some embodiments, the method reduces the severity of ascites, e.g., from grade 3 to grade 2, from grade 2 to grade 1, or from grade 1 to the absence of ascites. "Grade 1" ascites is understood to mean a small amount of ascites that can only be detected by imaging or ultrasound. "Grade 2" ascites is understood to mean a moderate amount of ascites that manifests as moderate symmetrical abdominal distension. "Grade 3" ascites is understood to mean a large or severe amount of ascites that is characterized by a marked abdominal distension.

[0127] In certain aspects, the present disclosure provides a method for reducing the combined effects of variceal bleeding, encephalopathy, ascites exacerbation or complications (e.g., bacterial peritonitis, hepato-pleural effusion or refractory ascites) time and all-cause mortality in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin. In some embodiments, the method comprises administering a composition (e.g., capsule or tablet) comprising about 0.25 mg to about 20 mg dapagliflozin and about 0.5 mg to about 10 mg zilpotentan. In some embodiments, the composition comprises about 1 mg, 2.5 mg or 5 mg zilpotentan and about 2.5 mg, 5 mg or 10 mg dapagliflozin.

[0128] The term "prevent" refers to preventing the onset, development or progression of a disease, disorder or condition for a period of minutes to indefinitely. Delay refers to preventing the onset, development or progression of a disease, disorder or condition for a period of minutes to indefinitely. The terms "reduce" or "mitigate" refer to reducing to a lesser extent, size, amount or number. Thus, "reducing the risk of decompensated cirrhosis" would include reducing the incidence and / or magnitude of decompensated cirrhosis.

[0129] In any of the above methods, the reduction or prevention or treatment can be absolute or relative to placebo or standard of care or a monotherapy (i.e., dapagliflozin monotherapy or zilpotentan monotherapy). Standard statistical considerations will apply (e.g., relative risk ratios, hazard ratios, odds ratios, etc.).

[0130] Also disclosed herein are methods of treating a subject having cirrhosis of the liver with or without clinically significant signs of portal hypertension, comprising:

[0131] a) determining the concentration of multiple clinical pathological markers of the subject;

[0132] b) providing the determined values ​​of multiple clinical pathological markers of the subject to the machine learning model;

[0133] c) receiving a prediction from the machine learning model as to whether the patient is likely to progress to a condition; and

[0134] d) if the subject shows a likelihood of progression to the condition, administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin.

[0135] In the methods disclosed above, the clinical pathological markers may be one or more of a demographic value (age, sex, race or ethnicity), a comorbidity value (diabetes status or obesity), a vital sign value (body mass index, blood pressure or heart rate), a blood test value or a disease progression value. In addition, the markers may include a history of decompensated or compensated cirrhosis with clinically significant portal hypertension features, including but not limited to esophageal varices, splenomegaly, low platelet count, liver stiffness>25kPa or>20kPa+platelet count<150×10 9 In the above methods, treatment can 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 (eg, within the past 2 to 3 months).

[0136] All references cited herein, including patents, patent applications, papers, textbooks, etc., and references cited therein, as well as references not yet cited, are hereby incorporated by reference in their entirety.

[0137] Example 1: Fixed-dose study of zilpotentan and dapagliflozin

[0138] A two-part phase (Part A and Part B), randomized, double-blind, placebo-controlled, parallel-group dose-ranging study will be conducted to evaluate the efficacy, safety, and tolerability of the combination of zilpotentan and dapagliflozin and dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension. Specifically, Part A evaluates the efficacy, safety, and tolerability of the combination of 2.5 mg zilpotentan and 10 mg dapagliflozin versus placebo in participants with Child-Pugh A cirrhosis with features of portal hypertension and no history of decompensation events. At the end of Part A, the safety profile was determined to be acceptable. Part B investigates the efficacy, safety, and tolerability of 1 mg, 2.5 mg, or 5 mg zilpotentan combined with 10 mg dapagliflozin and 10 mg dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension. Part B included a wider range of participants with Child-Pugh A and Child-Pugh B cirrhosis, including those with more severe disease, a history of a decompensated event, or current ascites.

[0139] 1. Overall Design of the Embodiment

[0140] Figure 1 The study design for the study as outlined in Example 1 is shown.

[0141] 1.1 Cycle

[0142] Part A1 was a parallel-group, 2-arm study with blinded participants, investigators, and sponsors. Part B was a parallel-group, 5-arm study with blinded participants, investigators, and sponsors. Parts A and B each consisted of a screening period, a treatment period, and a follow-up period.

[0143] Screening period up to 6 weeks; used to confirm participant eligibility and collect baseline data on vital signs; clinical chemistry, hematology and urinalysis; and ECHO / cardiac MRI (Part B only). Data were collected in two time periods (Visit 1 and Visit 2). At Visit 2, eligibility criteria were assessed, safety laboratory data were revalidated, and participants were provided with digital medical devices to measure their weight at home every day before the randomized visit. At Visit 2, baseline HVPG records were completed, and the quality of the HVPG records was judged by the HVPG central reviewer. Then, only participants whose HVPG quality was good enough to accurately determine HVPG were randomized.

[0144] The treatment period for Part A was 6 weeks and for Part B was 16 weeks. During the treatment period, data were collected from participants 5 times (Part A) or 8 times (Part B). At Visit 3 (Day 1), participants were randomized and received the first dose of the study intervention. At each data collection during the treatment period (except for HVPG assessment and VCTE / Fibroscan assessment days if the visit procedures were separated on different days), participants received a daily dose at the study center and provided a pre-dose blood sample for PK analysis, as well as other laboratory samples before ingesting the study intervention. At Visit 6 (or Visit 7) in Part A and Visit 8 (or Visit 9) in Part B, participants provided pre-dose and post-dose blood samples for PK analysis within approximately 5 hours.

