GLP-1/glucagon receptor agonists in the treatment of fatty liver disease and steatohepatitis

Abstract

The present invention relates to the medical use of specific GLP-1/glucagon receptor agonists in the prevention and/or treatment of metabolic liver disease, particularly non-alcoholic fatty liver disease (NAFLD), more particularly non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and/or NAFLD-associated liver fibrosis.

Claims

1. A method for treating non-alcoholic fatty liver disease (NAFLD) comprising administering to a subject in need thereof a compound or salt or solvate thereof having the general formula A: TABLE-US-00009 His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser- Lys-Gln-X14-X15-X16-X17-X18-Ala-X20-Asp-Phe-Ile- Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser-Gly-Ala- Pro-Pro-Pro-Ser-NH2 wherein: the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH); the subject is between 18 and 75 years of age and has a body mass index between 25 and 45 kg/m.sup.2; X14 is Lys, wherein the —NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea); X15 is Asp or Glu; X16 is Ser or Glu; X17 is Lys, Arg, or Gln; X18 is Ala, Arg or Leu; X20 is Gln or Lys; and X28 is Ala or Asn.

2. The method of claim 1, wherein the non-alcoholic steatohepatitis is associated with fibrosis.

3. The method of claim 1, wherein the method treats additional pathological conditions or risk factors, and wherein the additional pathological conditions or risk factors are obesity and/or type 2 diabetes mellitus.

4. The method of claim 1, wherein: X14 is Lys, wherein the —NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea); X15 is Asp or Glu; X16 is Ser or Glu; X17 is Lys or Gln; X18 is Ala or Leu; X20 is Gln or Lys; and X28 is Ala.

5. The method of claim 1, wherein: X14 is Lys, wherein the —NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm); X15 is Asp or Glu; X16 is Ser; X17 is Lys or Arg; X18 is Ala or Arg; X20 is Gln; and X28 is Ala or Asn.

6. The method of claim 1, wherein the compound is any one of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or a salt or solvate thereof.

7. The method of claim 1, wherein said compound has a high solubility at an acidic pH and/or a physiological pH.

8. The method of claim 7, wherein the pH is between 3.5 and 5.5.

9. The method of claim 8, wherein the pH is about 4.5.

10. The method of claim 7, wherein the pH is about 7.4.

11. A method for treating non-alcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound or salt or solvate thereof of formula A as an active agent together with at least one pharmaceutically acceptable carrier, wherein the general formula A is: His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-X16-X17-X18-Ala-X20-Asp-Phe-Ile-Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 wherein: the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH); the subject is between 18 and 75 years of age and has a body mass index (BMI) between 25 and 45 kg/m.sup.2; X14 is Lys, wherein the —NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea); X15 is Asp or Glu; X16 is Ser or Glu; X17 is Lys, Arg, or Gln; X18 is Ala, Arg or Leu; X20 is Gln or Lys; and X28 is Ala or Asn.

12. The method of claim 11, wherein the pharmaceutical composition is parenterally administered.

13. The method of claim 12, wherein the pharmaceutical composition is injected.

14. The method of claim 11, wherein the pharmaceutical composition is administered in combination with at least one further therapeutically active ingredient.

15. The method of claim 1, wherein the subject has at the onset of the treatment: (i) hepatocyte ballooning and steatosis scores greater than 0, or a hepatocyte ballooning score of 0, a steatosis score greater than 0, and an inflammation score greater than 1; and (ii) a Kleiner fibrosis score between 0 and 4.

16. The method of claim 1, wherein the subject achieves after treatment: (i) a decrease in the NAFLD activity score (NAS) and no increase in the Kleiner fibrosis score; or (ii) no increase in the NAFLD activity score (NAS) and a decrease in the Kleiner fibrosis score.

