Methods for treating patients with type 1 hepatorenal syndrome

Abstract

Principles and embodiments of the present disclosure relate to methods for using terlipressin to treat patients with renal dysfunction associated with liver disease. A method of treating an adult patient with Hepatorenal Syndrome Type 1 (HRS-1) may include administering a dose of terlipressin to the patient if the patient has a baseline Model for End-Stage Liver Disease (MELD) score <35, the patient has a serum creatinine (SCr) <5 mg / dl, the patient has an ACLF grade <3, or a combination thereof, and / or monitoring the patient's oxygenation level (SpO2) before and during treatment with terlipressin.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 17 / 340,765, filed June 7, 2021, the entire contents of which are incorporated herein by reference.

[0002] Incorporating sequence tables A computer readable text file entitled "105870_726724_SequenceListing_ST25.txt", created on or about Jun. 6, 2022, having a file size of approximately 1 kilobyte, contains the sequence listing for the present application and is incorporated by reference herein in its entirety.

[0003] Principles and embodiments of the present disclosure relate generally to methods of treating patients with type 1 hepatorenal syndrome. [Background technology]

[0004] Hepatorenal syndrome type 1 (HRS type 1 or HRS-1) is the development of acute renal failure in patients with late stage cirrhosis in the absence of any other cause. It is characterized by the rapid onset of renal failure with a high mortality rate of over 80% within 3 months. Renal failure is an identified complication of cirrhosis, and acute renal failure is known to have a poor prognosis for patients with cirrhosis. In various cases, renal failure may be caused by hypovolemia, hepatorenal syndrome without ongoing infection, or hepatorenal syndrome with ongoing infection. Unfortunately, patients with HRS type 1 may die of renal failure while waiting for a liver transplant. Currently, there is no way to determine which patients can maximally benefit from terlipressin treatment to reverse HRS type 1.

[0005] Hepatorenal syndrome (HRS) is indicated by renal vasoconstriction, splanchnic and peripheral arterial vasodilation resulting in reduced vascular resistance, and low glomerular filtration rate due to portal hypertension. HRS is indicated by cirrhosis with ascites, serum creatinine levels >133 μmol / l (1.5 mg / dL), improvement of serum creatinine levels (to levels ≦133 μmol / l) after at least 2 days of albumin diuretic withdrawal and volume expansion, and the absence of shock and parenchymal renal disease. Type 1 HRS is indicated by a doubling of initial serum creatinine levels to >226 μmol / l (2.56 mg / dL) in less than 2 weeks.

[0006] Normal creatinine levels range from 0.7 to 1.3 mg / dL in men and 0.6 to 1.1 mg / dL in women. 1 mg / dL of creatinine is equal to 88.4 μmol / L.

[0007] However, certain mechanisms that serve to maintain effective arterial blood volume and relatively normal arterial pressure in patients with cirrhosis can affect renal function, such as retention of sodium and solute-free water, leading to ascites and edema, as well as renal failure by causing intrarenal vasoconstriction and hypoperfusion. Ascites can result from a combination of portal hypertension and splanchnic arterial vasodilation, which alters intestinal capillary pressure and permeability, promoting the accumulation of retained fluid in the peritoneal cavity.

[0008] A contributing factor to ascites formation is splanchnic vasodilation resulting in a decrease in effective arterial blood volume. Portal hypertension may also result from increased hepatic resistance to portal blood flow in the cirrhotic liver, inducing splanchnic vasodilation. There may be a marked impairment in the excretion of solute-free renal water and renal vasoconstriction, resulting in HRS.

[0009] In various cases, signs of hepatic decompensation may be present, including an INR>1.5, ascites, and encephalopathy. Hyponatremia is also a frequent complication in patients with cirrhosis and ascites, and it is associated with increased morbidity.

[0010] Systemic inflammatory response syndrome (SIRS) is an inflammatory response that is not necessarily associated with infection, but may result from nonspecific injury that initially produces local cytokines. SIRS is typically characterized by: (1) a core temperature below 36°C (96.8°F) or above 38°C (100.4°F), (2) a heart rate above 90 beats per minute, (3) tachypnea (high respiratory rate) above 20 breaths per minute, or an arterial partial pressure of carbon dioxide (CO2) below 4.3 kPa (32 mmHg), and (4) a CO2 concentration above 4,000 cells / mm 3 (4×10 9 cells / L) or less than 12,000 cells / mm 3 (12×10 9 It is characterized by four criteria, including a white blood cell count of more than 100 cells / L, or more than 3% having immature neutrophils (band morphology), called bandemia or "left shift." SIRS can be diagnosed if two or more of these criteria are present.

[0011] Sepsis is defined as a systemic inflammatory response to infection, and septic shock is sepsis complicated by either hypotension or hyperlactatemia that is refractory to fluid resuscitation.

[0012] Mortality in patients with HRS and SIRS is very high and can approach 70%.

[0013] Several studies have been conducted on patients with end-stage liver disease and systemic inflammatory response. One such study described by Thabut et al., entitled "Model for End-Stage Liver Disease Score and Systemic Inflammatory Response Are Major Prognostic Factors in Patients with Cirrhosis and Acute Functional Renal Failure," published in HEPATOLOGY, Vol. 46, No. 6, 2007, which is incorporated herein by reference in its entirety, concluded that the presence of SIRS criteria, with or without infection, is a major independent prognostic factor in patients with cirrhosis and acute functional renal failure.

[0014] The presence of HRS and SIRS typically has a short life span if not effectively treated with appropriate medications within a short period of time. It is therefore of utmost importance to identify the most effective treatment for a patient with a particular presentation and to initiate an appropriate regimen as soon as possible.

[0015] Terlipressin is a synthetic analogue of vasotocin with long-lasting effects, acting as a peptide vasopressin VIa receptor agonist. Terlipressin is a derivative of vasotocin prepared by N-terminal extension by three amino acid residues and is used as a vasoactive drug in the management of hypotension. Terlipressin can be synthesized by stepwise coupling of amino acids to each other in liquid or solid phase using a peptide synthesizer. Terlipressin is a prodrug that metabolizes slowly to lysine-vasopressin, thus providing a long-lasting biological effect. In contrast to the short half-life of vasopressin, which is only 6 minutes (duration of action 30-60 minutes), the half-life of terlipressin is 6 hours (duration of action 2-10 hours).

[0016] The chemical structure of terlipressin (Gly-Lys-Pro-Cys-Asn-Gln-Phe-Tyr-Cys-Gly-Gly-Gly, SEQ ID NO: 1) in an injectable formulation is shown below: [ka]

[0017] Molecular formula:C 52 H 74 N 16 O 15 S2 Molecular weight: 1227.4 Daltons Appearance: Homogeneous freeze-dried white to off-white solid Solubility: Clear, colorless solution in saline Vial: Colorless glass vial containing 11 mg of white to off-white solid, 1 mg of active ingredient and 10 mg of mannitol.

[0018] The active ingredient, N-[N-(N-glycylglycyl)glycyl]-8-L-lysine vasopressin, is a synthetically produced hormone precursor of 8-lysine vasopressin, which has a characteristic ring structure of a cyclic nonapeptide consisting of 12 amino acids with a disulfide bridge between the 4th and 9th amino acids. Three glycyl amino acids are substituted at position 1 (cysteine) of 8-lysine-vasopressin. This N-terminal extension of 8-lysine-vasopressin significantly reduces the rate of metabolic degradation of the active ingredient, since the glycyl molecule inhibits rapid N-terminal enzymatic degradation. Terlipressin may be present in the pharmaceutical composition as a salt, diacetate, hydrate, and / or free base, such as terlipressin acetate or terlipressin diacetate pentahydrate. Summary of the Invention [Means for solving the problem]

[0019] Principles and embodiments of the present disclosure generally relate to methods of treating a patient with HRS-1 by administering terlipressin to the patient to obtain reversal of HRS-1. In one or more embodiments, the response criteria provide a novel and useful function that indicates the likelihood of an improved response by a patient to administration of terlipressin.

[0020] Some aspects of the present disclosure relate to a method of treating a patient with Hepatorenal Syndrome Type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient is listed for transplant at baseline and has a baseline Model for End-Stage Liver Disease (MELD) score of less than 35, and discontinuing or reducing the dose of terlipressin in patients with serum creatinine (SCr) > 5 mg / dl and / or acute-on-chronic liver failure (ACLF) grade > 3. Terlipressin may be administered every 6 hours by IV bolus injection over 2 minutes.

[0021] In some embodiments, the method may further include obtaining a baseline MELD score for the patient. In additional embodiments, the method may further include obtaining an SCr level in the patient prior to administering a dose of terlipressin to determine a baseline SCr level. In some instances, terlipressin may not be administered if baseline SCr is > 5 mg / dl and / or baseline ACLF grade > 3. In other embodiments, the patient's risk of death is reduced. The patient's position on the transplant list may not be compromised or affected by administration of terlipressin. In some embodiments, the patient may be at high risk of having their position on the transplant list compromised or affected by administration of terlipressin. In addition, the patient's overall length of ICU stay, non-ICU stay, and / or hospital stay may be shortened. In some embodiments, terlipressin administration is continued until there is a complete or partial response. In other embodiments, discontinuing administration of terlipressin or reducing its dose occurs in patients with respiratory failure. The patient may also have severe renal disease, pulmonary edema, respiratory distress, or a combination thereof. In various aspects, the method may further include monitoring the oxygen saturation of the patient during treatment with terlipressin. Monitoring the oxygen saturation reduces the occurrence of adverse events.

[0022] Further aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient has a baseline Model for End-Stage Liver Disease (MELD) score of less than 35 and is listed for transplant. The method may further comprise obtaining a baseline MELD score for the patient. In some aspects, the method may further comprise not administering, ceasing administration of, or reducing the dose of terlipressin in patients with a serum creatinine (SCr) of > 5 mg / dl and / or an Acute Exacerbation of Chronic Liver Failure (ACLF) grade > 3.

[0023] A further aspect of the present disclosure is a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient, obtaining an SCr level in the patient before administering a dose of terlipressin to determine a baseline SCr level, and administering a dose of terlipressin to the patient if the baseline MELD score is <35, the baseline SCr level is <5 mg / dl, the patient has an ACLF grade <3, or a combination thereof. In some aspects, the patient may be listed for transplant. In additional aspects, if the patient is not listed for transplant at baseline, the patient may have a MELD score >= 35. Terlipressin may be administered to the patient by intravenous (IV) injection.

[0024] Yet another aspect of the present disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, where the administration occurs only if the patient is listed for transplant at baseline and has a baseline Model for End-Stage Liver Disease (MELD) score < 35, the patient has a serum creatinine (SCr) < 5 mg / dl, the patient has an ACLF grade < 3, or a combination thereof. In some embodiments, the method may further comprise monitoring the patient for fluid overload during treatment with terlipressin, and reducing or discontinuing the terlipressin dose if fluid overload occurs. In addition, the method may further comprise administering a diuretic to the patient and / or measuring SCr levels in the patient.

[0025] Another aspect of the present disclosure relates to a method for increasing overall survival of a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient, obtaining an SCr level in the patient to determine a baseline SCr level, and administering a dose of terlipressin to the patient if the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg / dl. In some aspects, the patient may be listed for transplant at baseline. In additional aspects, if the patient is not listed for transplant at baseline, the patient may have a MELD score >= 35.

[0026] An additional aspect of the present disclosure relates to a method of reducing overall ICU or hospital stay for a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient, obtaining an SCr level in the patient to determine a baseline SCr level, and administering a dose of terlipressin to the patient if the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg / dl. In some aspects, the patient may be listed for transplant at baseline. In additional aspects, if the patient is not listed for transplant at baseline, the patient may have a MELD score >= 35.

[0027] An additional aspect of the present disclosure relates to a method for increasing complete response in patients with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in the patient to determine a baseline SCr level; administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg / dl; measuring the SCr level in the patient during administration of terlipressin; and continuing administration of terlipressin until the patient's SCr level is ≦1.5 mg / dl. In some aspects, the patient may be listed for transplant at baseline. In additional aspects, if the patient is not listed for transplant at baseline, the patient may have a MELD score ≧35.

[0028] A further aspect of the present disclosure relates to a method of increasing partial response in patients with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in the patient to determine a baseline SCr level; administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg / dl; measuring the SCr level in the patient during administration of terlipressin; and continuing administration of terlipressin until the patient experiences a greater than 20% improvement in serum creatinine. Administration may be continued until the patient experiences a greater than 30% improvement in serum creatinine. In some aspects, the patient may be listed for transplant at baseline. In additional aspects, if the patient is not listed for transplant at baseline, the patient may have a MELD score of ≧35.

[0029] Another aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection, where the patient is excluded from treatment if the patient has a MELD score > 35 and is listed for liver transplantation.

[0030] A further aspect of the present disclosure relates to a method of treating a patient with Hepatorenal Syndrome Type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection, wherein the patient is treated only if the patient belongs to a patient population for which the median wait time from listing to transplant is 5.6 months or greater.

[0031] A still further aspect of the present disclosure relates to a method of treating a patient with Hepatorenal Syndrome Type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection, wherein the patient is excluded from treatment if the patient belongs to a patient population with a median waiting time from listing to transplant of 0.23 months or less.

[0032] Some aspects of the disclosure relate to a method of treating patients with Hepatorenal Syndrome Type 1 (HRS-1), comprising narrowing a population of patients eligible for treatment to a mitigated population to reduce a risk selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof, and administering a dose of terlipressin to patients in the mitigated population by intravenous (IV) injection.

[0033] Additional aspects of the disclosure relate to a method of administering terlipressin to treat a patient with hepatorenal syndrome type 1 (HRS-1), the patient being listed for transplant with a baseline Model End-Status Liver Disease (MELD) score of less than 35, the method comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, and discontinuing or reducing the dose of terlipressin in patients with a serum creatinine (SCr) level of >5 mg / dl and / or an Acute Progression of Chronic Liver Failure (ACLF) grade >3. In some aspects, the method may further comprise obtaining an SCr level in the patient prior to administering the dose of terlipressin to determine a baseline SCr level. The patient's risk of death may be reduced. The patient's position on the transplant list may not be impaired or affected. The patient's overall length of ICU stay, non-ICU stay, and / or hospital stay may be shortened. In some aspects, terlipressin administration is continued until there is a complete or partial response. In other embodiments, the administration of terlipressin is stopped or the dose is reduced in patients with respiratory failure. The patient may also have severe renal disease, pulmonary edema, dyspnea, or a combination thereof. Terlipressin may be administered every 6 hours by IV bolus injection over 2 minutes. In some embodiments, the method may further include monitoring the oxygenation level of the patient via pulse oximetry during treatment with terlipressin. Monitoring oxygenation level reduces the occurrence of adverse events.