[0145] The follow-up period is 2 weeks. Participants will not receive the study intervention during the follow-up period and will return for a follow-up assessment approximately 2 weeks after their last dose of the study intervention.

[0146] The study intervention was a once-daily dose of the designated study intervention (oral capsules and tablets) in addition to their standard of care therapy 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) was approximately 13 weeks for Part A and approximately 24 weeks for Part B.

[0147] Table 1 shows the timeline of activities for Part A.

[0148] Table 1: Timeline of activities for Part A

[0149]

[0150] Table 1: Timeline of activities for Part A

[0151]

[0152] aVisits can take place on up to 3 different days.

[0153] bParticipants must fast for at least 8 hours before study interventions and until HVPG and VCTE / Fibroscan assessments have been performed. Participants will be allowed to drink water 1 hour before and 2 hours after study interventions and after HVPG and VCTE / Fibroscan examinations are completed. If participants are taking non-selective beta blockers to lower HVPG, the morning dose should not be taken but should be taken after HVPG and Fibroscan assessments.

[0154] cBrief physical examination.

[0155] dResults need to be obtained before the baseline visit.

[0156] e will be assessed ≥3 hours after administration of the study intervention. Note that randomization should not occur until the first HVPG record at the study center has been reviewed and concluded to be of good quality. If the assessment of the HVPG record concludes that it is of insufficient quality, study participants will not be randomized.

[0157] f will be performed prior to dosing unless otherwise specified.

[0158] gPK samples were collected only at the Early Stop Visit. If no dose was given, PK samples were collected at any time during the site visit.

[0159] Take samples at any time and record the exact date and time.

[0160] hSamples for PK profiling were collected within 5 hours at the study center. Sampling time: before dosing, 0.5 hours to 1.0 hours, 1.5 hours to 2.0 hours, 2.5 hours to 3.0 hours, 3.5 hours to 4.0 hours, 4.5 hours to 5.5 hours after dosing; the exact clock time needs to be recorded.

[0161] iIf this is not possible at Visit 6, PK profiling may be completed at Visit 7. On the day selected for PK profiling, the study intervention must be administered at the site to allow for planned PK sampling.

[0162] j Participants should abstain from using nicotine-containing products the night before and during the visit.

[0163] kIf an SAE occurs within 48 hours of the last dose, a PK sample will be collected whenever possible. The exact time of the last dose and blood draw will be recorded.

[0164] l HDL, total cholesterol, and triglycerides.

[0165] mNote that randomization should not occur until the first HVPG record at the site has been reviewed by the site reviewer. nIntake of study interventions will occur at the site, except for visits for HVPG assessment and VCTE / Fibroscan assessment.

[0166] Participants can take the study intervention at home at this time, with the visit procedures separated on different days (although if PK profiling is performed at the visit, intake of the study intervention will take place at the site).

[0167] o If medication is given at the study center, collect a pre-dose sample; when the study intervention is given at home, collect a sample during the visit.

[0168] Collect post-dose samples at any time during the study period (record the exact time of administration and sampling).

[0169] p VCTE / Fibroscan can be performed on a separate day (Day 5 to Day 1) and after administration of study intervention

[0170] VCTE / Fibroscan assessment of spleen stiffness should be performed only when it is technically feasible to complete an accurate spleen stiffness measurement and at the discretion of the site investigator.

[0171] q ECG evaluation will be completed during the HVPG procedure.

[0172] Abbreviations: AUDIT = Alcohol Use Disorders Identification Test; BMI = body mass index; ECG = electrocardiogram; ECHO = echocardiogram; eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; h = hour; 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 = randomization and trial supply management; SAE = serious adverse event; VCTE = vibration-controlled transient elastography.

[0173] Table 2 shows the timeline of activities for Part B.

[0174] Table 2: Timeline of activities for Part B

[0175]

[0176] Table 2: Timeline of activities for Part B

[0177]

[0178] Table 2: Timeline of activities for Part B

[0179]

[0180] aVisits can take place on up to 3 different days.

[0181] bParticipants must fast for at least 8 hours before study interventions and until HVPG and VCTE / Fibroscan assessments have been performed. Participants will be allowed to drink water 1 hour before and 2 hours after study interventions and after HVPG and VCTE / Fibroscan examinations are completed. If participants are taking non-selective beta blockers to lower HVPG, the morning dose should not be taken but should be taken after HVPG and Fibroscan assessments.

[0182] cBrief physical examination.

[0183] dResults need to be obtained before the baseline visit.

[0184] e will be assessed ≥3 hours after administration of the study intervention. Note that randomization should not occur until the first HVPG record at the study center has been reviewed and concluded to be of good quality. If the assessment of the HVPG record concludes that it is of insufficient quality, study participants will not be randomized.

[0185] f will be performed prior to dosing unless otherwise specified.

[0186] gOnly when historical data within the previous 12 months is not available.

[0187] hPK samples were collected only at the Early Stop Visit. If no dose was given, any time during the site visit

[0188] Take samples at any time and record the exact date and time.

[0189] iSamples for PK profiling were collected within 5 hours at the study center. Sampling time: before administration, 0.5

[0190] Hours to 1.0 hour, 1.5 hours to 2.0 hours, 2.5 hours to 3.0 hours, 3.5 hours to 4.0 hours, 4.5 hours to 5.5 hours; the exact clock time needs to be recorded.