17. A method for treating non-alcoholic fatty liver disease (NAFLD) comprising administering to a subject in need thereof a compound or salt or solvate thereof having the general formula A: TABLE-US-00010 His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser- Lys-Gln-X14-X15-X16-X17-X18-Ala-X20-Asp-Phe-Ile- Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser-Gly-Ala- Pro-Pro-Pro-Ser-NH.sub.2 wherein: the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH); the subject is between 18 and 75 years of age and has a body mass index between 25 and 45 kg/m.sup.2; the subject has at the onset of the treatment: (i) hepatocyte ballooning and steatosis scores greater than 0, or a hepatocyte ballooning score of 0, a steatosis score greater than 0, and an inflammation score greater than 1; and (ii) a Kleiner fibrosis score between 0 and 4; the subject achieves after treatment no increase in the NAFLD activity score (NAS) and a decrease in the Kleiner fibrosis score; X14 is Lys, wherein the —NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea); X15 is Asp or Glu; X16 is Ser or Glu; X17 is Lys, Arg, or Gln; X18 is Ala, Arg or Leu; X20 is Gln or Lys; and X28 is Ala or Asn.

Description

FIGURE LEGENDS

(1) FIGS. 1A-1F. Effect of treatment with compound 2 (SEQ ID NO.: 2) at a dose of 10 μg/kg twice daily over eight weeks in mice with AMLN-diet-induced NASH, compared to vehicle-treated control animals on the same diet. (FIG. 1A) Body weight at baseline and after 52 days of treatment; (FIG. 1B) Overall NAFLD activity score after termination of treatment on day 56; (FIG. 1C) Individual change in NAFLD activity score vs. pre-biopsy before start of treatment; (FIG. 1D) Individual components of the NAFLD activity score (hepatic steatosis, lobular inflammation, hepatocyte ballooning) at end of the study for compound-vs vehicle-treated animals; (FIG. 1E) Fibrosis score at baseline and after eight weeks of treatment. (FIG. 1F) Change in fibrosis score vs. baseline.

(2) FIGS. 2A-2E. Effect of treatment with compound 3 (SEQ ID NO.: 3) at a dose of 30 μg/kg once daily, liraglutide (SEQ ID NO.: 4) at a dose of 200 μg/kg once daily over eight weeks in mice with AMLN-diet-induced NASH, compared to vehicle-treated control animals on the same diet. (FIG. 2A) Body weight at baseline and after 56 days of treatment; (FIG. 2B) Overall NAFLD activity score after termination of treatment on day 56; (FIG. 2C) Individual change in NAFLD activity score vs. pre-biopsy before start of treatment; (FIG. 2D) Individual components of the NAFLD activity score (hepatic steatosis, lobular inflammation, hepatocyte ballooning) at end of the study for compound-vs vehicle-treated animals; (FIG. 2E) Change in fibrosis score vs. baseline.

(3) FIGS. 3A-3E. Effect of treatment with compound 1 (SEQ ID NO.: 1) at doses of 10 and 30 μg/kg twice daily, liraglutide (SEQ ID NO.: 4) at a dose of 100 μg/kg twice daily over eight weeks in mice with AMLN-diet-induced NASH, compared to vehicle-treated control animals on the same diet. (FIG. 3A) Body weight at baseline and after 55 days of treatment; (FIG. 3B) Overall NAFLD activity score after termination of treatment on day 56; (FIG. 3C) Individual change in NAFLD activity score vs. pre-biopsy before start of treatment; (FIG. 3D) Individual components of the NAFLD activity score (hepatic steatosis, lobular inflammation, hepatocyte ballooning) at end of the study for compound-vs vehicle-treated animals; (FIG. 3E) Change in fibrosis score vs. baseline.

METHODS

(4) Test compounds were investigated in a mouse model of NASH (murine diet-induced NASH model) as described in Kristiansen et al (World Journal of Hepatology 2016, vol. 8, pp. 673-684). C57BL/6J mice were given ad libitum access to a diet (D09100301, Research Diet, United States) high in fat (40%, of these 18% trans-fat), carbohydrates (40%, of these 20% fructose) and cholesterol (2%) that has previously been described as AMLN diet (Clapper et al., Am J Physiol Gastrointest Liver Physiol 2013, vol. 305, pp. G483-G495). A control group was kept on regular rodent chow (Altromin 1324, Brogaarden, Denmark).

(5) After 26 weeks on the diet, a liver biopsy was performed for histological assessment of NASH and fibrosis at baseline. For this purpose, about 100 mg liver tissue were collected from the left lateral lobe, fixed overnight in 4% paraformaldehyde, paraffin-embedded and sectioned (3 μm thickness). For histological assessment, sections were stained with hematoxylin, eosin or Sirius Red and followed by analysis with Visiomorph software (Visiopharm, Denmark). Histological scoring was performed by a pathologist blinded to the study. NAFLD activity score and fibrosis score were determined according to the clinical criteria outlined by Kleiner et al (Hepatology 2005, vol. 14, pp. 1313-1321).

