阅读说明：本技术 用于治疗非酒精性脂肪性肝病和非酒精性脂肪性肝炎的组合物 (Composition for treating non-alcoholic fatty liver disease and non-alcoholic steatohepatitis ) 是由 M·O·索纳 R·G·史密斯 于 2019-02-14 设计创作，主要内容包括：本申请描述了一种单独使用促生长激素分泌素或将其与选自二肽基肽酶-4拮抗剂、胰高血糖素样肽受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2拮抗剂和二甲双胍的药物联用用于治疗诸如非酒精性脂肪性肝病和非酒精性脂肪性肝炎的疾病的新方法。还提供了与此相关的组合物。(The present application describes a novel method for the treatment of diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis using somatotropin secretin alone or in combination with an agent selected from the group consisting of dipeptidyl peptidase-4 antagonists, glucagon-like peptide receptor agonists, thiazolidinediones, sodium glucose transporter 2 antagonists and metformin. Compositions related thereto are also provided.)

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

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

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

4. The method of claim 1, wherein the GSH is ibumorren.

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

6. A method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), the method comprising the step of administering to a patient in need thereof:

a therapeutically effective amount of a Growth Hormone Secretagogue (GHS); and

a therapeutically effective amount of a second agent selected from the group consisting of: dipeptidyl peptidase-4 (DPP4) antagonists, glucagon-like peptide (GLP-1) receptor agonists, thiazolidinediones, sodium glucose transporter 2(SGLT2) antagonists, metformin, and vitamin E.

7. The method according to claim 6, wherein the GHS is Ebrimorren.

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

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

10. The method according to claim 6, wherein the DPP4 antagonist is sitagliptin.

11. The method in accordance with claim 6, wherein the GHS is ibutamoren and the second drug sitagliptin.

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

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

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

15. The method in accordance with claim 6, wherein the GHS is ibutamoren and the second drug is pioglitazone.

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

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

18. The method in accordance with claim 6, wherein the GHS is Ebrimoram and the second drug is metformin.

19. A method of treating NAFLD or NASH, comprising administering to a patient in need thereof:

a therapeutically effective amount of a Growth Hormone Secretagogue (GHS);

b a therapeutically effective amount of a second agent selected from the group consisting of: dipeptidyl peptidase-4 (DPP4) antagonists, glucagon-like peptide (GLP-1) receptor agonists, thiazolidinedione and sodium glucose transporter 2(SGLT2) antagonists; and

c a therapeutically effective amount of a third agent which is metformin.

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

21. The method in accordance with claim 19, wherein the GHS is ibutamoren and the second drug is sitagliptin.

22. The method in accordance with claim 19, wherein the GHS is ibumoram and the second drug is pioglitazone.

23. A pharmaceutical composition comprising:

a therapeutically effective amount of GHS;

b a therapeutically effective amount of a second agent selected from the group consisting of: a DPP4 antagonist, thiazolidinedione, SGLT2 antagonist, metformin and vitamin E; and the combination of (a) and (b),

c a pharmaceutically acceptable carrier;

wherein the composition is for use in the treatment of NAFLD and/or NASH.

24. The pharmaceutical composition according to claim 23, wherein the GHS is ibumoram.

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

26. A pharmaceutical composition comprising:

a therapeutically effective amount of GHS;

b a therapeutically effective amount of a second agent selected from the group consisting of: DPP4 antagonists, thiazolidinediones and SGLT2 antagonists;

c a therapeutically effective amount of a third agent which is metformin; and the combination of (a) and (b),

d a pharmaceutically acceptable carrier;

wherein the composition is for use in the treatment of NAFLD and/or NASH.

27. The pharmaceutical composition according to claim 26, wherein the GHS is ibumoram.

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

Technical Field

The present invention relates to a novel method for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis using a somatotropin secretagogue or combining a somatotropin secretagogue with a drug selected from the group consisting of dipeptidyl peptidase-4 antagonists, glucagon-like peptide receptor agonists, thiazolidinediones, sodium glucose transporter 2 antagonists, metformin, and vitamin E.