[0034] Some aspects of the present disclosure relate to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising obtaining a baseline oxygenation level (SpO2) via pulse oximetry, administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient is not experiencing hypoxia, and monitoring the patient's SpO2 during treatment with terlipressin. Monitoring the oxygenation level may reduce the occurrence of adverse events. In some aspects, the patient's oxygen saturation is monitored for hypoxia. The method may further include ceasing administration of terlipressin or reducing its dose if hypoxia is detected. For example, terlipressin may not be administered or may be discontinued if the patient's SpO2 at baseline or during treatment is less than 90% and / or the patient's FiO2 is greater than 0.36. The patient's SpO2 may be monitored at least three times a day during administration of terlipressin.

[0035] A still further aspect of the present disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection and discontinuing or reducing the dose of terlipressin in patients with serum creatinine (SCr) > 5mg / dl. An additional aspect of the present disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising measuring serum creatinine (SCr) levels in the patient and administering a dose of terlipressin to the patient if the patient has serum creatinine (SCr) < 5mg / dl, the patient has ACLF grade < 3, or a combination thereof. Terlipressin may be administered to the patient by intravenous (IV) injection. Further aspects of the disclosure include a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, where administration does not occur if the patient has a serum creatinine (SCr) > 5 mg / dl, the patient has an ACLF grade > 3, or a combination thereof. In yet another aspect, the invention includes a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, where administration occurs only if the patient has a serum creatinine (SCr) < 5 mg / dl, the patient has an ACLF grade < 3, or a combination thereof. The method may further include monitoring the patient for fluid overload during treatment with terlipressin and reducing terlipressin treatment if fluid overload occurs. As used herein, the terms "reducing terlipressin therapy" and "reducing terlipressin dose" can include lowering the terlipressin dose, discontinuing the terlipressin dose, and / or not increasing the dose if the patient is previously prescribed or scheduled for a dose increase. Discontinuing a terlipressin dose can include temporarily suspending the dose until the adverse event subsides, until further notice, or until the patient has a serum creatinine (SCr) > 5 mg / dl.In additional embodiments, the method may further include measuring SCr levels in the patient. In some embodiments, the overall length of a patient's ICU stay, non-ICU stay, and / or hospital stay may be shortened. Terlipressin administration may be continued until there is a complete or partial response.

[0036] In an additional aspect, a method of treating a patient with hepatorenal syndrome type 1 (HRS-1) includes administering a dose of terlipressin to the patient by intravenous (IV) injection and managing fluid overload by reducing or discontinuing administration of albumin, other fluids, and / or judicious use of diuretics. As used herein, judicious use of diuretics means use of an effective amount of diuretics. For clarity, reducing administration of albumin may include lowering the dose or discontinuing a dose of albumin. If fluid overload persists, the method of treating may further include reducing or discontinuing terlipressin treatment. In a further aspect, managing fluid overload may reduce mortality or incidence of adverse events in a patient or patient population treated according to the invention described herein. In another aspect, a method of treating a patient with Hepatorenal Syndrome Type 1 (HRS-1) comprises administering a dose of terlipressin to the patient by intravenous (IV) injection and managing fluid overload by reducing or discontinuing the administration of albumin, other fluids, and / or judicious use of diuretics, wherein the patient further has respiratory failure, severe renal disease, pulmonary edema, dyspnea, tachypnea, ischemia, or a combination thereof.

[0037] In an additional aspect, a method of treating a patient with hepatorenal syndrome type 1 (HRS-1) comprises administering a dose of terlipressin to the patient by intravenous (IV) injection, wherein the dose of terlipressin is not increased in the presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, ongoing serious adverse reactions, existing severe coronary artery disease, or a combination thereof. In an additional aspect, a method of treating a patient with hepatorenal syndrome type 1 (HRS-1) comprises administering a dose of terlipressin to the patient by intravenous (IV) injection, wherein the dose of terlipressin is reduced or discontinued in the presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, ongoing serious adverse reactions, existing severe coronary artery disease, or a combination thereof. Another aspect of the disclosure includes a method of treating a patient with hepatorenal syndrome type 1 (HRS-1) comprising administering a dose of terlipressin to the patient by intravenous (IV) bolus injection over two minutes every six hours, monitoring the patient for fluid overload during treatment with terlipressin, and reducing or discontinuing terlipressin treatment if fluid overload persists.

[0038] Ischemic events (e.g., inadequate blood supply to the skin, heart, blood vessels, or gastrointestinal tissues) may occur following administration of terlipressin. The most common ischemia-related adverse events may include skin discoloration, cyanosis, intestinal ischemia, and combinations thereof. Serious ischemic events in patients treated with terlipressin may include intestinal ischemia, vascular skin disorders, cyanosis, livedo reticularis, myocardial infarction, poor peripheral circulation, myocardial ischemia, or combinations thereof. Terlipressin should be used with caution in patients with a history of ischemic events and certain cardiac diseases. In patients who experience signs or symptoms suggestive of an ischemic adverse reaction, the terlipressin dose should be reduced or permanently discontinued. An additional aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) bolus injection over two minutes every six hours, where treatment of the patient with terlipressin is reduced or discontinued in the presence of ischemia. In another aspect, the invention includes a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) bolus injection over two minutes every six hours, where treatment of the patient with terlipressin is reduced or discontinued in the presence of skin, cardiac, vascular, or gastrointestinal ischemia in the patient, or a combination thereof. The terms "ischemia" and "ischemic event" may be used interchangeably.

[0039] Yet another aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) bolus injection over two minutes every six hours, wherein the dose of terlipressin is not increased in the presence of fluid overload, pneumonia, bronchospasm, or pulmonary edema.A further aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) bolus injection over two minutes every six hours, monitoring the patient for fluid overload during treatment with terlipressin, and reducing or discontinuing the dose of terlipressin if fluid overload occurs. In yet another aspect of the disclosure, a method of treating a patient with hepatorenal syndrome type 1 (HRS-1) comprises administering to the patient a dose of terlipressin by intravenous (IV) bolus injection over 2 minutes every 6 hours, wherein treatment with terlipressin is immediately discontinued in the presence of treatment-emerging pulmonary edema, new or worsening pneumonia, or unresolved hepatic encephalopathy > grade 3 with risk of aspiration.

[0040] A further aspect of the disclosure relates to a method of increasing overall survival or a patient with Hepatorenal Syndrome Type 1 (HRS-1), comprising measuring serum creatinine (SCr) levels in the patient and administering a dose of terlipressin to the patient if the patient has a serum creatinine (SCr) <5 mg / dl.A further aspect of the disclosure relates to a method of decreasing overall ICU or hospital stay in a patient with Hepatorenal Syndrome Type 1 (HRS-1), comprising measuring serum creatinine (SCr) levels in the patient and administering a dose of terlipressin to the patient if the patient has a SCr <5 mg / dl.

[0041] An additional aspect of the disclosure relates to a method of increasing a complete response in a patient having hepatorenal syndrome type 1 (HRS-1), comprising measuring serum creatinine (SCr) levels in the patient, administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient's SCr level is <5 mg / dl, and continuing administration of terlipressin until the patient's SCr level is ≦1.5 mg / dl. Yet a further aspect of the disclosure relates to a method of increasing a partial response in a patient having hepatorenal syndrome type 1 (HRS-1), comprising measuring serum creatinine (SCr) levels in the patient, administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient's SCr level is <5 mg / dl, and continuing administration of terlipressin until the patient experiences a greater than 20% improvement in serum creatinine.

[0042] Additional aspects and features are set forth in part in the description which follows, and will become apparent to those skilled in the art upon examination of the specification or may be learned by practice of the disclosed subject matter.

[0043] Further features of the embodiments of the present disclosure, their nature and various advantages will become more apparent from consideration of the following detailed description in conjunction with the accompanying drawings, which also illustrate the best mode contemplated by the applicant, and in which like reference characters refer to like parts throughout. [Brief description of the drawings]

[0044] [Figure 1] 1 shows an exemplary embodiment of a terlipressin treatment protocol. [Diagram 2] 1 shows an exemplary embodiment of a terlipressin treatment protocol. [Diagram 3] 1 shows a series of unexpected results from an exemplary embodiment of a terlipressin treatment protocol. [Figure 4] 1 shows an exemplary embodiment of a terlipressin treatment protocol. [Diagram 5]1 is a graph showing 90-day survival of patients treated with and without terlipressin according to ACLF grade. [Figure 6A-B] (FIG. 6A) Percentage of patients with renal failure at baseline and end of treatment for patients treated with terlipressin and placebo (FIG. 6B) Percentage of patients with respiratory failure at baseline and end of treatment for patients treated with terlipressin and placebo. [Figure 6C] The percentages of patients with respiratory failure with ACLF grade < 2 and ACLF grade > 3 for terlipressin and placebo treated patients are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Principles and embodiments of the present disclosure relate to methods of improving a patient's renal condition that include a treatment protocol that includes terlipressin. Accordingly, various embodiments of the present disclosure provide methods of treating a patient with terlipressin or terlipressin and albumin.

[0046] As used herein, the use of "terlipressin" may refer to terlipressin, or its salts, diacetates, hydrates, and / or free base. For example, the use of terlipressin may include terlipressin acetate or terlipressin diacetate pentahydrate. In additional examples, terlipressin may refer to any other suitable salt or hydrate thereof, or any other biologically acceptable salt or hydrate thereof.

[0047] As used herein, the terms "reducing terlipressin therapy" and "reducing terlipressin dose" can include lowering the terlipressin dose, discontinuing the terlipressin dose, and / or not increasing the dose if the patient is previously prescribed or scheduled for a dose increase. Discontinuing a terlipressin dose can include temporarily suspending the dose until the adverse event subsides, until further notice, or until the patient has a serum creatinine (SCr) > 5 mg / dl.

[0048] As used herein, a "attenuated population" or "subset of patients" includes HRS-1 patients with baseline ACLF grade 0-2, baseline serum creatinine <5 mg / dL, and / or baseline MELD < 35. For example, the attenuated population excludes patients listed for transplant at baseline with baseline ACLF grade 3, baseline serum creatinine ≥5 mg / dL, and / or baseline MELD ≥35.

[0049] In embodiments of the present disclosure, a patient is evaluated to determine the specific diseases and / or syndromes to which the patient may be afflicted, and a treatment regimen is initiated for those patients who would benefit from administration of terlipressin.

[0050] In various embodiments, the patient has end stage liver disease complicated by acute renal failure, such as HRS, and is treated with terlipressin.

[0051] In various embodiments, the end stage liver disease can be cirrhosis or fulminant hepatic failure, hi various embodiments, the end stage liver disease is complicated by renal dysfunction.

[0052] HRS-1 in decompensated cirrhosis is associated with hemodynamic abnormalities.Terlipressin improves renal perfusion in HRS-1 by improving intravascular volume through splanchnic vasoconstriction.In some embodiments, terlipressin can be more effective than placebo in albumin-treated patients with decompensated cirrhosis and HRS-1.Embodiments of the present disclosure relate to methods for diagnosing patients who show improved response to terlipressin treatment, as indicated by an increased probability of reversing HRS.

[0053] In one or more embodiments, a method for identifying an HRS-1 patient having an increased likelihood of responding to a terlipressin treatment regimen includes identifying a patient with end-stage renal disease and impaired renal function and determining whether the patient also exhibits at least two of three criteria for SIRS, the three response criteria being: (1) 4,000 cells / mm 3 Less than or equal to 12,000 cells / mm 3 (1) a white blood cell count (WBC) greater than 85 BPM, (2) a heart rate greater than 90 beats per minute (BPM), and (3) HCO3 < 21 mmol / L, where HCO3 is considered a surrogate measure that approximates the response criterion of an arterial partial pressure of carbon dioxide (PaCO2) < 32 mmHg. In various embodiments, a heart rate > 85 BPM and / or HCO3 < 23 mmol / L may be applied as the response criteria.

[0054] An embodiment of the present disclosure relates to terlipressin for use in treating HRS-1 in a subject who also exhibits at least two of the following three response criteria: (a) White blood cell count (WBC) is 4,000 cells / mm 3 Less than or equal to 12,000 cells / mm 3 Super, (b) a heart rate greater than 90 beats per minute (BPM); and (c) HCO3<21 mmol / L, where HCO3 is considered a surrogate measure that approximates the response criterion of arterial pressure of carbon dioxide (PaCO2)<32 mmHg. In various embodiments, one or more single dosages of terlipressin are administered to a subject to treat HRS-1.

[0055] In various embodiments, the terlipressin dosage is administered to the patient as a series of single doses in the range of about 0.5 mg to about 2.0 mg every 4-6 hours, such that the patient receives a single dose in the range of about 0.5 mg to about 2.0 mg of terlipressin, followed by another single dose 4-6 hours later. In various embodiments, the patient may receive 4-6 doses over a 24 hour period, each dose ranging from about 0.5 mg to about 2.0 mg. In various embodiments, the total dosage does not exceed 4.0 mg over a 24 hour period.

[0056] An exemplary embodiment of a method of treating a patient via an embodiment of a terlipressin treatment protocol as shown in FIG.

[0057] In various embodiments, a patient initially identified as having end-stage liver disease in which treatment with a vasodilator would result in improved renal function is tested to determine the patient's degree of cirrhosis and renal failure.

[0058] At 110, a patient is first identified as having end stage liver disease and renal dysfunction. In various embodiments, the patient may suffer from cirrhosis or fulminant hepatic failure, and a patient identified as having cirrhosis may have a Child-Pugh score of A, B, or C. In various embodiments, a patient identified as having cirrhosis with a Child-Pugh score of B or C may be considered a viable candidate for terlipressin treatment. In various embodiments, a patient identified as having cirrhosis with a Child-Pugh score of C may be considered a viable candidate for terlipressin treatment. Various complications of end stage liver disease and particularly cirrhosis are recognized and have a significantly poorer prognosis.