[0191] j If this is not possible at Visit 8, PK profiling may be completed at Visit 9. On the day selected for PK profiling, the study intervention must be administered at the site such that PK sampling is feasible according to the schedule.

[0192] kTwo bottles of the assigned study intervention.

[0193] l Participants should abstain from using nicotine-containing products the night before and during the visit.

[0194] mIf an SAE occurs within 48 hours of the last dose, a PK sample will be collected whenever possible. The exact time of the last dose and blood draw will be recorded.

[0195] n HDL, total cholesterol, and triglycerides.

[0196] o Note that randomization should not occur until the first HVPG record at the site has been reviewed by the central reviewer. pIntake study interventions will be performed at the site, except at the visits for HVPG assessment (Visit 7) and VCTE / Fibroscan assessment (Visits 7 and 10), when participants can perform the study interventions at home, with the visit procedures separated on different days (however, if PK profiling is performed at that visit, intake study interventions will be performed at the site).

[0197] q If medication is given at the study center, collect a pre-dose sample; when the study intervention is given at home, collect a sample during the visit.

[0198] Collect post-dose samples at any time during the study period (record the exact time of administration and sampling).

[0199] r VCTE / Fibroscan can be performed on a separate day (Day 5 to Day 1) and after administration of study intervention

[0200] VCTE / Fibroscan assessment of spleen stiffness should be performed only when it is technically feasible to complete an accurate spleen stiffness measurement and at the discretion of the site investigator.

[0201] s ECG evaluation will be completed during the HVPG procedure.

[0202] Abbreviations: AUDIT = Alcohol Use Disorders Identification Test; BMI = body mass index; ECG = electrocardiogram; ECHO = echocardiogram; eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; h = hour; 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 = randomization and trial supply management; SAE = serious adverse event; VCTE = vibration-controlled transient elastography.

[0203] 1.2 Participants .

[0204] In Part A, approximately 30 participants with good-quality baseline HVPG will be randomized to 2 treatment groups of 15 participants each. Given an estimated 20% of participants discontinuing treatment prematurely, this allows for the inclusion of 12 evaluable participants per treatment group with evaluable HVPG measurements at baseline and Week 6 (primary endpoint).

[0205] In Part B, approximately 110 participants with good-quality baseline HVPG will be randomized to 5 treatment groups of 22 participants each. Given an estimated 20% of participants discontinuing treatment prematurely, this will allow each treatment group to include 18 evaluable participants with evaluable HVPG measurements at baseline and Week 6 (primary endpoint).

[0206] 1.3 Intervention groups and duration .

[0207] In Part A, participants who met the eligibility criteria and agreed to participate in the trial were randomly assigned to one of the following 2 treatment groups (15 participants in each group):

[0208] Treatment Group 1: Placebo matching zilpotentan capsules + placebo matching dapagliflozin tablets.

[0209] Treatment group 2: Zipotentan capsules 2.5 mg + dapagliflozin tablets 10 mg.

[0210] The study intervention was a once-daily dose of the designated study intervention (oral capsules and tablets) in addition to their standard of care therapy for 6 weeks. The total study duration for participants in Part A was approximately 14 weeks (including the screening and follow-up periods).

[0211] In Part B, participants who met the eligibility criteria and agreed to participate in the trial were randomly assigned to one of the following 5 treatment groups (22 participants in each group):

[0212] Treatment Group 1: Placebo matching zilpotentan capsules + placebo matching dapagliflozin tablets.

[0213] Treatment group 2: placebo matching zilpotentan capsules + dapagliflozin tablets 10 mg.

[0214] Treatment group 3: 1 mg of zilpotentan capsules + 10 mg of dapagliflozin tablets.

[0215] Treatment group 4: 2.5 mg of zilpotentan capsules + 10 mg of dapagliflozin tablets.

[0216] Treatment group 5: 5 mg of zilpotentan capsules + 10 mg of dapagliflozin tablets.

[0217] A staggered randomization scheme was applied in Part B. Eligible participants were randomly assigned to treatment groups 1-4 in an equal configuration of 22 participants per treatment group (approximately 88 participants total).

[0218] In some embodiments, participants in Part B are stratified according to the presence of clinically detectable (grade 2) ascites at the time of randomization to ensure approximate balance between treatment groups within each subpopulation.

[0219] The study intervention was a once-daily dose of the designated study intervention (oral capsules and tablets) in addition to their standard of care therapy for 16 weeks. The total study duration for participants in Part B was approximately 24 weeks (including the screening and follow-up periods).

[0220] Eligibility criteria for participants in Part A:

[0221] (a) Clinical and / or histological diagnosis of cirrhosis, meeting the following requirements: (i) with features of portal hypertension or (ii) liver stiffness ≥ 21 kPa.

[0222] (b) MELD score <15.

[0223] (c) Child-Pugh score ≤6.

[0224] (d) No clinically apparent ascites.

[0225] (e) No evidence of worsening liver function (e.g., no clinically significant changes in signs, symptoms, or laboratory parameters of liver disease) within the last month prior to dosing, as determined by the investigator or general practitioner.

[0226] (f) The central reviewer judged that the quality of the HVPG record was adequate.

[0227] Eligibility criteria for participants in Part B:

[0228] (a) Clinical and / or histological diagnosis of cirrhosis with features of portal hypertension.

[0229] (b) MELD score <15.

[0230] (c) Child-Pugh score <10.

