Compositions for treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Abstract

To provide a pharmaceutical composition for treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).SOLUTION: Provided is a pharmaceutical composition comprising a. ibutamoren, b. pioglitazone, and c. a pharmaceutically acceptable carrier.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for treating non-alcoholic fatty liver disease and non-alcoholic steatohepatitis by a growth hormone secretagogue or a combination of a growth hormone secretagogue and a drug selected from a dipeptidyl peptidase-4 antagonist, a glucagon-like peptide receptor agonist, a thiazolidinedione, a sodium-glucose cotransporter 2 antagonist, metformin, and vitamin E.

[0002] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each such publication, patent, patent application, or other reference were individually and specifically indicated to be incorporated herein by reference in its entirety for all purposes. The citation of a reference herein should not be construed as an admission that such citation is prior art to the present invention. [Background technology]

[0003] Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. It is a condition in which excess fat accumulates in the liver. This condition is not caused by heavy alcohol consumption (which is called alcoholic liver disease). NAFLD has become a major health problem because it can lead to hepatitis, fibrosis, and hepatocellular carcinoma, and is associated with an increasing prevalence of obesity, insulin resistance, type 2 diabetes, and metabolic disease. Its incidence in the US population is estimated to be 25-30% and is increasing. Approximately 20% of people with NAFLD also have nonalcoholic steatohepatitis (NASH). NASH can lead to complications such as cirrhosis and liver cancer. Treating NAFLD and / or NASH is considered an alternative approach to treating obesity, insulin resistance, type 2 diabetes, and metabolic disease.

[0004] Currently, there are no effective treatments for either NAFLD or NASH, and therefore, the development of methods to treat these diseases is desirable. Summary of the Invention

[0005] In one aspect, the present invention provides a novel method for treating non-alcoholic fatty liver disease using growth hormone secretagogues (GHS).

[0006] In one aspect, the present invention provides a novel method for treating NAFLD by combining GHS with an agent selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a thiazolidinedione, a sodium-glucose cotransporter 2 (SGLT2) antagonist, metformin, and vitamin E.

[0007] In another aspect, the present invention provides a novel method for treating non-alcoholic steatohepatitis with a growth hormone secretagogue.

[0008] In one aspect, the present invention provides a novel method for treating NASH by combining GHS with an agent selected from a dipeptidyl peptidase-4 antagonist, a glucagon-like peptide receptor agonist, a thiazolidinedione, a sodium-glucose cotransporter 2 antagonist, metformin, and vitamin E. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present inventors have discovered that growth hormone secretagogues (e.g., ibutamoren) alone or in combination with agents selected from dipeptidyl peptidase-4 antagonists, glucagon-like peptide receptor agonists, thiazolidinediones, sodium-glucose cotransporter 2 antagonists, metformin, and vitamin E are expected to be effective in treating diseases such as NAFLD and NASH.

[0010] For example, the present inventors have discovered that a novel therapeutic approach, combining the growth hormone secretagogue ibutamoren with the DPP antagonist Januvia, is useful for treating NAFLD and NASH. Both ibutamoren and Januvia are orally active, and their safety profiles are well established. The present inventors believe that formulating this combination, for example, in a single tablet, will enable the utilization of ibutamoren's ability to normalize GH and Januvia's ability to promote glucose-stimulated insulin release. Based on their different mechanisms of action, the present inventors believe that the combination of these two agents will exhibit synergistic, or at least additive, effects in the treatment / prevention of NAFLD. The structure of ibutamoren (sometimes referred to herein as ibutamoren mesylate) is shown below. [ka] Ibutamoren is commercially available from suppliers such as Sigma Aldrich and Caymen Chemical.

[0011] NAFLD and Growth Hormone (GH)

[0012] NAFLD, which can lead to hepatitis, fibrosis, and hepatocellular carcinoma, has become a major health problem and is associated with an increased prevalence of obesity, insulin resistance, type 2 diabetes, and metabolic diseases. A cross-sectional study of 7,146 individuals showed an association between NAFLD and low blood growth hormone (GH) levels (Xu, Xu et al. 2012). Adults with GH deficiency have low levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP3) and are insulin resistant. Both IGF-1 and IGFBP3 are positively regulated by GH.

[0013] Studies in hypophysectomized rats have shown that GH is crucial for regulating LDL receptor expression and circulating lipoprotein concentrations (Rudling, Norstedt et al. 1992). In addition to increasing IGF-1 and IGFBP3, GH treatment regulates the activity of key enzymes involved in cholesterol and bile acid biosynthesis. Additionally, GH regulates the expression of genes that enhance triglyceride (TG) hydrolysis, reducing TG storage and increasing diacylglycerol synthesis (Zhao, Cowley et al. 2011).

[0014] GH binding to the GH receptor (GHR) in the liver activates the transcription factor STAT5. Liver-selective loss of GHR or STAT5 in mice results in fatty liver, insulin resistance, glucose intolerance, increased triglyceride synthesis, and reduced excretion (Fan, Menon et al. 2009; Baik, Yu et al. 2011; Liu, Cordoba-Chacon et al. 2016). GH-STAT5 also regulates bile acid synthesis and metabolism. These properties lead to the conclusion that restoring GH to normal levels is a potential therapeutic approach for NAFLD.

[0015] GH controls local cortisol production through regulation of 11β-hydroxysteroid dehydrogenase type 1 (HSD1). HSD1 is an enzyme responsible for the local conversion of cortisone to the active glucocorticoid cortisol. Cortisol regulates gluconeogenesis and lipid deposition. HSD1 is expressed in the liver, adipose tissue, and brain. Overexpression of HSD1 in the liver increases cortisol-induced gluconeogenesis by increasing the expression of phosphoenolpyruvate carboxykinase, a rate-limiting gluconeogenic enzyme. In addition, overexpression of HSD1 in omental fat stimulates lipogenesis, potentially leading to central obesity. Therefore, inhibiting HSD1 activity, which reduces local cortisol production, is a potential approach for the prevention and treatment of type 2 diabetes, obesity, age-related cognitive impairment, and NAFLD. HSD1 inhibitors improve insulin sensitivity and reverse hepatic steatosis in db / db mice (Yuan, Li et al. 2016). Impaired GH production increases HSD1 expression, and GH-deficient patients exhibit high cortisol / cortisone ratios, which can be reversed by treatment with low doses of GH.

