Use of tenapanor for the treatment or prevention of hepatic encephalopathy

Abstract

The present invention describes the treatment of hepatic encephalopathy using tenapanor or a salt thereof. The invention also describes the reduction of the likelihood of a subject developing hepatic encephalopathy by administering tenapanor or a salt thereof to the subject.

Description

USE OF TENAPANOR FOR THE TREATMENT OR PREVENTION OF HEPATIC ENCEPHALOPATHYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application includes a claim of priority under 35 U.S.C. §119(e) to U.S. provisional patent application No. 63 / 612,741, filed December 20, 2023, the entirety of which is hereby incorporated by reference.FIELD OF INVENTION

[0002] This invention relates to patients with hepatic encephalopathy. The use of tenapanor can treat and prevent the development of hepatic encephalopathy.BACKGROUND

[0003] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] Global number of prevalent cases of cirrhosis was 125 million in 2017. The prevalence of MHE is 40-60% in patients with cirrhosis. There were a total of 149,048 male and 55,970 female cases of Hepatic Encephalopathy in 2020 in the United States. A high number of undiagnosed and unreported cases contribute to the lack of awareness of hepatic encephalopathy.

[0005] Hepatic encephalopathy disrupts personality, self-reliance, and capability for everyday living. The experience of hepatic encephalopathy is highly distressing and perceived by the patient as the experience of multiple losses, such independence, social interaction, social isolation, driving in certain instances, and a sustained fear of recurrence. This, together with the disruption in mood and sleep cycle, weakening of cognitive coherence, and exacerbation of confusion status, gives rise to a serious loss in quality of life (QOL). The personality disruption also poses widespread distress, uncertainty and anxiety to caregivers, particularly those in the family.

[0006] There are limited treatment options available. Currently, the mainstay of the treatment of hepatic encephalopathy are lactulose (beta-galactosidofructose), lactitol (beta-galactosidosorbitol), as well as the second-line agents, which include oral antibiotics (rifaximin). They can promote acidification of the intestine, reduce urease-producing bacteria, and act as an osmotic laxative, resulting in decreased ammonia production and absorption through the gastrointestinal tract. However, these medications are often not accessible or tolerated by a significant proportion of the patients. Lactulose requires multiple dose administration throughout the day, has a sweet taste, causes a significant bloating sensation, and can raise serum blood glucose levels in individuals living with diabetes. Missing a dose of lactulose can also lead to exacerbation of hepatic encephalopathy at times. These reasons have mitigated the adherence to the prescription and the treatment effectiveness. Rifaximin, on the other hand, is limited by high medication costs, among other reasons.

[0007] Accordingly, there remains a need in the art for treating hepatic encephalopathy and cirrhosis.SUMMARY OF THE INVENTION

[0008] The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope.

[0009] Various embodiments provide for a method of treating hepatic encephalopathy (HE), in a subject in need thereof, comprising: administering a quantity of a tenapanor or a salt thereof to the subject.

[0010] In various embodiments, the method can further comprise identifying the subject as having HE prior to administering the quantity of tenapanor c to the subject. In various embodiments, the method can further comprise identifying the subject as having HE prior to administering the quantity of tenapanor or the salt thereof to the subject, based on the recognition that the subject the tenapanor or the salt thereof will treat HE in the subject.

[0011] In various embodiments, the subject does not have kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. In various embodiments, the subject does not have chronic kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. In various embodiments, the subject does not have irritable bowel syndrome, kidney disease, or both. In various embodiments, the subject does not have constipation predominant irritable bowel syndrome. In various embodiments, the subject does not have chronic kidney disease. In various embodiments, the subject is not on dialysis, wherein the subject is not in need of areduction in serum phosphorus, or wherein the subject is not being administered a phosphate binder.

[0012] In various embodiments, the tenapanor salt can be tenapanor hydrochloride.

[0013] In various embodiments, the quantity of tenapanor or the salt thereof can be about 2.5 mg to 100 mg. In various embodiments, the quantity of tenapanor or the salt thereof can be about 10 mg, 20 mg, 30 mg, or 50 mg. In various embodiments, the quantity of tenapanor or the salt thereof can be administered once daily, twice daily or thrice daily. In various embodiments, the quantity of tenapanor or the salt thereof can be administered twice daily.

[0014] Various embodiments provide for a method of reducing the likelihood of having hepatic encephalopathy (HE), in a subject in need thereof, comprising: administering a quantity of tenapanor or a salt thereof to the subject.

[0015] In various embodiments, the method can further comprise identifying the subject as being susceptible to having HE prior to administering the quantity of tenapanor or the salt thereof to the subject. In various embodiments, the method can further comprise identifying the subject as being susceptible to having HE prior to administering the quantity of tenapanor or the salt thereof to the subject, based on the recognition that the tenapanor or the salt thereof will reduce the likelihood of having HE in the subject.

