WO2023183339A1

WO2023183339A1 - Selective vasopressin receptor agonist for end-stage liver disease

Info

Publication number: WO2023183339A1
Application number: PCT/US2023/015825
Authority: WO
Inventors: Stan BUKOFZER; Geoff Harris
Original assignee: Ocelot Bio, Inc.
Priority date: 2022-03-22
Filing date: 2023-03-21
Publication date: 2023-09-28

Abstract

Provided herein are methods of treating end-stage liver disease (ESLD), cirrhosis, or complications related thereto, such as hepatorenal syndrome acute kidney injury (HRS-AKI) and ascites, in an individual using a selective V1A partial agonist.

Description

SELECTIVE VASOPRESSIN RECEPTOR AGONIST FOR END-STAGE LIVER

DISEASE

CROSS REFERENCE TO OTHER APPLICATIONS

[0001] This application claims the benefits of U.S. Provisional Patent Application No. 63/322,590, filed on March 22, 2022, U.S. Provisional Patent Application No. 63/432,973 filed on December 15, 2022, U.S. Provisional Patent Application No. 63/322,591 filed on March 22, 2022, and U.S. Provisional Patent Application No. 63/322,592 filed on March 22, 2022, each incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] End-stage liver disease (ESLD), such as decompensated cirrhosis, complications account for approximately 1 million deaths per year. Patients suffering from ESLD develop portal hypertension. Cirrhotic patients are prone to a variety of decompensating events that can compromise the perfusion pressure of the kidneys and result in progressive functional kidney injury.

[0003] Ascites represents the most common decompensating event and is associated with a high risk of developing further complications which include bacterial infection and acute kidney injury (AKI). Hepatorenal syndrome with acute kidney injury (HRS-AKI) is a lifethreatening decompensation that develops in patients with end-stage liver disease with an untreated mortality approaching 90%. If treated promptly, however, HRS-AKI is potentially reversible.

SUMMARY OF THE INVENTION

[0004] Complications from end-stage liver disease (ESLD) are serious and rapidly progressive and can lead to acute renal failure and often death. Complications from ELSD impact hundreds of thousands of individuals per year, and most complications are associated with a high mortality rate following diagnosis. As the incidence of liver disease increases, the prevalence of complications is anticipated to also increase. There has been no therapeutic drug innovation for many of such complications, and there are no FDA-approved treatments for most of the complications.

[0005] Ascites and hepatorenal syndrome with acute kidney injury (HRS-AKI) are serious and rapidly progressive consequences of end-stage liver disease (ESLD) that lead to acute renal failure and often death. Ascites impacts up to an estimated 60,000 - 100,000 individuals per year and is associated with a mortality rate of approximately 50 percent at 3 years following diagnosis, with a 1-year survival rate of less than 50%. HRS-AKI impacts up to an estimated 75,000 individuals per year and is associated with a mortality rate of more than 50 percent at 90 days following diagnosis. As the incidence of liver disease increases, the prevalence of ascites and HRS-AKI is anticipated to also increase. There are no FDA-approved treatments for ascites or HRS-AKI, and there has been no therapeutic drug innovation for HRS-AKI in over two decades.

[0006] Unapproved therapeutic interventions produce only modest effects and often fall short in achieving the goals of reversing renal failure and prolonging survival in critically-ill patients. [0007] Full VIA receptor (VI AR) agonists reduce portal pressure by increasing splanchnic arteriolar vasoconstriction, thereby redistributing blood volume to the systemic circulation which in turn can lead to increased glomerular filtration rate and improved renal perfusion. However, using full VI AR agonists, like vasopressin, to maintain the therapeutic goal of increasing mean arterial pressure (MAP) by 10-15 mmHg, which strongly correlates with the reversal of HRS-AKI, is difficult. Due to the pharmacokinetics of the vasopressin system and very steep concentration-response curve, it can be easier to either underdose (and lose clinical efficacy) or to produce too much vasoconstriction, which can lead to severe, potentially lifethreatening adverse events (AEs). Secondarily, individuals with decompensated cirrhosis can already have high endogenous vasopressin levels, which facilitates water retention through the V2-mediated antidiuretic effect. Clinical vasopressin agonists are first V2 agonists, acting secondarily as Via agonists at pharmacologic concentrations. The inherent V2 activity might contribute to the adverse event profile related to fluid overload and respiratory complications for clinical vasopressin agonists.

[0008] Provided in some embodiments herein is a compound that has selectivity for the Via receptor. In some embodiments, the compound reaches and maintains a (target) level of vasoconstriction and avoids fluid retention, such as through a uniform dosing profile. In some instances, the compound has a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some instances, it is not necessary to titrate the compound, such as to achieve a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some instances, a compound described herein (e.g., a partial Via receptor agonist) is administered at a higher dose (than necessary) and effectively reaches maximum efficacy. Contrarily, administering a comparatively high dose of a full Via agonist, like terlipressin, can become toxic and lead to (serious) adverse events. [0009] Provided in some embodiments herein is a compound (e.g., a partial Via receptor agonist, such as Compound 1) that provides a therapeutic effect in an individual (e.g., in need thereof) without excessive vasoconstriction over a broad dose range, such as 10 pg/kg to 500 pg/kg. In some instances, a selective VIA partial agonist provided herein reduces portal pressure, such as, by increasing splanchnic arteriolar vasoconstriction. In some embodiments, the selective VIA partial agonist is Compound 1.

[0010] In some embodiments, a compound described herein (e.g., a partial Via receptor agonist, such as Compound 1) achieves a therapeutic ceiling, such that even after increasing the dose of the compound (e.g., to doses as high as 100 to 500 pg/kg), an effect does not (significantly) change (e.g., increase or decrease).

[0011] In some instances, increasing the dose of a compound described herein (e.g., a full VI AR receptor agonist, such as terlipressin) does provide a (significant) change (e.g., an increase) in an effect (e.g., mean arterial pressure (MAP)). In some instances, increasing doses of a compound described herein (e.g., a full VI AR receptor agonist, such as terlipressin) continues pushing an effect (e.g., MAP) into levels that can be detrimental and/or can lead to (severe) side effects in the individual receiving the compound.

[0012] In some instances, increasing a dose of a partial Via receptor agonist described herein, such as Compound 1, does not continue increasing an effect in an individual (e.g., even at doses as high as 100 to 500 pg/kg), whereas increasing a dose of a full Via agonist, such as terlipressin, does continue increasing the effect in an individual. In some instances, partial Via receptor agonists described herein, such as Compound 1, are safely used to treat HRS-AKI, such as without the risk of an individual developing (serious) side effects and/or having an effect, such as MAP, develop to dangerous or harmful levels. In some instances, the therapeutic window (and safety profile) of partial Via receptor agonists described herein, such as Compound 1, is significantly improved compared to VI AR agonists (e.g., that do not comprise a discrete VI AR antagonist portion), such as terlipressin.

[0013] In some embodiments, a compound described herein has an agonist portion (e.g., DI). In some embodiments, a compound described herein has an antagonist portion (e.g., D2). In some embodiments, a compound described herein has an agonist portion (e.g., DI) and an antagonist portion (e.g., D2). In some embodiments, the antagonist portion (e.g., D2) has no (agonist) activity or substantially less (agonist) activity than the agonist portion (e.g., DI), such as having at least about 1.5x less agonist activity than the agonist portion (e.g., DI), at least about 2x less agonist activity than the agonist portion (e.g., DI), at least about 3x less agonist activity than the agonist portion (e.g., DI), 5x less agonist activity than the agonist portion (e.g., DI), at least about lOx less agonist activity than the agonist portion (e.g., DI), or at least about lOOx less agonist activity than the agonist portion (e.g., DI). In some embodiments, the agonism and/or antagonism is of VI AR.