[0016] Genetic studies have linked NAFLD to polymorphisms in the gene encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3). Although the mechanism remains unclear, the variant PNPLA3-148M is associated with all NAFLD pathologies (Boursier and Diehl 2015). Studies in obese Hispanic children expressing the genetic variant and in mice expressing human PNPLA3-148M suggest that the pathogenesis of NAFLD depends on a high-carbohydrate rather than a high-fat diet (Davis, Le et al. 2010; Boursier and Diehl 2015; Smagris, Basu, Ray et al. 2015). Recent evidence suggests that PNPLA3 is excreted by a mechanism involving ubiquitination, but that PNPLA3-148M is resistant to this mechanism, resulting in the accumulation of the mutant protein on lipid droplets (BasuRay, Smagris et al. 2017). A mouse study (Smagris, BasuRay et al. 2015) showed that increasing or decreasing PNPLA3 in subjects with two wild-type alleles had minimal effect on hepatic steatosis, whereas increasing PNPLA3-148M exacerbated hepatic steatosis. Because GH increased the expression of the native PNPLA3-WT (Zhao, Cowley et al. 2011), GH treatment may be effective in treating PNPLA3-148M heterozygotes.

[0017] The role of insulin and growth hormone in hepatic steatosis

[0018] Obesity and type 2 diabetes are associated with insulin resistance. This resistance is primarily mediated by skeletal muscle and the ability of insulin to suppress gluconeogenesis in the liver. Suppression of hepatic gluconeogenesis depends on a decrease in free fatty acids derived from adipose tissue (Bergman and Iyer 2017). Therefore, the resistance is present in skeletal muscle and adipose tissue and is entirely extrahepatic, yet the liver remains insulin sensitive to stimulate lipogenesis. This is referred to as "selective insulin resistance" (see Titchenell, Quinn et al. 2016).

[0019] Diabetes treatment requires a balance between controlling and regulating hyperglycemia and avoiding increased hepatic lipid synthesis. Therefore, increasing insulin levels through exogenous insulin or sulfonylureas does not contribute to the treatment of NAFLD. However, GLP-1 agonists, which prolong the activity of endogenous GLP-1, or DPP4 antagonists, are preferable because they enhance insulin release in response to glucose and reduce blood glucose levels, thereby reducing the liver's ability to promote lipid synthesis. It is now clear that insulin action on adipose tissue inhibits hepatic gluconeogenesis, inhibiting lipolysis and, in turn, controlling early-stage insulin secretion. Therefore, DPP4 antagonists are ideal therapeutic options for inhibiting this process (Mest and Mentlin 2005).

[0020] Obesity and type 2 diabetes have been associated with suppressed GH secretion. Insulin and GH are secreted in a pulsatile manner, and the two are tightly regulated. For example, increased insulin secretion rapidly suppresses IGFBP-1, which leads to an increase in free IGF-I, which feedback inhibits GH secretion. After a meal, elevated insulin levels promote glucose transport into cells and enhance energy storage as lipids. The liver is the integrating center of metabolism, storing glycogen and fat for use during times of increased energy availability, such as exercise or starvation (Cahill 1971). After 12–14 hours of starvation, liver glycogen stores are depleted, and the body begins to convert fat into energy. In addition to fat stored in the liver, fat is also stored in white adipose tissue (primarily subcutaneous fat), which can be mobilized as needed. Insulin and GH are the two primary hormones that regulate fat storage and, subsequently, mobilization in the liver and adipose tissue. Therefore, the longer the time after a meal, the lower the insulin level and the higher the GH level. When we eat, insulin rises and GH is suppressed. While the regulation of insulin and GH is complex, both hormones are regulated by two other hormones produced in the digestive system: insulin by GLP-1 and GH by ghrelin. GLP-1 and ghrelin act in a similar way, enhancing the normal amplitude of insulin and GH pulses, respectively. Importantly, insulin and GH are secreted at the appropriate times and usually in opposing ways: when insulin levels are high, GH levels are suppressed.

[0021] Daily oral administration of ibutamoren restores normal endogenous GH profiles

[0022] Because endogenous GH is released pulsatilely from the anterior pituitary gland throughout the day, simple injection of recombinant GH (rhGH) does not restore the physiological profile of GH release. In GH-deficient subjects, administration of low doses of GH improves insulin sensitivity, whereas high levels of GH lead to insulin resistance. Therefore, selecting an appropriate therapeutic dose is difficult. Endogenous GH release is subject to feedback regulation, but administration of exogenous rhGH bypasses the GH negative feedback pathway. In contrast, the stimulatory effect of ibutamoren on GH pulsatility is influenced by natural inhibitory feedback mediated by IGF-1. Therefore, administration of the GH secretagogue ibutamoren enhances the magnitude of endogenous GH pulsatile release and normalizes GH. Therefore, overstimulation of the GH / IGF-1 axis is avoided (Smith, Van der Ploeg et al. 1997). Thus, ibutamoren is ideal for increasing insulin sensitivity in the treatment / prevention of NAFLD by mimicking normal GH physiology.