[0059] In one or more embodiments, a treatment protocol including a dosage of terlipressin surprisingly provides reversal of one or more co-morbid factors, such as vasodilation, and reduces mortality from associated complications within 90 days of initiating treatment.

[0060] In one or more embodiments, a terlipressin treatment protocol includes identifying a patient with end stage liver disease and impaired renal function, the identified patient being able to benefit from treatment including administration of terlipressin; determining whether the patient exhibits at least two of three response criteria; excluding the patient from administration of terlipressin if the patient exhibits uncontrolled infection, sepsis, or septic shock that would preclude the patient from terlipressin treatment; and initiating terlipressin treatment by administering a daily dosage of terlipressin to the patient in an amount effective to produce improvement in renal function, as indicated by at least a 25% reduction in SCr from baseline, a reversal of HRS (defined as a decrease in SCr levels to ≦1.5 mg / dL), and / or a confirmed reversal of HRS (defined as two serum creatinine values ​​≦1.5 mg / dL at least 48 hours apart).

[0061] In one or more embodiments, the patient is alive 90 days after initiating terlipressin treatment. For example, a patient who experiences a reversal of HRS, a verified reversal of HRS, and / or an improvement in SCr of greater than 30% after receiving terlipressin may have at least a 60%, 65%, or 70% chance of being alive at 90 days. In other embodiments, the patient is alive 90 days after initiating terlipressin treatment and has not undergone a transplant. For example, a patient who experiences a reversal of HRS, a verified reversal of HRS, and / or an improvement in SCr of greater than 30% after receiving terlipressin may have at least a 35%, 40%, or 45% chance of being alive and not undergoing a transplant at 90 days.

[0062] In one or more embodiments, the terlipressin dosage may range from about mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or 0.5 mg to about mg, or about 1.0 mg to about 2.0 mg per single dose. In various embodiments, the injection may be administered intravenously as a slow bolus injection over 2 minutes, and the dose may be repeated every 4 to 6 hours. On the fourth day of treatment (after a minimum of 10 doses), if the SCr has decreased but is less than 30% from the baseline value, the dose may be increased to 2 mg (8 mg / day) every 6 hours (± 30 minutes). If the subject has coronary artery disease or is in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm, the dose may not be increased. The terms "circulatory overload" and "fluid overload" may be used interchangeably. In various embodiments, if dosing is discontinued due to a non-ischemic adverse event, terlipressin may be resumed at the same or lower dose (i.e., 0.5-1 mg q6h).

[0063] In 180, patients without diagnosed end-stage liver disease and renal impairment are excluded from terlipressin treatment.

[0064] In one or more embodiments, patients are tested for three specific response criteria, the criteria being: (1) white blood cell count (WBC) of 4,000 cells / mm 3 Less than or equal to 12,000 cells / mm 3 (2) whether the patient has a heart rate greater than 90 beats per minute (BPM), and / or (3) whether the patient has tachypnea of ​​greater than 20 breaths per minute or HCO3<21 mmol / L, where HCO3 is considered a surrogate measure that approximates the response criterion of an arterial partial pressure of carbon dioxide (PaCO2)<32 mmHg. In various embodiments, the response criterion of a patient's core body temperature being less than 36° C. (96.8° F.) or greater than 38° C. (100.4° F.) is not measured or considered in determining whether the patient has two or more response criteria. In some examples, the response criterion may be a SIRS criterion. In various embodiments, the criteria may be tested in any order.

[0065] At 120, patients were tested to determine whether their WBC was <4,000 or >12,000 cells / mm 3 In various embodiments, the test specifically determines whether the patient has a white blood cell count of 4000 cells / mm 3 (4×10 9 cells / L) or less than 12,000 cells / mm 3 (12×10 9 In various embodiments, the present invention is directed to determining whether a patient has a WBC of <5,000 or >12,000 cells / mm. 3 If the patient is, the patient will be considered to meet the response criteria. In various embodiments, the patient is not tested for the presence of more than 10% immature neutrophils (band type). In various embodiments, the test method for determining WBC can be any of the methods known in the art.

[0066] Patients with 4,000-12,000 cells / mm 3 If the patient is not found to have a WBC outside the range of 0.1, the patient can still be diagnosed with SIRS if they meet the other two response criteria.

[0067] In various embodiments, WBC<4,000 or >12,000 cells / mm 3 Patients with are considered to meet the response criteria.

[0068] 130: 4,000-12,000 cells / mm 3 Patients without a WBC outside the range are tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria. The test method for determining the patient's heart rate can be any of those known in the art.

[0069] In various embodiments, between 5,000 and 12,000 cells / mm 3Patients with a WBC outside the range are tested to determine if their heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria.

[0070] 185, WBC < 4,000 or > 12,000 cells / mm 3 Patients who do not present with both a blood pressure of > 90 BPM and a heart rate > 90 BPM are considered ineligible for two of the three response criteria and therefore do not meet the requirement to be treated with terlipressin. Patients who do not meet at least two of the three response criteria are excluded from terlipressin treatment. Such patients may instead be treated with one or more other pharmacological agents, such as norepinephrine, vasopressin, or a combination of midodrine and octreotide. Alternatively or additionally, any of the following may be used: N-acetylcysteine, misoprostol, and / or BQ123. Another option is transjugular intrahepatic portosystemic shunting (TIPS). Renal support in the form of dialysis is commonly introduced to manage acute fluid overload in HRS-1 patients, especially when pharmacological therapy has failed. The only effective and permanent treatment for end-stage cirrhosis and HRS is liver transplantation.

[0071] 140: 4,000-12,000 cells / mm 3 Patients with a WBC outside the range of 1.0 to 1.5 mmHg or a heart rate that is >90 BPM are tested to determine if the patient has >20 breaths per minute or HCO3<21 mmol / L. If the patient has >20 breaths per minute or HCO3<21 mmol / L, the patient will be considered to meet the response criteria. In various embodiments, patients with HCO3<23 mmol / L will be considered to meet the response criteria. The test method for determining the patient's respiration rate or HCO3 can be any of the methods known in the art.

[0072] In various embodiments, between 5,000 and 12,000 cells / mm 3 Patients with WBC outside the range are tested to determine if they have a respiration rate >20 breaths per minute or HCO3 <21 mmol / L. If the patient has a respiration rate >20 breaths per minute or HCO3 <21 mmol / L, the patient will be considered to meet the response criteria. In various embodiments, patients with HCO3 <23 mmol / L will be considered to meet the response criteria.

[0073] In one or more embodiments, the patient has between 4,000 and 12,000 cells / mm 3 If the patient has a WBC outside the range of 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1.6, 1.7, 1.8, 1.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,

[0074] In one or more embodiments, if a patient has a heart rate that is >90 BPM and the patient has a respiratory rate >20 breaths per minute or HCO3 <21 mmol / L, the patient is considered eligible for two of the three response criteria and thus meets the requirements to be treated with terlipressin, unless otherwise excluded.

[0075] 135, 4,000-12,000 cells / mm 3 Patients with a WBC outside the range of >20 breaths per minute, or HCO3 <21 mmol / L are tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria.

[0076] Patients with 5,000-12,000 cells / mm 3In one or more embodiments, where the patient has a WBC outside the range of >20 breaths per minute, or HCO3 <21 mmol / L, but the patient does not have >20 breaths per minute, or HCO3 <21 mmol / L, the patient is tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, a patient with a heart rate >85 BPM will be considered to meet the response criteria.

[0077] In one or more embodiments, if a patient has a respiratory rate >20 breaths per minute or a heart rate >90 BPM with HCO3 <21 mmol / L, and if the patient has a respiratory rate >20 breaths per minute or HCO3 <21 mmol / L, the patient is considered eligible for two of the three response criteria and thus meets the requirement to be treated with terlipressin, unless otherwise excluded.

[0078] In 186, patients who do not (1) have a respiratory rate >20 breaths per minute or HCO3 <21 mmol / L and (2) do not have a heart rate >90 BPM are considered ineligible for at least two of the three response criteria and therefore do not meet the requirements to be treated with terlipressin. Patients who do not meet at least two of the three response criteria are excluded from terlipressin treatment. Optional alternative treatments for such patients are described above.

[0079] Although the tests of the response criteria are described in a particular order for the illustrative embodiment, the tests may be performed in any particular order.

[0080] In one or more embodiments, patient temperature is not a response criterion because it may not provide an accurate indication of the patient's response to terlipressin, hi various embodiments, patient temperature is excluded from the set of response criteria.

[0081] At 150, patients with end stage liver disease with renal impairment and who qualify for at least two of the three response criteria are initiated on terlipressin. In one or more embodiments, patients with uncontrolled infection, sepsis, or septic shock are excluded from terlipressin treatment. In various embodiments, terlipressin is administered to the patient for one to four days. In various embodiments, the patient is administered terlipressin for four days unless the patient experiences an adverse event. In various embodiments, terlipressin is administered to the patient as an IV infusion.

[0082] In one or more embodiments, a terlipressin treatment protocol comprises administering a dosage of about 0.1 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or about 0.5 mg to about 1.0 mg, or about 1.0 mg to about 2.0 mg, as an IV infusion to a patient over a period of about 4 to about 6 hours.

[0083] In one or more embodiments, the patient is administered terlipressin as an IV about every 4-6 hours for 1-4 days. In various embodiments, terlipressin may be administered for at least 4 days.

[0084] In one or more embodiments, the patient is administered terlipressin as a slow bolus over 2 minutes about every 4-6 hours for 1-4 days. In various embodiments, terlipressin may be administered for at least 4 days.

[0085] At 160, the patient receiving terlipressin is tested at least once during the 1-4 day administration period to determine if the patient is responding to terlipressin. In various embodiments, the patient may be tested once before initiating administration of terlipressin to establish a baseline, and once during the 1-4 day administration of terlipressin, or once before initiating administration of terlipressin to establish a baseline, and once at the end of the 4 day administration of terlipressin. In various embodiments, the patient's creatinine level is measured to determine if there has been a reduction in the patient's serum creatinine, where a reduction in serum creatinine level of greater than about 1.0 mg / dL or in the range of about 1.0 mg / dL to about 2.0 mg / dL, or a reduction of about 1.7 mg / dL from the patient's initial baseline value indicates improvement in renal function and that the patient is responding to terlipressin.

[0086] In various embodiments, improvement in renal function is indicated by a decrease in serum creatinine levels of about 25% or about 30% in patients receiving terlipressin.

[0087] In one or more embodiments, a patient may have serum creatinine levels measured once daily or once every other day for each of four days after administration of terlipressin is initiated, and the measurement taken on the first day of terlipressin administration may be recorded and used as the baseline creatinine level.

[0088] In various embodiments, the method may include testing the patient's SCr levels for 1-4 days of terlipressin administration and determining whether the patient has a reduction in SCr levels by the end of 1-4 days of terlipressin administration.

[0089] Serum creatinine levels can be measured by any method known in the art, for example, the Jaffe reaction using alkaline picrate.

[0090] GFR can be measured directly by clearance studies of exogenous markers such as inulin, iohexol, iothalamate, and Cr51-EDTA, or by estimated glomerular filtration rate (eGFR) using a creatinine test method traceable to an isotope dilution mass spectrometry (IDMS) based reference method.

[0091] At 170, the patient who shows a positive response to administration of terlipressin as evidenced by a reduction in the patient's serum creatinine level is continued on terlipressin at a dosage ranging from about 0.1 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or about 0.5 mg to about 1.0 mg, or about 1.0 mg to about 2.0 mg. In various embodiments, the dosage administered to the patient may be adjusted based on the measured serum creatinine level. In various embodiments, the patient receiving terlipressin may have their serum creatinine level monitored for the entire period the patient is receiving terlipressin. In one or more embodiments, the patient's serum creatinine level may be tested daily, or every other day, or every 3 days, or every 4 days to ensure that the patient is still responding positively to terlipressin treatment.

[0092] In various embodiments, a patient's terlipressin dosage may be increased by about 0.5 mg to about 1.0 mg to about 1.0 mg to about 2.0 mg after 2-3 days of terlipressin administration to the patient if there is a decrease in SCr of <1.5 mg / dL during the first 2-3 days of treatment.

[0093] In various embodiments, dosages may be repeated every 4-6 hours for a period of one or more days until the patient shows recovery or until the patient no longer shows improvement. Terlipressin may be administered to the patient for a period ranging from about 2 days to about 16 days, or from about 4 days to about 8 days. In various embodiments, the period ranges from about 7 days. In various embodiments, terlipressin treatment may be continued until there is a complete response. In various embodiments, the period of treatment of the patient with terlipressin may be from 1 to 28 days.

[0094] At 190, patients who do not show any improvement by the end of four days may discontinue terlipressin, with improvement being indicated by a decrease in serum creatinine levels over days 1-4 that terlipressin is administered. In various embodiments, patients may be tested on the third or fourth day after initiating treatment with terlipressin to determine whether there is a decrease in serum creatinine levels indicating a response to treatment.

[0095] In one or more embodiments, the patient is provided with two days of anti-infective therapy for a documented or suspected infection prior to initiating administration of terlipressin if an infection is suspected. In various embodiments, the patient may be initiated on a terlipressin treatment protocol after receiving the anti-infective therapy.

[0096] FIG. 2 illustrates an exemplary embodiment of a terlipressin treatment protocol.

[0097] Principles and embodiments of the present disclosure also relate to providing terlipressin IV every 4-6 hours to patients identified by HRS-1 and two or more of three specific response criteria.

[0098] In one or more embodiments, patients are tested for: (1) white blood cell count (WBC) <4 or >12 cells / μL, (2) heart rate (HR) >90 beats per minute (bpm), and (3) HCO3 <21 mmol / L.

[0099] Non-SIRS patients are defined as subjects with less than two of the above response criteria.

[0100] In various embodiments, body temperature is not used as a response criterion.

[0101] In one or more embodiments of the disclosure, terlipressin is administered to patients exhibiting a specific set of symptoms to relieve vasoconstriction in the kidney and improve renal function as indicated by a reduction in serum creatinine levels of about 1.7 mg / dL from an initial baseline.