(6) Animals were randomized into different treatment groups according to body weight and extent of fibrosis. Treatment period was eight weeks during which animals remained on the AMLN diet. Compounds were given by once-daily or twice-daily subcutaneous injection. Vehicle-treated animals on AMLN diet and non-treated animals on regular rodent chow were included as controls. Group sizes were between 8 and 14 animals.

(7) After treatment, terminal liver samples were collected and analysed as for the pre-biopsy.

(8) The invention is further illustrated by the following examples.

EXAMPLES

Example 1: Investigation of Efficacy of Dual GLP-1/Glucagon Receptor Agonists in a Murine Diet-Induced Nash Model

(9) Dual-agonistic GLP1R/GCGR agonistic peptides were investigated in a murine model of NASH as described in the methods section. Treatment duration was eight weeks over which animals remained on the NASH-inducing AMLN diet. The GLP1R-specific agonist liraglutide (SEQ ID NO.: 4) was included as a reference compound.

(10) Results:

(11) Three GLP1R/GCGR dual agonistic peptides (SEQ ID NO.: 1; SEQ ID NO.: 2 and SEQ ID NO.: 3) were investigated in the murine diet-induced NASH model.

(12) In the diet-induced murine NASH model, compounds were administered at the following doses (all via subcutaneous injections): SEQ ID NO.: 2 10 μg/kg b.i.d., SEQ ID NO.:3 30 μg/kg q.d. in comparison to liraglutide (SEQ ID NO.: 4) at 200 μg/kg q.d., SEQ ID NO.: 1 10 μg/kg b.i.d. or 30 μg/kg b.i.d. in comparison to liraglutide (SEQ ID NO.: 4) at 100 μg/kg b.i.d.

(13) The treatment effects of the compound of SEQ ID NO.: 2 are summarized in FIGS. 1A-1F, those of the compound of SEQ ID NO.: 3 in comparison to liraglutide (SEQ ID NO.: 4) in FIGS. 2A-2E and those of the compound of SEQ ID NO.: 1 in comparison to liraglutide (SEQ ID NO.: 4) in FIGS. 3A-3E.

(14) After 26 weeks on the AMLN diet, the average body weight of the animals in the groups assigned to different treatments was between 36 and 40 grams, whereas mice that had remained on normal rodent chow weighed between 29 and 32 grams. Over the eight-week treatment period, vehicle-treated mice gained up to 2 grams of body weight. In contrast, animals that received liraglutide or GLP1R/GCGR dual agonists showed significant weight loss.

(15) For SEQ ID NO.: 2, weight loss was 2.8 gram (7.7%) vs baseline whereas vehicle-treated animals in the same study gained 2.1 grams (5.6%), i.e. weight loss vs vehicle was 4.9 grams or 13.5% of body weight at baseline (FIG. 1A).

(16) Upon eight-week administration of SEQ ID NO.: 3, animals lost 3.9 grams (10.5%) whereas mice given vehicle injections gained 1.1 grams (3.0%). In the same study, injection of liraglutide (SEQ ID NO.: 4) over eight weeks was associated with a weight loss of 3.2 gram (8.7% of body weight at baseline, FIG. 2A).

(17) Animals treated with either 10 μg/kg or 30 μg/kg SEQ ID NO.: 1 twice daily over eight weeks lost 3.0 grams (8.5%) or 3.9 grams (11.4%) respectively. In this study, vehicle-treated mice gained 0.5 grams (1.3%) whereas animals treated with 100 μg/kg liraglutide (SEQ ID NO.: 4) twice daily lost 2.4 grams (6.4%, FIG. 3A)).

(18) While body weight change was highly significantly different from vehicle for liraglutide and all dual GLP1R/GCGR agonists tested (p<0.001), it was not significantly different between the dual agonists and liraglutide tested in the same studies.