[0023] Limitations of NAFLD treatment with GLP-1 analogues or DPP4 inhibitors

[0024] GLP-1 receptor agonists or inhibitors of the GLP-1-degrading enzyme DPP4 enhance the glucose sensitivity of pancreatic β cells. Although the magnitude of pulsatile insulin release in response to glucose increases, there is no general agreement that insulin sensitivity is improved (Tominaga, Ikezawa et al. 1996; Ahren, Karsson et al. 1997). Because a key aspect of NAFLD is its association with insulin resistance, targeting the GLP-1 pathway alone is unlikely to provide sufficient therapeutic benefit. Indeed, this is supported by the results reported in clinical trials. For example, when type 2 diabetes patients receiving metformin and / or sulfonylureas were assigned to 12 weeks of treatment with the GLP-1 receptor agonist liraglutide and / or the DPP4 inhibitor sitagliptin (Januvia), neither treatment reduced hepatic steatosis or fibrosis (Smits, Tonneijck et al. 2016). A 24-week study involving 50 NAFLD patients concluded that sitagliptin was equivalent to placebo in reducing liver fat (Cui, Philo et al. 2016). Another study, treating 12 subjects with sitagliptin for 24 weeks, failed to demonstrate improvement in fibrosis (Joy, McKenzie et al. 2017). The present inventors have demonstrated that the limitation of solely targeting the GLP-1 pathway in the treatment of NAFLD is insufficient to fully alleviate NAFLD-associated insulin resistance.

[0025] Proposed Treatment of NAFLD with Ibutamoren in Combination with Januvia

[0026] The ideal treatment for NAFLD would restore bile acid secretion and hepatic lipid metabolism by correcting the GH secretion defect, thereby enhancing insulin secretion in a timely manner. The inventors believe this could be achieved, for example, by combining ibutamoren with Januvia, where ibutamoren mimics ghrelin and Januvia enhances endogenous GLP-1 by inhibiting DPP4, which normally destroys GLP-1. Ibutamoren has a distinct advantage over ghrelin because ghrelin is not orally active and inhibits insulin release from pancreatic beta cells. In stark contrast, ibutamoren does not suppress glucose-stimulated insulin secretion and therefore does not negate the stimulatory effect of GLP-1 on insulin release. Therefore, a tablet containing a combination of ibutamoren and a DPP4 inhibitor, such as Januvia, is believed to have the properties necessary for the treatment / prevention of NAFLD.

[0027] Animal studies have demonstrated that GH is a key regulator of hepatic fat metabolism. Fat accumulation in visceral adipose tissue and in the liver increases with age. This is associated with a 50% decline in GH secretion every 7–10 years beginning in mid-adolescence. This leads to GH levels in older adults comparable to those of GH-deficient young adults. GH-deficient adults have an increased incidence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. GH replacement therapy reverses this process. It is hypothesized that GH secretagogues, such as ibutamoren, may restore pulsatile GH secretion and reduce visceral fat. This hypothesis is based on the finding that endogenous GH secretion is inversely correlated with visceral fat mass and liver fat accumulation (NAFLD), and that low-dose GH reverses this process. HIV lipodystrophy is associated with both increased visceral fat accumulation and steatohepatitis. This condition has been treated with both supraphysiological rhGH injections and tesamorelin (a long-acting GHRH analog). This hypothesis is supported by evidence that ibutamoren enhances GH secretion, increases serum IGF-1, and increases lean body mass in obese individuals. Ibutamoren has been proposed as a treatment for NAFLD and NAFLD-associated steatohepatitis. To mitigate the mildly diabetogenic effects of ibutamoren-induced enhanced GH secretion, combination with various agents that improve insulin sensitivity has been proposed.

[0028] Vitamin E

[0029] Oxidative stress has been shown to play an important role in the progression of NASH. Vitamin E is a well-known free radical scavenger and has been prescribed for the treatment of NASH. One year of vitamin E treatment reduced serum transaminase activity along with TGF-β1 in adult patients with NASH who were refractory to dietary intervention. In a comparison of pioglitazone, vitamin E, and placebo in the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, vitamin E (800 mg / day) was superior to placebo in improving NASH histology in adult patients with NASH without diabetes or cirrhosis.

[0030] Random-effects model analysis of five studies showed that vitamin E significantly reduced serum hepatobiliary enzymes, liver fat, inflammation, and hepatocyte hypertrophy compared with control groups, but no improvement in fibrosis was observed in these studies.

[0031] In Japan, long-term vitamin E treatment (300 mg / day) for more than two years can reverse liver fibrosis in NASH patients, especially in those who can improve serum transaminase activity and insulin resistance. This result indicates that metabolic factors should be controlled even when vitamin E is administered.

[0032] Currently, vitamin E is only recommended for nondiabetic, biopsy-proven NASH patients based on the PIVENS trial, which has been associated with histologic improvement regardless of diabetes status. However, the primary concern regarding the use of vitamin E to treat NASH is the potential for toxicity with long-term or high-dose use. Although some conflicting results exist, vitamin E treatment may increase all-cause mortality, prostate cancer (SELECT trial), and cerebral hemorrhage. When administering vitamin E to NASH, lower doses of this agent (300–400 mg / day rather than 800 mg) should be considered.

[0033] Embodiments of the present invention In one aspect, the present invention provides a novel method for treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), comprising administering a therapeutically effective amount of a growth hormone secretagogue (GHS) to a patient in need thereof.

[0034] In another aspect, the novel method further comprises administering a therapeutically effective amount of a second drug selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a thiazolidinedione, a sodium-glucose cotransporter 2 (SGLT2) antagonist, metformin, and vitamin E.

[0035] Patient means a human patient, either a child or an adult.

[0036] In another aspect, the disease is NAFLD.

[0037] In another aspect, the disease is NASH.

[0038] In another aspect, the GHS is ibutamoren (ibutamoren mesylate).

[0039] In another aspect, 10 to 50 mg of ibutamoren is administered, for example, once daily. In one embodiment, 25 to 50 mg of ibutamoren is administered once daily. Other examples of ibutamoren amounts administered include 10, 15, 20, 25, 30, 35, 40, 45, and 50 mg. In another aspect, ibutamoren is administered orally.