[0016] In various embodiments, the subject does not have a history of hepatic encephalopathy (HE).

[0017] In various embodiments, the subject can have one or more prior episodes of hepatic encephalopathy (HE) and the method reduces the likelihood of additional episodes of HE. In various embodiments, the subject can have liver disfunction, acute liver disease or chronic liver disease.

[0018] In various embodiments, the subject can have gastrointestinal bleeding, infection, excessive dietary protein intake, consumption of alcohol, or combinations thereof. In various embodiments, the subject can have a transjugular intrahepatic portosystemic shunt (TIPS).

[0019] In various embodiments, the subject does not have irritable bowel syndrome, kidney disease, or both. In various embodiments, the subject does not have constipation predominant irritable bowel syndrome. In various embodiments, the subject does not have chronic kidney disease. In various embodiments, the subject does not have kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. In various embodiments, the subject does not have chronic kidney disease at commencement ofinitial treatment of HE with the quantity of tenapanor or the salt thereof. In various embodiments, the subject is not on dialysis, wherein the subject is not in need of a reduction in serum phosphorus, or wherein the subject is not being administered a phosphate binder.

[0020] In various embodiments, the tenapanor salt can be tenapanor hydrochloride.

[0021] In various embodiments, the quantity of tenapanor or the salt thereof can be about 2.5 mg to 100 mg. In various embodiments, the quantity of tenapanor or the salt thereof can be about 10 mg, 20 mg, 30 mg, or 50 mg. In various embodiments, the quantity of tenapanor or the salt thereof can be administered once daily, twice daily or thrice daily. In various embodiments, the quantity of tenapanor or the salt thereof can be administered twice daily.

[0022] Other features and advantages of the invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, various features of embodiments of the invention.DESCRIPTION OF THE INVENTION

[0023] All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 3rded., Revised, J. Wiley & Sons (New York, NY 2006); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 7thed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 4thed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012), provide one skilled in the art with a general guide to many of the terms used in the present application. For references on how to prepare antibodies, see D. Lane, Antibodies: A Laboratory Manual 2nded. (Cold Spring Harbor Press, Cold Spring Harbor NY, 2013); Kohler and Milstein, (1976) Eur. J. Immunol. 6: 511; Queen et al. U. S. Patent No. 5,585,089; and Riechmann et al., Nature 332: 323 (1988); U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); Ward et al., Nature 334:544-54 (1989); Tomlinson I. and Holliger P. (2000) Methods Enzymol, 326, 461-479; Holliger P. (2005) Nat. Biotechnol. Sep;23(9): 1126-36).

[0024] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the presentinvention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below.

[0025] As used herein the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 5% of that referenced numeric indication, unless otherwise specifically provided for herein. For example, the language “about 50%” covers the range of 45% to 55%. In various embodiments, the term “about” when used in connection with a referenced numeric indication can mean the referenced numeric indication plus or minus up to 4%, 3%, 2%, 1%, 0.5%, or 0.25% of that referenced numeric indication, if specifically provided for in the claims.

[0026] As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” when used in reference to a disease, disorder or medical condition, refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to reverse, alleviate, ameliorate, inhibit, lessen, slow down or stop the progression or severity of a symptom or condition. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disease, disorder or medical condition is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation or at least slowing of progress or worsening of symptoms that would be expected in the absence of treatment. Also, “treatment” may mean to pursue or obtain beneficial results, or lower the chances of the individual developing the condition even if the treatment is ultimately unsuccessful. Those in need of treatment include those already with the condition as well as those prone to have the condition or those in whom the condition is to be prevented. Non-limiting examples of treatments or therapeutic treatments include at least one selected from pharmacological therapies, biological therapies, interventional surgical treatments, and combinations thereof.

[0027] “Beneficial results” or “desired results” may include, but are in no way limited to, lessening or alleviating the severity of the disease or condition, preventing the disease or condition from worsening, curing the disease or condition, preventing the disease or condition from developing, lowering the chances of a patient developing the disease or condition, decreasing morbidity and mortality, and prolonging a patient’s life or life expectancy. As nonlimiting examples, “beneficial results” or “desired results” may be alleviation of one or more symptom(s), diminishment of extent of the deficit, stabilized (i.e., not worsening) state of adisease, delay or slowing of a disease, and amelioration or palliation of symptoms associated with a disease.

[0028] As used herein, a “subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, and canine species, e.g., dog, fox, wolf. The terms, “patient”, “individual” and “subject” are used interchangeably herein. In an embodiment, the subject is mammal. The mammal may be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. In some embodiments, the subject is a human.