[0014] In some embodiments, compounds described herein (e.g., partial Via receptor agonists, such as Compound 1) are not full Via receptor agonists. In some embodiments, administration of compounds described herein (e.g., partial Via receptor agonists, such as Compound 1) is not toxic (at therapeutic levels), e.g., even at doses as high as 100 to 500 pg/kg. In some embodiments, compounds described herein (e.g., partial Via receptor agonists, such as Compound 1) have a wide therapeutic index and are selective for the Via receptor, such as at therapeutic doses. In some embodiments, such as after administration of a compound described herein (e.g., partial Via receptor agonists, such as Compound 1), a change in an effect plateaus, or reaches a therapeutic maximum, after a period of time. In some instances, such as after administration of a compound described herein (e.g., a full Via agonist, such as terlipressin), an effect rapidly increases and peaks after a period of time.

[0015] In some embodiments, Compound 1 is used for the treatment of end-stage liver disease (e.g., cirrhotic portal hypertension) and complications thereof, such as ascites and HRS-AKI. In some instances, Compound 1 provides a substantially improved therapeutic index (e.g., arising from a lower maximal vasoconstrictive effect and lower risk for tissue hypoxia), such as, when compared to full VIA receptor agonists. In some instances, Compound 1 provides about half of the maximal vasoconstriction produced by full agonists, such as, without any concomitant signs of ischemia. In some instances, Compound 1 is a (clinically) efficacious vasoconstrictor (e.g., having a favorable benefit/risk profile, such as, having low to no organ toxicities).

[0016] Provided in some embodiments herein is a method of reducing serum creatinine (sCr) in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual. In some embodiments, the individual has end-stage liver disease (ESLD). In some embodiments, the individual has (e.g., decompensated) cirrhosis.

[0017] Provided in some embodiments herein is a method of treating end-stage liver disease (or complications thereof) in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0018] Provided in some embodiments herein is a method of treating cirrhotic portal hypertension in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0019] Provided in some embodiments herein is a method of treating (e.g., decompensated) cirrhosis (or complications thereof) in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0020] Provided in some embodiments herein is a method of treating ascites in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual. In some embodiments, the individual has end-stage liver disease (ESLD). In some embodiments, the individual has (e.g., decompensated) cirrhosis.

[0021] Provided in some embodiments herein is a method of treating hepatorenal syndrome with acute kidney injury (HRS-AKI) in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual. In some embodiments, the individual has end-stage liver disease (ESLD).

[0022] In some embodiments, treating HRS-AKI includes treating the disease itself and/or disease(s) associated therewith, such as ESLD or ascites. In some embodiments, treating HRS-AKI includes improving or managing quality of life, extending life, such as through treatment of symptoms and/or complications associated therewith (e.g., ascites).

[0023] In some embodiments, the individual has (developed) ascites as a complication of endstage liver disease (ESLD).

[0024] In some embodiments, the individual has (developed) HRS-AKI as a complication of end-stage liver disease (ESLD).

[0025] In some embodiments, the individual has decompensated cirrhosis (e.g., such as the functional deterioration of a structure of system (e.g., renal system) that had been previously working (e.g., with the help of allostatic compensation)).

[0026] In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 5 micrograms (pg)/hour (hr) to about 55 pg/hr (e.g., about 8 pg/hr to about 50 pg/hr or about 20 pg/hr to about 35pg/hr (e.g., about 30 pg/hr)). In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 5 pg/hour to about 55 pg/hr (e.g., about 8 pg/hr to about 50 pg/hr, or about 10 pg/hr to about 30 pg/hr (e.g., 15 pg/hr)). [0027] In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual intravenously.

[0028] In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual by intravenous infusion.

[0029] In some embodiments, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on a first day and a second day (e.g., one or more days after the first day).

[0030] In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), on the first day (e.g., to acclimate the individual to vasoconstriction before receiving a first assigned treatment dose (e.g., on the second day)). In some embodiments, the initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is a low dose, such as a dose of about 5 pg/hr to about 15 pg/hr, such as about 8 pg/hr. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual on the first day (e.g., by intravenous infusion) for a period of about 4 hr to about 8 hr, such as about 6 hr.

[0031] In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on multiple days.

[0032] In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more (e.g., consecutive) days after the first day.

[0033] In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on consecutive and/or non-consecutive days after the first day. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual for 4 to 10 days (e.g., after the first day). In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual (e.g., via continuous intravenous infusion) over a 24-hr period. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual (e.g., via continuous intravenous infusion over a 24-hr period per day) for up to 9 days. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 0.2 milligrams (mg)/day to about 2 mg/day (e.g., about 0.5 mg/day to about 1.5 mg/day (e.g., about 1.2 mg/day)). [0034] In some embodiments, the individual has a reduction in serum creatinine (sCr) (value) (e.g., of about 10% to about 50% (e.g., compared to a baseline measurement before treatment)). [0035] In some embodiments, the individual has a sCr value of 3.5 mg/dL or less before (e.g., weeks before) treatment.

[0036] In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual until the individual has a sCr value of 1.5 milligrams (mg)/deciliters (dL) or less (e.g., on (e.g., 2 or more) consecutive days).

[0037] In some instances, serum creatinine (sCr) levels decrease in individuals administered Compound 1. In some instances, at some doses, such as at lower doses, sCr concentration substantially decreases, such as to levels that achieve the primary endpoint (e.g., less than or equal to 1.5 mg/dL, such as on 2 consecutive days). In some instances, sCr levels remain unchanged or increase when administered a placebo, as compared to sCr levels of a subject administered Compound 1. In some instances, individuals receiving Compound 1 have a (e.g., substantial) decrease in sodium urine content. In some instances, at some doses, such as at lower doses, urine sodium concentration (e.g., substantially) decreases.

[0038] In some instances, individuals administered Compound 1 achieve the primary endpoint, such as sCr levels of less than or equal to 1.5 mg/dL for an amount of time, such as at least 2 hours apart. In some instances, individuals administered Compound 1 achieve the primary endpoint by the end of Day 14 or by discharge. In some instances, individuals administered Compound 1 survive without renal replacement therapy (e.g., dialysis) for a period of time (e.g., at least ten days). In some instances, Compound 1 compares similarly or better than terlipressin. In some instances, Compound 1 compares similarly or better than terlipressin in fewer days.

[0039] In some embodiments, the mean arterial pressure (MAP) of the individual increases (e.g., compared to a baseline measurement before treatment), such as increasing by up to 15 mmHg.

[0040] In some embodiments, the individual has a Model for End-Stage Liver Disease (MELD) score of 35 or less before (e.g., days before) treatment.

[0041] In some embodiments, the individual has proteinuria of 500 mg/dL or less before (e.g., weeks before) treatment.

[0042] In some embodiments, the individual has a pulse oximeter reading of about 90% on 2 liter (L) or more before (e.g., days before) treatment. [0043] In some embodiments, the individual has large volume paracentesis of 4 L or less before (e.g., weeks before) treatment.

[0044] In some embodiments, the individual has a systolic blood pressure of 140 mmHg or less and/or a diastolic blood pressure of 100 mmHg or less (e.g., before treatment).

[0045] In some embodiments, the individual is receiving albumin (and has had appropriate diuretic withdrawal (e.g., days (e.g., at least 48 hrs) before treatment).

[0046] In some embodiments, the individual has a lack in sustained renal function improvement (e.g., after diuretic withdrawal and/or plasma volume expansion with albumin).

[0047] In some instances, Compound 1 a structure represented by Formula (I- A):

Formula (I- A) or a pharmaceutically acceptable salt thereof.