[0040] In another aspect, the second drug is a DPP4 antagonist.

[0041] In another aspect, the DPP4 antagonist is selected from sitagliptin (trade name Januvia, typically administered orally at 25-100 mg / day), vildagliptin (trade name Salvus, typically administered orally at 50 mg twice daily), saxagliptin (trade name Onglyza, typically administered orally at 2.5 or 5 mg / day), linagliptin (trade name Tradjenta, typically administered orally at 5 mg / day), and alogliptin (trade name Nesina, typically administered orally at 6.25, 12.5, and 25 mg / day).

[0042] In another aspect, the second drug is a GLP-1 receptor agonist.

[0043] In another aspect, the GLP-1 receptor agonist is selected from exenatide (brand names Byetta and Bydureon, typically administered by injection at 2 mg once a week), liraglutide (brand names Victoza and Saxenda, typically administered by injection at 1.2 mg / day), lixisenatide (brand name Adylxin, typically administered by injection at 20 μg / day), albiglutide (brand name Tanzeum, typically administered by injection at 30 mg once a week), dulaglutide (brand name Trulicity, typically administered by injection at 0.75 to 1.5 mg once a week), and semaglutide (brand name Ozempic, typically administered by injection at 0.5 to 1 mg once a week).

[0044] In another aspect, the second drug is a thiazolidinedione (TZD). Thiazolidinediones (also called glitazones) are a class of drugs that have hypoglycemic effects (e.g., antihyperglycemic and / or antidiabetic drugs).

[0045] In another aspect, the TZD is selected from pioglitazone (trade name Actos, typically administered orally at 15 mg, 30 mg, or 45 mg / day) and rosiglitazone (trade name Avandia, typically administered orally at 4 mg (2 mg + 2 mg or 4 mg in a single dose) or 8 mg / day).

[0046] In another aspect, the second agent is a sodium-glucose cotransporter 2 (SGLT2) antagonist.

[0047] In another aspect, the SGLT2 antagonist is selected from empagliflozin (trade name Jardiance, typically administered orally at 5, 10, or 12.5 mg / day, depending on whether it is administered alone or in combination with metformin); and dapagliflozin (trade name Farxiga, typically administered orally at 2.5, 5, or 10 mg / day, depending on whether it is administered alone or in combination with metformin).

[0048] In another aspect, the second drug is metformin. Metformin is available in a wide variety of doses, including 500, 850, and 1000 mg immediate-release tablets and 500, 750, and 1000 mg extended-release tablets. Metformin is typically administered orally at doses of 1500, 2000, 2500, and 2550 mg per day.

[0049] In another aspect, in the method of treatment, the GHS is ibutamoren and the second drug is (i.) Sitagliptin, (ii.) vildagliptin, (iii.) saxagliptin, (iv.) linagliptin, (v.) alogliptin, (vi.) pioglitazone, (vii.) rosiglitazone, (viii.) empagliflozin, (ix.) dapagliflozin, and (x.) Metformin is selected from.

[0050] In another aspect, in the method of treatment, the GHS is ibutamoren and the second agent is sitagliptin.

[0051] In another aspect, in the method of treatment, the GHS is ibutamoren and the second agent is pioglitazone.

[0052] In another aspect, in the method of treatment, the GHS is ibutamoren and the second agent is metformin.

[0053] In another aspect, the present invention provides a novel method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), comprising: (i.) a therapeutically effective amount of a growth hormone secretagogue (GHS); (ii.) a therapeutically effective amount of a second agent selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a thiazolidinedione, and a sodium-glucose cotransporter 2 (SGLT2) antagonist; and (iii.) a therapeutically effective amount of a third agent that is metformin. to a patient in need thereof.

[0054] In another aspect, the second agent is selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, and a sodium-glucose cotransporter 2 (SGLT2) antagonist.

[0055] In another aspect, the second agent is a dipeptidyl peptidase-4 (DPP4) antagonist.

[0056] In another aspect, the second agent is a thiazolidinedione.

[0057] In another aspect, the second agent is a sodium-glucose cotransporter 2 (SGLT2) antagonist.

[0058] In another aspect, in the method of treatment, the GHS is ibutamoren, the second agent is sitagliptin, and the third agent is metformin.

[0059] In another aspect, in the method of treatment, the GHS is ibutamoren, the second agent is pioglitazone, and the third agent is metformin.

[0060] The timing of administration of the first drug (i.e., GHS) and the second drug (or the first drug, the second drug, and the third drug) depends on their independent administration regimens. Examples of the timing of administration include (i.) to (iv). (i.) Simultaneous administration, single formulation. This can be achieved by co-forming the (two or three) agents into a single formulation (e.g., oral administration) and subsequently administering that single formulation. (ii.) Simultaneous Administration, Different Formulations. This can be achieved by administering independent drugs at approximately the same time (e.g., separate oral, oral / injection, or injection doses). (iii.) Simultaneous Administration + Booster. For overlapping medications, use one of the regimens in (i) or (ii), followed by the booster medication. (iv.) Non-concurrent Administration. For multiple agents administered at different times (e.g., weekly injections vs. daily oral administration), the agents may be administered according to their individual protocols.

[0061] One potential advantage of the present invention is that it allows for simultaneous administration of a first agent and a second agent (or a first agent, a second agent, and a third agent). For example, if the second agent (or the second agent and the third agent) can be administered orally, the first agent and the second agent (or the second agent and the third agent) can be formulated into a single oral dosage form (e.g., a pill, tablet, capsule, powder, liquid suspension, etc.).

[0062] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i.) a therapeutically effective amount of a growth hormone secretagogue (GHS); (ii.) a therapeutically effective amount of a second agent selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, a sodium-glucose cotransporter type 2 (SGLT2) antagonist, and metformin; and (iii.) A pharmaceutically acceptable carrier and is useful for treating NAFLD and / or NASH.