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

Background

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. This is a condition in which excess fat is stored in the liver. This condition is not caused by heavy drinking (which would be alcoholic liver disease). NAFLD causes inflammation, fibrosis and hepatocellular carcinoma in the liver, which has become a major health problem and is associated with increased prevalence of obesity, insulin resistance, type 2 diabetes and metabolic diseases. Its incidence in the us population is estimated to be 25-30% and is also increasing. It is also estimated that approximately 20% of people with NAFLD also have nonalcoholic steatohepatitis (NASH), which can lead to complications such as cirrhosis and liver cancer. Treatment of NAFLD and/or NASH is considered another approach to the treatment of obesity, insulin resistance, type 2 diabetes, and metabolic diseases.

Currently, there is no effective treatment for NAFLD or NASH. Therefore, it is desirable to develop methods for treating these diseases.

Disclosure of Invention

In one aspect, the invention provides a novel method of treating non-alcoholic fatty liver disease using Growth Hormone Secretagogue (GHS).

In one aspect, the present invention provides a novel method of treating NAFLD using GSH in combination with an agent selected from the group consisting of: dipeptidyl peptidase-4 (DPP4) antagonists, glucagon-like peptide (GLP-1) receptor agonists, thiazolidinediones, sodium glucose transporter 2(SGLT2) antagonists, metformin, and vitamin E.

In another aspect, the invention provides a novel method of treating non-alcoholic steatohepatitis using a somatotropin secretagogue.

In one aspect, the invention provides a novel method of treating NASH using GSH in combination with an agent selected from the group consisting of: dipeptidyl peptidase-4 antagonists, glucagon-like peptide receptor agonists, thiazolidinediones, sodium glucose transporter 2 antagonists, metformin, and vitamin E.

Detailed Description

The inventors have found that the use of growth hormone secretagogues (e.g., ibutemoren) alone or in combination with a drug selected from the group consisting of NAFLD and NASH is expected to treat diseases such as NAFLD and NASH: dipeptidyl peptidase-4 antagonists, glucagon-like peptide receptor agonists, thiazolidinediones, sodium glucose transporter 2 antagonists, metformin, and vitamin E.

For example, the inventors have discovered that the use of a growth hormone secretagogue, ibutemeron, in combination with a DPP4 antagonist, cinolone^TMThe combined new therapeutic method of ibemolan is useful for the treatment of NAFLD and NASH. Ibumomen and fenovir^TMAll have oral activity and good safety. The inventors believe that compositions formulated, for example, as individual pills take advantage of the properties of ibutamoren to normalize GH, whereas fenovir^TMThe glucose stimulated insulin release is enhanced. Based on their different mechanisms of action, the inventors believe that a combination of the two will prove to be synergistic or at least additive for the treatment/prevention of NAFLD.

The structure of ibulamon (also referred to herein as ibulamon mesylate) is shown below:

ebamoren is commercially available from suppliers such as Sigma Aldrich and Caymen Chemical.

NAFLD and Growth Hormone (GH)

NAFLD causes inflammation, fibrosis and hepatocellular carcinoma in the liver, which has become a major health problem and is associated with increased prevalence of obesity, insulin resistance, type 2 diabetes and metabolic diseases. A cross-sectional study of 7,146 subjects showed that NAFLD was associated with lower levels of circulating Growth Hormone (GH) (Xu, Xu et al, 2012). GH-deficient adults have low levels of insulin-like growth factor (IGF-1) and IGF binding protein-3 BP3(IGFBP3) and have insulin resistance. GH has a positive regulatory effect on both IGF-1 and IGFBP 3.

Studies in hypophysectomized rats have shown that GH is critical for the regulation of LDL receptor expression and circulating lipoprotein levels (Rudling, Norstedt et al, 1992). In addition to increasing IGF-1 and IGFBP3, GH therapy also controls the activity of key enzymes involved in cholesterol and bile acid biosynthesis. In addition, GH controls the expression of genes that enhance Triglyceride (TG) hydrolysis, decrease TG storage, and increase diacylglycerol synthesis (Zhao, Cowley et al, 2011).

Binding of GH to the GH receptor (GHR) in the liver activates the transcription factor STAT 5. Liver-selective ablation of GHR or STAT5 in mice results in hepatic steatosis, insulin resistance, glucose intolerance, increased triglyceride synthesis and decreased efflux (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.