[0048] In some instances, Compound 1 is administered in the form of an acetate salt. [0049] In some instances, Compound 1 is administered in the form described in Example 4.

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0051] FIG. 1 illustrates exemplary dose-response curves for full agonists, partial agonists, and weak agonists. FIG. 1 generally illustrates that a broader therapeutic window for vasoconstriction can be achieved with curve 2 than curves 1 or 3. Portion A illustrates levels of full agonists where vasoconstriction can be lethal. Portion A illustrates levels of full agonists where vasoconstriction can induce serious side-effects.

[0052] FIG. 2 illustrates an exemplary dose response curve of maximal possible effect at human Via (hVla) receptors for a full Via agonist and a partial Via agonist.

[0053] FIG. 3 illustrates an exemplary dose response curve of maximal possible effect at human Via (hVla) receptors and human V2 (hV2) receptors for a partial Via agonist.

[0054] FIG. 4 illustrates an exemplary dose response curve for contractility of human mesenteric resistance arteries in response to a partial Via agonist.

DETAILED DESCRIPTION OF THE INVENTION

Certain Definitions

[0055] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of the described features.

[0056] The terms “treat,” “treating,” or “treatment” as used herein, include reducing, alleviating, abating, ameliorating, managing, relieving, or lessening the symptoms associated with a disease, disease state, condition, or indication (e.g., provided herein) in either a chronic or acute therapeutic scenario. Also, treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, disorder, or indication.

[0057] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0058] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0059] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0060] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0061] Systemic hemodynamic complications can be indicative of cirrhosis and portal hypertension (PHT). Individuals can often develop elevations of portal pressure (PP) due to an increase in intrahepatic resistance. The combination of increased blood flow and elevated intrahepatic resistance can lead to the development of PHT and the common manifestations of decompensated cirrhosis. Clinical PHT can occur when the hepatic venous pressure gradient (HVPG) is >5 mmHg. PHT can then lead to a hyperdynamic state characterized by a decrease in splanchnic and systemic vascular resistance, which can further increase portal blood flow. As advanced cirrhosis progresses, splanchnic arteriolar vasodilation can worsen PHT, which can then lead to further increases in the HVPG, further leading to hypoperfusion of the kidneys at 10 mmHg or above. The kidney can sense low perfusion pressure and reduced glomerular filtration rate as hypovolemia, which can then activate the renin-angiotensin-aldosterone (RAAS) and vasopressin systems, leading to severe vasoconstriction within the kidney and retention of sodium and water. If hypoperfusion of the kidneys is severe enough, it can result in the development of ascites and renal injury in the form of hepatorenal syndrome-acute kidney injury (HRS-AKI).

[0062] HRS-AKI is a severe complication of cirrhosis; only 50% of patients with HRS-AKI are expected to respond to currently available treatments, and more than half of patients die within 90 days. However, with early intervention, HRS-AKI is reversible.

[0063] Management of HRS-AKI often focuses on restoring systemic arterial blood pressure and reducing PHT through splanchnic vasoconstriction, with the vasopressin system being a target, and a long-term goal being liver transplantation. While challenging to monitor and titrate, increases in vasoconstriction (i.e., mean arterial pressure (MAP)) have been correlated with improved hemodynamic parameters. Vasoconstrictive agents, including terlipressin, norepinephrine, and midodrine/octreotide, have been used as therapy for patients with HRS- AKI in an attempt to restore renal perfusion and function. Terlipressin (a vasopressin analog) plus albumin has been used as first-line therapy for HRS-AKI, as it reduces short-term mortality compared with placebo. Albumin is added to increase circulating volume. Terlipressin is approved by the US Food and Drug Administration for the treatment of adults with HRS with rapid reduction in kidney function.

[0064] There are three vasopressin receptors: Via, Vlb, and V2. Via receptors are found throughout the circulatory system and modulate vasoconstriction. The V2 receptors modulate aquaresis through an antidiuretic effect at the level of the kidney by mediating water reabsorption in collecting tubules. Vlb receptors are found in the anterior pituitary and peripheral tissues, and one potential role is to mediate the release of adrenocorticotropin hormone, which can stimulate water retention. Vasopressin, also known as arginine vasopressin (A VP) or anti diuretic hormone, is a peptide involved in water balance and vascular tone. At normal physiologic concentrations, there is little to no activity on the Via system; only at supraphysiologic concentrations is there meaningful vasoconstriction. With pharmacologic application, intense vasoconstriction can be achieved in a concentration-dependent manner.

[0065] Unless stated otherwise herein, Via or VIA, Vlb or V1B, and V2 refer to the Via, Vlb, and V2 receptors, respectively.

[0066] Arginine vasopressin (A VP) is the endogenous ligand of the vasopressin VIA, V1B, and V2 G-protein-coupled receptors (VI AR, V1BR, V2R). Homeostatic functions of the vasopressin system, such as regulation of blood osmolality and pressor effects, are mediated by the V2 and VIA receptor subtypes. Activation of V2 receptors located in kidney collecting ducts plays a role in the regulation of fluid balance through antidiuretic action. Activation of VIA receptors located on vascular smooth muscle cells provides vasoconstriction and increased arterial pressure.

[0067] Lysine vasopressin (LVP), the active metabolite of terlipressin, has activity at Via, Vlb, and V2 receptors and is a full Via agonist. Despite significantly improving renal function, terlipressin use is associated with serious adverse events, including gastrointestinal disorders, sepsis, and respiratory failure. These adverse effects, which can be attributed to the strength of LVP binding to Via and therapeutically undesirable activity at V2 and/or off-target effects on V2, may lead to further water retention. As a result of the potential for serious side effects, terlipressin carries a black box warning from the US FDA for serious or fatal respiratory failure. [0068] The pressor activity of vasopressin receptor agonists is of clinical interest, as demonstrated by the use of AVP and its analogs (e.g., terlipressin and ornithine vasopressin). However, a significant drawback of existing VIA receptor full agonists is the potential to induce severe vasoconstriction and tissue hypoperfusion when used at therapeutic doses. The pharmacological activity of VI AR partial agonists (e.g., compounds that have a reduced maximal efficacy at the VI A receptor) could be used in a variety of conditions where a modest increase in blood flow and/or blood pressure without risk of excessive vasoconstriction and/or tissue hypoperfusion is desirable. For example, such indications could include hepatorenal syndrome, refractory ascites, bleeding esophageal varices, anesthesia-induced hypotension, vasodilatory shock, paracentesis-induced circulatory dysfunction, and spontaneous bacterial peritonitis.

[0069] Individuals with liver cirrhosis often develop numerous clinical complications, among which ascites accumulation is paramount and indicates poor prognosis. In some instances, ascites formation results from the homeostatic activation of endogenous sodium and water retaining systems in attempt to counteract the circulatory dysfunction, such as developed in patients with advanced liver disease. In some instances, a feature of the circulatory dysfunction is the existence of splanchnic vasodilation and portal hypertension.

[0070] In some embodiments, a compound described herein (e.g., Compound 1) is a selective vasopressin Via receptor partial agonist. In some embodiments, a compound described herein (e.g., Compound 1) is a selective for VI AR. In some embodiments, a compound described herein (e.g., Compound 1) is a selective for VI AR over vasopressin 2 (V2) receptor (V2R). In some instances, a compound described herein (e.g., Compound 1) has no functional V2R activity. In some instances, a compound described herein (e.g., Compound 1) has no functional V2R activity at therapeutic concentrations. In some embodiments, the therapeutic concentration is a concentration sufficient to modulate V1AR.

[0071] In some instances, the activity and selectivity of a compound described herein (e.g., a partial Via agonist, such as Compound 1) is demonstrated by Tables 4 and 5. In some instances, the activity and selectivity of a compound described herein (e.g., a partial Via agonist, such as Compound 1) is demonstrated by FIGs. 2-4.