[0102] At 210, one or more patients who may exhibit end-stage liver disease are tested to determine whether they have cirrhosis with ascites and whether they have a serum level of creatinine >133 μmol / L. Patients identified as having HRS are further tested and / or their medical history checked to determine whether their initial serum level of creatinine doubled to above 226 μmol / L in less than two weeks, indicative of type 1 HRS.

[0103] Patients with HRS-1 and at least two of the three response criteria surprisingly showed improved response to terlipressin treatment compared to non-SIRS HRS-1 patients, as indicated by reversal of HRS symptoms. In addition, patients with HRS-1, at least two of the three response criteria, and no uncontrolled infection, sepsis, or septic shock surprisingly showed improved response to terlipressin treatment compared to non-SIRS HRS-1 patients. HRS symptoms can include serum creatinine levels.

[0104] Patients with HRS-1 and SIRS may experience reversal of HRS, verified reversal of HRS, or greater than 30% improvement in SCr after receiving terlipressin. In one or more embodiments, the patient is alive 90 days after initiating terlipressin treatment. For example, patients who experience reversal of HRS, verified reversal of HRS, and / or greater than 30% improvement in SCr after receiving terlipressin may have at least a 60%, 65%, or 70% chance of being alive at 90 days. In other embodiments, patients are alive and not transplanted at 90 days after initiating terlipressin treatment. For example, patients who experience reversal of HRS, verified reversal of HRS, and / or greater than 30% improvement in SCr after receiving terlipressin may have at least a 35%, 40%, or 45% chance of being alive and not transplanted at 90 days.

[0105] At 220, once a patient is identified as having HRS-1, the patient is examined to determine whether the same patient exhibits at least two of three criteria indicative of SIRS, the three criteria including: (1) WBC<4 or >12 cells / μL, (2) HR>90 bpm, and (3) HCO3<21 mmol / L.

[0106] In various embodiments, patients who are not identified as exhibiting at least two of the three response criteria in addition to HRS-1 are excluded from the terlipressin treatment protocol. Patients who have HRS-1 and exhibit at least two of the three response criteria surprisingly showed improved response to terlipressin treatment compared to non-SIRS HRS-1 patients, as shown by reversal of HRS symptoms, as shown in Figure 3.

[0107] At 230, patients identified as having HRS-1 and exhibiting at least two response criteria are tested to determine whether they may also have uncontrolled infection, sepsis, or septic shock, and patients identified as exhibiting uncontrolled infection, sepsis, or septic shock are excluded from the terlipressin treatment protocol.

[0108] At 240, the patient who has HRS-1, at least two of the three response criteria, and does not have uncontrolled infection, sepsis, or septic shock is initiated with terlipressin therapy. In one or more embodiments, terlipressin therapy is initiated within 48 hours of the initial diagnosis that the patient has both HRS-1 and at least two of the three response criteria. In various embodiments where the determination that the patient does or does not have uncontrolled infection, sepsis, or septic shock occurs 48 hours after the initial diagnosis of both HRS-1 and the response criteria, the treatment protocol is initiated within 48 hours of the initial diagnosis, and treatment may be terminated once uncontrolled infection, sepsis, or septic shock appears or is determined.

[0109] In various embodiments, a baseline serum creatinine level may be determined for a patient prior to initiating administration of terlipressin to the patient, and administration of terlipressin may be initiated within 2 days, or within 3 days, or within 4 days of determining the baseline serum creatinine level. In various embodiments, the patient may be tested at least once daily within 4 days of initiating administration of terlipressin to determine whether the patient exhibits a decrease in serum creatinine level compared to the previously determined baseline serum creatinine level.

[0110] At 250, terlipressin treatment of the patient is initiated and the patient receives a dosage of terlipressin. In one or more embodiments, terlipressin may be administered to the patient as a slow infusion over 24 hours, and the dosage over the 24 hours may range from about 2.0 mg to about 12 mg. In various embodiments, the dosage over the 24 hours may range from about 2.0 mg to about 4.0 mg. In various embodiments, terlipressin is administered as a continuous intravenous (IV) infusion lasting from about 4 hours to about 6 hours and includes a dosage of about 0.5 mg to about 2.0 mg.

[0111] In one or more embodiments, the terlipressin dosage may be a dosage of about 0.5 mg to about 2.0 mg administered intravenously as a slow bolus injection over 2 minutes every 4 to 6 hours. The dosage may be administered by slow IV bolus injection about every 4 hours, about every 5 hours, about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, or about every 12 hours. In at least one example, the dosage may be administered by slow IV bolus injection about every 6 hours. The bolus injection may be given over about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes. In at least one example, the bolus injection may be given over about 2 minutes.

[0112] In one or more embodiments, terlipressin is used to treat patients who exhibit HRS-1 and at least two of the three response criteria. In various embodiments, the patient is also tested to determine that the patient does not have uncontrolled infection, sepsis, or septic shock prior to using terlipressin to treat the HRS-1 patient.

[0113] In various embodiments, the terlipressin dosage is given as a continuous IV supply.

[0114] In one or more embodiments, the terlipressin dosage is 1 mg administered intravenously as a slow bolus injection over 2 minutes every 6 hours.

[0115] In various embodiments, the terlipressin dosage is not given as a bolus.

[0116] Terlipressin may be administered to the patient for up to four days, and the patient may be tested each of the four days to determine if the patient is responding to terlipressin treatment. In various embodiments, response to terlipressin treatment may be indicated by a change in the patient's serum creatinine level, and the symptom may be a reduction in SCr of at least 25% from baseline. In various embodiments, terlipressin may be administered for at least four days.

[0117] At 260, the amount of serum creatinine change after 4 days of treatment with terlipressin was determined, and if the serum creatinine level improved, treatment with terlipressin was continued. In various embodiments, a sufficient improvement in serum creatinine level after 4 days of treatment is indicated by a decrease in serum creatinine level of at least 1.0 mg / dL, or a decrease in serum creatinine level of about 1.7 mg / dL.

[0118] In various embodiments, the patient receives terlipressin for an additional 3-8 days if the patient shows improvement over the previous 1-4 days.In various embodiments, the patient receives terlipressin for an additional 3-4 days if the patient shows improvement over the previous 1-4 days.

[0119] In various embodiments, if the patient exhibits a decrease in serum creatinine levels, administration of terlipressin to the patient is continued for an additional 3 to 12 days beyond the initial 4 days. In various embodiments, administration of terlipressin to the patient may be continued until at least one SCr value <1.5 mg / dL is obtained. In various embodiments, the treatment period may be extended up to 15 or 16 days if reversal of HRS is first achieved on days 13 or 14, respectively. In various embodiments, the treatment period of the patient with terlipressin may be 1 to 28 days. In various embodiments, the decrease in serum creatinine levels may be indicated by a reduction in SCr of at least 1%, or at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 25% from baseline.

[0120] In one or more embodiments, the patient may be administered albumin prior to beginning a terlipressin treatment protocol and / or prior to determining that the patient has at least two of the three response criteria, HRS-1. In various embodiments, the albumin may be administered to the patient 7 to 2 days prior to beginning administration of terlipressin to the patient. In various embodiments, the albumin treatment comprises administering to the patient 1 gram of albumin per kg of patient body weight, up to a maximum of 100 g per day. In various embodiments, the albumin may be administered in a range of about 20 g / day to about 50 g / day, and the albumin may be administered for the period the patient is administered terlipressin.

[0121] Non-limiting embodiments of methods of treating HRS-1 patients exhibiting at least two of the three response criteria with terlipressin include administering to a patient in need of such treatment a dosage of terlipressin in the range of 2.0 mg to 12.0 mg per day for 1 to 28 days, or 2.0 mg to 4.0 mg per day for 1 to 7 days, which dosage may be administered as a continuous IV feed or as a slow bolus injection.

[0122] Embodiments of the present disclosure also relate to treating patients who have HRS-1 and meet two or more response criteria with a dose of terlipressin once every six hours, the dose being in the range of about 0.5 mg to 2.0 mg for three to eight days to achieve reversal of HRS-1.

[0123] Embodiments of the present disclosure also relate to initiating terlipressin treatment within 48 hours of determining that a patient presents with HRS-1 and at least two of the three response criteria but without sepsis, septic shock, or uncontrolled infection.

[0124] Another aspect of the present disclosure relates to a method of distributing a pharmaceutical product.

[0125] In one or more embodiments, the method of distribution includes providing terlipressin to a health care provider, who may be responsible for treating a patient suffering from type 1 hepatorenal syndrome. In various embodiments, the patient does not have overt sepsis, septic shock, or uncontrolled infection. In various embodiments, the method includes providing terlipressin to a patient suffering from type 1 hepatorenal syndrome who does not have overt sepsis, septic shock, or uncontrolled infection and (1) has a white blood cell count (WBC) of 4,000 cells / mm3. 3 Less than or equal to 12,000 cells / mm 3The method includes providing a recommendation to a health care provider to treat a patient with type 1 hepatorenal syndrome who has at least two of the following: (1) a blood glucose level greater than 100 or (2) a heart rate greater than 90 beats per minute (BPM), or (3) HCO3 < 21 mmol / L with an amount of terlipressin effective to reduce SCr. In one or more embodiments, the health care provider follows the recommendation and treats ...100 or (3) HCO3 < 21 mmol / L with an amount of terlipressin effective to reduce SCr. 3 Less than or equal to 12,000 cells / mm 3 Patients with at least two of the following: (1) a heart rate greater than 90 beats per minute (BPM); or (2) a heart rate greater than 90 beats per minute (BPM); or (3) HCO3 < 21 mmol / L are treated with an amount of terlipressin effective to reduce SCr.

[0126] The efficacy of placebo vs. terlipressin in achieving the reversal of verified HRS-1 may be more pronounced among the subgroup of patients with systemic inflammatory response syndrome (SIRS). Proinflammatory cytokines are involved in the pathogenesis of HRS-1. Without being limited to any one theory, terlipressin may reduce the degree of bacterial translocation across the intestinal wall in patients with decompensated cirrhosis through its ability to reduce portal vein pressure, resulting in reduced endotoxemia and reduced production of proinflammatory cytokines, thus facilitating patients to respond to the hemodynamic effects of terlipressin.

[0127] FIG. 3 illustrates the unexpected results produced by an exemplary treatment protocol.

[0128] Aspects of the present disclosure relate to methods of treating and / or reversing HRS-1. An exemplary embodiment of a method of treating an adult patient with HRS-1 via an embodiment of a terlipressin treatment protocol, as shown in FIG.

[0129] In various embodiments, a patient initially identified as having end-stage liver disease in which treatment with a vasodilator may result in improved renal function may be tested to determine the extent of the patient's cirrhosis and renal failure. In an embodiment, the patient to be treated is an adult patient diagnosed with HRS-1.

[0130] In one or more embodiments, a method of treating an adult patient with hepatorenal syndrome type 1 (HRS-1) includes assessing a baseline serum creatinine (SCr) level prior to administration of terlipressin to the patient, initiating dosing of about 0.5 mg to about 1 mg of terlipressin by IV every 6 hours for 1 to 3 days, assessing the serum creatinine level in the patient on day 4 ± 1 day after dosing commencement, and administering a revised dosage of terlipressin based on a comparison of the serum creatinine level assessed on day 4 ± 1 day to the baseline serum creatinine level. In some embodiments, the method may further include continuing administration until 24 hours after two consecutive serum creatinine levels of ≦1.5 mg / dL at least 2 hours apart for up to 14 days.

[0131] In one or more embodiments, the terlipressin dosage can range from about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or 0.5 mg to about 1.0 mg, about 0.85 mg to about 1.7 mg, or about 1.0 mg to about 2.0 mg per single dose.

[0132] In embodiments, the terlipressin administered may be terlipressin acetate. The dosage of terlipressin acetate may be administered to a patient in the range of about 0.5 mg to about 2.0 mg. In various examples, the dosage of terlipressin acetate may be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg.

[0133] Terlipressin may be prepared for injection as a white to off-white lyophilized powder in a single dose vial for reconstitution at a dosage of 0.85 mg terlipressin (equivalent to 1 mg terlipressin acetate). In some embodiments, the terlipressin acetate dosage may be given at an initial dose of about 0.5 mg or about 1 mg. In at least one example, dosing may begin at 1 mg terlipressin acetate. In other embodiments, the terlipressin dosage may be modified after a period of administering the initial dose. In at least one example, the modified dosage may be about 2 mg terlipressin acetate.

[0134] In various embodiments, the injection may be administered intravenously as a slow bolus injection over a period of 2 minutes, and the dose may be repeated every 4 to 6 hours. In one or more embodiments, the injection may be administered to the patient as an IV infusion over a period of about 4 to about 6 hours.

[0135] In examples, an initial terlipressin dosage is administered to a patient as a series of single doses in the range of about 0.5 mg to about 1.0 mg every 4-6 hours, such that the patient receives a single dose in the range of about 0.5 mg to about 1.0 mg of terlipressin, followed by another single dose 4-6 hours later. In various embodiments, the patient may receive 4-6 doses over a 24 hour period, each dose ranging from about 0.5 mg to about 1.0 mg. In various embodiments, the total dosage does not exceed 4.0 mg over a 24 hour period. In some examples, the terlipressin dosage can be about 0.85 mg or about 1.0 mg of terlipressin acetate.

[0136] At step 410, in some embodiments, a baseline serum creatinine level may be measured prior to administering terlipressin on day 1. An initial dose of terlipressin may then be administered to the patient with HRS-1. In examples, the initial dose of terlipressin may be about 0.5 mg to about 1.0 mg and may be administered every 6 hours for about 1 to 3 days. In at least one example, the initial dosage may be about 1.0 mg of terlipressin acetate (i.e., 0.85 mg of terlipressin).

[0137] At step 420, on day 4 of administration ±1 day (e.g., after a minimum of 10 doses), serum creatinine levels may be assessed and compared to baseline levels. In various embodiments, patients receiving terlipressin may be assessed at least once between days 1-4 ±1 day of administration to determine if the patient is responding to terlipressin. In various embodiments, patients may be tested once at the end of 3 or 4 days of administration of terlipressin. In some instances, serum creatinine levels may be assessed continuously (e.g., daily) until administration is discontinued. In various embodiments, the dosage administered to the patient may be adjusted based on the measured serum creatinine levels. In various embodiments, patients receiving terlipressin may have their serum creatinine levels monitored for the entire period the patient is receiving terlipressin. In one or more embodiments, the patient's serum creatinine levels may be tested daily, or every other day, or every 3 days, or every 4 days to ensure that the patient is still responding positively to terlipressin treatment.