[0063] In another aspect, the composition is administrable orally or parenterally.

[0064] In another aspect, the second agent is a DPP4 antagonist.

[0065] In another aspect, the GHS is ibutamoren and the second agent is sitagliptin.

[0066] In another aspect, the second agent is a thiazolidinedione.

[0067] In another aspect, the GHS is ibutamoren and the second agent is pioglitazone.

[0068] In another aspect, the second agent is an SGLT2 antagonist.

[0069] In another aspect, the second agent is metformin.

[0070] In another aspect, the GHS is ibutamoren and the second agent is metformin.

[0071] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i) a therapeutically effective amount of a growth hormone secretagogue (GHS), and (ii) a therapeutically effective amount of a second agent selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, and a sodium-glucose cotransporter type 2 (SGLT2) antagonist; (iii) a therapeutically effective amount of a third agent that is metformin; (iv) a pharmaceutically acceptable carrier; and is useful for the treatment of NAFLD and / or NASH.

[0072] In another aspect, the triple drug composition can be administered orally or parenterally.

[0073] In another aspect, the second agent in such triple combination is a DPP4 antagonist.

[0074] In another aspect, in such triple combination, the GHS is ibutamoren and the second drug is sitagliptin.

[0075] In another aspect, the second drug in such triple combination is a thiazolidinedione.

[0076] In another aspect, in such triple combination, the GHS is ibutamoren and the second drug is pioglitazone.

[0077] In another aspect, the second agent in such triple combination is an SGLT2 antagonist.

[0078] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i.) at least one first compartment comprising a therapeutically effective amount of a growth hormone secretagogue (GHS) and a pharmaceutically acceptable carrier; (ii.) at least one second compartment comprising a therapeutically effective amount of a second agent selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, a sodium-glucose cotransporter type 2 (SGLT2) antagonist, and metformin, and a pharmaceutically acceptable carrier; A novel packaging kit is provided, comprising:

[0079] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i.) at least one first compartment comprising a therapeutically effective amount of a growth hormone secretagogue (GHS) and a pharmaceutically acceptable carrier; (ii.) at least one second compartment comprising a therapeutically effective amount of a second agent selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, a sodium-glucose cotransporter type 2 (SGLT2) antagonist, and a pharmaceutically acceptable carrier; (iii.) at least one third compartment containing a therapeutically effective amount of a third agent, wherein the third agent is metformin and a pharmaceutically acceptable carrier; A novel packaging kit is provided, comprising:

[0080] In another aspect, the present invention provides the use of a first agent and a second agent in the manufacture of a medicament for the treatment of an indication described herein.

[0081] In another aspect, the present invention provides the use of a first agent, a second agent, and a third agent for the manufacture of a medicament for the treatment of an indication described herein.

[0082] In another aspect, the present invention provides novel compositions comprising a first agent and a second agent for use in treating the indications described herein.

[0083] In another aspect, the present invention provides novel compositions comprising a first agent, a second agent, and a third agent for use in treating the indications described herein.

[0084] Most of the approved drugs described herein have specific pharmaceutical salts (e.g., ibutamoren mesylate). The approved salts are those mentioned above, but it should be understood that other pharmaceutically acceptable salts are also part of the claimed invention.

[0085] The present invention may be embodied in other specific embodiments without departing from the spirit or essential attributes thereof. The present invention includes all combinations of the embodiments of the present invention described herein. It should be understood that any and all embodiments of the present invention may be combined with other embodiments to describe additional embodiments. It should also be understood that each individual element of these embodiments is intended to be construed separately as an independent embodiment in itself. It should also be understood that any element of one embodiment may be combined with any and all elements of any other embodiment to describe additional embodiments.

[0086] definition

[0087] "Treating" or "treatment" encompasses the treatment of a condition in a mammal, and includes (a) preventing the onset of the condition in the mammal (particularly when the mammal is predisposed to the condition but has not yet been diagnosed with it); (b) inhibiting the condition, e.g., arresting its onset; and / or (c) alleviating the condition, e.g., causing the condition to regress until a desired endpoint is reached. Treatment also includes ameliorating symptoms of the condition (e.g., reducing pain or discomfort), where such amelioration may or may not be one that directly affects the condition (e.g., cause, transmission, manifestation, etc.).

[0088] "Pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, and refers to acid or base salts prepared by modification of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic salts of basic residues (e.g., amines), alkali or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 1,2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, iodine, and the like. Included are salts derived from inorganic and organic acids selected from the group consisting of benzoic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthyl acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0089] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. The organic solvent is generally a water-insoluble solvent, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0090] A "therapeutically effective amount" includes an amount of a compound of the present invention that is effective when administered alone or in combination to treat obesity, diabetes, dyslipidemia, cardiovascular disorders, inflammatory diseases, liver disorders, cancer, and combinations or co-morbidities thereof, or any other indication listed herein. A "therapeutically effective amount" also includes an amount of a combination of compounds of the present invention that is effective to treat the desired indication. A combination of compounds may be a synergistic combination. As described, for example, in Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, synergy occurs when the effect achieved by combined administration of multiple compounds is greater than the sum of the effects achieved by each compound administered alone as a single agent. Generally, synergy is most evident at or below suboptimal doses of the compounds. Synergy may be seen in terms of reduced cytotoxicity, increased efficacy, or some other beneficial effect when the combination of multiple components is compared to the administration of the components individually.

[0091] In the present invention, the compounds of the present invention can be administered in any convenient manner (e.g., enterally or parenterally). Examples of administration methods include oral and transdermal. As will be appreciated by those skilled in the art, the route of administration of the compounds of the present invention can be varied. In addition to other oral administration methods, sustained and / or controlled release compositions are also preferred. Other acceptable routes include injection (e.g., intravenous, intramuscular, subcutaneous, and intraperitoneal), subcutaneous placement, and buccal, sublingual, topical, rectal, vaginal, and intranasal administration. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable administration systems may be used. Examples of oral formulations include tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, powders, granules, and suspensions.