GH controls the local production of cortisol by modulating 11 β -hydroxysteroid dehydrogenase type 1 (HSD1), which is responsible for the local conversion of cortisone to the active glucocorticoid cortisol; cortisol regulates gluconeogenesis and fat deposition. HSD1 is expressed in liver, adipose tissue and brain. Overproduction of HSD1 in the liver increases cortisol-induced gluconeogenesis by increasing the expression of the rate-limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase. Furthermore, overexpression of HSD1 in omental fat stimulates adipogenesis, which may lead to central obesity. It follows that inhibition of HSD1 activity to reduce local cortisol production is a potential approach for the prevention and treatment of type 2 diabetes, obesity, age-related cognitive dysfunction and NAFLD. HSD1 inhibitors improved insulin sensitivity and improved hepatic steatosis in db/db mice (Yuan, Li et al, 2016). Impaired Gh production increases HSD1 expression, and Gh deficient patients exhibit an elevated cortisol/cortisone ratio, which can be reversed by administration of low doses of Gh.

Genetic studies have shown that NAFLD is associated with a genetic polymorphism encoding protein 3(PNPLA3) comprising a patatin-like phospholipase domain. Although the mechanism is still unclear, the variant PNPLA3-148M is associated with all aspects of NAFLD pathology (Boursier and Diehl 2015). Studies carried out on obese hispanic children expressing this gene variant and mice expressing human PNPLA3-148M showed that the development of NAFLD was dependent on intake of high carbohydrate rather than high fat diets (Davis, Le et al 2010, Boursier and Diehl 2015, Smagris, basura et al 2015). Recent evidence suggests that PNPLA3 is cleared by a mechanism involving ubiquitination, but PNPLA3-148M is resistant, resulting in accumulation of variant proteins on lipid droplets (BasuRay, Smigris et al, 2017). According to mouse studies (Smagris, basura et al 2015), increasing or decreasing PNPLA3 had little effect on steatosis in subjects with both WT alleles, whereas increasing PNPLA3-148M aggravated steatosis. Since GH increases expression of wild-type PNPLA3-WT (Zhao, Cowley et al, 2011), GH treatment should prove effective in treating PNPLA3-148M heterozygotes.

Effects of insulin and growth hormone in hepatic steatosis

Obesity and type 2 diabetes are associated with insulin resistance. This resistance is mediated primarily in skeletal muscle and the ability of insulin to inhibit hepatic gluconeogenesis. Inhibition of hepatic gluconeogenesis depends on a reduction in free fatty acids in adipose tissue (Bergman and Iyer 2017). Thus, resistance is purely extrahepatic in skeletal muscle and adipose tissue, while the liver retains its sensitivity to insulin to stimulate lipogenesis-referred to as "selective insulin resistance", see (titchenll, Quinn et al, 2016).

Treatment of diabetes is a balance, on the one hand, to regulate and control hyperglycemia without increasing liver adipogenesis. Thus, increasing insulin levels by exogenous insulin or sulfonylurea drugs does not play a role in treating NAFLD. However, GLP-1 agonists or DPP4 antagonists that prolong endogenous GLP-1 activity are preferred because they enhance insulin release in response to glucose and lower blood glucose, which reduces the ability to enhance lipogenesis in the liver. Since it has been determined that the effect of insulin on adipocyte inhibition of lipolysis inhibits hepatic gluconeogenesis and that it is regulated by the first phase secretion of insulin, DPP4 inhibitors are ideal therapies to inhibit this process (Mest and Mentlein 2005).

Obesity and type 2 diabetes are associated with inhibited GH secretion. Insulin and GH are secreted in a pulsed manner, and both are tightly regulated. For example, IGFBP-1 is rapidly inhibited when insulin secretion increases, which then results in an increase in free IGF-1, which IGF-1 feeds back to inhibit GH secretion. After a meal, insulin levels increase to facilitate transport of glucose into the cell and enhance energy storage in the form of fat. The liver is critical for the integration of metabolism, storing glycogen and fat for use when energy utilization is enhanced (e.g., exercise or hunger) (Cahill 1971). After 12 to 14 hours of starvation, glycogen stores in the liver are depleted and the body switches to energy harvesting from fat. In addition to storing fat in the liver, it is also stored in white adipose tissue (primarily subcutaneous fat), which can be mobilized as needed. Insulin and GH are two hormones that are primarily used to regulate the deposition and subsequent mobilization of fat in the liver and adipose tissue. Thus, as time increases after a meal, insulin levels fall and GH levels rise. Upon feeding, insulin rises and GH is inhibited. The regulation of insulin and GH is complex, but both are regulated by two other hormones produced in the gastrointestinal tract (GLP-1 against insulin and ghrelin against GH). Both GLP-1 and ghrelin function in a similar manner, enhancing the normal amplitude of insulin and GH pulses, respectively. Importantly, insulin and GH are normally secreted in a reverse manner to each other at the appropriate time, i.e. GH levels are inhibited when insulin levels are high.