[0138] Serum creatinine levels can be measured by any of the methods known in the art, such as the Jaffe reaction using alkaline picrate. GFR can be measured directly by clearance studies of exogenous markers such as inulin, iohexol, iothalamate, and Cr51-EDTA, or by estimated glomerular filtration rate (eGFR) using a creatinine test method traceable to a reference method based on isotope dilution mass spectrometry (IDMS).

[0139] In various embodiments, the patient's creatinine level is assessed to determine whether there has been a reduction in the patient's serum creatinine, where a reduction in serum creatinine level of greater than about 1.0 mg / dL or in the range of about 1.0 mg / dL to about 2.0 mg / dL, or a reduction of about 1.7 mg / dL from the patient's initial baseline value indicates improved renal function and that the patient is responding to terlipressin. In some examples, the assessed serum creatinine level may be greater than 30% below the baseline serum creatinine level, may be between 1% and 29% below the baseline serum creatinine level, or may be greater than 0% below the baseline serum creatinine level. At steps 430, 440, and 450, a revised dosage of terlipressin may then be administered based on a comparison of the serum creatinine level assessed on day 4±1 day to the baseline serum creatinine level.

[0140] At step 430, if the assessed SCr level has decreased by 30% or more from the baseline SCr level on day 4±1 day, a dosage of about 0.5 mg to about 1.0 mg of terlipressin may continue to be administered to the patient every 6 hours. For example, if the assessed SCr level has decreased by 30% or more from the baseline SCr level, the revised dosage may be the same as the initial dosage (e.g., 0.5 mg to 1.0 mg).

[0141] At step 440, if the assessed SCr level has decreased by less than 30% from the baseline level on day 4 ± 1 day, the dosage of terlipressin may be increased to about 1.0 mg to about 2.0 mg every 6 hours. For example, if the assessed SCr level has decreased but is less than 30% from the baseline level, the revised dosage may be about 0.1 mg to about 2.0 mg of terlipressin (8 mg / day) every 6 hours (± 30 minutes). In at least one example, the revised dosage may be an assessed dose that may not be increased from the initial dose if the subject has coronary artery disease or is in a clinical situation of circulatory overload, pulmonary edema, or treatment refractory bronchospasm. In various embodiments, if dosing is discontinued due to a non-ischemic adverse event, terlipressin may be resumed at the same or a lower dose (i.e., 0.5-1 mg q6h).

[0142] In step 450, administration of terlipressin may be discontinued if the assessed SCr level is at or above the baseline SCr level on day 4±1 day. For example, the modified dosage may be discontinuation of administration of terlipressin if the assessed SCr level is at or above the baseline SCr level.

[0143] In step 460, administration of terlipressin may continue for up to 24 hours after the patient achieves a second consecutive serum creatinine value of ≦1.5 mg / dL at least two hourly intervals, or for up to 14 days. In various embodiments, dosages may be repeated every 4-6 hours for a period of one or more days until the patient shows recovery or until the patient no longer shows improvement. In various embodiments, the duration of treatment of the patient with terlipressin may be 1-14 days. In various embodiments, terlipressin may be administered for at least 4 days. In various embodiments, the patient is administered terlipressin for up to 14 days, unless the patient experiences an adverse event. In various embodiments, terlipressin may be administered for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days. In some examples, terlipressin may be administered to a patient for a period ranging from about 2 days to about 14 days, or from about 4 days to about 8 days. In various embodiments, the period ranges from about 7 days. In various embodiments, terlipressin treatment may be continued until there is a complete response.

[0144] In one or more embodiments, a treatment protocol including a dosage of terlipressin surprisingly provides reversal of one or more co-morbid factors, such as vasodilation, and reduces mortality from associated complications within 90 days of initiating treatment.

[0145] Treatment of a patient can include improvement in renal function, as indicated by a reduction in SCr of at least 25% or 30% from baseline, reversal of HRS (defined as a reduction in SCr levels to ≦1.5 mg / dL), and / or confirmed reversal of HRS (defined as two serum creatinine values ​​≦1.5 mg / dL at least 48 hours apart).

[0146] In one or more embodiments, the patient is alive 90 days after initiation of terlipressin treatment. For example, a patient who experiences a reversal of HRS, a verified reversal of HRS, and / or an improvement in SCr of greater than 30% after receiving terlipressin may have at least a 60%, 65%, or 70% chance of being alive at 90 days. In other embodiments, the patient is alive 90 days after liver transplantation after initiation of terlipressin treatment. For example, a patient who experiences a reversal of HRS, a verified reversal of HRS, and / or an improvement in SCr of greater than 30% after receiving terlipressin may have at least a 35%, 40%, or 45% chance of being alive at 90 days.

[0147] In various embodiments, adult patients with HRS-1 are also SIRS positive. In one or more embodiments, patients with uncontrolled infection, sepsis, or septic shock are excluded from terlipressin treatment.

[0148] In one or more embodiments, the patient is also given up to 100 g of albumin per day for each day the patient is treated with terlipressin. In some instances, the patient may continue to receive albumin after terlipressin is discontinued.

[0149] The percentage of patients who can achieve a verified reversal of HRS can be significantly higher with terlipressin than with placebo. In some instances, patients receiving terlipressin can achieve two consecutive SCr values ​​of 1.5 mg / dL or less at least two hours apart while receiving treatment by day 14 or discharge. This indicates a robust and clinically significant improvement in renal function. In additional instances, patients receiving terlipressin can achieve the absence of renal replacement therapy (RRT) for at least 10 days, which highlights the durability of this improvement in renal function. The durability of HRS reversal with terlipressin can also persist until at least day 30 without the need for RRT. In other instances, patients receiving terlipressin can achieve at least 10 days of survival, which establishes the effect of treatment on the primary clinical outcome of early survival. Terlipressin can be superior to placebo in inducing a response across all levels of baseline SCr, with response rates to terlipressin being inversely related to baseline SCr.

[0150] Renal replacement therapy poses particular challenges for patients with acute exacerbations of HRS-1 and advanced chronic liver failure, and the lower rate of RRT and longer survival without RRT in the terlipressin group are clinically relevant. Because post-transplant RRT is a significant predictor of post-transplant morbidity with worsening graft survival and resource utilization, the marked reduction in the need for RRT extending into the post-transplant period in the terlipressin group has important clinical implications.

[0151] In a further aspect of the disclosure, a method of increasing survival in a patient with HRS-1 and low MAP comprises administering an effective dose of terlipressin to a patient in need thereof by intravenous (IV) bolus injection over about 2 minutes about every 6 hours, the dose being sufficient to result in an increase in MAP and a decrease in heart rate in the patient.

[0152] In another embodiment of the disclosure, a method of increasing survival of a patient with HRS-1 includes administering an effective dose of terlipressin to a patient in need thereof by intravenous (IV) bolus injection over about 2 minutes about every 6 hours, the dose being sufficient to cause an increase in diastolic, systolic, and MAP, and a decrease in heart rate in the patient. In a further embodiment of the disclosure, a method of increasing survival of a patient with HRS-1 includes administering an effective dose of about 0.5 mg to about 2 mg of terlipressin acetate to a patient in need thereof by intravenous (IV) bolus injection over about 1 to 5 minutes about every 4 to 10 hours, the dose being sufficient to cause an increase in MAP and a decrease in heart rate in the patient.

[0153] Terlipressin may cause adverse effects generally consistent with its mechanism of action (MOA) and class effect that may increase the risk of certain serious adverse events. Patient selection is very important when using terlipressin. Efficacy and safety outcomes in patients with serum creatinine ≥ 5 mg / dL and / or Model for End-Stage Liver Disease (MELD) score ≥ 35 at the time of starting terlipressin may be turning points for clinical outcomes. For example, SCr ≥ 5 mg / dL, MELD score ≥ 35, and / or Acute Exacerbation of Chronic Liver Failure (ACLF) grade ≥ 3 may be thresholds for advanced disease symptoms, decreased renal function response, and increased adverse events. Clinicians may consider avoiding terlipressin in delayed HRS-1 or advanced acute exacerbation of chronic liver failure if the likelihood of benefit is low. Use of terlipressin in patients with SCr ≥ 5 mg / dL may only be considered if the expected benefit to the patient outweighs the potential risks. In other embodiments, the use of terlipressin in patients with at least about SCr ≧ 5 mg / dL may be considered only if the expected benefits to the patient outweigh the potential risks. Adverse events may include ischemia or respiratory symptoms that may lead to severe or fatal outcomes. For example, one of the possible respiratory symptoms is severe respiratory failure, which may be a major safety concern. In one embodiment, the risk of respiratory failure may not be reliably predicted and managed. There may be multiple potential causes of respiratory failure. Other adverse events may be ischemia, pneumonia, or sepsis without a clear mechanism. Fluid overload and the associated risk of albumin use may complicate the clinical presentation and management of the event.

[0154] The management of adverse events, side effects, and undesirable symptoms of the present invention may include various mitigation strategies. In one embodiment, the method of the present invention includes a mitigation strategy of actively managing fluid overload during therapy. Actively managing fluid overload may include reducing or ceasing administration of albumin, other fluids, and / or judicious use of diuretics. For clarity, reducing administration of albumin may include lowering the dose or discontinuing a dose of albumin. If fluid overload persists, the method of treating may further include reducing or ceasing terlipressin therapy. Management of fluid overload by reducing or ceasing administration of albumin, other fluids, and / or judicious use of diuretics may also occur when the patient also has respiratory failure, severe renal disease, pulmonary edema, dyspnea, tachypnea, ischemia, or a combination thereof.

[0155] Aggressively managing fluid overload can include, for example, modifying the terlipressin dose if symptoms persist. Aggressively managing fluid overload can also include reducing the terlipressin dose, interrupting dosing, or ceasing dosing (i.e., ceasing treatment) if symptoms, side effects, or adverse events persist. In another embodiment, the method of the present invention includes a mitigation strategy of monitoring oxygen saturation during therapy. By monitoring oxygen saturation via pulse oximetry, patients at risk of developing serious adverse respiratory events can be identified.

[0156] Patients with acute exacerbation of chronic liver failure (ACLF) grade ≧3 and / or serum creatinine ≧5 mg / dl treated according to the presently claimed invention may be at significant risk of severe or fatal respiratory failure. In one embodiment, the mitigation strategy may be to stop or discontinue treatment in patients with serum creatinine ≧5 mg / dl or patients with ACLF grade ≧3. Another mitigation strategy in the present invention is to stop or discontinue treatment in patients with hepatic encephalopathy score ≧3. Another mitigation strategy used in the present invention is to exclude patients with serum creatinine ≧5 mg / dl or hepatic encephalopathy score ≧3, and / or ACLF grade ≧3 from treatment (i.e., exclusion criteria). In other words, the present invention also includes embodiments in which only patients are treated if they have serum creatinine <5 mg / dl, or hepatic encephalopathy score <3, and / or ACLF grade <3 (i.e., inclusion criteria). In some embodiments, terlipressin may be administered to patients with serum creatinine below a critical or threshold level. In some instances, the critical or threshold level may be about 5 mg / dl. In at least one instance, terlipressin may be administered to a patient if the patient has a serum creatinine level of <5 mg / dl.

[0157] In some embodiments, the duration of terlipressin treatment may be about 6 to about 7 days in patients with SCr<5 mg / dL compared to about 6 to about 11 days in patients with SCr>5 mg / dL treated with terlipressin. There may be no significant differences between groups in the proportion of patients receiving antibiotics or albumin.

[0158] In additional embodiments, patients with serum creatinine levels of <5 mg / dl and administered a dose of terlipressin may have a reduced likelihood of adverse events, increased overall survival, reduced overall ICU, non-ICU, or hospital stays, increased likelihood of a complete response, and / or increased likelihood of a partial response compared to patients with serum creatinine levels of ≥5 mg / dl administered terlipressin. A complete response may be when the patient's SCr level decreases to ≤1.5 mg / dl. In some instances, terlipressin may continue to be administered to the patient until the patient's serum creatinine level is ≤1.5 mg / dl. In other instances, terlipressin may continue to be administered to the patient up to 24 hours after two consecutive measured SCr levels of ≤1.5 mg / dl, at least two hours apart. A partial response may be when the patient's SCr level decreases by ≥20%, or preferably ≥30%, but is >1.5 mg / dL. In an example, terlipressin may continue to be administered to a patient until the patient's serum creatinine level improves by more than 20%.

[0159] A higher SCr may be associated with lower efficacy in patients with HRS-1. For example, patients with SCr > 5 mg / dL may be significantly more likely to develop adverse events when administered terlipressin compared to patients with SCr < 5 mg / dL. In some examples, a complete response may be achieved in about 50% to about 60% of patients with SCr < 5 mg / dL compared to about 10% to about 20% of patients with SCr > 5 mg / dL when administered terlipressin. In other examples, a partial response may be achieved in about 50% to about 60% of patients with SCr < 5 mg / dL compared to about 15% to about 25% of patients with SCr > 5 mg / dL when administered terlipressin. In additional examples, patients with SCr > 5 mg / dL may be more likely to develop fluid overload or pulmonary edema (about 20% to about 30%) and multiple organ failure (about 25% to about 35%) when administered terlipressin, compared to patients with SCr < 5 mg / dL (about 10% to about 20% and about 5% to about 10%, respectively). Overall survival may be significantly better in patients with SCr < 5 mg / dL than in patients with SCr > 5 mg / dL when administered terlipressin. In further examples, patients with SCr < 5 may have a significantly shorter ICU stay of about 0.5 to about 1.5 days when administered terlipressin, compared to about 5 to about 10 days for patients with SCr > 5 mg / dL. In yet a further example, a patient with an SCr<5 may have a significantly shorter non-ICU stay of about 20 to about 25 days when administered terlipressin, compared to about 30 to about 40 days for a patient with an SCr>=5 mg / dL. In yet a further example, a patient with an SCr<5 may have a significantly shorter total hospital stay of about 20 to about 25 days when administered terlipressin, compared to about 40 to about 45 days for a patient with an SCr>=5 mg / dL.