[0072] In some embodiments, a compound described herein (e.g., Compound 1) is selective for VI AR over V2R by more than 10-fold. In some embodiments, a compound described herein (e.g., Compound 1) is selective for V1AR over V2R by more than 100-fold. In some embodiments, a compound described herein (e.g., Compound 1) is selective for VI AR over V2R by more than 1,000-fold. In some embodiments, a compound described herein (e.g., Compound 1) is selective for V1AR over V2R by more than 10,000-fold. In some embodiments, a compound described herein (e.g., Compound 1) is inactive at V2R.

[0073] In some embodiments, a compound described herein (e.g., Compound 1) comprises a first portion having agonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a second portion having antagonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a first portion having agonist activity and a second portion having antagonist activity.

[0074] In some embodiments, a compound provided herein has a ratio of agonist to antagonist activity of about 90: 10 to about 10:90. In some embodiments, a compound provided herein has a ratio of agonist to antagonist activity of about 50:50.

[0075] In some embodiments, an agonist-antagonists refers to a compound having an agonist portion and an antagonist portion. In specific embodiments, the agonist portion and the antagonist portion are discrete.

[0076] In some embodiments, a compound described herein (e.g., Compound 1) has a wider therapeutic window than a VI AR agonist. In some embodiments, a compound described herein (e.g., Compound 1) has a selective Via agonist portion and a selective Via antagonist portion. In some instances, either the selective Via agonist portion or the selective Via antagonist portion binds to V1AR, such that both the selective Via agonist portion and the selective Via antagonist portion do not bind to the V1AR simultaneously. In some instances, the Via antagonist portion competes with the selective Via agonist portion for binding to VI AR. In some instances, VI AR agonism provides a (desired) vasoconstrictive effect. In some instances, V1AR antagonism prevents maximal activation of the Via pathway. [0077] In some instances, FIG. 1, curve 1 illustrates a concentration-response curve for a compound (e.g., a full Via agonist, such as terlipressin) that provides a lethal level of vasoconstriction (e.g., at relatively high doses, depicted as portion A in FIG. 1) and/or serious adverse events (e.g., at doses above therapeutic levels and at doses below lethal levels of vasoconstriction, depicted as portion B in FIG. 1). In some embodiments, a compound described herein (e.g., a full Via agonist, such as terlipressin) has a concentration-response curve illustrated in FIG. 1, line 1. In some instances, FIG. 1, line 1 illustrates that a compound described herein (e.g., a full Via agonist, such as terlipressin) has a relatively narrow therapeutic window. In some instances, FIG. 1, line 1 illustrates that at relatively high doses, a compound described herein (e.g., a full Via agonist, such as terlipressin) provides a level of vasoconstriction that is lethal (depicted as portion A in FIG. 1) and/or associated with serious adverse events (depicted as portion B in FIG. 1), such as elevated lactate and/or vasoconstriction with ischemia.

[0078] In some embodiments, FIG. 1, curve 2 illustrates a concentration-response curve for a compound (e.g., a partial Via agonist, such as Compound 1) that has a safe and efficacious profile. In some embodiments, a compound described herein (e.g., a partial Via agonist, such as Compound 1) has a concentration-response curve illustrated in FIG. 1, line 2. In some instances, FIG. 1, line 2 illustrates that even at high doses, a compound described herein (e.g., a partial Via agonist, such as Compound 1) has a relatively large therapeutic window. In some instances, FIG. 1, line 2 illustrates that even at high doses, a compound described herein (e.g., a partial Via agonist, such as Compound 1) is safe and efficacious.

[0079] In some instances, FIG. 1, curve 3 illustrates a concentration-response curve for a compound that does not reach therapeutic levels. In some instances, FIG. 1, curve 3 illustrates a concentration-response curve for a full Via agonist or a partial Via agonist, such as a compound that has relatively low activity for VI AR.

[0080] In some instances, FIGs. 1-4 demonstrate that a compound described herein (e.g., a partial Via agonist, such as Compound 1) can be safely used (over a large dose range) to treat HRS-AKI or diseases and/or complications associated therewith. In some instances, FIG. 1 demonstrates that even at excessively high concentrations, a compound described herein (e.g., a partial Via agonist, such as Compound 1) provides a maximal effect in an individual. In some instances, FIGs. 1-4 demonstrate that a compound described herein (e.g., a partial Via agonist, such as Compound 1) provides a robust effect in an individual. In some instances, FIGs. 1-4 demonstrate that a compound described herein (e.g., a partial Via agonist, such as Compound 1) reaches, maintains, and does not go above a safe and efficacious therapeutic effect. In some instances, FIGs. 1-4 demonstrate that a compound described herein (e.g., a partial Via agonist, such as Compound 1) maintains (a safe level of) therapeutic efficacy over a prolonged period of time, such as for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, or 100 minutes or more. In some instances, FIGs. 1-4 demonstrate that a compound described herein (e.g., a full Via agonist, such as terlipressin) quickly reaches toxic and potentially harmful concentrations, such as at relatively high doses. In some instances, FIGs. 1-4 demonstrate that a compound described herein (e.g., a full Via agonist, such as terlipressin) the effect of full Via agonists diminishes rapidly, such as quickly falling below therapeutic levels after a relatively short period of time (e.g., after about 80 mins or more).

[0081] In some instances, Compound 1 is Glycinamide, L-cysteinyl-L-phenylalanyl-L- isoleucyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-N4-(phenylacetyl-O-methyl-D- tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-alanyl-L-prolyl-L-arginyl-L- isoglutamyl-N5-acetyl-L-lysyl-L-£-lysyl)-L-2,4-diaminobutyryl-, cyclic (1— >6)-disulfide. [0082] In some instances, Compound 1 has an empirical molecular formula of C110H161N31O27S2.

[0083] In some instances, Compound 1 has an average molecular mass of 2413.78 u.

[0084] In some instances, Compound l is a white to off-white powder.

[0085] In some instances, Compound 1 has a solubility in water of at least 10 mg/mL.

[0086] In some instances, Compound 1 a structure represented by Formula (I- A):

Formula (I- A) or a pharmaceutically acceptable salt thereof.

[0087] In some instances, Compound 1 is a 20-mer monocyclic, branched peptide, such as, containing natural and unnatural amino acids, such as, from non-animal origin. In some instances, Compound 1 has an S-S bridge between the Cys¹ and Cys⁶ residues. In some instances, the branch is linked through the position 8 side chain amino function.

[0088] In some instances, provided herein is a compound having a structure represented by Formula (I-B):

Formula (I-B) or a pharmaceutically acceptable salt thereof, wherein:

Dab is 2,4-diamino butyric acid, D-Tyr(Me) is O-methyl-D-tyrosine and

PhAc is phenylacetic acid (e.g., wherein L-2,4-diamino butyric acid, N-c-acetyl-L- lysine, L-isoglutamine and O- methyl-D-tyrosine are unnatural, and the N-terminal moiety is substituted with phenylacetic acid). [0089] In some instances, Compound 1 is provided as a pharmaceutically acceptable salt. In some instances, Compound 1 is provided as an acetate salt. In some instances, Compound 1 is administered in the form described in Example 4.

[0090] In some instances, Compound 1 has an empirical molecular formula of CnoHi6iN3i027S2-(AcOH)z, where z is any integer (e.g., from 1-100).

[0091] Provided in some embodiments herein are methods of treating (e.g., decompensated) cirrhosis, end-stage liver disease, or complications thereof in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual. In some embodiments, the individual has cirrhotic portal hypertension.

100921 Provided in some embodiments herein are methods of treating complications of cirrhosis, end-stage liver disease, such as, ascites or HRS-AKI, or complications thereof in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual. In some embodiments, the individual has cirrhotic portal hypertension.