Daily oral administration of ibumomam restores the normal state of endogenous GH

Since endogenous GH is released by the anterior pituitary gland pulse throughout the day, injection of recombinant GH (rhgh) alone cannot restore the physiological properties of GH release. In GH-deficient subjects, low doses of GH can improve insulin sensitivity, but high levels of GH produce insulin resistance; therefore, selecting an appropriate therapeutic dose is challenging. Release of endogenous GH is affected by regulatory feedback mechanisms, but administration of exogenous rhGH bypasses the GH negative feedback pathway. In contrast, administration of the GH secretagogue, ibumoram, enhanced the magnitude of endogenous GH pulse release and normalized GH, since the stimulatory effect of ibumoram on GH pulses is effected by IGF-1 mediated natural inhibitory feedback; thus, overstimulation of the GH/IGF-1 axis is avoided (Smith, Van der Ploeg et al, 1997). Therefore, by repeating normal GH physiological effects, ibobromin is ideal for increasing insulin sensitivity in the treatment/prevention of NAFLD.

Treatment of limitations of NAFLD using GLP-1 analogs or DPP4 inhibitors

While increasing the magnitude of pulsatile insulin release in response to glucose, the knowledge of whether insulin sensitivity is improved is not generally consistent (Tominaga, Ikezawa et al, 1996, Ahren, Larsson et al, 1997). since one important aspect of NAFLD is its relationship to insulin resistance, targeting only the GLP-1 pathway is unlikely to have sufficient therapeutic benefit, indeed, this is supported by clinical studies reporting.e.type 2 diabetes patients using metformin and/or sulfonylurea drugs are assigned to receive the GLP-1 receptor agonist liraglutide and/or the DPP4 inhibitor sitagliptin (Tenowentin)^TM) Treatment is carried out for 12 weeks; neither treatment reduced hepatic steatosis or fibrosis (Smits, Tonneijck et al, 2016). In a 24-week study of 50 patients with NAFLD, it was concluded that sitagliptin was not better at reducing liver fat than placebo (Cui, philio et al, 2016). In additionOne study on 12 subjects treated with sitagliptin for 24 weeks showed no improvement in fibrosis (Joy, McKenzie et al, 2017). The inventors propose that a limitation of targeting only the GLP-1 pathway for the treatment of NAFLD is that it does not adequately alleviate insulin resistance associated with NAFLD.

Proposed treatment of NAFLD using a combination of ibumoram and jiranol

The ideal treatment for NAFLD is to restore deficient GH secretion, then restore bile acid secretion and hepatic lipid metabolism, and increase timed insulin secretion appropriately. The inventors believe this can be achieved by, for example, ibremoam and fenovir^TMBy using ibutamoren to mimic the growth hormone releasing peptide, and by using fenovir^TMIncreasing endogenous GLP-1 by blocking DPP4, which normally destroys GLP-1, ibutamoren has a clear advantage over ghrelin because, in addition to having no oral activity, ghrelin also inhibits insulin release from pancreas β -cells direct comparison shows that ibutamoren does not inhibit glucose-stimulated insulin secretion and therefore, ibutamoren does not negate GLP-1 stimulation of insulin release^TMThe combined pill of (a) will have the properties necessary to treat/prevent NAFLD.