[0160] A further mitigation strategy in the present invention is to stabilize patients with respiratory events. Among other factors, the present invention may further include managing fluid overload and pneumonia before treatment. Mitigation strategies that may be used as part of the present invention may result in reduced adverse events, reduced risk of death, reduced incidence of mortality, and combinations thereof. Reduced risk of death or reduced incidence of mortality may include overall survival (e.g., measured as survival 90 days after initiation of treatment).

[0161] Higher baseline MELD score may be associated with lower efficacy (e.g., lower survival) in patients with HRS-1.For example, patients with a baseline MELD score of more than 35 may be significantly more likely to develop adverse events when administered terlipressin compared with patients with a baseline MELD score of less than 35.If a patient is listed for liver transplantation with a MELD score of ≥ 35, the patient may be excluded from treatment.

[0162] In some embodiments, provided herein are methods of treating patients with HRS-1 by administering a dose of terlipressin to the patient by IV injection if the patient has a baseline Model for End-Stage Liver Disease (MELD) score of less than 35. In some examples, the patient is listed for transplant at baseline and has a baseline MELD < 35. In other examples, the patient is not listed for transplant at baseline and has a MELD score < 35 or ≧ 35. Administration of terlipressin to this subset of patients may result in an increase in overall patient survival, a decrease in the patient's overall ICU or hospital stay, an increase in the patient's complete response, and / or an increase in the patient's partial response. In some embodiments, overall survival at day 90 of patients with a baseline MELD score < 35 treated with terlipressin may be increased by about 5% to 50%, about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50% compared to placebo and / or compared to patients with a baseline MELD score > 35 treated with terlipressin. In some embodiments, transplant-free survival at day 90 of patients with a baseline MELD score < 35 treated with terlipressin may be increased by about 5% to 50%, about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50% compared to placebo and / or compared to patients with a baseline MELD score > 35 treated with terlipressin.

[0163] In some embodiments, patients with a MELD score <35 may also have severe renal disease, pulmonary edema, dyspnea, or a combination thereof.

[0164] The method may further include obtaining a baseline MELD score for the patient, obtaining a serum creatinine (SCr) level for the patient prior to administering a dose of terlipressin to determine a baseline SCr level, and / or determining an Acute on Chronic Liver Failure (ACLF) grade for the patient. In some embodiments, terlipressin may not be administered if the baseline SCr is > 5 mg / dl and / or the ACLF grade is > 3. In other embodiments, the method may include discontinuing or reducing the dose of terlipressin in patients with an SCr > 5 mg / dl and / or an ACLF grade > 3. In further embodiments, a dose of terlipressin may be administered to a patient if the patient has a baseline MELD score < 35 and a baseline SCr level < 5 mg / dl. Patients with a baseline MELD score less than 35 may be further monitored for SCr levels greater than 5 mg / dl and / or an ACLF grade of 3 or greater for discontinuation of terlipressin administration. In some instances, the patient is listed for transplant at baseline and has a baseline MELD < 35. In other instances, the patient is not listed for transplant at baseline and has a MELD score < 35 or ≧ 35.

[0165] In some embodiments, administering terlipressin to a patient with a baseline MELD score of <35 may reduce the patient's risk of death (i.e., increase survival). A patient may be listed for transplant and have a MELD score of <35. In embodiments, treating a patient on the transplant list at baseline with a baseline MELD score of <35 may further help keep the patient's place on the transplant list intact. In some embodiments, a patient may have a reduced risk of having their place on the transplant list compromised or affected by administration of terlipressin.

[0166] Only patients who are actively listed for transplantation can receive available organs. Their waiting time from being listed to receiving a liver transplant depends on other factors (i.e. MELD score, geographic region, blood type) and can vary from a few days to several months based on their MELD score. By excluding patients who are likely to receive a transplant during or immediately after terlipressin treatment, the risk of such patients not receiving a transplant due to any adverse effects of terlipressin therapy, such as respiratory failure, can be reduced. This also prioritizes patients who are at the highest risk of dying while waiting for a liver, thus directing livers to those who need them most.

[0167] For example, a patient on the transplant list with a MELD score of ≧35 may be high on the transplant list and therefore may have a faster treatment time by waiting for a liver transplant rather than being treated with terlipressin. Thus, not treating a patient listed for liver transplant with a baseline MELD score ≧35 may allow the patient to maintain a place on the transplant list and receive a transplant sooner than if they were initially treated with terlipressin. In at least one embodiment, the patient may be treated only if the patient belongs to a patient population with a median waiting time from listing to transplant of about 5.6 months or more. In another embodiment, the patient may be excluded from treatment if the patient belongs to a patient population with a median waiting time from listing to transplant of 0.23 months (about 7 days) or less. In additional embodiments, the overall duration of the patient's ICU stay, non-ICU stay, and / or hospital stay may be shortened due to the patient having a baseline MELD score <35, a baseline SCr level <5 mg / dl, and / or an SCLF grade <3.

[0168] In some embodiments, terlipressin administration is continued until there is a complete or partial response. In some embodiments, terlipressin administration is discontinued or the dose is reduced in patients with respiratory failure. For example, administering terlipressin to a patient with a baseline MELD score of <35 may reduce the likelihood that the patient has respiratory failure compared to a patient with a baseline MELD score of ≧35.

[0169] The administered dose of terlipressin may be 0.5 mg to about 2 mg of terlipressin acetate and may be administered by IV bolus injection over about 1 to 5 minutes every 4 to 10 hours. In at least one example, terlipressin may be administered by IV bolus injection over 2 minutes every 6 hours.

[0170] In some embodiments, the method may further include monitoring the patient's oxygen saturation during treatment with terlipressin. Monitoring oxygen saturation may reduce the occurrence of adverse events. For example, a method of treating a patient with HRS may include obtaining a baseline oxygenation level (SpO2) via pulse oximetry, administering a dose of terlipressin to the patient by IV injection if the patient is not experiencing hypoxia, and monitoring the patient's SpO2 during treatment with terlipressin. The patient's SpO2 may be obtained at baseline before the first dose of terlipressin and then monitored at least three times a day, at least four times a day, at least five times a day, at least six times a day, or continuously during administration of terlipressin. The patient's oxygen saturation (SpO2) may be monitored for hypoxia. An SpO2 value of <90% may indicate some degree of hypoxia. The fraction of inspired oxygen (FiO2) may also be monitored as an index of pulmonary function. In an example, an FiO2 > 0.36 can be an indicator of impaired pulmonary function. In an embodiment, the method can further include ceasing administration of or reducing the dose of terlipressin if hypoxia is detected.

[0171] In additional embodiments, the method may further include monitoring the patient for fluid overload during treatment with terlipressin. If fluid overload occurs, the terlipressin dose may then be reduced or discontinued. If fluid overload occurs, a diuretic may also be administered to the patient.

[0172] In embodiments, the method may further include measuring SCr levels in the patient during administration of terlipressin. Administration may then be continued until the patient's SCr level is ≦1.5 mg / dl or until the patient experiences a greater than 20% improvement in SCr. In some instances, administration is continued until the patient experiences a greater than 30% improvement in serum creatinine.

[0173] Also provided herein is a method of treating patients with HRS-1 by narrowing the population of patients eligible for treatment to a de-escalated population, reducing the risk selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof, and then administering a dose of terlipressin to the de-escalated population of patients by IV injection. The de-escalated population excludes patients listed for transplant at baseline with baseline ACLF grade 3, baseline serum creatinine > 5 mg / dL, and / or baseline MELD > 35. It was surprising that this de-escalated population had improved survival, reduced incidence of respiratory failure, and reduced pre-transplant mortality compared to the full population treated with terlipressin. Treating HRS-1 patients who are listed for transplant at baseline with baseline ACLF grade 0-2, baseline SCr < 5 mg / dL, and / or baseline MELD < 35 may beneficially impact the occurrence of liver transplantation and minimize the risk that patients listed for liver transplantation are prevented from undergoing transplantation due to potential adverse effects of terlipressin.

[0174] Treating this subset of HRS patients (e.g., the attenuated population) results in a higher rate of verified HRS reversal with terlipressin, a lower incidence of renal replacement therapy (RRT), and beneficial RRT-free survival compared to placebo. For example, this subset of treated patients may have reduced risks compared to the overall population, including a lower incidence of respiratory failure, overall mortality, and pre-transplant mortality. In some embodiments, overall patient survival, verified HRS reversal, HRS reversal, persistence of HRS reversal, HRS reversal in SIRS subgroups, and / or verified HRS reversal without recurrence of HRS by day 30 in the attenuated population treated with terlipressin may be increased by about 5% to 50%, including about 5% to 15%, about 10% to 20%, about 25% to 35%, or about 30% to 40%, compared to the overall population treated with terlipressin. In other embodiments, overall patient survival, verified reversal of HRS, reversal of HRS, persistence of reversal of HRS, reversal of HRS in SIRS subgroups, and / or verified reversal of HRS without recurrence of HRS by day 30 in the attenuated population treated with terlipressin may be increased by about 5% to 100%, including about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, about 40% to 50%, about 50% to 60%, about 60% to 70%, about 70% to 80%, about 80% to 90%, or 90% to 100%, compared to the overall population or the attenuated population given placebo. In additional embodiments, the incidence of RRT for patients surviving by day 90 may be reduced by about 5%-50%, about 5%-15%, about 10%-20%, about 25%-35%, about 30%-40%, about 35%-45%, or about 40%-50% for patients in the attenuated population treated with terlipressin compared to the full population or attenuated population given placebo. In various embodiments, patients in the attenuated population treated with terlipressin may have an increased likelihood of survival without RRT by day 14, day 30, or day 60 compared to patients in the full population treated with terlipressin.For example, patients in the attenuated population treated with terlipressin may have about a 2% to about 20%, about a 5% to 15%, or about a 10% to 20% increase in the likelihood of survival without RRT by day 14, day 30, or day 60 compared to patients in the full population treated with terlipressin. In further embodiments, patients in the attenuated population treated with terlipressin may have an increase in the likelihood of survival without RRT by day 14, day 30, day 60, or day 90 compared to the full population or attenuated population given a placebo. For example, patients in the attenuated population treated with terlipressin may have about a 2% to about 40%, about a 5% to 10%, about a 10% to 20%, about a 20% to 30%, or about a 30% to 40% increase in the likelihood of survival without RRT by day 14, day 30, day 60, or day 90 compared to the full population or attenuated population given a placebo. EXAMPLES

[0175] Example 1: A randomized, placebo-controlled, double-blind study ("REVERSE") was conducted to evaluate the efficacy of terlipressin in type 1 HRS. The purpose of the study was to determine the efficacy and safety of intravenous terlipressin compared with placebo in the treatment of adult patients with type 1 HRS receiving intravenous albumin. Men and women aged 18 years or older with cirrhosis, ascites, and a diagnosis of type 1 HRS based on the 2007 International Club of Ascites (ICA) diagnostic criteria (Salerno F, Gerbes A, Gines P, Wong F, Arroyo V., Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Gut. 2007;56:1310-1318) were eligible to participate. Patients with SCr levels >2.5 mg / dL and either a doubling of SCr within 2 weeks or a change in SCr level over time showing a trajectory with a slope equal to or greater than a doubling within 2 weeks were enrolled.

[0176] The exclusion criteria were intended to generate a patient sample limited to individuals with functional renal impairment secondary to cirrhosis and ascites, who could safely receive terlipressin, and who could be expected to survive throughout the active study period. Among the original exclusion criteria was that of patients with systemic inflammatory response syndrome (SIRS), defined as the presence of two or more of the following findings: (1) temperature >38°C or <36°C, (2) heart rate >90 / min, (3) respiratory rate >20 / min or PaCO2 <32 mmHg, (4) white blood cell count >12,000 cells / μL or <4,000 / gL. This was based on concerns about enrolling patients with uncontrolled infections. However, it has also been recognized that patients with decompensated liver disease often have SIRS criteria in the presence of uncontrolled infection or sepsis, and the presence of two or more SIRS criteria is associated with a poor prognosis (Thabut, et al., “Model for End-Stage Liver Disease Score and Systemic Inflammatory Response Are Major Prognostic Factors in Patients with Cirrhosis and Acute Functional Renal Failure,” HEPATOLOGY, Vol. 46, No. 6, December 2007, pp. 1872-1882). Furthermore, the IAC criteria for the definition of type 1 HRS allow patients with ongoing bacterial infection (as opposed to infection-related renal dysfunction) but no sepsis or uncontrolled infection to be considered to have type 1 HRS (Salerno F, Gerbes A, Gines P, Wong F, Arroyo V., Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Gut. 2007;56:1310-1318). The study protocol required 2 days of anti-infective therapy for documented or suspected infections and allowed enrollment if any SIRS criteria were most likely explained by underlying hepatic decompensation or other non-infectious clinical circumstances.Patients with overt sepsis, septic shock, or uncontrolled infection were excluded. This approach appeared to minimize the possibility of enrolling patients at high risk for serious infection while not unduly restricting enrollment of subjects with type 1 HRS.

[0177] Patients clinically selected for treatment fulfilled the criteria for type 1 HRS, and the ICA criteria for type 1 HRS allow patients with ongoing bacterial infection but no sepsis to be considered as having type 1 HRS, as opposed to infection-related renal dysfunction. If patients remained with overt symptoms of uncontrolled infection despite antibiotic treatment, the diagnosis of HRS was not made.

[0178] During the active study period, treatment with the blinded study drug continued until at least two SCr values ​​less than 1.5 mg / dL were obtained at least 48 hours apart, or for a maximum of 14 days. The treatment period was extended up to 15 or 16 days if reversal of HRS was first achieved on days 13 or 14, respectively. Patients in the active treatment group received terlipressin 1 mg intravenously every 6 hours as a slow bolus injection over 2 minutes. Criteria for dose escalation, study discontinuation, treatment resumption, and treatment completion during the active study period were provided. The dosing regimen for patients in the placebo (6 mL lyophilized mannitol solution) group was identical to the terlipressin regimen. The follow-up period began after the end of study treatment and ended 90 days after the start of study treatment. Survival, renal replacement therapy, and transplantation were assessed.