[0029] A subject may be one who has been previously diagnosed with or identified as suffering from or having a disease, disorder or condition in need of treatment or one or more complications related to the disease, disorder, or condition, and optionally, have already undergone treatment for the disease, disorder, or condition or the one or more complications related to the disease, disorder, or condition. Alternatively, a subject can also be one who has not been previously diagnosed as having a disease, disorder, or condition or one or more complications related to the disease, disorder, or condition. For example, a subject may be one who exhibits one or more risk factors for a disease, disorder, or condition or one or more complications related to the disease, disorder, or condition or a subject who does not exhibit risk factors. A “subject in need” of treatment for a particular disease, disorder, or condition may be a subject suspected of having that disease, disorder, or condition, diagnosed as having that disease, disorder, or condition, already treated or being treated for that disease, disorder, or condition, not treated for that disease, disorder, or condition, or at risk of developing that disease, disorder, or condition.

[0030] Tenapanor, the first-in-class medication of NHE-3 blocker, is an FDA- approved medication for irritable bowel syndrome-constipation. It has a well-characterized safety profile. As shown herein, it can be prescribed to patients with hepatic encephalopathy.

[0031] Sodium / hydrogen exchangers-3 (NHE-3) is found on the apical surface of the small intestine and colon. It plays important role in sodium absorption. Tenapanor, the first- in-class medication, is an orally-administered small molecule that selectively inhibits NHE-3 from the gastrointestinal tract, where the majority of sodium absorption occurs into the bloodstream.

[0032] Hepatic encephalopathy is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Ammonia and inflammation are major triggers for the appearance of hepatic encephalopathy. Stool softening promotes the evacuation of the stool and improves hepatic encephalopathy.

[0033] The sodium / hydrogen exchangers-3 (NHE-3) blocker, such as Tenapanor, can promote the stool evacuation and elimination of ammonia as well as decrease the absorption of ammonia. In addition, it can decrease the absorption of sodium, an important mechanism to reduce the formation of ascites.

[0034] Moreover, given its well -documented safety profile in treating irritable bowel syndrome-constipation, Tenapanor offers a safer therapeutic alternative for patients with cirrhosis to treat or prevent hepatic encephalopathy.

[0035] Tenapanor for hepatic encephalopathy as used herein can be offered in tablet form. This dosage is based, at least in part, on its sodium channel-blocking effect, which can be helpful in evacuating stool and reducing the intestinal load of ammonia, a pathological mechanism of hepatic encephalopathy. However, other dosages and administrations are also contemplated as additional embodiments of the present invention, as described herein.

[0036] Using Tenapanor, we have shown evidence in treating and preventing hepatic encephalopathy in 5 patients. These patients showed improvement in hepatic encephalopathy and prevented recurrence of exacerbation of hepatic encephalopathy. They presented high medication adherence and there was no serious adverse event.

[0037] As a non-absorbable medication, Tenapanor has demonstrated a favorable side effect profile. This approach was also able to address the root cause by decreasing bacterial load in the gut.

[0038] Accordingly, the present invention is based, at least in part on these findings.

[0039] Various embodiments provide for a method for treating hepatic encephalopathy (HE), in a subject in need thereof, comprising: administering a quantity of tenapanor or a salt thereof to the subject. In various embodiments, the subject also has cirrhosis. In other embodiments, the subject also has portal hypertension.

[0040] In various embodiments, the method further comprises identifying the subject as having HE prior to administering the quantity of tenapanor or the salt thereof to the subject. In various embodiments, the method further comprises identifying the subject as having HE prior to administering the quantity of tenapanor or a salt thereof to the subject, based on the recognition that tenapanor or the salt thereof will treat HE in the subject. Assuch, in various embodiments, the method comprises identifying the subject as having HE, and administering a quantity of tenapanor or a salt thereof to the subject.

[0041] In various embodiments, the method comprises identifying the subject as having HE for treatment with tenapanor or a salt thereof based on the recognition that tenapanor or the salt thereof will treat HE in the subject, and administering a quantity of tenapanor or a salt thereof to the subject.

[0042] Identifying the subject as having HE for treatment with tenapanor or a salt thereof can be made by a medical practitioner (e.g., doctor, nurse practitioner, nurse, physician assistant, etc.), or by the subject (e.g., self-identification after being diagnosed with HE).

[0043] Identifying the subject as having HE comprises can include using the Stroop test, inhibitory control test, animal naming test and psychometric hepatic encephalopathy score, West Haven score / Conn score or combinations thereof, which can diagnose and / or categorize HE.

[0044] In various embodiments, the subject does not have kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. In some instances, the subject will start a treatment regimen with tenapanor or a salt thereof and when starting the treatment regimen, the subject does not have kidney disease. However, over time some patients with HE can develop kidney disease, yet continue treatment with tenapanor or a salt thereof for HE. In various embodiments, for the purposes of the present invention, these patient populations differ from and do not overlap with patient populations who initially had kidney disease when the treatment regimen with tenapanor or a salt thereof started. In various embodiments, for the purposes of the present invention, these patient populations differ from and do not overlap with patient populations having kidney disease who are receiving tenapanor or a salt thereof to treat their kidney disease.