Animal studies indicate that GH is an important regulator of hepatic fat metabolism. Visceral fat and fat accumulation in the liver increase with age, which is associated with a 50% gradual decrease in GH secretion from mid-puberty every 7-10 years, so that GH levels in the elderly are similar to GH-deficient young people. GH deficient adult alcoholic fatty liver disease (NAFLD) and steatohepatitis have increased incidence. GH replacement therapy reverses this process. The hypothesis is that GH secretagogues such as ibumoram will restore pulsed GH secretion and reduce visceral fat; this is based on the following observations: endogenous GH secretion is negatively associated with visceral fat mass and liver fat accumulation (NAFLD), while low doses of GH reverse this process. HIV lipodystrophy is associated with increased visceral fat accumulation and steatohepatitis. It has been treated by supraphysiological rhGH injection and tesamolin (a long-acting GHRH analogue). This hypothesis is supported by the demonstration that ibtemoram enhances GH secretion, increases serum IGF-1 and increases lean body mass in obese individuals. It is proposed to use ibutamoren as a therapeutic drug for NAFLD and steatohepatitis caused by NAFLD. Combinations with various agents that improve insulin sensitivity are proposed to mitigate the mild diabetogenic effects of increased GH secretion induced by Ebriam.

Vitamin E

Oxidative stress plays an important role in the progression of NASH. Vitamin E is a well-known free radical scavenger that has been prescribed for the treatment of NASH. In adult NASH patients refractory to dietary intervention, treatment with vitamin E for 1 year reduced serum transaminase activity as well as TGF-. beta.1. In a pioglitazone versus vitamin E versus placebo trial of non-diabetic patients with non-alcoholic steatohepatitis (PIVENS), vitamin E (800 mg/day) was superior to placebo in improving the histology of NASH in adult NASH without diabetes and cirrhosis.

According to the stochastic effect model analysis of the five studies, vitamin E significantly reduced serum hepatobiliary enzyme, hepatic steatosis, inflammation and hepatocyte swelling (ballooning) compared to the control group. However, in those studies, no improvement in fibrosis was confirmed.

In Japan, chronic administration of vitamin E (300 mg/day) for more than 2 years improves hepatic fibrosis in NASH patients, particularly those with improved serum transaminase activity and insulin resistance. The results indicate that metabolic factors should be controlled even if vitamin E is administered.

Although vitamin E is now only suggested for biopsy-confirmed non-diabetic NASH patients according to the PIVENS test, vitamin E is associated with histological improvement regardless of the diabetic state. However, a major problem with vitamin E for NASH treatment is that long-term or high dose use may produce toxicity. Vitamin E treatment may increase all-cause mortality, prostate cancer (SELECT test), and hemorrhagic stroke, although there are some conflicting results. When vitamin E is used in NASH, drug therapy at lower doses (300-400 mg/day rather than 800mg) should be considered.

Certain embodiments of the invention

In one aspect, the present invention provides a novel method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), the method comprising: administering to a patient in need thereof a therapeutically effective amount of a Growth Hormone Secretagogue (GHS).

In another aspect, the novel method further comprises: administering a therapeutically effective amount of a second agent selected from the group consisting of: dipeptidyl peptidase-4 (DPP4) antagonists, glucagon-like peptide (GLP-1) receptor agonists, thiazolidinediones, sodium glucose transporter 2(SGLT2) antagonists, metformin, and vitamin E.

Patient refers to a human patient, whether child or adult.

In another aspect, the disease is NAFLD.

In another aspect, the disease is NASH.

In another aspect, the GHS is ibulamen (ibulamen mesylate).

In another aspect, for example, 10-50mg of ibutamoren is administered once daily. In one embodiment, 25-50mg of ibutamoren is administered once daily. Other examples of the amount of ibrutinam administered include 10, 15, 20, 25, 30, 35, 40, 45 and 50 mg. In another aspect, the ibutamoren is administered orally.

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

In another aspect, the DPP4 antagonist is selected from:

sitagliptin (trade name)Administered orally, usually at a dose of 25-100 mg/day); vildagliptin (trade name)Administered orally, typically at a dose of 50mg twice per day);

saxagliptin (saxagliptin) (trade name)

Administered orally, usually at a dose of 2.5 or 5 mg/day);

linagliptin (linagliptin) (trade name)Administered orally, typically at a dose of 5 mg/day); and

alogliptin (trade name)Typically administered at doses of 6.25, 12.5 and 25 mg/day, orally).

In another aspect, the second agent is a GLP-1 receptor agonist.

In another aspect, the GLP-1 receptor agonist is selected from the group consisting of:

exenatide (Exenatide) (trade name)And

administered, injected, usually at a dose of 2mg once per week);

liraglutide (trade name)And

administered, usually at a dose of 1.2 mg/day, injected);

lixisenatide (trade name)Administered, injected, usually at a dose of 20 μ g/day);

albiutide (trade name)

Administered, injected, typically at a dose of 30mg once per week);

dulaglutide (trade name)Administered, injected, usually at a dose of 0.75-1.5mg once per week); and

semaglutide (trade name)Usually administered in a dose of 0.5-1mg once/week, injected).