[0231] (d) No ascites or ascites increased to grade 2 with no change in diuretic therapy in the last month before the first dose, and no paracentesis in the last month of screening or no paracentesis planned in the next 4 months after screening.

[0232] (e) No evidence of worsening liver function (e.g., no clinically significant changes in signs, symptoms, or laboratory parameters of liver disease) within the last month prior to dosing, as determined by the investigator or general practitioner.

[0233] (f) The central reviewer judged that the quality of the HVPG record was adequate.

[0234] Exclusion criteria

[0235] Participants were excluded from this study if any of the following criteria applied:

[0236] Medical conditions (all participants)

[0237] 1. Evidence of any clinically significant illness that the investigator deems undesirable for the participant to participate in this study.

[0238] 2. Cirrhosis caused by chronic cholestatic liver disease.

[0239] 3. ALT or AST ≥ 150U / L, and / or total bilirubin ≥ 3×ULN.

[0240] 4. Any history of hepatocellular carcinoma.

[0241] 5. Any history of portal vein thrombosis.

[0242] 6. Liver transplantation or expected to undergo liver transplantation within 6 months after screening.

[0243] 7. History of TIPS or plan to undergo TIPS within 6 months from the date of enrollment in this study.

[0244] 8. Positive alcohol breath test at screening, or positive screening for drugs of abuse (excluding drugs prescribed by the participant's regular physician).

[0245] 9. Continuous heavy drinking or a history of heavy drinking that is expected to interfere with proper compliance with study procedures.

[0246] 10. Actively treated for HCV in the past year, or HBV antiviral therapy for less than 1 year.

[0247] 11. Active urinary tract infection or genital infection

[0248] 12. Uncontrolled diabetes (HbA1c>8% or>64mmol / mol in the last month).

[0249] 13. Participants have T1DM.

[0250] 14. Kidney transplantation, chronic renal replacement therapy, or short-term dialysis within the past 6 months.

[0251] 15. eGFR < 60 mL / min / 1.73 m 2 (eGFRcr[AS]).

[0252] 16. Acute coronary syndrome event occurred within 3 months before screening.

[0253] 17. Orthostatic hypotension or low blood pressure (systolic blood pressure <95 mmHg or diastolic blood pressure <60 mmHg).

[0254] 18. Use of strong CYP3A4 drugs within 14 days (21 days for St. John's wort) after study intervention

[0255] Participants treated with inhibitors or strong or moderate CYP3A4 inducers ( Table 7 );

[0256] This includes grapefruit and grapefruit juice if consumed more often than occasionally, or in larger quantities.

[0257] 19. According to the investigator's judgment, the patient has a history of allergic reaction / hypersensitivity reaction or is experiencing allergic reaction / hypersensitivity reaction to SGLT2i (e.g., dapagliflozin, empagliflozin), zilpotentan, or drugs with similar chemical structure to zilpotentan.

[0258] 20. Any clinically significant chronic disease or condition (e.g., cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, serious physical impairment) that, in the investigator's judgment, may place the participant at risk due to participation in this study or that, in the investigator's judgment, is a possible alternative primary cause of the participant's symptoms.

[0259] For example:

[0260] a. Anemia, defined as a hemoglobin (Hb) level <100 g / L or 10 g / dL.

[0261] b. Wernicke's encephalopathy or Korsakoff's syndrome.

[0262] c.History of HIV.

[0263] 21. With respect to COVID-19, any of the following:

[0264] a. Developed symptoms of COVID-19 infection within 14 days prior to enrollment in this study or recently tested positive.

[0265] b. Participants who have been hospitalized for COVID-19 infection within the past 3 months and required inpatient medical care (oxygen therapy, mechanical ventilation, admission to the intensive care unit, etc.).

[0266] 22. Acute liver damage caused by drug toxicity or infection.

[0267] Medical Conditions (Part A only)

[0268] 1. INR>1.5.

[0269] 2. Serum / plasma albumin level ≤35 g / L.

[0270] 3. Platelet count <75×10 9 / L.

[0271] 4. History of ascites

[0272] 5. History of hepatic pleural effusion

[0273] 6. History of portopulmonary syndrome

[0274] 7. History of hepatic encephalopathy

[0275] 8. History of varicose bleeding

[0276] 9. History of acute kidney injury

[0277] 10. History of heart failure, including high-output heart failure (eg, due to thyroid dysfunction)

[0278] Hyperactivity or Paget's disease

[0279] Medical Conditions (Part B only)

[0280] 1. INR>1.7.

[0281] 2. Serum / plasma albumin level ≤28 g / L.

[0282] 3. Platelet count <50×10 9 / L.

[0283] 4. Acute kidney injury occurs within 3 months after screening.

[0284] 5. History of West Haven encephalopathy of grade 2 or above.

[0285] 6. History of varicose bleeding within 6 months prior to screening.

[0286] 7. Individuals with NYHA functional heart failure class III or IV, or unstable heart failure requiring hospitalization for optimization of heart failure treatment, and individuals whose heart failure treatment has not been stable within 6 months prior to screening.

[0287] 8. Heart failure due to cardiomyopathy that primarily requires specific additional therapy: e.g., cardiomyopathy due to pericardial disease, 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).

[0288] 9. High-output heart failure (eg, due to hyperthyroidism or Paget's disease).

[0289] 10. Heart failure due to primary heart valve disease / dysfunction, severe functional mitral or tricuspid regurgitation, or planned heart valve repair / replacement

[0290] 1.4 Statistical methods .