[0045] In various embodiments, the subject does not have chronic kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. Alike the aforementioned discussion, in some instances, the subject will start a treatment regimen with tenapanor or a salt thereof and when starting the treatment regimen, the subject does not have chronic kidney disease. However, over time some patients with HE can develop chronic kidney disease, yet continue treatment with tenapanor or a salt thereof for HE. In various embodiments, for the purposes of the present invention, these patient populations differ from and do not overlap with patient populations who initially had chronic kidney disease when the treatment regimen with tenapanor or a salt thereof started. Invarious embodiments, for the purposes of the present invention, these patient populations differ from and do not overlap with patient populations having chronic kidney disease who are receiving tenapanor or a salt thereof to treat their kidney disease.

[0046] In various embodiments, the subject does not have irritable bowel syndrome, kidney disease, or both. In various embodiments, the subject does not have constipation. In various embodiments, the subject does not have constipation predominant irritable bowel syndrome. In various embodiments, the subject does not have chronic kidney disease.

[0047] In various embodiments, the subject is not on dialysis, the subject is not in need of a reduction in serum phosphorus, or the subject is not being administered a phosphate binder.

[0048] In various embodiments, the subject has not taken tenapanor or a salt thereof for an indication other than HE.

[0049] In various embodiments, the tenapanor salt is tenapanor hydrochloride.

[0050] In various embodiments, the quantity of tenapanor or a salt thereof is about 2.5 mg to 100 mg. In various embodiments, the quantity of tenapanor or a salt thereof is about 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg.

[0051] In various embodiments, the quantity of tenapanor or a salt thereof is about 10 mg, 20 mg, or 30 mg. In various embodiments, the quantity of tenapanor or a salt thereof is about 50 mg. In various embodiments, the quantity of tenapanor or a salt thereof is about 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, or 2000 mg.

[0052] In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 2.5-5mg / day, 2.5-10mg / day, 2.5-15mg / day, 2.5- 20mg / day or 2.5-25mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 10-20mg / day, 10-30mg / day, 10-40mg / day, or 10-50mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 50-100mg / day, 100-150mg / day, 150-200mg / day, or 100- 200mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 200-300mg / day, 300-400mg / day, 400-500mg / day, 500- 600mg / day, 600-700mg / day, 700-800mg / day, 800-900mg / day, or 900-1000mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the rangeof about 1000-1 lOOmg / day, 1100-1200mg / day, 1200-1300mg / day, 1300-1400mg / day, 1400- 1500mg / day, 1500-1600mg / day, 1600-1700mg / day, 1700-1800mg / day, 1800-1900mg / day or 1900-2000mg / day.

[0053] In various embodiments, the quantity of tenapanor or a salt thereof is administered twice daily. In other embodiments, the quantity of tenapanor or a salt thereof is administered once daily. In other embodiments, the quantity of tenapanor or a salt thereof is administered three times daily.

[0054] In various embodiments, the quantity of tenapanor or a salt thereof is administered for about 1 week, two weeks, three weeks, or four weeks. In various embodiments, the quantity of tenapanor or a salt thereof is administered for about 1 month, 2 months, or 3 months. In various embodiments, the quantity of tenapanor or a salt thereof is administered for about 1-3 months, 4-6 months, 7-9 months, or 9-12 months. In various embodiments, the quantity of tenapanor is administered indefinitely.

[0055] In various embodiments, administering comprises administering the quantity of quantity of tenapanor or the salt thereof until HE is improved. In other embodiments, administering comprises administering the quantity of quantity of tenapanor or the salt thereof until HE is resolved, or until the episode of HE is resolved.

[0056] In various embodiments, administering comprises administering the quantity of quantity of tenapanor or the salt thereof until the subject has about 3-4 loose stools per day. In various embodiments, the quantity of quantity of tenapanor or the salt thereof is an effective amount to achieve about 3-4 loose stools per day by the subject. Loose stool refers to Bristol Stool Form Scale 6-7.

[0057] In various embodiments tenapanor or a salt thereof is administered orally. In other embodiments, tenapanor or a salt thereof is administered via a feeding tube.

[0058] Various embodiments provide for a method of reducing the likelihood of hepatic encephalopathy (HE), in a subject in need thereof, comprising: administering a quantity of tenapanor or a salt thereof to the subj ect.