In another aspect, the second agent is a Thiazolidinedione (TZD). Thiazolidinediones (also known as glitazones) are a class of drugs (e.g., antihyperglycemic and/or antidiabetic) that have hypoglycemic effects.

In another aspect, the TZD is selected from:

pioglitazone (pioglitazone) (trade name)

Administered orally, typically at a dose of 15mg, 30mg or 45 mg/day); and

rosiglitazone (rosiglitazone) (trade name)

It is usually administered orally at 4mg (2mg +2mg or 4mg in one dose) or 8 mg/day.

In another aspect, the second drug is a sodium glucose transporter 2(SGLT2) antagonist.

In another aspect, the SGLT2 antagonist is selected from:

empagliflozin (empagliflozin) (trade name)

Usually administered at a dose of 5, 10 or 12.5 mg/day, orally, depending on whether administered alone or in combination with metformin); and

dapagliflozin (da)pagliflozin) (trade name)

Usually administered at a dose of 2.5, 5 or 10 mg/day, orally, depending on whether administered alone or in combination with metformin).

In another aspect, the second agent is metformin. Metformin is available in a variety of dosage options, including 500, 850 and 1000mg immediate release tablets and 500, 750 and 1000mg sustained release tablets. Metformin is typically administered orally at a dosage of 1500, 2000, 2500 to 2550 mg/day.

In another aspect, in the method of treatment, the GHS is ibumoram and the second drug is selected from:

(i.) sitagliptin;

(ii) vildagliptin;

(iii) saxagliptin;

(iv) linagliptin;

(v.) alogliptin;

(vi.) pioglitazone;

(vii) rosiglitazone;

(viii.) engeletzin;

(ix.) dapagliflozin; and the combination of (a) and (b),

(x.) metformin.

In another aspect, in the method of treatment, the GHS is ibutamoren and the second drug is sitagliptin.

In another aspect, in the method of treatment, the GHS is ibutemam and the second agent is pioglitazone.

In another aspect, in the method of treatment, the GHS is ibumoram and the second drug is metformin.

In another aspect, the present invention provides a novel method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), the method comprising: administering to a patient in need thereof:

(i.) a therapeutically effective amount of Growth Hormone Secretagogue (GHS);

(ii) a therapeutically effective amount of a second agent selected from the group consisting of: dipeptidyl peptidase-4 (DPP4) antagonists, glucagon-like peptide (GLP-1) receptor agonists, thiazolidinedione and sodium glucose transporter 2(SGLT2) antagonists; and the combination of (a) and (b),

(iii.) a therapeutically effective amount of a third agent which is metformin.

In another aspect, the second agent is selected from the group consisting of a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, and a sodium glucose transporter 2(SGLT2) antagonist.

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

In another aspect, the second agent is a thiazolidinedione.

In another aspect, the second drug is a sodium glucose transporter 2(SGLT2) antagonist.

In another aspect, in the method of treatment, the GHS is ibumoram, the second drug is sitagliptin and the third drug is metformin.

In another aspect, in the method of treatment, the GHS is ibumoram, the second agent is pioglitazone, and the third agent is metformin.

The timing of the administration of the first (i.e., GSH) and second (or first, second, and third) drugs depends on their independent dosing regimen. Examples of timing of administration include:

(i.) simultaneous administration, single formulation. This can be accomplished by co-formulating the drugs (two or three) into a single formulation (e.g., an oral formulation) and then administering the single formulation.

(ii.) simultaneous administration, different formulations. This may be achieved by separate administration (e.g., different oral, oral/injectable, or injectable formulations) at about the same time.

(iii.) simultaneous + additional administrations. For drugs administered on overlapping occasions (e.g., morning, but only one in the evening), one of the regimens (i.) or (ii.) may be used, followed by additional dosing.

(iv) non-simultaneous administration. For drugs administered at different occasions (e.g., daily oral formulation versus weekly injections), the drugs may be administered according to their respective schedules.