(19) Treatment with the compound of SEQ ID NO.: 2 (10 μg/kg b.i.d) resulted in a reduction in NAFLD activity score (NAS) by 2.3 points whereas there was a slight increase by 0.2 points for the vehicle-treated group (FIGS. 1A-1C). A reduction in score was seen for all three components of NAS, i.e. the steatosis, inflammation and hepatocyte ballooning scores (FIG. 1D). Also, there was an improvement in fibrosis compared to the vehicle group: While the mean fibrosis stage did not change in the vehicle group, it decreased from 1.2 to 0.6 in the group treated with the compound of SEQ ID NO.: 2 (FIG. 1A1E).

(20) Treatment with the compound of SEQ ID NO.: 3 (30 μg/kg q.d.) or liraglutide (200 μg/kg q.d.) over eight weeks also resulted in a significant improvement in NAS vs. baseline compared to vehicle-treated animals (FIGS. 2B, 2C): Whereas NAS increased by 0.8 points in the vehicle group, it decreased by 1.6 points in the group treated with the compound of SEQ ID NO.: 3 and by 0.3 points in the liraglutide group. Of note, the treatment effect of SEQ ID NO.: 3 was statistically significant versus both vehicle (p<0.001) and liraglutide (p<0.05). The mean fibrosis score increased upon vehicle treatment by 0.1 points, upon treatment with SEQ ID NO.: 4 by 0.2 points, whereas it remained unchanged in animals treated with compound SEQ ID NO.: 3. (FIG. 2D). Average baseline fibrosis scores were 1.5 for the vehicle group and the group treated with SEQ ID NO.: 3, and 1.4 for the liraglutide (SEQ ID NO.: 4) group, respectively.

(21) The compound of SEQ ID NO.: 1 at 10 or 30 μg/kg b.i.d. or liraglutide at 100 μg/kg b.i.d. led to a significant improvement in NAS vs baseline compared to vehicle: While the mean NAS increased by 0.2 points in the vehicle-treated animals, it decreased by 2.0 points with 10 μg/kg, by 1.9 points with 30 μg/kg SEQ ID NO.: 1 and by 1.1 points with liraglutide (FIGS. 3B, 3C). Improvement in NAS with the compound of SEQ ID NO.: 1 was significantly better than with liraglutide for the 30 μg/kg dose (p<0.05). A trend to an improvement in fibrosis was noted for both doses of the compound of SEQ ID NO.: 1 (FIG. 3E), but not for vehicle- or liraglutide (SEQ ID NO.: 4) treated animals. Baseline fibrosis levels were similar across the groups (1.3-1.6).

(22) Thus, it was demonstrated that representative examples of the dual GLP1R/GCGR agonistic peptides of the present invention lead, at a similar degree of weight loss compared to the GLP1R agonist liraglutide, to pronounced improvement in NAFLD activity score.

Example 2: 48-Week Treatment of Biopsy-Proven Non-Alcoholic Steatohepatitis (NASH) with a Formulation Containing SEQ ID NO.: 1

(23) Subject of the example is a double-blind, randomized, placebo-controlled, 48-weeks study to assess the effect of SEQ ID NO.: 1, a dual GLP-1/glucagon agonist, at daily subcutaneous doses of 200 μg in patients with and without type 2 diabetes mellitus with biopsy-proven non-alcoholic steatohepatitis (NASH) on disease progression.

(24) Estimated patient enrolment is between approximately 60 and 120 randomized patients.

(25) The primary study objective is to compare the effect of 200 μg SEQ ID NO.: 1 subcutaneous (SC) once daily versus placebo on histological resolution of non-alcoholic steatohepatitis (NASH) after 12 months of treatment vs baseline, defined as the ballooning component of the NAFLD activity score of zero in the absence of worsening of fibrosis.

(26) The secondary study objectives are, inter alia, to assess from baseline to 12 months: Changes in the magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) calculated total liver fat content (after 6 months of treatment vs baseline and after 12 months of treatment vs baseline) Changes in the overall NAFLD activity score at 12 months Changes in the individual components of the NAFLD activity score (steatosis, hepatocyte ballooning, lobular inflammation) at 12 months Changes in the Kleiner fibrosis stage at 12 months Pharmacokinetics of the compound of SEQ ID NO.:1

(27) The study design is that of a randomized, placebo-controlled, double-blind, parallel-group study for SEQ ID NO.: 1 versus placebo.