[0059] In various embodiments, the method further comprises identifying the subject as being susceptible to having HE prior to administering the quantity of tenapanor or the salt thereof to the subject. In various embodiments, the method further comprises identifying the subject as being susceptible to having HE prior to administering the quantity of tenapanor or a salt thereof to the subject, based on the recognition that tenapanor or a salt thereof will reduce the likelihood of HE in the subject. As such, in various embodiments, the methodcomprises identifying the subject as being susceptible of having HE, and administering a quantity of tenapanor or a salt thereof to the subj ect.

[0060] In various embodiments, the method comprises identifying the subject as being susceptible of having HE for treatment with tenapanor or a salt thereof based on the recognition that tenapanor or the salt thereof will reduce the likelihood of HE in the subject, and administering a quantity of tenapanor or a salt thereof to the subject.

[0061] Identifying the subject as being susceptible of having HE for treatment with tenapanor or a salt thereof can be made by a medical practitioner (e.g., doctor, nurse practitioner, nurse, physician assistant, etc.), or by the subject (e.g., self-identification after previously being diagnosed with HE).

[0062] In various embodiments, the subject has portal hypertension, liver dysfunction, acute liver disease, or chronic liver disease. In particular embodiments, the subject has cirrhosis. In particular embodiments, the subject has portal hypertension. In various embodiments, the subject has gastrointestinal bleeding, infection, excessive dietary protein intake, consumption of alcohol, or combinations thereof. In various embodiments, the subject has a transjugular intrahepatic portosystemic shunt (TIPS).

[0063] In various embodiments, the subject does not have kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. In some instances, the subject will start a treatment regimen with tenapanor or a salt thereof and when starting the treatment regimen, the subject does not have kidney disease. However, over time some patients with HE can develop kidney disease, yet continue treatment with tenapanor or the salt thereof for HE. In various embodiments, for the purposes of the present invention, these patient populations differ from and do not overlap with patient populations who initially had kidney disease when the treatment regimen with tenapanor or a salt thereof started. In various embodiments, for the purposes of the present invention, these patient populations differ from and do not overlap with patient populations having kidney disease who are receiving tenapanor or a salt thereof to treat their kidney disease.

[0064] In various embodiments, the subject does not have chronic kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof. Alike the aforementioned discussion, in some instances, the subject will start a treatment regimen with tenapanor or a salt thereof and when starting the treatment regimen, the subject does not have chronic kidney disease. However, over time some patients with HE can develop chronic kidney disease, yet continue treatment with tenapanor or the salt thereof for HE. In various embodiments, for the purposes of the present invention, these patientpopulations differ from and do not overlap with patient populations who initially had chronic kidney disease when the treatment regimen with tenapanor or a salt thereof started. In various embodiments, for the purposes of the presently claimed method, these patient populations differ from and do not overlap with patient populations having chronic kidney disease who are receiving tenapanor or a salt thereof to treat their kidney disease.

[0065] In various embodiments, the subject does not have irritable bowel syndrome, kidney disease, or both. In various embodiments, the subject does not have constipation. In various embodiments, the subject does not have constipation predominant irritable bowel syndrome. In various embodiments, the subject does not have chronic kidney disease. In various embodiments, the subject is not on dialysis, wherein the subject is not in need of a reduction in serum phosphorus, or wherein the subject is not being administered a phosphate binder.

[0066] In various embodiments, the subject has not taken tenapanor or a salt thereof for an indication other than HE.

[0067] In various embodiments, the tenapanor salt is tenapanor hydrochloride.

[0068] In various embodiments, the quantity of tenapanor or a salt thereof is about 2.5 mg to 100 mg. In various embodiments, the quantity of tenapanor or a salt thereof is about 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg.

[0069] In various embodiments, the quantity of tenapanor or a salt thereof is about 10 mg, 20 mg, or 30 mg. In various embodiments, the quantity of tenapanor or a salt thereof is about 50 mg.

[0070] In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 2.5-5mg / day, 2.5-10mg / day, 2.5-15mg / day, 2.5- 20mg / day or 2.5-25mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 10-20mg / day, 10-30mg / day, 10-40mg / day, or 10-50mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 50-100mg / day, 100-150mg / day, 150-200mg / day, or 100- 200mg / day. In some embodiments of the invention, the quantity of tenapanor or a salt thereof can be in the range of about 200-300mg / day, 300-400mg / day, 400-500mg / day, 500- 600mg / day, 600-700mg / day, 700-800mg / day, 800-900mg / day, 900-1000mg / day.

[0071] In various embodiments, the quantity of tenapanor or a salt thereof is administered twice daily. In other embodiments, the quantity of tenapanor or a salt thereof is administered once daily. In other embodiments, the quantity of tenapanor or a salt thereof is administered three times daily.