[0093] In some embodiments, Compound 1 provides a substantially improved therapeutic index (e.g., arising from a lower maximal vasoconstrictive effect and lower risk for tissue hypoxia), such as, when compared to full VIA receptor agonists. In some embodiments, Compound 1 provides about half of the maximal vasoconstriction produced by full agonists, such as, without any concomitant signs of ischemia. In some embodiments, Compound l is a (clinically) efficacious vasoconstrictor (e.g., having a favorable benefit/risk profile, such as, having low to no organ toxicities).

[0094] Provided in some embodiments herein is a method of treating hepatorenal syndrome with acute kidney injury (HRS-AKI) in an individual, such as an individual who has developed HRS-AKI as a complication of cirrhosis with ascites, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0095] In some embodiments, the individual has liver disease (ESLD). In some embodiments, the individual has HRS-AKI as a complication of end-stage liver disease (ESLD). In some embodiments, the individual has developed HRS-AKI as a complication of end-stage liver disease (ESLD).

[0096] In some embodiments, the individual has liver disease (ESLD). In some embodiments, the individual has ascites as a complication of end-stage liver disease (ESLD). In some embodiments, the individual has developed ascites as a complication of end-stage liver disease (ESLD).

[0097] Provided in some embodiments herein is a method of treating end-stage liver disease in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0098] Provided in some embodiments herein is a method of treating cirrhotic portal hypertension in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0099] In some embodiments, the individual has (e.g., decompensated) cirrhosis. In some embodiments, the individual has decompensated cirrhosis. In some embodiments, the individual has decompensated cirrhosis with ascites.

[0100] Provided in some embodiments herein is a method of treating cirrhosis in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0101] In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg to about 55 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 8 pg to about 50 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 20 pg to about 35 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 25 pg to about 35 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 30 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg to about 30 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 10 pg to about 20 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 15 pg. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered over a period of time, such as over several hours (e.g., continuously for up to 24-hr) for several days (e.g., up to 10 days). [0102] In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual intravenously. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual by intravenous infusion.

[0103] In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg/hr or more. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 55 pg/hr or less. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg/hr to about 55 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 8 pg/hr to about 50 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 10 pg/hr to about 30 pg/hr (e.g., 15 pg/hr). In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 20 pg/hr to about 35 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 25 pg/hr to about 35 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 30 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg/hr to about 30 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 10 pg/hr to about 20 pg/hr. In some embodiments, the therapeutically effective amount of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 15 pg/hr.

[0104] In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on a first day and a second day. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual one or more days after the first day. In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), on the first day. In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), on the first day to acclimate the individual to vasoconstriction before receiving a first assigned treatment dose, such as on the second day. In some embodiments, the initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is a low dose. In some embodiments, the initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is a dose of about 5 pg/hr to about 15 pg/hr. In some embodiments, the initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is a dose of about 8 pg/hr. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual on the first day (e.g., by intravenous infusion) for a period of about 4 hr to about 8 hr. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual on the first day (e.g., by intravenous infusion) for a period of about 6 hr.

[0105] In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on multiple days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more days. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on subsequent days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on consecutive and/or non-consecutive days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more consecutive days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more non-consecutive days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more consecutive days after the first day. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more non-consecutive days after the first day.

[0106] In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual for up to 11 days, such as for us to 10 days after the first day. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual for 4 to 10 days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual for 4 to 10 days after the first day. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual for up to 9 days. In some embodiments, the days are consecutive days. In some embodiments, the days are non-consecutive days. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual (e.g., via continuous intravenous infusion) over a 24-hr period. In some embodiments, the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual via continuous intravenous infusion over a 24-hr period per day for up to 9 days. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of up to about 2 milligrams (mg)/day. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 0.2 mg/day to about 2 mg/day. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 0.5 mg/day to about 1.5 mg/day. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 1.2 mg/day. [0107] Unless stated otherwise, weights (e.g., doses) of Compound 1 provided herein are calculated based-on the free base of Compound 1 (e.g., not a pharmaceutically acceptable salt of Compound 1). In some instances, the acetate salt of Compound 1 is administered to the individual receiving a treatment provided herein.

[0108] In some instances, an individual receiving a treatment described herein achieves one or more outcome measurement described herein, such as described in Example 2, while and/or subsequent to receiving treatment. In some instances, an individual receiving a treatment described herein meets one or more inclusion criteria provided in Table 2. In some instances, an individual receiving a treatment described herein meets each inclusion criteria provided in Table 2. In some instances, an individual receiving a treatment described herein fails to meet one or more exclusion criteria provided in Table 3. In some instances, an individual receiving a treatment described herein fails to meet each exclusion criteria provided in Table 3. In some embodiments, an individual receiving a treatment described herein is administered Compound 1 until one or more primary and/or secondary outcome measurements, such as a primary and/or secondary outcome measurement provided in Example 2, is met. In some instances, an individual is administered Compound 1 until the individual has a sCr value of 1.5 milligrams (mg)/deciliters (dL) or less on (e.g., 2 or more) consecutive days.

[0109] Provided in some embodiments herein is a method of reducing serum creatinine (sCr) in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual. [0110] Unless stated otherwise, a measurement described herein (such as a measurement in sCr, MAP, etc.) can be measured immediately before, hours before, days before, or weeks before Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), is administered to an individual receiving a treatment described herein.

[OHl] In some embodiments, an individual receiving a treatment described herein has a sCr value of up to 3.5 mg/dL before treatment, such as at the time of randomization for the study described in Example 1, such as days before treatment.

[0112] In some embodiments, an individual receiving a treatment described herein has a reduction in sCr. In some embodiments, an individual receiving a treatment described herein has a substantial reduction in sCr. In some embodiments, an individual receiving a treatment described herein has a significant reduction in sCr. In some embodiments, an individual receiving a treatment described herein has a reduction in sCr value of about 10% or more, such as compared to a baseline measurement before treatment. In some embodiments, an individual receiving a treatment described herein has a reduction in sCr value of about 50% or less, such as compared to a baseline measurement before treatment. In some embodiments, an individual receiving a treatment described herein has a reduction in sCr value of about 10% to about 50%, such as compared to a baseline measurement before treatment. In some embodiments, an individual receiving a treatment described herein has a reduction in sCr value of about 20% to about 50%, such as compared to a baseline measurement before treatment. In some embodiments, an individual receiving a treatment described herein has a reduction in sCr value of about 30% to about 50%, such as compared to a baseline measurement before treatment. In some embodiments, an individual receiving a treatment described herein has a reduction in sCr value of about 40% to about 50%, such as compared to a baseline measurement before treatment. In some instances, the reduction in sCr value after treatment with Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is significantly more compared to the reduction in sCr value after treatment with other treatment options.

[0113] In some embodiments an individual receiving a treatment described herein is administered Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual until the individual has a sCr value of 1.5 milligrams (mg)/deciliters (dL) or less on consecutive days. In some embodiments an individual receiving a treatment described herein is administered Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual until the individual has a sCr value of 1.5 mg/dL or less on 2 or more consecutive days. [0114] In some instances, provide herein is a compound for improving ESLD or a complication thereof, such as ascites and HRS-AKI, in an individual in need thereof. In some instances, an improvement in ESLD or a complication thereof is determined by measuring a change in (e.g., a level of) a biomarker of ESLD or a complication thereof, such as serum creatinine (sCr) and/or urine sodium. In some instances, sCr levels of the individual decrease after a compound described herein (e.g., Compound 1) is administered to the individual. In some instances, urine sodium levels of the individual decrease after a compound described herein (e.g., Compound 1) is administered to the individual. In some instances, serum creatinine (sCr) and/or urine sodium decreases compared to terlipressin on a similar timeframe. In some instances, serum creatinine (sCr) and/or urine sodium decreases compared to placebo on a similar timeframe. In some instances, at some doses of a compound described herein (e.g., Compound 1), such as at lower doses, sCr concentration in the individual substantially decreases, such as to levels that achieve a primary endpoint (e.g., less than or equal to 1.5 mg/dL, such as on 2 consecutive days). In some instances, at some doses of a compound described herein (e.g., Compound 1), such as at lower doses, urine sodium concentration (e.g., substantially) decreases. In some instances, Compound 1 compares similarly or better than terlipressin. In some instances, Compound 1 compares similarly or better than terlipressin after fewer doses (e.g., fewer days of administration).