One of the potential benefits of the present invention is the possibility of administering the first and second (or first, second and third) drugs simultaneously. For example, if the second (or second and third) medicament is capable of oral administration, the first and second (or second and third) medicaments may be formulated as a single oral formulation (e.g., pill, tablet, capsule, powder, liquid suspension, etc.).

In another aspect, the present invention provides a novel pharmaceutical composition comprising:

(i.) a therapeutically effective amount of Growth Hormone Secretagogue (GHS);

(ii.) the therapeutically effective amount of the second agent is selected from: dipeptidyl peptidase-4 (DPP4) antagonists, thiazolidinediones, sodium glucose transporter 2(SGLT2) antagonists, and metformin; and the combination of (a) and (b),

(iii) a pharmaceutically acceptable carrier;

wherein the composition is for use in the treatment of NAFLD and/or NASH.

In another aspect, the composition may be administered orally or parenterally.

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

In another aspect, the GHS is ibutamoren and the second drug is sitagliptin.

In another aspect, the second agent is a thiazolidinedione.

In another aspect, the GHS is ibutemam and the second drug is pioglitazone.

In another aspect, the second drug is an SGLT2 antagonist.

In another aspect, the second agent is metformin.

In another aspect, the GHS is ibutamoren and the second drug is metformin.

In another aspect, the present invention provides a novel three-drug composition comprising:

(i.) a therapeutically effective amount of Growth Hormone Secretagogue (GHS); and the combination of (a) and (b),

(ii) a therapeutically effective amount of a second agent selected from the group consisting of: dipeptidyl peptidase-4 (DPP4) antagonists, thiazolidinedione and sodium glucose transporter 2(SGLT2) antagonists;

(iii.) a therapeutically effective amount of a third agent which is metformin;

(iv) a pharmaceutically acceptable carrier;

wherein the composition is for use in the treatment of NAFLD and/or NASH.

In another aspect, the three-drug composition is administered orally or parenterally.

In another aspect, in a triple combination, the second agent is a DPP4 antagonist.

In another aspect, in a triple combination, the GHS is ibutamoren and the second drug is sitagliptin.

In another aspect, in a triple combination, the second drug is a thiazolidinedione.

In another aspect, in a triple combination, the GHS is ibutamoren and the second drug is pioglitazone.

In another aspect, in the triple combination, the second drug is an SGLT2 antagonist.

In another aspect, the present invention provides a novel packaged kit 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 the group consisting of: a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione, a sodium glucose transporter 2(SGLT2) antagonist, and metformin, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a novel packaged kit 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 the group consisting of: a dipeptidyl peptidase-4 (DPP4) antagonist, a thiazolidinedione and sodium glucose transporter 2(SGLT2) antagonist, and a pharmaceutically acceptable carrier;

(iii.) at least one third compartment comprising: a therapeutically effective amount of a third agent which is metformin, and a pharmaceutically acceptable carrier.

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

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

In another aspect, the present invention provides the use of a novel composition comprising a first drug and a second drug in the manufacture of a medicament for the treatment of the indications described herein.

In another aspect, the present invention provides the use of a novel composition comprising a first drug, a second drug and a third drug in the manufacture of a medicament for the treatment of the indications described herein.

Most of the approved drugs cited in this application have specific pharmaceutically acceptable salts (e.g., ibtemopram is mesylate, ibtemopram mesylate). Although approved salts are cited above, other pharmaceutically acceptable salts are also considered part of the presently claimed invention.

The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention includes all combinations of aspects described herein. It is to be understood that any and all embodiments of the present invention may be combined with any other embodiment or embodiments to describe additional embodiments. It should also be understood that each separate element of an embodiment is intended to be considered separately as its own independent embodiment. Moreover, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

Definition of

"treating" or "treatment" encompasses the treatment of a disease state in a mammal and includes: (a) preventing the occurrence of a disease state in a mammal, particularly when such mammal is predisposed to the disease state but has not yet been diagnosed as having the disease; (b) inhibiting the disease state, e.g., arresting its development; and/or (c) alleviating the disease state, e.g., causing regression of the disease state, until a desired endpoint is reached. Treatment also includes ameliorating the symptoms of a disease (e.g., reducing pain or discomfort), where such amelioration may or may not directly affect the disease (e.g., cause, transmission, expression, etc.).

"pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids of basic residues (e.g., amines); alkali metal or organic salts of acidic residues (e.g., carboxylic acids); and so on. 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, those derived from inorganic and organic acids selected from the group consisting of: 1, 2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, ethylenediamine, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylsalicylic acid (glycosalicylanilic), hexylresorcinol, hydrabamic acid (hydrabamic), hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (napsylic), nitric acid, oxalic acid, methylenepamoic acid (pamoic acid), pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid (suberic), succinic acid, sulfamic acid (sulfamic acid), sulfanilic acid (bacterial), sulaniic acid (bacterial), succinic acid (sulaniic acid), Sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile may be used. A list of suitable salts can be found in Remington's pharmaceutical Sciences, 18 th edition, Mack Publishing Company, Easton, PA,1990, p 1445, the entire contents of which are incorporated herein by reference.

"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 disease, inflammatory disease, liver disease, cancer, and combinations or complications thereof or other indications listed in the present application. "therapeutically effective amount" also includes the amount of the combination of claimed compounds effective to treat the indications in need thereof. The combination of compounds may be a synergistic combination. For example, Chou and Talalay, adv. enzyme Regul.1984,22:27-55, describe that synergistic effects occur when the compounds are administered in combination more than the additive effect of the compounds when administered as a single agent. In general, synergy is most clearly shown in sub-optimal or lower doses of the compound. Synergy may reduce cytotoxicity, enhance efficacy, or produce some other beneficial effect in combination, as compared to the individual components.

In the present invention, one or more compounds of the present invention may be administered in any conventional manner (e.g., enterally or parenterally). Examples of methods of administration include oral and transdermal. Those skilled in the art will appreciate that the route of administration of the compounds of the present invention may vary widely. In addition to other oral administrations, sustained and/or modified release compositions may also be advantageous. Other acceptable routes may include injection (e.g., intravenous, intramuscular, subcutaneous, and intraperitoneal); a subcutaneous implant; and, buccal, sublingual, topical, rectal, vaginal and intranasal administration. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable administration systems may also be used. Examples of oral formulations include tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, powders, granules and suspensions.

If solid compositions in tablet form are prepared, one or more active ingredients may be admixed with a pharmaceutical carrier, examples of which include silicon dioxide, starch, lactose, magnesium stearate and talc. The tablets may optionally be coated with sucrose or other suitable material, or may be treated so as to have a sustained or delayed activity, and so as to release a predetermined amount of the active ingredient continuously. For example, capsules can be obtained by mixing one or more active ingredients with a diluent and then incorporating the resulting mixture into soft capsules or two-piece hard capsules. For example, a syrup or elixir may contain one or more of the active ingredient(s) together with a sweetening agent, typically zero calorie, a preservative (e.g., methylparaben and/or propylparaben), a flavoring agent and appropriate coloring. For example, a water dispersible powder or granule may contain one or more active ingredients in admixture with a dispersing or wetting agent or with a suspending agent, such as polyvinylpyrrolidone, together with a sweetening or flavoring agent. Rectal administration may use suppositories, which are prepared with binders that melt at the rectal temperature (e.g., cocoa butter and/or polyethylene glycols), gels or foams. Parenteral administration can be carried out using aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing pharmacologically compatible dispersing or wetting agents (e.g., propylene glycol and/or polyethylene glycol). One or more active ingredients may also be formulated as microcapsules or microspheres, optionally together with one or more carriers or additives. One or more active ingredients may also be present in the form of a complex of cyclodextrins (e.g. alpha-, beta-or gamma-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and/or methyl-beta-cyclodextrin).

The dosage of the compounds of the invention administered daily will vary from person to person and may depend to some extent on the severity of the disease being treated (e.g., NAFLD or NASH). The dosage of the compounds of the invention will also vary depending on the drug or drugs being administered. Examples of dosages of the compounds of the present invention have been provided above, but may vary based on the synergistic effect of the combination of two or three drugs.

The compounds may be administered in a single dose or in multiple smaller doses over a period of time. The length of time the compound is administered varies from person to person and may be continued until the desired result is achieved (i.e., reduction of body fat or prevention of body fat gain).

The present disclosure is further illustrated by the following examples, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments and are therefore not intended to limit the scope of the present disclosure. It should also be understood that various other embodiments, modifications, and equivalents thereof may be suggested to those skilled in the art without departing from the spirit of the disclosure and/or scope of the appended claims.