[0072] In various embodiments, the quantity of tenapanor or a salt thereof is administered for about 1 week, two weeks, three weeks, or four weeks. In various embodiments, the quantity of tenapanor or a salt thereof is administered for about 1 month, 2 months, or 3 months. In various embodiments, the quantity of tenapanor or a salt thereof is administered for about 1-3 months, 4-6 months, 7-9 months, or 9-12 months. In various embodiments, the quantity of tenapanor is administered indefinitely.

[0073] In various embodiments, administering comprises administering the quantity of quantity of tenapanor or the salt thereof until the subject has about 3-4 loose stools per day. In various embodiments, the quantity of quantity of tenapanor or the salt thereof is an effective amount to achieve about 3-4 loose stools per day by the subject. Loose stool refers to Bristol Stool Form Scale 6-7.

[0074] In various embodiments, the present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of tenapanor or a salt thereof. “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.

[0075] In certain embodiments, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts, esters, amides, and prodrugs” as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use of the compounds of the invention. The term “salts” refers to the relatively non-toxic, inorganic, and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. These may include cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethyl ammonium, tetraethyl ammonium, methyl amine, dimethyl amine,trimethylamine, triethylamine, ethylamine, and the like (see, e.g., Berge S. M., et al. (1977) J. Pharm. Sci. 66, 1, which is incorporated herein by reference).

[0076] The term “pharmaceutically acceptable esters” refers to the relatively nontoxic, esterified products of the compounds of the present invention. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst. The term is further intended to include lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl, and propyl esters.

[0077] As used herein, “pharmaceutically acceptable salts ” are salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0078] In various embodiments, the pharmaceutical compositions according to the invention may be formulated for delivery via any route of administration. “Route of administration” may refer to any administration pathway known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal, or parenteral.

[0079] “Parenteral” refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders.

[0080] Via the enteral route, the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles, or polymer vesicles allowing controlled release. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection.

[0081] The pharmaceutical compositions according to the invention can also contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid orsolid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0082] The pharmaceutical compositions according to the invention can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols, and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

[0083] The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing, and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

[0084] The pharmaceutical compositions according to the invention may be delivered in a therapeutically effective amount. The precise therapeutically effective amount is the amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, for instance, by monitoring a subject’s response to the administration of a compound and adjusting the dosage accordingly. For additional guidance, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0085] Typical dosages of an effective amount of tenapanor or a salt thereof can be in the ranges recommended by the manufacturer where known therapeutic compounds are used, and also as indicated to the skilled artisan by the in vitro responses or responses in animal models. Such dosages typically can be reduced by up to about one order of magnitude in concentration or amount without losing the relevant biological activity. Thus, the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based, for example, on the in vitro responsiveness of the relevant primary cultured cells or histocultured tissue sample, such as biopsied malignant tumors, or the responses observed in the appropriate animal models, as previously described.

[0086] In some embodiments of the invention, the effective amounts of tenapanor or a salt thereof can be in the range of about 10-20mg / day, 10-30mg / day, 10-40mg / day, or 10- 50mg / day. In some embodiments of the invention, the effective amounts of tenapanor or a salt thereof can be in the range of about 50-100mg / day, 100-150mg / day, 150-200mg / day, or 100-200mg / day. In some embodiments of the invention, the effective amounts of tenapanor or a salt thereof can be in the range of about 200-3 OOmg / day, 300-400mg / day, 400- 500mg / day, 500-600mg / day, 600-700mg / day, 700-800mg / day, 800-900mg / day, 900- lOOOmg / day.KITS

[0087] The present invention is also directed to a kit to treat hepatic encephalopathy (HE) or to lower the chances of developing HE. The kit is useful for practicing the inventive method of treating HE or lowering the chances of developing HE. The kit is an assemblage of materials or components, including at least one of the inventive compositions. Thus, in some embodiments the kit contains a composition including tenapanor or a salt thereof as described herein.

[0088] The exact nature of the components configured in the inventive kit depends on its intended purpose. For example, some embodiments are configured for the purpose of treating HE. In one embodiment, the kit is configured particularly for the purpose of treating mammalian subjects. In another embodiment, the kit is configured particularly for the purpose of treating human subjects.

[0089] Instructions for use may be included in the kit. “Instructions for use” typically include a tangible expression describing the technique to be employed in using the components of the kit to effect a desired outcome, such as to treat HE or to lower the chances of developing HE. Optionally, the kit also contains other useful components, such as,diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.