[0092] To prepare a solid composition in tablet form, the active ingredient may be mixed with a pharmaceutical vehicle. Examples of such vehicles include silica, starch, lactose, magnesium stearate, and talc. Tablets may optionally be coated with sucrose or other suitable substances, or may be treated to have sustained or delayed activity and release a predetermined amount of the active ingredient. Capsules can be obtained, for example, by mixing a diluent with the active ingredient and incorporating the resulting mixture into a soft capsule or a two-piece hard capsule. For example, syrups or elixirs may contain, in addition to one or more active ingredients, typically a calorie-free sweetener, preservatives (e.g., methylparaben and / or propylparaben), flavorings, and suitable colorings. Furthermore, for example, water-dispersible powders or granules may contain, in addition to one or more active ingredients, dispersants or wetting agents, or suspending agents (e.g., polyvinylpyrrolidone), as well as sweeteners or flavor modifiers, in a mixed state. Rectal administration can be carried out using suppositories. Suppositories can be prepared using binders (e.g., cocoa butter and / or polyethylene glycol), gels, or foams that melt at rectal temperature. Parenteral administration can be carried out using aqueous suspensions, isotonic saline solutions, or injectable sterile solutions containing pharmacologically compatible dispersants and / or wetting agents (e.g., polypropylene glycol and / or polyethylene glycol). One or more active ingredients can also be formulated as microcapsules or microparticles, optionally with one or more carriers or additives. Furthermore, one or more active ingredients can be provided as a complex with cyclodextrins, such as α-, β-, or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and / or methyl-β-cyclodextrin.

[0093] When the compound of the present invention is administered daily, the dosage will vary from person to person and can be determined to some extent by the severity of the disease (e.g., NAFLD or NASH) being treated. The dosage of the compound of the present invention may also vary depending on the one or more drugs being administered. Examples of dosages of the compound of the present invention are provided above, but may also vary depending on the synergistic effect of combining two or three drugs.

[0094] The compound may be administered in a single dose or in several smaller doses over a period of time, the length of time over which the compound is administered will vary from individual to individual, but may continue until the desired result (i.e., reduction of body fat or prevention of body fat accumulation) is achieved.

[0095] The present disclosure will be further described based on the following examples, but these examples should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate some embodiments and are not intended to limit the scope of the present disclosure. It should also be understood that various other embodiments, modifications, and equivalents thereof that are obvious to those skilled in the art may be incorporated without departing from the spirit of the present disclosure and / or the appended claims. [Example]

[0096] Example 1:

[0097] Examples of oral compositions of the present invention are shown in the following table (only the active ingredients are shown). [Table 1]

[0098] Example 2:

[0099] Further examples of oral compositions of the present invention are shown in the following table (only the active ingredients are shown): [Table 2]

[0100] Example 3:

[0101] Growth hormone is a hormone produced by the pituitary gland that is involved in regulating metabolism and growth. Obese people, on average, secrete less growth hormone than non-obese people. There is evidence that growth hormone is involved in reducing fat mass in the liver and may also reduce inflammation in the liver. Both of these effects may be beneficial for patients with NAFLD. The purpose of this proposed study was to investigate whether treatment with ibutamoren (also known as ibutamoren mesylate), a growth hormone secretagogue, could reduce liver fat and improve liver inflammation and scarring in obese subjects with NAFLD. [Table 3]

[0102] Research type: Intervention trial (clinical trial) Estimated enrollment: 76 subjects Allocation: Randomization Intervention trial model: parallel group comparative study Details of the intervention study model: Randomized, double-blind, placebo-controlled study for 12 months, followed by an open-label study for 6 months, during which all subjects were actively treated with ibutamoren. Masking: Quadruple-blind (subjects, healthcare providers, researchers, outcome assessors) Primary purpose: treatment Official title: Growth hormone secretagogues for the improvement of nonalcoholic fatty liver disease and associated cardiovascular risk

[0103] Number of groups and intervention studies [Table 4]

[0104] Measuring Results Primary endpoint measures: - Liver fat content [Time frame: 12 months after change from baseline] -Liver fat content as measured by proton nuclear magnetic resonance Secondary endpoint measurements: - NAFLD Activity Score [Timeframe: 12 months after change from baseline] - NAFLD activity score (NAS, score between 0-8) from liver biopsy - Postprandial de novo hepatic lipid synthesis [Time frame: change from baseline to 12 months] -Hepatic de novo lipid synthesis as measured by stable isotope methods - Coronary artery plaque burden [Time frame: 12 months after change from baseline] Calcified and non-calcified plaque volume determined by coronary CT angiography (CCTA) - Non-High-Density Lipoprotein (Non-HDL) Cholesterol [Time Frame: 12 months after change from baseline] C-reactive protein [time frame: change from baseline to 12 months] Fibrosis Score [Time Frame: Change from Baseline to 12 Months] Fibrosis score from liver biopsy

[0105] Eligibility Criteria Eligible ages for the study: 18 to 70 years old (adults, elderly) Study eligibility: All Acceptance of healthy people: No

[0106] standard

[0107] Recruitment criteria: -Men and women aged 18-70 -Body mass index (BMI) ≧30kg / m2 - a) Grade 1+ fatty liver as determined by liver biopsy performed within 12 months of the baseline visit, or >10% loss in body weight or without additional medication for the treatment of fatty liver; b) fatty liver as demonstrated by either a hepatic fat fraction of ≥ 5% on proton nuclear magnetic resonance (1H-MRS) -Hepatitis C antibody and hepatitis B surface antigen negative - For women ≥ 50 years of age, negative mammogram within 1 year of baseline examination If you take ≥ 400 international units of vitamin E per day, take it consistently for ≥ 6 months.