[0291] For Part A, the primary efficacy endpoint was the absolute change in HVPG at Week 6, which was analyzed using ANCOVA with baseline values ​​used as covariates for comparisons between the zilpotentan / dapagliflozin group and the placebo group. In some embodiments, there was a difference of 2 mmHg or greater in the mean absolute change in HVPG at Week 6 between the zilpotentan / dapagliflozin group and the placebo group, and the common standard deviation (SD) of the HVPG difference was 2.5 mmHg (Bai et al., 2021) or less. In this case, 12 HVPG-evaluable participants in each group provided 80% power to detect differences at Week 6 with a type I error of 15% (one-sided). Part A randomized a total of 30 participants (15 in each group), with an estimated 20% of participants discontinuing treatment prematurely.

[0292] For Part B, the primary efficacy endpoint was HVPG response, with responders defined as a ≥20% decrease in HVPG from baseline or a decrease in HVPG from baseline to less than 12 mmHg at Week 6. HVPG response at Week 6 was analyzed by the Cochran Mantel-Haenszel test, taking into account stratification. Pairwise comparisons of the combination of zilpotentan and dapagliflozin versus placebo were performed. With a one-sided type I error of 5%, 18 HVPG-evaluable participants in each group in Part B provided 80% power to detect a difference between a 9% placebo HVPG response rate and a 45% zilpotentan / dapagliflozin response rate at Week 6, assuming that zilpotentan / dapagliflozin was similarly effective to nonselective beta-blockers. With an estimated 20% of participants discontinuing treatment prematurely, Part B randomized 22 participants in each of the five treatment groups to allow for 90 participants (18 participants in each treatment group) to have evaluable HVPG measurements at baseline and Week 6. Therefore, up to 110 participants were randomized in this study.

[0293] The changes of body weight, body water content, body fat mass, loop diuretic equivalent cumulative dose and blood pressure in Part A and Part B are analyzed using a mixed model repeated measures (MMRM) method. The analysis model includes fixed categorical effects of stratification factors, treatment, visits and visit-by-visit treatment interactions, and continuous covariates of baseline measurements. In some embodiments, the model also includes a covariate (by randomization) as a covariate in the case of randomized adjustment. Unstructured covariance structure is used for intra-participant error.

[0294] In a previous oncology Phase III program, 10 mg of zilpotentan was used, and extensive safety data for this dose are available. Based on the zilpotentan liver impairment study (Tomkinson et al., 2011), exposure in participants with moderate hepatic impairment is expected to be 1.45 times that of healthy control participants. Example 1 includes participants with mild or moderate hepatic impairment and normal or mild renal impairment (MELD score <15 and eGFR>60 mL / min / 1.73 m2), and the dosing is adjusted as described below.

[0295] 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 receive 2.5 mg of zilpotentan combined with 10 mg of dapagliflozin, or placebo. After determining that the combination therapy is safe for these participants, Part B then begins, which also includes participants with Child-Pugh B, a history of decompensation events, or ascites. In Part B, only two dose levels of zilpotentan, 1 mg and 2.5 mg, in combination with dapagliflozin were initially studied, conservatively representing 1 / 10 and 1 / 4 of the zilpotentan dose in the previous oncology project. After the safety and tolerability of the two lower dose levels have been evaluated, a cohort of 5 mg of zilpotentan combined with 10 mg of dapagliflozin is recruited. This is intended to increase the dose range to 5 times and evaluate the potential benefits of the 5 mg dose, while protecting the subjects enrolled in this study with a staggered design.

[0296] 10mg dapagliflozin has been extensively studied as a monotherapy. Compared with healthy participants, it is expected that the exposure of dapagliflozin in participants with renal impairment and / or hepatic impairment is higher, but considering the safety and tolerability profile of dapagliflozin, no dose adjustment is required. In both chronic kidney disease (≥25mL / min / 1.73m2; DAPA-CKD results study) and heart failure populations (DAPA HF results study), dapagliflozin once a day 10mg did not produce any unique safety or tolerability signals in participants with renal impairment. Healthy volunteers taking multiple doses of up to 100mg of dapagliflozin for 14 consecutive days have been shown to be tolerable. Therefore, 10mg dapagliflozin once a day has also been selected for planned clinical projects for cirrhosis with portal hypertension features (Dapagliflozin Investigator's Manual).

[0297] 2. Administration of the Study Intervention .

[0298] 2.1 Study intervention .

[0299] As shown in Table 3 below, all participants received 1 capsule (zipotentan or matching placebo) and 1 tablet (dapagliflozin or matching placebo) at each dosing.

[0300] Table 3 :

[0301]

[0302] GMP = good manufacturing practice; HDPE = high-density polyethylene; IMP = investigational medicinal product; NA = not applicable; NIMP = noninvestigational medicinal product.

[0303] 3. Evaluation

[0304] 3.1 Efficacy evaluation

[0305] 3.1.1 Main variable: hepatic venous pressure gradient

[0306] HVPG assessments were performed at the time points specified in Tables 1 and 2. On the day of the HVPG assessment, participants were required to fast and refrain from using nicotine-containing products until the HVPG assessment had been completed. If participants were taking nonselective beta-blockers, the dose should not be taken in the morning before the HVPG assessment but rather immediately after 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 and the intake of the study intervention at Visit 7 was carefully planned. Before participants could be randomized, the central reviewer reviewed the baseline records and found them to be of sufficient quality. An HVPG record of sufficient quality is the result of a record that meets all requirements of the experiment. An acceptable tracing that can be used to derive HVPG data, while not completely satisfactory, still allows the derivation of more important information from several (although not all three) measurements of WHVP, FHVP, and HVPG, even if these tracings have artifacts or even if some auxiliary measurements (i.e., right atrial pressure, inferior vena cava pressure) are missing, the results are consistent.