(28) SEQ ID NO.: 1 or placebo is provided as a solution for injection in cartridges containing 3 mL solution for injection, at a concentration of 500 μg/mL SEQ ID NO.: 1 or matching placebo. Tactipen® injector will be used to deliver subcutaneous doses of SEQ ID NO.: 1 and matching placebo. 3 dose steps (after starting dose) are planned for SEQ ID NO.: 1 during dose titration to reach a final targeted dose of 200 μg SC once daily (QD): 60-120-160-200 μg/day.

(29) Doses should be administered in the morning at the same time and approximately 1 hour after breakfast for both SEQ ID NO.: 1 and placebo, except on clinic visit days. On the clinical visit days, SEQ ID NO.: 1 and placebo should be administered after blood test/ECG measurements in the morning and be coordinated with the PK sampling time.

(30) SEQ ID NO.: 1 and matching placebo treatment regimens plan to include a 3-week dose increase period before the maintenance dose is reached, as follows: Active drug: 3 dose increase steps after 1 week each (if no significant tolerability issues [for example, nausea and vomiting] are observed): 60 μg, ie, 12U/Day 1 to Day 7) 120 μg, ie, 24U (Day 8 to Day 14) 160 μg, ie, 32U (Day 15 to Day 21) 200 μg, ie, 40U (from Day 22 on, this dose is intended to be administered for 49 weeks) Placebo: patients will be allocated to the same dose increase regimen.

(31) At randomization, all patients randomized will start with the 60 μg daily dose step. The dose will be increased to 120 μg daily after one week treatment, if no significant tolerability issues (for example, nausea and vomiting) are observed. The dose will be further increased to 160 μg daily after one further week if no significant tolerability issues (for example, nausea and vomiting) are observed. The dose will finally be further increased to 200 μg daily after one further week if no significant tolerability issues (for example, nausea and vomiting) are observed.

(32) The same dose increase regimen scheme will be conducted for patients assigned to placebo treatment, however with placebo instead of SEQ ID NO.: 1. The daily maintenance dose level will then be continued for the remainder of the treatment period (in total 49 weeks on final dose).

(33) Primary endpoint of the study is the resolution of NASH, defined as hepatocyte ballooning score=0 and absence of lobular inflammation (score=0) or presence of mild lobular inflammation (score=1), without worsening in the Kleiner fibrosis score at 12 months and as compared to baseline.

(34) Secondary endpoints of the study are, inter alia, changes in MRI-PDFF calculated total liver fat burden; changes in the overall NAFLD activity score; changes in the individual components of the NAFLD activity score (steatosis, hepatocyte ballooning, lobular inflammation); changes in the Kleiner fibrosis stage; and Pharmacokinetic parameters including apparent clearance (CL/F), volume of distribution (V/F), and C.sub.trough levels.

(35) Patients will be assigned to either placebo or SEQ ID NO.: 1. There will be an approximately equal number of patients per each of the two treatment arms (placebo, SEQ ID NO.: 1).

(36) The screening period will last for up to 6 weeks. Efficacy will be assessed at 12 months after randomization by a liver biopsy, for which patients could be hospitalized for up to 48 hours after the biopsy according to local guidelines and a 28 days posttreatment follow-up period.

(37) Inclusion criteria for the study population are: Male and female patients, aged ≥18 and ≤75 years, with histologically confirmed presence of NASH (within the last 6 months prior to randomization) and FFPE-liver specimen available for re-analysis. Liver biopsy is allowed to be carried out during the screening phase. Histopathologic confirmation of NASH will be done by a central reading lab. NAFLD activity score has to be Patients have to be on diet/exercise and in case of diabetic patients on treatment with metformin (stable dose of ≥1500 mg/day or maximal tolerated dose) for at least 3 months prior to screening. Signed informed consent is required.