[0108] Exclusion criteria: Heavy alcohol use, defined as consumption of >20 grams per day for women and >30 grams per day for men for at least 3 consecutive months over the past 5 years, assessed using the Lifetime Drinking History Questionnaire - Known diagnosis of diabetes, use of any antidiabetic treatment (including thiazolidinediones or metformin), fasting blood glucose >126 mg / dL, or hemoglobin Alc (HbAlc) ≥ 7% Use of any specific pharmacological treatment for NAFLD / non-alcoholic steatohepatitis except vitamin E - Known cirrhosis, Child-Pugh classification ≥ 7, stage 4 fibrosis by biopsy, or clinical evidence of cirrhosis or portal hypertension by imaging or testing. If a subject is not known to have cirrhosis at screening but is found to have cirrhosis based on the results of the liver biopsy at baseline, the subject will be referred to a hepatologist for clinical care and will be excluded from further participation in the study. Chronic systemic corticosteroid use for ≤6 months prior to the baseline study visit -Chronic use of Actigol, methotrexate, amiodarone, or tamoxifen - known diagnosis of alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis Use of growth hormone or growth hormone-releasing hormone or GH secretagogues within the past year - Changes in lipid lowering or antihypertensive therapy within 2 months of screening -Hemoglobin <10.0g / dL or creatinine >1.5mg / dL - Active malignant tumor For men, a personal history of prostate cancer or evidence of prostate malignancy with a prostate-specific antigen (PSA) >5 ng / mL - Severe chronic illness that the investigator determines contraindicates the subject - History of hypopituitarism, head irradiation or any other condition known to affect the GH axis - Physiological testosterone (men) or estrogen or progesterone (women) use without stable use for ≥1 year prior to study entry - Routine magnetic resonance imaging (MRI) exclusion criteria, such as the presence of a pacemaker or cerebral aneurysm clipping - Weight loss surgery within 2 years prior to the baseline survey. Weight loss surgery more than 2 years prior to the baseline survey visit is acceptable as long as it does not result in significant weight loss (<10% weight loss over the past 6 months). - For women, a positive urine pregnancy test (hCG), attempting to achieve pregnancy, or breastfeeding. - Known hypersensitivity to ibutamoren - Contraindicated to receiving beta-blockers or nitroglycerin (part of coronary angiography) - Significant radiation exposure, including any history of radiation therapy, or any of the following within 12 months prior to randomization: a) ≥2 percutaneous coronary interventions; b) ≥2 myocardial perfusion studies; c) ≥2 computed tomography angiography - Prospective investigation for a procedure or treatment involving significant radiation exposure as defined above within 12 months following randomization - Failure or inability to adhere to the dose schedule and required procedures per protocol - Subjects who are judged by the investigator to be inappropriate for the study for reasons not detailed above

[0109] Example 4:

[0110] The aim of this proposed study is to investigate whether treatment with the growth hormone secreting agent ibutamoren (also known as ibutamoren mesylate) in combination with a second active ingredient can reduce liver fat and improve liver inflammation and scarring in obese subjects with NAFLD. [Table 5]

[0111] Groups and interventions [Table 6]

[0112] Measuring Results Primary endpoint measures: - Liver fat content [Time frame: 12 months after change from baseline] -Liver fat content as measured by proton nuclear magnetic resonance Secondary endpoint measurements: - NAFLD Activity Score [Timeframe: 12 months after change from baseline] NAFLD activity score (NAS, a score between 0 and 8) from liver biopsy - Postprandial de novo hepatic lipid synthesis [Time frame: change from baseline to 12 months] Hepatic de novo lipid synthesis as measured by stable isotope methods Coronary artery plaque burden [Time frame: 12 months after change from baseline] Calcified and non-calcified plaque volume determined by coronary CT angiography (CCTA) - Non-High-Density Lipoprotein (Non-HDL) Cholesterol [Time Frame: 12 months after change from baseline] -C-reactive protein [time frame: change from baseline to 12 months] Fibrosis Score [Time Frame: Change from Baseline to 12 Months] Fibrosis score from liver biopsy

[0113] Eligibility Criteria Eligible ages for the study: 18 to 70 years old (adults, elderly) Study eligibility: All Acceptance of healthy people: No

[0114] standard

[0115] Recruitment criteria: -Men and women aged 18-70 -Body mass index (BMI) ≧30kg / m2 - a) Grade 1+ fatty liver as determined by liver biopsy performed within 12 months of the baseline visit, or >10% loss in body weight or without additional medication for the treatment of fatty liver; b) fatty liver as demonstrated by either a hepatic fat fraction of ≥ 5% on proton nuclear magnetic resonance (1H-MRS) -Hepatitis C antibody and hepatitis B surface antigen negative -Hepatitis C antibody and hepatitis B surface antigen negative - For women ≥ 50 years of age, negative mammogram within 1 year of baseline examination If you take ≥ 400 international units of vitamin E per day, take it consistently for ≥ 6 months.