[0115] In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein increases. In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein increases compared to a baseline measurement before treatment. In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein increases (e.g., compared to a baseline measurement before treatment) by about 15 mmHg or less. In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein increases (e.g., compared to a baseline measurement before treatment) by about 15 mmHg.

[0116] In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein remains significantly unchanged (e.g., compared to a baseline measurement before treatment). In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein remains significantly unchanged compared to a baseline measurement before treatment.

[0117] In some embodiments, an individual receiving a treatment described herein has a Model for End-Stage Liver Disease (MELD) score of up to about 35 before treatment, such as at the time of randomization for the study described in Example 1, such as days before treatment. [0118] In some embodiments, an individual receiving a treatment described herein has proteinuria of up to about 500 mg/dL before treatment, such as at the time of randomization for the study described in Example 1, such as days before treatment.

[0119] In some embodiments, an individual receiving a treatment described herein has a pulse oximeter reading of at least about 90% on 2 liter (L) before treatment, such as at the time of randomization for the study described in Example 1, such as days before treatment.

[0120] In some embodiments, an individual receiving a treatment described herein has large volume paracentesis of up to about 4 L before treatment, such as at the time of randomization for the study described in Example 1, such as weeks before treatment.

[0121] In some embodiments, an individual receiving a treatment described herein has a systolic blood pressure of up to about 140 mmHg. In some embodiments, an individual receiving a treatment described herein has a diastolic blood pressure of up to about 100 mmHg. In some embodiments, an individual receiving a treatment described herein has a systolic blood pressure of 140 mmHg or less and a diastolic blood pressure of 100 mmHg or less. In some instance the systolic blood pressure and/or diastolic blood pressure of the individual are measured before treatment, such as at the time of randomization for the study described in Example 1, such as weeks before treatment.

[0122] In some embodiments, an individual receiving a treatment described herein is receiving albumin. In some embodiments, an individual receiving a treatment described herein is receiving albumin and has had appropriate diuretic withdrawal before treatment. In some embodiments, an individual receiving a treatment described herein is receiving albumin and has had appropriate diuretic withdrawal days before treatment. In some embodiments, an individual receiving a treatment described herein is receiving albumin and has had appropriate diuretic withdrawal at least 48 hrs before treatment.

[0123] In some embodiments, an individual receiving a treatment described herein has a lack in sustained renal function improvement. In some embodiments, an individual receiving a treatment described herein has a lack in sustained renal function improvement after diuretic withdrawal. In some embodiments, an individual receiving a treatment described herein has a lack in sustained renal function improvement after plasma volume expansion with albumin. In some embodiments, an individual receiving a treatment described herein has a lack in sustained renal function improvement after diuretic withdrawal and plasma volume expansion with albumin.

[0124] In some instances, an individual receiving a treatment described herein is in need of the treatment described herein. [0125] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

EXAMPLES

Example 1: Study Description

[0126] Compound 1, or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, is administered by intravenous infusion to 100 individuals (biological males and females who are 18 to 70 years old) who have end-stage liver disease (ESLD), such as cirrhosis with ascites or hepatorenal syndrome-acute kidney injury (HRS-AKI) as a complication of endstage liver disease (ESLD). The individuals receive treatment until (primary) endpoints or discontinuation criteria are met (e.g., see Example 2 and Example 3). Individuals are assigned a cohort and receive Compound 1, or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, according to Table 1. The studies are randomized and quadruple masked (participant, care provider, investigator, outcomes assessor). The studies are double-blind and placebo controlled.

[0127] In some instances, an individual of the study receives an initial 6-hr lead-in of placebo or an initial 6-hr lead-in of Compound 1, or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, by intravenous infusion. In some instances, the initial 6-hr lead-in is a low dose of Compound 1 (e.g., about 5 pg/hr to about 15 pg/hr), or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, such as to acclimate the individual to vasoconstriction prior to receiving a first assigned treatment dose (e.g., of about 8, 15, 30, 50 pg/hr). In some instances, such as after the initial 6-hr lead-in, the individual receives placebo or an assigned dose of Compound 1 (e.g., of about 8, 15, 30, 50 pg/hr), or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1. In some instances, the individual receives placebo or the assigned dose of Compound 1 (e.g., of about 8, 15, 30, 50 pg/hr), or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, via 24-hour continuous intravenous infusions over a 4 to 10 day period. In some instances, the individual receives placebo or the assigned dose of Compound 1 (e.g., of about 8, 15, 30, 50 pg/hr), or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, via nine 24-hour continuous intravenous infusions (e.g., over a 10 day period). In some instances, the maximum dose of Compound 1 (e.g., of about 8, 15, 30, 50 pg/hr), or a pharmaceutically acceptable salt, such as the acetate salt of Compound 1, administered to the individual is up to 15 mg.

Table 1

[0128] Clinical results suggest improvement in ESLD, including ascites and HRS-AKI (e.g., biomarkers thereof). For example, clinical results demonstrate reduction in serum creatinine levels and reduction in urine sodium levels (e.g., compared to terlipressin on a similar timeframe).

Example 2: Outcome Measures

[0129] In some instances, individuals are administered Compound 1 until one or more of the following primary and/or secondary outcome measurements are met. In some instances, individuals are administered Compound 1 until the primary outcome measurement provided herein is met.

[0130] Primary outcome measure: time to measurement of serum creatinine (sCr) value less than 1.5 mg/dL on 2 consecutive days (Time Frame: From Day 1 infusion start to Last Day of infusion end). [0131] Secondary outcome measure: Average Steady State Concentration (Css) of

Compound 1 (Time Frame: From Day 1 infusion start to Last Day of infusion end).

[0132] Secondary outcome measure Total Body Clearance (CL) of Compound 1 (Time

Frame: From Day 1 infusion start to Last Day of infusion end).

[0133] Secondary outcome measure: Elimination Half-Life (ti/2) of Compound 1 (Time

Frame: From Day 1 infusion start to Last Day of infusion end).

[0134] Secondary outcome measure: Steady-State Volume of Distribution (Vss) of

Compound 1 (Time Frame: From Day 1 infusion start to Last Day of infusion end).

[0135] Secondary outcome measure: Change in Mean Arterial Pressure (MAP) measurement

(Time Frame: From Day 1 infusion start to Last Day of infusion end).

[0136] Secondary outcome measure: Change in Mean Arterial Pressure (MAP) Percentage

(Time Frame: From Day 1 infusion start to Last Day of infusion end).

[0137] Secondary outcome measure: Change in Pulse Measurement (Time Frame: From Day

1 infusion start to Last Day of infusion end).

[0138] Secondary outcome measure: Change in Pulse Percentage (Time Frame: From Day 1 infusion start to Last Day of infusion end).

[0139] Secondary outcome measure: Change in Serum Creatinine (sCr) Measurement (Time

Frame: From Day 1 infusion start to Last Day of infusion end).

Example 3: Eligibility

[0140] Individuals of the study described in Example 1 meet the inclusion criteria provided in Table 2.