[0090] The materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility. For example the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures. The components are typically contained in suitable packaging material(s). As employed herein, the phrase “packaging material” refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like. The packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment. The packaging materials employed in the kit are those customarily utilized in the treatment of liver diseases such as HE. As used herein, the term “package” refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components. Thus, for example, a package can be a plastic bottle used to contain suitable quantities of an inventive composition containing tenapanor or a salt thereof. The packaging material generally has an external label which indicates the contents and / or purpose of the kit and / or its components.EXAMPLES

[0091] The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.Example 1

[0092] The patient has a history of decompensated cirrhosis secondary to nonalcoholic associated fatty metabolic dysfunction associated steatotic liver disease. She has hepatic encephalopathy (hepatic encephalopathy scoring algorithm grade 1, with 5 / 6 items being positive). She has been prescribed both lactulose three times daily and rifaximin. However, she was not able to tolerate the sweet taste of lactulose. Therefore, she had poor adherence to lactulose, and her condition of hepatic encephalopathy was not well controlledby using rifaximin alone, which only provided partial efficacy in treating her hepatic encephalopathy.

[0093] She took tenapanor 50mg once daily for a few days, then increased the dose to twice daily. After receiving tenapanor for a week, her bowel movement increased from 2 to 3 times per day to 3 to 4 times per day. She liked the fact that the tenapanor pill was tasteless.

[0094] After a week of treatment, her hepatic encephalopathy has improved (hepatic encephalopathy scoring algorithm grade 1 (5 / 6 positive) to grade 0 (1 / 6 positive). She was able to complete a course of one month of therapy. There was no severe adverse event.Example 2

[0095] The patient has a history of decompensated alcoholic cirrhosis. He has a history of hepatic encephalopathy and ascites. He has been taking lactulose three times daily and rifaximin but was not able to fully adhere to the prescription of three times daily. Therefore, the frequency of his bowel movement was 0 to 1 per day. The severity of his hepatic encephalopathy was grade 1, with 4 / 6 items being positive, particularly with daily fogginess.

[0096] The patient received a one-month supply of tenapanor. He started taking tenapanor with a frequency of once daily. He increased the frequency to twice daily but there was no increase in the number of his bowel movement. During the last week of his one- month supply, he changed the use from taking with breakfast and dinner to lunch and dinner. This has increased the number of his bowel movement and his fogginess improved. There was no severe adverse event.Example 3

[0097] The patient has a history of decompensated cirrhosis secondary to metabolic dysfunction associated steatotic liver disease. She has hepatic encephalopathy (hepatic encephalopathy scoring algorithm grade 1, with 4 / 6 items being positive). She had a fracture two years ago, for which she had to take narcotic medication (Norco (combination of acetaminophen and hydrocodone) 5mg twice daily to three times daily) which had resulted in chronic constipation and limited the efficacy of lactulose. Despite using Naloxegol, a medication for opioid-induced constipation, the frequency of her bowel movement only improved to once daily.

[0098] After 7 days of combining tenapanor 50mg twice daily with her Naloxegol and lactulose, she was able to achieve 1 to 2 bowel movements per day. The characteristic of thestool had improved from hard, small, pebble-like to soft, form stool. Her hepatic encephalopathy was restored (hepatic encephalopathy scoring algorithm grade 1, 0 / 6).

[0099] After a month of use, patient’s tenapanor was discontinued. She became more constipated and the frequency of her bowel movement decreased significantly to once every few days. Meanwhile her hip and back pain exacerbated. With the use of opioid medication and exacerbation of the constipation, her HE progressed to grade 1.Example 4

[0100] The patient has a history of decompensated cirrhosis secondary to MASH and chronic constipation. She did not tolerate lactulose with immediate nausea after taking lactulose which had happen for all her attempts in taking it. She has HE grade 1 with 5 / 6 items of hepatic encephalopathy scoring algorithm being positive. She does not have rifaximin.

[0101] She has received tenapanor and has taken it for 2 weeks. Her bowel movements (BM) have increased to once daily or every other day and her stool became loose. Patient’s HE has improved to grade 0.

[0102] Notably, she had been having constipation for years and never had loose stool. The development of loose stool has resulted in occasional fecal incontinence.Example 5

[0103] The patient has a history of MASH-associated decompensated cirrhosis, complicated by hepatic encephalopathy which resulted in falls for multiple times. She also had chronic constipation, which happened before the diagnosis of cirrhosis. She is currently taking rifaximin and miralax and have mild HE (changing between grade 0 and 1) but she is worried about recurrence as miralax at high dose only results in BM frequency at 1-2 daily. She did not tolerate lactulose due to nausea and vomiting. Symptoms developed whenever she had lactulose and resolved after discontinuing it. Trulance provided limited benefit.

[0104] During the first week of taking tenapanor, patient had improvement of the frequency and consistency of bowel movement. However, she had an episode of leakage as she has not had loose or watery stool for years. The incontinence resolved after that, and she continued to have close to daily bowel movement except one week when she had 6 days without bowel movement then resolved. Her HE was improved after taking tenapanor. Even during the week when she had six days not having bowel movement, she continued to be free from HE symptoms.

[0105] Various embodiments of the invention are described above in the Detailed Description. While these descriptions directly describe the above embodiments, it is understood that those skilled in the art may conceive modifications and / or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall within the purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s).