[0179] The SIRS subgroup of patients in this study was defined as any subject with two or more of three criteria available from the research database, including: (1) WBC<4 or >12 cells / μL, (2) HR>90 bpm, and (3) HCO3<21 mmol / L. The latter criterion represented an approximation of the SIRS-criterion PaCO2 of <32 mmHg. This approximation was derived from the observed HCO3 in subjects with HRS for whom PaCO2 values ​​were available, and the calculated HCO3 in subjects with decompensated liver disease and a PaCO2 of <32 mmHg. The non-SIRS subgroup was defined as subjects with fewer than two of the above criteria. Terlipressin responses were analyzed in the SIRS and non-SIRS subgroups to determine whether the SIRS condition had any effect on terlipressin efficacy.

[0180] A total of 196 patients were enrolled in this study. Of the 196 patients enrolled, 58 were initially identified as having two or more SIRS criteria, including WBC <4 or >12 cells / μL, HR >90 bpm, and HCO3 <21 mmol / L, and this population was identified as the SIRS subgroup. Based on the criteria defining the SIRS subgroups, baseline WBC and heart rate were slightly higher and bicarbonate slightly lower in the SIRS subgroup compared to the non-SIRS and total study populations. The analysis results are shown in Figure 3.

[0181] It has also been recognized that patients with decompensated liver disease, often in the presence of uncontrolled infection or sepsis, have SIRS criteria, and the presence of two or more SIRS criteria is associated with a poor prognosis.

[0182] In one or more embodiments, reversal of HRS is indicated by a decrease in SCr levels to ≦1.5 mg / dl, with confirmed reversal of HRS defined as two SCr values ​​≦1.5 mg / dL at least 48 hours apart.

[0183] As shown in Figure 3, patients identified as having at least two of the three criteria for HRS-1 and SIRS on the terlipressin treatment protocol showed a statistically significant increase in confirmed reversal of HRS (32.1% vs. 3.3%, p<0.005), reversal of HRS (42.9% vs. 6.7%, p<0.002), and renal function (change from baseline in SCr, mg / dL, -1.7 vs. -0.5, p<0.0001) compared to placebo. In contrast, in the group of patients with less than two of the HRS-1 and SIRS criteria, the confirmed reversal of HRS vs. placebo was 14.5% vs. 17.4%, the reversal of HRS vs. placebo was 15.9% vs. 18.8%, and the change in renal function vs. placebo was -0.8 vs. -0.7 mg / dL. These results indicate that the presence of two or more of the SIRS criteria indicates that a patient is more likely to have a positive response to treatment with terlipressin.

[0184] In addition, in the treatment group, patients with HRS-1 and two or more SIRS criteria had similar overall survival rates as patients with HRS-1 but without at least two of the three SIRS criteria (57.1% vs. 58%).

[0185] Example 2: A randomized, placebo-controlled, double-blind study ("CONFIRM") was conducted to evaluate the efficacy of terlipressin in HRS type 1. The purpose of the study was to characterize the efficacy and safety of terlipressin plus albumin versus albumin alone for the treatment of HRS-1 in patients with well-defined HRS-1. The study used inclusion and exclusion criteria similar to those described in Example 1.

[0186] Specifically, HRS-1 was defined as rapidly worsening renal function to SCr ≥ 2.25 mg / dL with actual or predicted doubling of SCr within 2 weeks without improvement in renal function (< 20% decrease in SCr after both diuretic withdrawal and albumin fluid challenge 48 hours) in adult patients with cirrhosis and ascites based on modified a priori criteria outlined by the International Club of Ascites (ICA). Subjects were randomized 2:1 to terlipressin (1 mg IV every 6 hours) or placebo, plus albumin, in both groups. Treatment was continued through day 14 unless the following occurred: verified HRS reversal (VHRSR), renal replacement therapy (RRT), liver transplantation (LT), or SCr at or above baseline (BL) on day 4. The primary endpoint, VHRSR, was defined as two consecutive SCr values ​​≦1.5 mg / dL at least 2 hours apart with subjects surviving without RRT for at least 10 days after the second SCr ≦1.5 mg / dL, and reversal of HRS (HRSR) was a decrease in SCr to ≦1.5 mg / dL. Secondary endpoints included reversal of HRS (any on-treatment SCr value ≦1.5 mg / dL), reversal of HRS without RRT by day 30, reversal of HRS in patients with systemic inflammatory response syndrome, and verified reversal of HRS without recurrence by day 30.

[0187] Patients were at least 18 years old, had cirrhosis, ascites, and rapidly progressive renal failure, and had a doubling of SCr to at least 2.25 mg / dL within 14 days. Major exclusion criteria included SCr >7.0 mg / dL, one or more large volume paracentesis of 4 L or more within 2 days of randomization, evidence of parenchymal renal disease or obstructive uropathy, or the presence of sepsis and / or uncontrolled bacterial infection. Patients with severe cardiovascular disease or recent (within 4 weeks) renal replacement therapy (RRT) were excluded.

[0188] The study enrolled 300 subjects. Of the 300 subjects, 199 were randomized to terlipressin and 101 to placebo (albumin only). Patients were stratified by eligibility for SCr (<3.4 mg / dL or ≥3.4 mg / dL) and large volume paracentesis before enrollment (at least one single event of ≥4 L or <4 L within 3–14 days before randomization). Concomitant albumin was administered to 82.9% of patients in the terlipressin group (165 of 199, mean [SD] total dose of 199.4 [146.8] g) versus 91.1% in the placebo group (92 of 101, mean [SD] dose of 239.5 [183.6] g) (P = .06). One hundred and forty-five patients (72.9%) in the terlipressin group and 72 (71.3%) in the placebo group had previously received midodrine and octreotide.

[0189] Demographic and BL clinical characteristics were similar between treatment groups. For example, the two treatment groups had similar mean age, weight, height, gender distribution, ethnicity distribution, racial distribution, presence of alcoholic hepatitis, baseline serum creatinine, large volume paracentesis (LVP) randomization strata, baseline Model for End-Stage Liver Disease (MELD) score, baseline Child-Pugh score, baseline white blood cell count, baseline bilirubin, baseline mean arterial pressure (MAP), baseline heart rate, baseline blood urea nitrogen (BUN), baseline bicarbonate (HCO3) or carbon dioxide (CO2), baseline temperature, baseline respiratory rate, baseline Acute Chronic Liver Failure (ACLF) grade, baseline Chronic Liver Failure-Sepsis Organ Failure Assessment (CLIF-SOFA) score, and presence of prior conditions / treatments such as esophageal variceal bleeding (EVH) banding, pneumonia, urinary tract infection (UTI), spontaneous bacterial peritonitis (SBP), and receipt of albumin. The percentage of patients in each group who received LT was 23.1% for terlipressin and 28.7% for placebo.

[0190] Baseline SCr values ​​were assessed before patients received their assigned treatment. Patients received 1 mg of the blinded assigned treatment (terlipressin or placebo) administered intravenously over 2 minutes every 6 hours (± 30 minutes). In line with current guidelines, it was strongly recommended that all subjects receive albumin (1 g / kg to a maximum of 100 g on day 1, and 20–40 g / day thereafter). If SCr decreased <30% from baseline values ​​on day 4, after at least 10 doses of study drug, a dose increase to 2 mg (8 mg / day) every 6 hours (± 30 minutes) was mandatory, except for subjects with coronary artery disease or in the setting of circulatory overload, pulmonary edema, or bronchospasm. Dose resumption was permitted after discontinuation of an adverse event, except for cardiac or mesenteric ischemia, in which treatment was permanently discontinued.

[0191] The primary efficacy endpoint was the incidence of verified HRS reversal, defined as the proportion of patients who survived RRT-free for at least 10 days after achieving verified HRS reversal and had two consecutive SCr values ​​≤1.5 mg / dL at least 2 hours apart, excluding post-RRT SCr values, transjugular intrahepatic portosystemic shunting, liver transplantation, or open-label vascular compression from the primary endpoint analysis. Fifty-eight patients (29.1%) treated with terlipressin achieved verified HRS reversal compared with 16 (15.8%) treated with placebo (P=0.01).

[0192] Secondary efficacy endpoints included the incidence of HRS reversal defined as the percentage of patients with on-treatment SCr values ​​of 1.5 mg / dL or less, durability of HRS reversal defined as the percentage of patients with RRT-free HRS reversal by day 30, incidence of HRS reversal among patients with systemic inflammatory response syndrome, and incidence of verified HRS reversal without HRS recurrence by day 30. 36.2% of patients treated with terlipressin achieved HRS reversal versus 16.8% treated with placebo (P<0.001). 31.7% of patients treated with terlipressin achieved HRS reversal without RRT by day 30 versus 15.8% treated with placebo (P=0.003). The reduction in the need for RRT with terlipressin appeared to extend into the post-liver transplant period, with only 9 of 46 patients (19.6%) requiring post-transplant RRT, a significantly lower number than observed in the placebo group (13 of 29 patients or 44.8%) (P=0.04). A slightly lower percentage of patients in the terlipressin group underwent liver transplantation (23.1% [46 of 199]) compared with placebo (28.7% [29 of 101]). 24.1% of patients treated with terlipressin achieved verified reversal of HRS without recurrence by day 30, compared with 15.8% treated with placebo (P=0.09).

[0193] 132 / 300 (44%) of subjects met the systemic inflammatory response syndrome (SIRS) criteria as defined in Example 1. Patients with overt sepsis, septic shock, or uncontrolled infection were excluded. In the SIRS subgroup, 84 patients were treated with terlipressin according to the protocol of Example 1 and 48 patients were given albumin alone (placebo).

[0194] Some baseline values ​​for SIRS patients treated with terlipressin or placebo are shown in Table 1 below. [Table 1]

[0195] As seen in Table 2, 33.3% of patients with SIRS and treated with terlipressin experienced reversal of HRS compared to only 6.3% of patients with SIRS given placebo. In addition, 26.2% of patients with SIRS and treated with terlipressin experienced reversal of verified HRS compared to only 4.2% of patients with SIRS given placebo. [Table 2]

[0196] Table 3 shows transplant-free survival up to 90 days for subjects with reversal of HRS and / or greater than 30% improvement in serum creatinine (SCr) compared to subjects without reversal of HRS and with 30% or less improvement in SCr in the SIRS subgroup of the intent-to-treat population. 45.5% of the terlipressin-treated SIRS subgroup with reversal of HRS and / or at least 30% improvement in SCr were alive and transplant-free at day 90 compared to 28.6% of placebo. 72.7% of the terlipressin-treated SIRS subgroup with reversal of HRS and / or at least 30% improvement in SCr were alive and transplant-free at day 90 compared to 57.1% of placebo. [Table 3]

[0197] A significantly higher proportion of subjects in the SIRS subgroup of the intention-to-treat (ITT) population achieved reversal of HRS in the terlipressin group (33.3%) than in the placebo group (6.3%). Among subjects with SIRS at baseline, the incidence of RRT was lower in the terlipressin group than in the placebo group at all follow-up time points (Table 4). The mean cumulative frequency of RRT by day 90 was 7.3 days in the terlipressin group compared with 15.2 days in the placebo group. [Table 4]

[0198] The median time to first RRT was 6.0 days in the terlipressin group and 5.5 days in the placebo group. Transplant-free survival estimates up to 90 days were higher in the terlipressin group than in the placebo group for subjects with SIRS at baseline (Table 5). [Table 5]

[0199] After day 30, overall survival estimates up to day 90 were slightly higher in the terlipressin group than in the placebo group for subjects with SIRS at baseline. For the SIRS subgroup, overall survival of subjects up to day 90 was analyzed to compare the difference between subjects who achieved verified HRS reversal or >30% improvement in serum creatinine and those who did not). For the SIRS subgroup, survival estimates were higher in responders than non-responders in both treatment groups up to day 90. RRT-free survival estimates up to day 90 were higher in the terlipressin group than in the placebo group for subjects with SIRS at baseline.

[0200] A lower percentage of subjects with SIRS at baseline in the terlipressin group were admitted to the ICU: 14 subjects (16.7%) in the terlipressin group compared with 12 subjects (25.0%) in the placebo group. Subjects with SIRS in the terlipressin group had a shorter mean length of stay in the ICU (6.3 days) than in the placebo group (12.1 days).

[0201] Applying the strict criteria defining HRS-1, this study demonstrated a significant reversal of worsening renal function in cirrhotic patients treated with terlipressin plus albumin when compared with patients treated with albumin alone, including patients with SIRS criteria. This response was durable and associated with less need for early RRT. Thus, terlipressin is effective in improving renal function and achieving reversal of HRS in patients with HRS-1 and progressive advanced liver disease.

[0202] Example 3: As seen in Figures 6A-B, the incidence of respiratory failure was increased in patients receiving terlipressin but not in patients receiving placebo. In Figure 6B, the incidence of respiratory failure was based on the CLIF-SOFA score definition of respiratory failure. Thus, this study evaluated whether the presence of severe or grade 3 ACLF according to the EASL-CLIF system at baseline was a risk factor for the development of respiratory failure with terlipressin use in patients with HRS1.

[0203] The study was a double-blind, placebo-controlled trial. Three hundred patients with HRS-1 were randomized 2:1 to receive terlipressin versus placebo, both with albumin, as an iv bolus injection of 1-2 mg every 6 hours. HRS-1 was defined as a rapid rise in serum creatinine (SCr) to ≥ 2.25 mg / dL in less than 14 days without response to volume challenge or evidence of structural renal disease.

[0204] All patients were evaluated for organ failure (OF) according to EASL-CLIF criteria and then classified into grades of acute exacerbation of chronic liver failure (ACLF). All patients had a minimum of grade 1 ACLF due to the presence of HRS-1, with grades 2 and 3 ACLF representing 2 or 3 OF, respectively. Patients were divided into grade ≦2 and grade 3 ACLF subgroups. The effect of terlipressin versus placebo on the occurrence of RF between these subgroups was compared. Table 6 shows the patient demographics and Table 7 shows the baseline clinical and laboratory parameters in the patients in the study. [Table 6] [Table 7]

[0205] FIG. 5 is a graph showing 90-day survival of patients treated with and without terlipressin according to ACLF grade. Patients with an ACLF grade of 3 and treated with terlipressin were less likely to survive than patients with an ACLF grade of 0-2 and treated with terlipressin or patients treated with placebo regardless of ACLF grade. FIG. 6C shows that the percentage of patients with respiratory failure among patients treated with terlipressin was similar to placebo among patients with ACLF grades of 0-2. The percentage of patients with respiratory failure among patients treated with terlipressin and with an ACLF score of 3 was much higher than placebo. The percentage of respiratory failure in FIG. 6C was based on investigator reporting of respiratory failure during the study.