Table 2

_

[0141] Individuals having any one of the exclusion criteria provided in Table 3 are excluded from the study described in Example 1. Table 3

Example 4: Formulation

[0142] In some instances, Compound 1 is formulated as an aseptically manufactured aqueous solution of Compound 1, 1 mg/mL to about 10 mg/mL, in 10 mM acetate buffer pH 4.5 with mannitol (for isotonicity). In some instances, the formulation comprising Compound 1 is filled into glass vials (1.5 mL withdrawable volume) and sealed with rubber stoppers and plastic caps. In some instances, the formulation comprising Compound 1 is diluted to the appropriate concentrations with 0.9% sodium chloride injection prior to administration.

Example 5: Potent and Selective Partial VI AR Agonists

[0143] In some instances, the binding data provided herein below suggests Compound 1 binds to a given receptor with either its agonist portion or its antagonist portion and that over a population of Compound 1-occupied vasopressin receptors, a fraction are occupied by the agonist portion while another fraction are occupied by the antagonist portion, such as resulting in effective partial agonism of the receptor and limiting the maximum vasoconstriction observed.

Methods and Materials

[0144] Cell Lines Studies were conducted with cell lines expressing rat (r) or human (h) Via, Vlb, V2, or OT receptors. For the experiments with human receptors, human embryonic kidney (HEK)-flp-in cells stably expressing the lacZ-Zeocin™ fusion gene were used for expression of hVla and hVlb. These cells were designed for use with the Flp-ln™ expression vector containing the gene of interest (here hVla or hVlb) and the Flp recombinase expression plasmid, pOG44. For hV2 and hOTR, HEK-293 cells transiently expressing hV2 were used. For experiments with rat receptors, A7r5 rat thoracic aorta smooth muscle cells endogenously expressing rVla (ATCC), FLP -In 293 (HEK-293) cells stably expressing rVlb, HEK-293 cells (ATCC) transiently transfected with rV2, and Chinese hamster ovary (CHO)-Kl cells (ATCC) transiently expressing rOTR were used.

[0145] Cell Maintenance. HEK-flp-in cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% (v/v) heat-inactivated fetal bovine serum (FBS), 4 mM GlutaMAX™-!, and 25 pg/mL hygromycin B at 37°C under 5% CO2 in a humidified atmosphere. The culture medium for hVlb-expressing cells also contained 100 U/mL penicillin and 100 pg/mL streptomycin. HEK-293 cells transiently expressing hV2 were maintained in DMEM containing 10% (v/v) heat-inactivated FBS and 4 mM L-glutamine or GlutaMAX-I at 37°C under 5% CO2 in a humidified atmosphere. CHO-K1 cells stably expressing hOTR were maintained in DMEM-F12 containing 5% (v/v) heat-inactivated FBS, 2 mM L-glutamine or GlutaMAX-I, and 900 pg/mL G418 sulfate at 37°C under 5% CO2 in a humidified atmosphere. A7r5 cells were maintained in DMEM containing 10% (v/v) heat-inactivated FBS, 4 mM GlutaMAX-1 at 3°C under 5% CO2 in a humidified atmosphere. On the day prior to the assay, cells were removed from culture flasks using trypsin EDTA, harvested in the medium used for cell culture, and seeded into 384-well (for Via) or 96-well (for other receptors) poly-d-Iy sine- treated plates at 7.5 x 10⁴ cells in 20 pL/well for rVla, 2.5 x 10⁴ cells in 20 pL/well for hVla, and 4-5 x 10⁴ cells in 100 pL/well for all other receptors.

[0146] Test Compounds. Compound 1 (97.3% peptide purity) and AVP (reference agonist) were used in the functional cell-based assays. Compounds were prepared in 100% DMSO as 10 mM stock concentrations (or 5 mM for AVP), stored at -20°C, and allowed to thaw just before the assay. The compounds were serially diluted to 10x working solutions in cell media. Blanks consisting of dilution media supplemented with 0. 1% (v/v) DMSO were also used as controls in each study. No inhibitory effect of DMSO was seen at 0.1%. For the contractility assay, Compound 1 was formulated as a 23.5 pM stock solution in physiological salt solution (PSS; 120 mM NaCI, 4.6 mM KCI, 1.5 mM NaH₂P0₄- 1H₂O, 0.7 mM Na₂HP0₄, 11.5 mM D- glucose, 25 mM NaHCOs, 2.4 mM CaCI₂, 1.2 mM MgCI₂ [pH 7.35-7.45]). The stock solution was serially diluted in PSS to concentrations allowing for a further 1/100 dilution upon addition of the compound to the test apparatus in a cumulative fashion from lowest concentration to highest to obtain the final test concentration.

[0147] Functional Cell-Based Assays. To detect activity generated by binding of the test compounds to endogenous rVl a receptors or the stably expressed hVl a receptors, Fluorometric Imaging Plate Reader (FL1PR) calcium assays were performed. Briefly, real-time fluorescence of an intracellular calcium-sensitive dye was measured immediately upon addition of the test compound at various concentrations. The endogenous ligand of Via, AVP, was used as the reference agonist. Reporter gene assays were used to monitor agonist-induced activity at the human and rat Vlb, V2, and OT receptors. Cells expressing the receptor of interest were transiently transfected with a luciferase reporter gene under the control of transcriptional regulatory elements responsive to receptor activation. Expression of the luciferase gene was determined after 5-h incubation with various concentrations of test compound. AVP was used as the reference agonist in Vlb assays, desmopressin (dDAVP) was used as the reference agonist in V2R assays, and carbetocin was the reference agonist in the OT receptor assays. For Via receptor response, area under the curve of the real-time calcium traces, expressed as relative fluorescence units, was determined. For Vlb, V2, and OT receptor response, luciferase activity was expressed in luminescent counts per second. Compound potency was expressed as the concentration that produced a half-maximal response (EC50), calculated by a four- parameter non-linear regression analysis of concentration-response curves using ActivityBase™ software. Efficacy was expressed in relative terms as percent maximal possible effect (%MPE) relative to the maximal response of the reference agonist for each assay (AVP for Via and Vlb, dDAVP for V2R, and carbetocin for OTR).

[0148] Arterial Contractility Assay. Resistance arteries were isolated from human mesenteric tissue and finely dissected under a stereomicroscope while bathed in carbogen- aerated PSS maintained at 37°C. Arterial segments (2 mm) were mounted in a pressure myograph system between two glass cannulae in 7-mL tissue baths containing aerated PSS. Arteries were gradually pressurized to 60 mmHg. Arterial contractility was stabilized by potassium-induced depolarization with three consecutive exposures to a solution with a high potassium concentration (PSS with 124.34 mM KCI and no NaCI; 124K+PSS), each followed by a wash of the bath with aerated PSS. Cumulative concentration-response curves (CCRC) were then generated for the compounds. Arteries were bathed in aerated PSS containing the initial compound concentration (0.1 nM Compound 1), and each following dose was added to the bath without draining, taking into account the amount of compound already in the chamber when calculating the final concentration. The concentrations used were 0.1, 0.3, 1, 3, 10, 32, and 100 nM Compound 1. Only a single CCRC was generated in each arterial segment tested. Contractile activity was determined by measuring the arterial outer diameter via digital video edge detection in response to each 124K+PSS depolarization and each compound concentration. Throughout the experiment, vessel diameter data were collected continuously using DMT Vessel Acquisition Suite software. For each 124K+PSS stimulation or compound concentration, data were collected until the vessel diameter was judged to have reached a plateau before proceeding to the next experimental step. The vessel diameters for each artery preparation (in millimeters) were analyzed by using a Microsoft Excel template. Data collected in response to the three 124K+PSS depolarization cycles were first used to determine artery stability. The contraction induced by the last stimulation (3rd 124K+PSS) was then used as the internal reference response of each artery (i.e., 100% contraction) for reporting contractile activity. Arteries that could not be stabilized with three cycles of depolarization-induced contraction were excluded from the study.