[0307] A balloon catheter was introduced into the hepatic vein via a transjugular approach under ultrasound / fluoroscopic guidance. Mild sedation was provided to keep the participant comfortable. Midazolam was the drug of choice for sedation as it did not affect HVPG. Of note, zilpotentan resulted in a 20% increase in midazolam exposure, however, this is unlikely to be clinically relevant with standard midazolam dosing. Once the catheter was in place in the hepatic vein, the initial venous free pressure was measured, followed by the wedge pressure. The HVPG was calculated from these two values. The HVPG was measured in triplicate.

[0308] 3.1.2 Auxiliary variables

[0309] 3.1.2.1 Measuring weight with an electronic scale .

[0310] Body weight was measured at study visits. In addition, participants measured their weight each morning using a provided digital device.

[0311] 3.1.2.2 Bioimpedance spectroscopy .

[0312] Bioimpedance spectroscopy (BIS) was performed at the time points specified in the SoA (Tables 1 and 2) to monitor body fluid volume. This non-invasive procedure uses skin electrodes to pass a low-level alternating current through the body and measures the impedance to this current flow. Tissue (such as fat and bone) acts as an insulator; whereas electrolyte body fluids conduct the current, and as body fluid 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, the cell membrane does not conduct electricity and the current only passes through the extracellular fluid, while at high frequencies, the current passes through the cell membrane in addition to the extracellular and intracellular fluids.

[0313] 3.1.3 Exploratory variables

[0314] 3.1.3.1 Vibration Controlled Transient Elastography (VCTE) .

[0315] VCTE was performed in the fasting state, and at the time points specified in Tables 1 and 2, and ≥3 hours after administration of the study intervention. If the participant was taking a nonselective beta-blocker, the dose was not taken in the morning before the VCTE, but immediately after the VCTE assessment. A Fibroscan device that allows the measurement of spleen stiffness was used. Spleen stiffness was collected as an exploratory endpoint to investigate the extent to which it can be used as a surrogate marker for changes in the hepatic portal vein pressure gradient. The measurement was preferably performed by the same examiner in all cases.

[0316] VCTE / Fibroscan assessment of spleen stiffness should only be performed if it is technically feasible to complete accurate spleen stiffness measurement.

[0317] 3.1.3.2 Analysis of serum creatinine and cystatin C (eGRF) .

[0318] For eligibility and safety, participants' eGFR was calculated based on serum creatinine concentration alone according to the 2021 CKD EPI equation (Inker et al., 2021), hereafter referred to as eGFR1. In addition, the eGFR used for exploratory assessment was calculated based on both serum creatinine and serum cystatin C concentrations (Inker et al., 2021), hereafter referred to as eGFR2.

[0319] The estimated GFR using serum creatinine alone or together with serum cystatin C is calculated as follows:

[0320] eGFR1=142×min(Scr / κ,1) -0.241(如果是女性) / 0.302(如果是男性) ×max(Scr / κ,1) -1.200 ×

[0321] 0.994 年龄 ×1.012[if female]

[0322] eGFR2=135×min(Scr / κ,1) -0.219(如果是女性) / 0.144(如果是男性) ×max(Scr / κ,1) -0.544 ×

[0323] min(Scys / 0.8,1) -0.323 ×max(Scys / 0.8,1) -0.778 ×0.996 年龄 ×0.963 [if female] where:

[0324] S cr = Serum creatinine (mg / dL)

[0325] S cys = Serum cystatin C (mg / L)

[0326] For females, κ = 0.7; for males, κ = 0.9

[0327] min = the minimum of Scr / κ or 1

[0328] max = the maximum of Scr / κ or 1

[0329] 3.1.3.3 Laboratory evaluation for exploratory analysis

[0330] Blood and urine samples were collected as indicated in the SoA (Tables 1 and 2) to measure the levels of the following biomarkers for analysis of exploratory variables:

[0331] Plasma / serum AST, ALT, FIB 4 derived from safety variables (Part B only).

[0332] The MELD score was calculated at each visit (MELD=3.78×ln[serum bilirubin (mg / dL)]+11.2×ln[INR]+9.57×ln[serum creatinine (mg / dL)]+6.43).

[0333] 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 in SoA.

[0334] Fasting plasma / serum glucose, fasting insulin, fasting β-hydroxybutyrate are fasting plasma biomarkers in SoA. Total cholesterol, triglycerides, and HDL cholesterol are additional fasting plasma biomarkers in SoA.

[0335] On-site urine tests for potassium, sodium, and creatinine, as well as urea, uric acid, osmolality, glucose, and albumin were measured at visits specified in the SoA.

[0336] eGFR was calculated at each visit.

[0337] The Child-Plugh score was calculated as shown in Table 5:

[0338] Table 5: Child-Pugh score

[0339]

[0340] 3.2.1 Vital signs

[0341] Vital signs were collected at the timelines specified in the SoA (Tables 1 and 2). Vital signs included supine and standing blood pressure, pulse, and temperature.

[0342] Routine blood pressure, pulse, and temperature were assessed as outlined in the SoA (Tables 1 and 2) before laboratory tests using fully automated equipment while participants rested in the supine position. Manual techniques were used only when automated equipment was unavailable.

[0343] All participants were also provided with a home blood pressure monitor that could be used if the participant had symptoms suggestive of low blood pressure or orthostatic hypotension.