[0106] The foregoing description of various embodiments of the invention known to the applicant at this time of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limit the invention to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed for carrying out the invention.

[0107] While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are useful to an embodiment, yet open to the inclusion of unspecified elements, whether useful or not. It will be understood by those within the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of’ or “consisting essentially of.”

[0108] Unless stated otherwise, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of claims) may be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.” No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[0109] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0110] Groupings of alternative elements or embodiments of the present disclosure disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating hepatic encephalopathy (HE), in a subject in need thereof, comprising: administering a quantity of a tenapanor or a salt thereof to the subject.

2. The method of claim 1, wherein the method further comprises identifying the subject as having HE prior to administering the quantity of tenapanor c to the subject.

3. The method of claim 1, wherein the method further comprises identifying the subject as having HE prior to administering the quantity of tenapanor or the salt thereof to the subject, based on the recognition that the subject the tenapanor or the salt thereof will treat HE in the subject.

4. The method of claim 1, wherein the subject does not have kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof.

5. The method of claim 1, wherein the subject does not have chronic kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof.

6. The method of claim 1, wherein the subject does not have irritable bowel syndrome, kidney disease, or both.

7. The method of claim 1, wherein the subject does not have constipation predominant irritable bowel syndrome.

8. The method of claim 1, wherein the subject does not have chronic kidney disease.

9. The method of claim 1, wherein the subject is not on dialysis, wherein the subject is not in need of a reduction in serum phosphorus, or wherein the subject is not being administered a phosphate binder.

10. The method of any one of claims 1-9, wherein the tenapanor salt is tenapanor hydrochloride.

11. The method of any one of claims 1-10, wherein the quantity of tenapanor or the salt thereof is about 2.5 mg to 100 mg.

12. The method of any one of claims 1-10, wherein the quantity of tenapanor or the salt thereof is about 10 mg, 20 mg, 30 mg, or 50 mg.

13. The method any one of claims 1-12, wherein the quantity of tenapanor or the salt thereof is administered once daily, twice daily or thrice daily.

14. The method of any one of claims 1-12, wherein the quantity of tenapanor or the salt thereof is administered twice daily.

15. A method of reducing the likelihood of having hepatic encephalopathy (HE), in a subject in need thereof, comprising: administering a quantity of tenapanor or a salt thereof to the subject.

16. The method of claim 15, wherein the method further comprises identifying the subject as being susceptible to having HE prior to administering the quantity of tenapanor or the salt thereof to the subject.

17. The method of claim 15, wherein the method further comprises identifying the subject as being susceptible to having HE prior to administering the quantity of tenapanor or the salt thereof to the subject, based on the recognition that the tenapanor or a salt thereof will reduce the likelihood of having HE in the subject.

18. The method of claim 15, wherein the subject does not have a history of hepatic encephalopathy (HE).

19. The method of claim 15, wherein the subject has one or more prior episodes of hepatic encephalopathy (HE) and the method reduces the likelihood of additional episodes of HE.

20. The method of any one of claims 15-19, wherein the subject has liver disfunction, acute liver disease or chronic liver disease.

21. The method of any one of claims 15-20, wherein the subject has gastrointestinal bleeding, infection, excessive dietary protein intake, consumption of alcohol, or combinations thereof.

22. The method of any one of claims 15-21, wherein the subject has a transjugular intrahepatic portosystemic shunt (TIPS).

23. The method of any one of claims 15-22, wherein the subject does not have irritable bowel syndrome, kidney disease, or both.

24. The method of any one of claims 15-22, wherein the subject does not have constipation predominant irritable bowel syndrome.

25. The method of any one of claims 15-22, wherein the subject does not have chronic kidney disease.

26. The method of any one of claims 15-22, wherein the subject does not have kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof.

27. The method of any one of claims 15-22, wherein the subject does not have chronic kidney disease at commencement of initial treatment of HE with the quantity of tenapanor or the salt thereof.

28. The method of any one of claims 15-22, wherein the subject is not on dialysis, wherein the subject is not in need of a reduction in serum phosphorus, or wherein the subject is not being administered a phosphate binder.

29. The method of any one of claims 15-28, wherein the tenapanor salt is tenapanor hydrochloride.

30. The method of any one of claims 15-29, wherein the quantity of tenapanor or the salt thereof is about 2.5 mg to 100 mg.

31. The method of any one of claims 15-29, wherein the quantity of tenapanor or the salt thereof is about 10 mg, 20 mg, 30 mg, or 50 mg.

32. The method of any one of claims 15-31, wherein the quantity of tenapanor or the salt thereof is administered once daily, twice daily or thrice daily.

33. The method of any one of claims 15-31, wherein the quantity of tenapanor or the salt thereof is administered twice daily.