Results

[0149] Functional Cell-Based Assays: When the effect of Compound 1 on hVla receptors was examined, the activity reached a mean of 39 %MPE relative to the activity with AVP, with a mean EC50 of 0.71 nM (Table 4), which indicates that Compound 1 acts as a partial agonist at Via receptors. The %MPE plateaued at a concentration of ~1 nM Compound 1, with no further increases in %MPE in response to further increases in concentration (FIG. 2). The partial agonism indicates that treatment with Compound 1 would result in vasoconstriction of the splanchnic vasculature in individuals with portal hypertension, such as reducing portal blood flow and pressure and improving the patient’s systemic hemodynamics with a lower risk of ischemia than a full Via agonist. In addition, Compound 1 was selective for hVla receptors at a wide range of concentrations, with much higher EC50 at hVlb, hV2, and hOT receptors than at Via receptors (Table 4). Similar results were seen for potency and activity at rat vasopressin receptors (Table 5). The dose-response curves of Compound 1 activity at hVla and hV2 receptors also differed, with Compound 1 showing ~600-fold more potency at hVla than at hV2 (FIG. 3). While Compound 1 elicited a higher maximal response at V2 (74 %MPE) than at Via receptors (39 %MPE), this occurred at concentrations about 1000 times higher than the lowest concentration that elicited the maximal response at Via receptors (FIG. 3), where no V2 response was observed. As such, at clinically relevant concentrations, Compound 1 has little to no activity at human V2 receptors.

Table 4

ECso (nM) %MPE

Test Receptor _J Mean 95% CI N Mean 95% CI N compound hVla Compound _{Q ? 1} 0.45-1.1 12 39 31-47 13

AVP 0.07 0.06-0.08 278 100 — 284 hVlb Compound ₁₃₄ 92-194 9 72 66-78 9

AVP 4.3 3.9-4.7 347 100 — 360 h_V2 Compound ₄₂₀ 278-634 13 74 67-82 13

AVP 0.05 0.04-0.07 120 95 92-97 137 hOTR Compound _{6 9 4 5}_n _{6 33 2}9-37 ₈

AVP 15 9.1-25 4 106 81-130 4

Table 5

ECso (nM) % MPE

Test Receptor _J Mean 95% CI N Mean 95% CI N compound rVla Compound _{Q 22 0}.06-0.83 7 30 25-35 7

AVP 0.08 0.06-0.09 197 100 — 206 rVlb Compound ₇₅ 43.130 8 97 86-109 8

AVP 16 14-18 37 100 — 38 rV2 Compound _{4 6} 4 2-5.0 13 83 71-94 13

AVP 0.04 0.03-0.05 67 98 96-101 63 rOTR Compound _{2 1} 1.1-4.0 6 95 79-111 6

AVP 0.93 0.48-1.8 10 82 74-160 17

[0150] Arterial Contractility Assay: Treatment of human mesenteric resistance arteries with Compound 1 resulted in an attenuated maximal response (40.0%) relative to the maximal depolarization achieved with potassium (expected to be close to the contraction elicited by the endogenous ligand, AVP) (FIG. 4), which helps confirm that Compound 1 acts as a partial agonist at Via receptors.

Claims

CLAIMS We claim:

1. A method of reducing serum creatinine (sCr) in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

2. A method of treating end-stage liver disease in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

3. A method of treating cirrhotic portal hypertension in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

4. A method of treating decompensated cirrhosis in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

5. A method of treating ascites in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

6. A method of treating hepatorenal syndrome with acute kidney injury (HRS-AKI) in an individual, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

7. The method of any one of the preceding claims, wherein the individual has (developed) a complication of end-stage liver disease (ESLD).

8. The method of claim any one of the preceding claims, wherein the individual has (developed) ascites as a complication of end-stage liver disease (ESLD).

9. The method of any one of the preceding claims, wherein the individual has (developed) HRS-AKI as a complication of end-stage liver disease (ESLD).

10. The method of any one of the preceding claims, wherein the individual has ESLD.

11. The method of any one of the preceding claims, wherein Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 5 (pg)/hour (hr) to about 55 pg/hr (e.g., about 8 pg/hr to about 50 pg/hr, about 10 pg/hr to about 30 pg/hr (e.g., 15 pg/hr), or about 20 pg/hr to about 35 pg/hr (e.g., about 30 pg/hr)). The method of any one of the preceding claims, wherein Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual intravenously. The method of any one of the preceding claims, wherein Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual by intravenous infusion. The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on a first day and a second day (e.g., one or more days after the first day). The method of any one of the preceding claims, wherein the individual receives an initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), on the first day (e.g., to acclimate the individual to vasoconstriction before receiving a first assigned treatment dose (e.g., on the second day)). The method of any one of the preceding claims, wherein the initial (e.g., intravenous infusion) dose of Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is a low dose, such as a dose of about 5 pg/hr to about 15 pg/hr, such as about 8 pg/hr. The method of any one of the preceding claims, wherein Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual on the first day (e.g., by intravenous infusion) for a period of about 4 hr to about 8 hr, such as about 6 hr. The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on multiple days. The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on one or more (e.g., consecutive) days after the first day. The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual on consecutive and/or non-consecutive days after the first day. The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual for 4 to 10 days (e.g., after the first day). The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual (e.g., via continuous intravenous infusion) over a 24-hr period. The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual (e.g., via continuous intravenous infusion over a 24-hr period per day) for up to 9 days. The method of any one of the preceding claims, wherein Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual in an amount of about 0.2 milligrams (mg)/day to about 2 mg/day (e.g., about 0.5 mg/day to about 1.5 mg/day (e.g., about 1.2 mg/day)). The method of any one of the preceding claims, wherein the individual has a reduction in serum creatinine (sCr) (value) (e.g., of about 10% to about 50% (e.g., compared to a baseline measurement before treatment)). The method of any one of the preceding claims, wherein the method comprises administering Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), to the individual until the individual has a sCr value of 1.5 milligrams (mg)/deciliters (dL) or less on (e.g., 2 or more) consecutive days. The method of any one of the preceding claims, wherein the mean arterial pressure (MAP) of the individual increases (e.g., compared to a baseline measurement before treatment). The method of any one of the preceding claims, wherein the individual has a sCr value of 3.5 mg/dL or less before (e.g., days before) treatment. The method of any one of the preceding claims, wherein the individual has a Model for End-Stage Liver Disease (MELD) score of 35 or less before (e.g., days before) treatment. The method of any one of the preceding claims, wherein the individual has proteinuria of 500 mg/dL or less before (e.g., days before) treatment. The method of any one of the preceding claims, wherein the individual has a pulse oximeter reading of about 90% on 2 liter (L) or more before (e.g., days before) treatment. The method of any one of the preceding claims, wherein the individual has large volume paracentesis of 4 L or less before (e.g., weeks before) treatment. The method of any one of the preceding claims, wherein the individual has a systolic blood pressure of 140 mmHg or less and/or a diastolic blood pressure of 100 mmHg or less (e.g., before treatment). The method of any one of the preceding claims, wherein the individual is receiving albumin (and has had appropriate diuretic withdrawal (e.g., days (e.g., at least 48 hrs) before treatment). The method of any one of the preceding claims, wherein the individual has a lack in sustained renal function improvement (e.g., after diuretic withdrawal and/or plasma volume expansion with albumin). The method of any one of the preceding claims, wherein Compound 1 is administered to the individual in the form of an acetate salt.