[0344] Participants rested for at least 5 minutes in a quiet environment without distractions (e.g., television, mobile phones) before measuring vital signs in the supine position, including 1 pulse, 1 temperature, and 3 blood pressures (3 consecutive blood pressure readings were recorded at least 1 minute apart). The average of the 3 blood pressure readings was recorded on the eCRF. In addition, standing blood pressure measurements should be recorded after 2 to 5 minutes in the standing position. These assessments are preferably performed in the morning. If orthostatic hypotension is confirmed during the trial, it is reported as AESI, including symptoms associated with orthostatic vital sign measurements (if present).

[0345] The study doctor will monitor the weight online data in real time for safety through the home monitoring device. If any significant weight gain (>2kg / week) is observed, the study doctor will alert the corresponding investigator.

[0346] 3.2.2 Electrocardiogram

[0347] At the visits outlined in the SoA (Tables 1 and 2), a single 12-lead ECG was performed after the participant rested in the supine position for at least 10 minutes.

[0348] Throughout the study, clinically relevant new findings or worsening of existing findings in the ECG (parameters or abnormal findings in the tracings) were considered AEs and recorded in the AE CRF form.

[0349] 3.2.3 Clinical safety laboratory evaluation

[0350] Blood and urine samples were collected for clinical chemistry, hematology, and urinalysis for safety analyses at the visits indicated in Tables 1 and 2. Laboratory assessments for exploratory analyses were as described above.

[0351] The following laboratory safety variables were measured, as shown in Table 5.

[0352] Table 5: Laboratory safety variables

[0353]

[0354]

[0355] 3.2 Pharmacokinetics

[0356] Plasma samples were collected for measurement of zilpotentan and dapagliflozin concentrations as specified in the SoA (Tables 1 and 2).

[0357] If necessary and agreed upon between the investigator and sponsor, for example, for safety reasons (such as SAEs), samples may be collected at additional time points during the study. Sampling times may be changed during the study (e.g., to obtain data closer to the time of peak or trough matrix concentrations) to ensure appropriate monitoring.

[0358] Samples for determination of drug concentrations in plasma are analyzed using an appropriately validated bioanalytical method. Analysis of sample reproducibility, if any, will be performed along with the bioanalysis of the test samples.

[0359] 3.3 Pharmacodynamics

[0360] Plasma / serum parameters were measured during this study to evaluate exploratory endpoints. Parameters were measured from blood samples collected for safety analysis at the central core laboratory. Blood samples were collected as described in the SoA (Tables 1 and 2) and analyzed by the central laboratory.

[0361] 3.4 Study Endpoints

[0362] The study endpoints are summarized in Tables 4 and 5. The primary efficacy objective of Part A was the absolute change from baseline in HVPG at week 6 in participants treated with 2.5 mg of zilpotentan plus 10 mg of dapagliflozin versus those treated with placebo. The primary efficacy objective of Part B was the proportion of participants treated with 1 mg, 2.5 mg, or 5 mg of zilpotentan plus 10 mg of dapagliflozin and 10 mg of dapagliflozin monotherapy versus those treated with placebo who achieved a ≥20% decrease in HVPG or a decrease in HVPG to less than 12 mm Hg. Secondary objectives in both Parts A and B included the percentage change in HVPG and assessments of body weight, body fat and water mass, cumulative dose of loop diuretic equivalents, and blood pressure.

[0363] Table 4: Objectives and endpoints of Part A .

[0364]

[0365]

[0366] a. Home balance.

[0367] b. Office balance.

[0368] c. 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg uric acid.

[0369] Abbreviations: AE = adverse event; AESI = adverse event of special interest; AKI = acute kidney injury; DAE = treatment discontinuation due to adverse event; ECG = electrocardiogram; GI = genital infection; HVPG = hepatic venous pressure gradient; SAE = serious adverse event; UTI = urinary tract infection.

[0370] d. VCTE / Fibroscan assessment of spleen stiffness should be performed only when it is technically feasible to complete an accurate spleen stiffness measurement and at the discretion of the investigator at the study center.

[0371] Abbreviations: AE = adverse event; AESI = adverse event of special interest; AKI = acute kidney injury; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CTproET-1 = C-terminal pro-endothelin-1; DAE = treatment 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 infection; HbA1c = hemoglobin A1c; HE = hepatic encephalopathy; HVPG = hepatic venous pressure gradient; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; UTI = urinary tract infection; VCTE = vibration-controlled transient elastography.

[0372] Table 5: Objectives and endpoints of Part B .

[0373]

[0374]

[0375] a. Home balance.

[0376] b. Office balance.

[0377] c. 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg ethacrynic acid. tVCTE / Fibroscan assessment of spleen stiffness should be performed only when it is technically feasible to complete an accurate spleen stiffness measurement and at the discretion of the site investigator.

[0378] AKI was 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 of 1.5 times baseline, known or presumed to have occurred within the past 7 days (or using the last available outpatient s-creatinine value within 3 months as the baseline value); or urine output <0.5 mL / kg / h for 6 hours.

[0379] v Clinical grading of ascites :

[0380] Level 1 ; Small amount of ascites, which can only be detected by imaging / ultrasound.

[0381] Level 2 ; Moderate ascites, manifested as moderate symmetrical abdominal distension.

[0382] Level 3 ; Large or severe ascites, causing obvious abdominal distension.

[0383] w West Haven Criteria for HE :

[0384] No HE .