[0206] Table 8 provides odds ratios of additional baseline parameters as predictors of respiratory failure with terlipressin use. [Table 8]

[0207] The results in Tables 4-6 indicate that terlipressin should be used with extreme caution in patients with HRS-1 and ACLF grade 3, especially in patients with compromised oxygen saturation. Patients with low baseline SpO2 are at risk for respiratory failure (RF) and increased mortality.

[0208] Example 4: The following analysis was performed to evaluate the impact of the proposed de-escalation strategy on the incidence of liver transplantation and pre-transplant mortality in subjects listed at baseline in two previous terlipressin studies (REVERSE [Example 1] and CONFIRM [Example 2]). The de-escalated population excludes data from subjects with baseline acute exacerbation of chronic liver failure grade 3 and baseline serum creatinine > 5 mg / dL, and subjects listed for transplant at baseline with baseline MELD > 35.

[0209] The incidence of liver transplantation in the terlipressin group was lower compared with placebo (23.1% vs. 28.7%) in the intent-to-treat (ITT) population, whereas the incidence of liver transplantation by day 90 in the attenuated population in CONFIRM was slightly higher in the terlipressin group compared with placebo (24.2% vs. 22.5%) (Table 9). [Table 9]

[0210] Similarly, the incidence of subjects listed at baseline who did not undergo transplantation and died by day 90 was substantially reduced from 21.4% (12 subjects) in the total population to 11.4% (4 subjects) in the attenuated population. Of the 12 subjects listed at baseline in the total population who did not undergo transplantation and died by day 90, 6 subjects were attenuated by excluding data for subjects with ACLF-3 and SCr ≥ 5 mg / dL, and an additional 2 subjects were attenuated by the MELD ≥ 35 cutoff criteria (Table 10). A similar effect of the attenuation strategy in the terlipressin group was observed in the REVERSE study. [Table 10]

[0211] Due to the limited number of donor organs available in the United States, only about half of all subjects on the waiting list in 2018 received a liver within a year, and many patients died without receiving a transplant or were removed from the waiting list (Kwong 2021). For example, 11.3% of all patients listed for liver transplant in 2016 died before receiving a transplant (Kwong 2021), and the 90-day pre-transplant mortality rate was 10.5% overall and 25.7% in patients with a MELD score of ≥35 (Nagai 2018).

[0212] Pretransplant mortality in the de-escalated population in the CONFIRM study and in the pooled data set of the CONFIRM and REVERSE studies was consistent with published data for all transplant-listed patients in the U.S. Collectively, these analyses provide evidence that de-escalation strategies beneficially impact liver transplantation occurrence in patients who received terlipressin and minimize the risk that patients listed for liver transplantation will be prevented from undergoing transplantation due to potential adverse effects of terlipressin.

[0213] In the attenuated population in the CONFIRM study, there were clinically significant reductions in overall SAEs, respiratory failure SAEs, overall fatal AEs, fatal respiratory failure AEs, and overall mortality in the terlipressin group compared with the overall population, respectively (Table 11). [Table 11]

[0214] In the attenuated population in CONFIRM, clinically significant reductions were observed in overall SAEs and incidence of SAEs due to respiratory failure (Table 11). The between-group difference in incidence of SAEs due to respiratory failure in the full study population of 8.4% (13.5% to 5.1%) was reduced to 2.8% (9.8% to 7.0%) in the attenuated population. For the terlipressin group, the overall incidence of SAEs in the attenuated population was lower than the full study population without attenuation (61.4% vs. 65.0%, respectively). In the attenuated population, the overall incidence of SAEs in the terlipressin group was similar to the placebo group (61.4% vs. 59.2%, respectively).

[0215] The incidence of overall AEs leading to death, fatal respiratory failure AEs, and overall mortality was substantially reduced in the attenuated population in CONFIRM. The between-group difference in incidence of respiratory failure fatal AEs in the total population of 7.5% (8.5% to 1.0%) was reduced to 3.9% (5.3% to 1.4%) in the attenuated population. The incidence of all AEs leading to death up to 30 days after treatment in the terlipressin group in the attenuated population was lower than the total population without attenuation (31.8% vs. 39.0%, respectively) and also lower than the placebo group in the attenuated population (31.8% vs. 36.6%, respectively).

[0216] The incidence of liver transplantation by day 90 in the derated population was slightly higher in the terlipressin group compared with the placebo group (24.2% vs. 22.5%, respectively) in contrast to the overall population, where transplantation rates were lower (23.1% vs. 28.7%, respectively; Table 8). Importantly, pre-transplant mortality by day 90 among subjects listed for transplant at baseline in the terlipressin group was reduced from 21.4% in the overall population to 11.4% in the derated population (Table 10), within the range reported for all subjects listed for liver transplantation in the United States.

[0217] The benefit of terlipressin therapy on reversal of verified HRS was demonstrated in the overall CONFIRM study population and was also observed in the attenuated population (Table 12). The benefit of terlipressin versus placebo was maintained for secondary endpoints as well. The effect of the primary endpoint on the major clinical outcomes of renal replacement therapy (RRT) and RRT-free survival was also maintained. As in the overall population, in the attenuated population, the incidence of RRT was lower in the terlipressin group than in the placebo group at all time points up to day 90. [Table 12]

[0218] The attenuated population has a similar risk of receiving RRT as the total population, as evidenced by the proportion of subjects receiving RRT by up to day 90 (Table 13). In these subjects, RRT-free survival remained numerically beneficial in the terlipressin group compared to the placebo group. [Table 13]

[0219] In the full CONFIRM population, overall survival estimates up to day 90 were numerically lower in the terlipressin group than in the placebo group (48.2% vs. 53.5%, respectively). In contrast, in the attenuated population, overall survival estimates up to day 90 were similar in the terlipressin group compared with the placebo group (55.3% vs. 54.9%, respectively).

[0220] The risk mitigation strategy maintained the beneficial effects of terlipressin as demonstrated in the full CONFIRM study population (i.e., statistical significance of the primary endpoint, lower incidence of RRT, and beneficial RRT-free survival with terlipressin compared to placebo). There was also a clinically significant risk reduction in the mitigated population compared to the full population, including lower incidence of respiratory failure, overall mortality, and pre-transplant mortality. Thus, the mitigated population represents a population in which the benefits of terlipressin treatment outweigh the risks in this rare complication of liver disease associated with high medical need and the lack of current FDA-approved or proven pharmacological treatments.

[0221] Although the disclosure herein has been described with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made to the disclosed devices, systems, and methods without departing from the spirit and scope of the disclosure. Thus, the disclosure is intended to cover modifications and variations that come within the scope of the appended claims and their equivalents.

[0222] References throughout this specification to "one embodiment," "a particular embodiment," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment may be included in at least one embodiment of the disclosure. Thus, the appearances of phrases such as "in one or more embodiments," "in a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

Claims

1. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient has a baseline Model for End-Stage Liver Disease (MELD) score of less than 35; and discontinuing or reducing the dose of terlipressin in patients with serum creatinine (SCr) > 5 mg / dl and / or acute-on-chronic liver failure (ACLF) grade > 3.

2. The composition described in claim 1, wherein the method further comprises obtaining the baseline MELD score for the patient.

3. The composition described in claim 1, wherein the method further comprises obtaining the SCr level in the patient prior to administering the dose of terlipressin to determine a baseline SCr level.

4. The composition of claim 1 , wherein the patient's risk of death is reduced.

5. The composition of claim 1 , wherein the patient's position on the transplant list is not compromised.

6. 10. The composition of claim 1, wherein the patient's overall length of ICU stay, non-ICU stay, and / or hospital stay is reduced.

7. The method of claim 1, wherein terlipressin administration is continued until there is a complete or partial response.

8. 2. The composition of claim 1, wherein ceasing administration of terlipressin or reducing the dose thereof occurs in patients with respiratory failure.

9. The composition of claim 1 , wherein the patient also has severe renal disease.

10. The composition of claim 1 , wherein the patient has pulmonary edema, dyspnea, or a combination thereof.

11. 2. The composition of claim 1, wherein the terlipressin is administered by IV bolus injection over 2 minutes every 6 hours.

12. The composition of claim 1, wherein the method further comprises monitoring the patient's oxygen saturation during treatment with terlipressin.

13. The composition of claim 12, wherein said monitoring of said oxygen saturation reduces the occurrence of adverse events.

14. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: A composition comprising administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient has a baseline Model for End-Stage Liver Disease (MELD) score of less than 35.

15. The composition described in claim 14, wherein the method further comprises obtaining the baseline MELD score for the patient.

16. The composition of claim 14, wherein the method further comprises discontinuing administration of or reducing the dose of terlipressin in patients with serum creatinine (SCr) ≧5 mg / dl and / or acute exacerbation of chronic liver failure (ACLF) grade ≧3.

17. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in said patient prior to administering a dose of terlipressin to determine a baseline SCr level; administering a dose of terlipressin to the patient if the baseline MELD score is <35, the baseline SCr level is <5 mg / dl, the patient has an ACLF grade <3, or a combination thereof.

18. 20. The composition of claim 17, wherein the terlipressin is administered to the patient by intravenous (IV) injection.

19. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: administering a dose of terlipressin to a patient by intravenous (IV) injection; The composition, wherein administration occurs only if the patient has a baseline Model for End-Stage Liver Disease (MELD) score <35, the patient has a serum creatinine (SCr) <5 mg / dl, the patient has an ACLF grade <3, or a combination thereof.

20. The method of claim 20, further comprising: monitoring the patient for fluid overload during treatment with terlipressin; 20. The composition of claim 19, further comprising reducing or ceasing the terlipressin dose if fluid overload occurs.

21. The composition of claim 20, wherein the method further comprises administering a diuretic to the patient.

22. The composition described in claim 19, wherein the method further comprises measuring the SCr level in the patient.

23. 1. A composition for use in a method for increasing overall survival in a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in the patient to determine a baseline SCr level; administering a dose of terlipressin to said patient if said patient's baseline MELD score is <35 and said baseline SCr level is <5 mg / dl.

24. 1. A composition for use in a method for reducing overall ICU or hospital stay in a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in the patient to determine a baseline SCr level; administering a dose of terlipressin to said patient if said patient's baseline MELD score is <35 and said baseline SCr level is <5 mg / dl.

25. 1. A composition for use in a method for increasing complete response in a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in the patient to determine a baseline SCr level; administering to the patient a dose of terlipressin by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg / dl; measuring the SCr level in the patient during administration of terlipressin; and continuing administration of terlipressin until the patient's SCr level is ≦1.5 mg / dl.

26. 1. A composition for use in a method for increasing partial response in a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: obtaining a baseline Model for End-Stage Liver Disease (MELD) score for the patient; obtaining an SCr level in the patient to determine a baseline SCr level; administering to the patient a dose of terlipressin by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg / dl; measuring the SCr level in the patient during administration of terlipressin; and continuing the administration of terlipressin until the patient experiences a greater than 20% improvement in serum creatinine.

27. 27. The composition of claim 26, wherein the administration is continued until the patient experiences greater than a 30% improvement in serum creatinine.

28. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: A composition comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, wherein if the patient has a MELD score of > 35 and is listed for liver transplant, the patient is excluded from treatment.

29. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: A composition comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, wherein the patient is treated only if the patient belongs to a patient population in which the median waiting time from listing to transplant is 5.6 months or greater.

30. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: A composition comprising administering a dose of terlipressin to the patient by intravenous (IV) injection, wherein the patient is excluded from treatment if the patient belongs to a patient population in which the median waiting time from listing to transplant is 0.23 months or less.

31. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said method comprising: Narrowing the population of patients eligible for treatment to a reduced population to reduce a risk selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof; administering a dose of terlipressin to said patient of said attenuated population by intravenous (IV) injection.

32. 1. A composition for use in a method of administering terlipressin to treat a patient having hepatorenal syndrome type 1 (HRS-1), said composition comprising terlipressin, said patient being listed for transplant with a baseline Model End Status Liver Disease (MELD) score of less than 35, said method comprising: administering to said patient a dose of terlipressin by intravenous (IV) injection; and discontinuing administration of terlipressin or reducing the dose in patients with a serum creatinine (SCr) level of ≧5 mg / dl and / or an acute exacerbation of chronic liver failure (ACLF) grade of ≧3.

33. The composition of claim 32, wherein the method further comprises obtaining the SCr level in the patient prior to administering the dose of terlipressin to determine a baseline SCr level.

34. 33. The composition of claim 32, wherein the patient's risk of death is reduced.

35. 33. The composition of claim 32, wherein the patient's position on the transplant list is not compromised.

36. 33. The composition of claim 32, wherein the overall length of the patient's ICU stay, non-ICU stay, and / or hospital stay is reduced.

37. 33. The composition of claim 32, wherein terlipressin administration is continued until there is a complete or partial response.

38. 33. The composition of claim 32, wherein ceasing administration of terlipressin or reducing the dose thereof occurs in a patient with respiratory failure.

39. 33. The composition of claim 32, wherein the patient also has severe renal disease.

40. 33. The composition of claim 32, wherein the patient has pulmonary edema, dyspnea, or a combination thereof.

41. 33. The composition of claim 32, wherein the terlipressin is administered by IV bolus injection over 2 minutes every 6 hours.

42. The composition described in claim 32, wherein the method further comprises monitoring the patient's oxygenation levels via pulse oximetry during treatment with terlipressin.

43. 43. The composition of claim 42, wherein said monitoring of said oxygenation levels reduces the occurrence of adverse events.

44. 1. A composition for use in a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), said method comprising administering terlipressin to a subject, the method comprising: Baseline oxygenation levels (SpO ２ ) and administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient is not experiencing hypoxia; During the terlipressin treatment, the patient's SpO ２ and monitoring the composition.

45. 45. The composition of claim 44, wherein said monitoring of said oxygenation levels reduces the occurrence of adverse events.

46. 45. The composition of claim 44, wherein the patient's oxygen saturation is monitored for hypoxia.

47. The composition described in claim 46, wherein the method further comprises ceasing administration of terlipressin or reducing the dose thereof if hypoxia is detected.

48. The patient's SpO ２ is monitored at least three times daily during administration of terlipressin.

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