[0116] Exclusion criteria: Heavy alcohol use, defined as consumption of >20 grams per day for women and >30 grams per day for men for at least 3 consecutive months over the past 5 years, assessed using the Lifetime Drinking History Questionnaire - Known diagnosis of diabetes, use of any antidiabetic treatment (including thiazolidinediones or metformin), fasting blood glucose >126 mg / dL, or hemoglobin Alc (HbAlc) ≥ 7% Use of any specific pharmacological treatment for NAFLD / non-alcoholic steatohepatitis except vitamin E - Known cirrhosis, Child-Pugh classification ≥ 7, stage 4 fibrosis by biopsy, or clinical evidence of cirrhosis or portal hypertension by imaging or testing. If a subject is not known to have cirrhosis at screening but is found to have cirrhosis based on the results of the liver biopsy at baseline, the subject will be referred to a hepatologist for clinical care and will be excluded from further participation in the study. Chronic systemic corticosteroid use for ≤6 months prior to the baseline study visit -Chronic use of Actigol, methotrexate, amiodarone, or tamoxifen - known diagnosis of alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis Use of growth hormone or growth hormone-releasing hormone or GH secretagogue within the past year - Changes in lipid lowering or antihypertensive therapy within 2 months of screening -Hemoglobin <10.0g / dL or creatinine >1.5mg / dL - Active malignant tumor For men, a personal history of prostate cancer or evidence of prostate malignancy with a prostate-specific antigen (PSA) >5 ng / mL - Severe chronic illness that the investigator determines contraindicates the subject - History of hypopituitarism, head irradiation or any other condition known to affect the GH axis - Physiological testosterone (men) or estrogen or progesterone (women) use without stable use for ≥1 year prior to study entry - Routine magnetic resonance imaging (MRI) exclusion criteria, such as the presence of a pacemaker or cerebral aneurysm clipping - Weight loss surgery within 2 years prior to the baseline survey. Weight loss surgery more than 2 years prior to the baseline survey visit is acceptable as long as it does not result in significant weight loss (<10% weight loss over the past 6 months). - For women, a positive urine pregnancy test (hCG), attempting to achieve pregnancy, or breastfeeding. - Administration of any medication that is a strong CYP3A4 antagonist, such as ketoconazole, some protease inhibitors (e.g., ritonavir) - Contraindicated to receiving beta-blockers or nitroglycerin (part of coronary angiography) - Significant radiation exposure, including any history of radiation therapy, or any of the following within 12 months prior to randomization: a) ≥2 percutaneous coronary interventions; b) ≥2 myocardial perfusion studies; c) ≥2 computed tomography angiography - Prospective investigation for a procedure or treatment involving significant radiation exposure as defined above within 12 months following randomization - Failure or inability to adhere to the dose schedule and required procedures per protocol -Data suggest that pioglitazone use may be associated with an increased risk of bladder cancer, as FDA has warned overall. - Subjects who are judged by the investigator to be inappropriate for the study for reasons not detailed above

[0117] Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

1. 1. A method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), comprising: A method comprising administering a therapeutically effective amount of growth hormone secretagogue (GHS) to a patient in need thereof.

2. 2. The method of claim 1, wherein the disease is NAFLD.

3. 2. The method of claim 1, wherein the disease is NASH.

4. 2. The method of claim 1, wherein the GHS is ibutamoren.

5. 5. The method of claim 4, wherein the therapeutically effective amount of ibutamoren is 25 to 50 mg / day.

6. 1. A method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), comprising: a therapeutically effective amount of growth hormone secretagogue (GHS); and a therapeutically effective amount of a second drug selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a thiazolidinedione, a sodium-glucose cotransporter 2 (SGLT2) antagonist, metformin, and vitamin E. to a patient in need thereof.

7. 7. The method of claim 6, wherein the GHS is ibutamoren.

8. 7. The method of claim 6, wherein the therapeutically effective amount of ibutamoren is 25 to 50 mg / day.

9. The method of claim 6, wherein the second drug is a DPP4 antagonist.

10. The method of claim 6, wherein the DPP antagonist is sitagliptin.

11. 7. The method of claim 6, wherein the GHS is ibutamoren and the second drug is sitagliptin.

12. 7. The method of claim 6, wherein the second drug is a GLP-1 receptor agonist.

13. 7. The method of claim 6, wherein the second drug is a thiazolidinedione.

14. 7. The method of claim 6, wherein the second drug is pioglitazone.

15. 7. The method of claim 6, wherein the GHS is ibutamoren and the second drug is pioglitazone.

16. 7. The method of claim 6, wherein the second drug is an SGLT2 antagonist.

17. 7. The method of claim 6, wherein the second drug is metformin.

18. 7. The method of claim 6, wherein the GHS is ibutamoren and the second drug is metformin.

19. 1. A method of treating NAFLD or NASH, comprising: a. a therapeutically effective amount of growth hormone secretagogue (GHS); b. a therapeutically effective amount of a second drug selected from a dipeptidyl peptidase-4 (DPP4) antagonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a thiazolidinedione, and a sodium-glucose cotransporter 2 (SGLT2) antagonist; and c. A therapeutically effective amount of a third drug that is metformin. to a patient in need thereof.

20. 20. The method of claim 19, wherein the therapeutically effective amount of ibutamoren is 25-50 mg / day.

21. 20. The method of claim 19, wherein the GHS is ibutamoren and the second drug is sitagliptin.

22. 20. The method of claim 19, wherein the GHS is ibutamoren and the second drug is pioglitazone.

23. 1. A pharmaceutical composition comprising: a. a therapeutically effective amount of GHS; b. a therapeutically effective amount of a second drug selected from a DPP4 antagonist, a thiazolidinedione, an SGLT2 antagonist, metformin, and vitamin E; and c. a pharmaceutically acceptable carrier; and is useful for treating NAFLD and / or NASH.

24. 24. The pharmaceutical composition of claim 23, wherein the GHS is ibutamoren.

25. 24. The pharmaceutical composition of claim 23, wherein the therapeutically effective amount of ibutamoren is 25 to 50 mg / day.

26. 1. A pharmaceutical composition comprising: a. a therapeutically effective amount of GHS; b. a therapeutically effective amount of a second drug selected from a DPP4 antagonist, a thiazolidinedione, and an SGLT2 antagonist; c. a therapeutically effective amount of a third drug that is metformin, and d. Pharmaceutically Acceptable Carriers and is useful for treating NAFLD and / or NASH.

27. 27. The pharmaceutical composition of claim 26, wherein the GHS is ibutamoren.

28. 27. The pharmaceutical composition of claim 26, wherein the therapeutically effective amount of ibutamoren is 25 to 50 mg / day.

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