[0385] Minimum HE ; Psychometric or neuropsychological changes in tests exploring psychomotor speed / executive function or neurophysiological changes without clinical evidence of psychological changes. Grade 1; Mild loss of consciousness, euphoria or anxiety, shortened attention span, impairment of addition and subtraction, altered sleep rhythm.

[0386] Level 2 ; lethargy or apathy, disorientation with time, obvious personality changes, inappropriate behavior, difficulty coordinating movements, and flapping tremors.

[0387] Level 3; Drowsiness to semi-coma, responsiveness to stimuli, confusion, severe disorientation, and bizarre behavior.

[0388] Level 4 ;coma.

[0389] 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 = treatment 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 infection; HbA1c = hemoglobin A1c; HE = hepatic encephalopathy; HVPG = hepatic venous pressure gradient; MELD = model for end-stage liver disease; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; UTI = urinary tract infection; VCTE = vibration-controlled transient elastography.

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Claims

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

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

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

4. The method according to any one of claims 1 to 3, wherein the subject's HVPG is greater than 7.5 mmHg.

5. The method according to any one of claims 1 to 4, wherein the subject's HVPG is greater than 10 mmHg.

6. The method according to any one of claims 1 to 5, wherein the subject suffers from at least one of the following diseases: esophageal varices, splenomegaly, variceal bleeding, recurrent variceal bleeding, ascites, refractory ascites, hepatic encephalopathy, recurrent hepatic encephalopathy, lower limb swelling, coagulopathy, pulmonary complications and portosystemic shunt.

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

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

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

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

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

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

13. The method according to any one of claims 1 to 12, wherein the subject has not experienced a decompensation event.

14. The method according to any one of claims 1 to 12, wherein the subject suffers 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 zilpotentan.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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. 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 an oral dosage form.

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

41. The method of any one of claims 1 to 40, wherein the composition is administered to the subject one to three times per day.

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

43. The method of any one of claims 1 to 42, wherein the composition is administered to the subject at least once to three times per day for at least 3 weeks.

44. The method of any one of claims 1 to 42, wherein the composition is administered to the subject at least once to three times per day for at least 6 weeks.

45. The method of any one of claims 1 to 42, wherein the composition is administered to the subject at least once to three times per day for at least 12 weeks.

46. ​​The method of any one of claims 1 to 42, wherein the composition is administered to the subject at least once to three times per day for at least 16 weeks.

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

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

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

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

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

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

56. The method of claim 55, wherein after administration of the composition to the subject, the subject has one or more of the following outcomes: (i) weight loss of at least 10%; (ii) a decrease in body water volume of at least 10%; (iii) a reduction in body fat mass of at least 10%; (iv) systolic blood pressure decreased to less than 120; (v) diastolic blood pressure decreases to less than 80; and (vi) Cumulative additional loop diuretic equivalent use is reduced by at least 10%.

57. The method of claim 56, wherein after administration of the composition to the subject, the subject has one or more of the following outcomes: (i) weight loss of at least 15%; (ii) a decrease in body water volume of at least 15%; (iii) a reduction in body fat mass of at least 15%; (iv) systolic blood pressure decreased to less than 110; (v) diastolic blood pressure decreases to less than 70; and (vi) Cumulative additional loop diuretic equivalent use is reduced by at least 15%.

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 of these.

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

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

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

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

63. The oral dosage form of claim 62, wherein the oral dosage form comprises about 0.5 mg to about 10 mg of zilpotentan and about 1 mg to about 20 mg of dapagliflozin.

64. The oral dosage form of claim 63, wherein the oral dosage form comprises about 1 mg to about 5 mg of zilpotentan and about 2.5 mg to about 10 mg of dapagliflozin.

65. The oral dosage form of claim 64, wherein the oral dosage form comprises about 1 mg zilpotentan and about 2.5 mg dapagliflozin.

66. The oral dosage form of claim 64, wherein the oral dosage form comprises about 1 mg zilpotentan and about 5 mg dapagliflozin.

67. The oral dosage form of claim 64, wherein the oral dosage form comprises about 2.5 mg zilpotentan and about 2.5 mg dapagliflozin.

68. The oral dosage form of claim 64, wherein the oral dosage form comprises about 2.5 mg zilpotentan and about 5 mg dapagliflozin.

69. The oral dosage form of claim 64, wherein the oral dosage form comprises about 2.5 mg zilpotentan and about 10 mg dapagliflozin.

70. The oral dosage form of claim 64, wherein the oral dosage form comprises about 5 mg zilpotentan and about 5 mg dapagliflozin.

71. The oral dosage form of claim 64, wherein the oral dosage form comprises about 5 mg zilpotentan and about 10 mg dapagliflozin.

72. A kit comprising: a. An oral dosage form comprising from about 0.25 mg to about 20 mg of zilpotentan and a pharmaceutically acceptable excipient; as well as b. An oral dosage form comprising about 0.5 mg to about 40 mg of dapagliflozin and a pharmaceutically acceptable excipient.

73. A kit comprising: a. An oral dosage form comprising about 2.5 mg of zilpotentan and a pharmaceutically acceptable excipient; as well as b. An oral dosage form comprising about 5 mg of dapagliflozin and a pharmaceutically acceptable excipient.

74. A method of reducing the risk of varicose bleeding and / or death in a subject in need thereof, or preventing and / or delaying the progression of varicose bleeding and / or death in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin.

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 zilpotentan.

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

77. A method of reducing the risk of decompensated cirrhosis in a subject in need thereof, or preventing and / or delaying the progression of decompensated cirrhosis in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of zilpotentan and dapagliflozin.

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 zilpotentan.

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

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