(38) Main exclusion criteria are: Any of the individual components of the NAFLD score (steatosis, ballooning, periportal inflammation) being <1 Kleiner fibrosis score of 4 Insulin dependent diabetes HbA1c at screening visit >10.0% FPG >270 mg/dL by the central laboratory at screening (Visit 1) and confirmed by a repeat test prior to randomization BMI <25 kg/m.sup.2 or >45.0 kg/m.sup.2 Diagnosis of type 1 diabetes mellitus Treatment with glucose-lowering agents(s) other than metformin, currently or within the 3 months prior to screening Previous insulin use, except for episode(s) of short-term treatment (≤15 consecutive days) for intercurrent illness, or use of insulin within the last 6 months Contraindication(s) to use of GLP-1 analogues Poorly controlled hypertension (a resting systolic blood pressure [SBP]>160 mm Hg and/or diastolic blood pressure [DBP]>95 mm Hg at screening) History of long QT syndrome and/or QTc more than 450 ms at screening visit History of pancreatitis or pancreatectomy History of weight loss surgery Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC Any prior exposure to drugs belonging to the class of GLP-1 receptor agonists or GLP-1 analogs Contraindications or known hypersensitivity reaction to glucagon Past medical history of liver transplantation, hepatocellular carcinoma (HCC), multiple endocrine neoplasia (MEN) syndrome, malignancy (within last 3 years, exception of treated skin malignancy) Other liver etiologies (i.e. drug-induced, viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, alpha 1 anti-trypsin deficiency, Wilsons disease) Participation in any clinical trial of an investigational therapy or agent within 3 months prior to randomization NAS<4 Child's B or C cirrhosis Liver enzymes >10-fold upper limit of normal Average alcohol consumption per week >21 units (210 g) for males, >14 units (140 g) for females within the last 5 years >5% weight loss since the diagnostic liver biopsy was obtained Known positivity for antibody to human immunodeficiency virus (HIV)

(39) The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Example 3: 52-Week Treatment of Biopsy-Proven Non-Alcoholic Steatohepatitis (Nash) with a Formulation Containing SEQ ID NO.: 1

(40) Subject of the example is a double-blind, randomized, placebo-controlled, 52-weeks study to assess the effect of two dose cohorts of SEQ ID NO.: 1, a dual GLP-1/glucagon agonist, at daily subcutaneous doses of up to either 120 μg or 200 μg in patients with and without type 2 diabetes mellitus with biopsy-proven non-alcoholic steatohepatitis (NASH) on disease progression in comparison to placebo.

(41) Estimated patient enrolment is between approximately 90 and 150 randomized patients.

(42) The primary study objective is to evaluate the dose response relationship of daily subcutaneous doses of two cohorts of up to 120 μg and up to 200 μg SEQ ID NO.: 1 compared to placebo and vs baseline on resolution of non-alcoholic steatohepatitis (NASH) with no worsening of fibrosis in diabetic and non-diabetic patients with histopathologically confirmed NASH.

(43) The secondary study objectives are, inter alia, to assess from baseline to 12 months: Changes in the magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) calculated total liver fat content (after 6 months of treatment vs baseline and after 12 months of treatment vs baseline) Changes in the overall NAFLD activity score at 12 months Changes in the individual components of the NAFLD activity score (steatosis, hepatocyte ballooning, lobular inflammation) at 12 months Changes in the Kleiner fibrosis stage at 12 months Pharmacokinetics of the compound of SEQ ID NO.:1

(44) The study design is that of a randomized, placebo-controlled, double-blind, parallel-group study for two dose levels of SEQ ID NO.: 1 versus placebo.

(45) SEQ ID NO.: 1 or placebo is provided as a solution for injection in cartridges containing 3 mL solution for injection, at a concentration of 500 μg/mL SEQ ID NO.: 1 or matching placebo. Tactipen® injector will be used to deliver subcutaneous doses of SEQ ID NO.: 1 and matching placebo. An appropriate number of dose steps (after starting dose) is planned for SEQ ID NO.: 1 during dose titration to reach a final targeted dose of either 120 μg SC or 200 μg SC once daily (QD). The titration phase is intended to optimize the tolerability of the final dose, which should be reached within 14 weeks after the first dose.

(46) Doses should be administered in the morning at the same time and approximately 1 hour after breakfast for both SEQ ID NO.: 1 and placebo, except on clinic visit days. On the clinical visit days, SEQ ID NO.: 1 and placebo should be administered after blood test/ECG measurements in the morning and be coordinated with the PK sampling time.

(47) Both dose cohorts of SEQ ID NO.: 1 and matching placebo treatment regimens plan to include a dose increase period before the maintenance dose is reached after maximally 14 weeks, as follows: Both cohorts of active drug: Appropriate number of weekly dose increase steps (if no significant tolerability issues [for example, nausea and vomiting] are observed): 20 μg, ie, 4U, Week 0, Day 1 to Day 7 40 μg, ie, 8U, reached earliest at Week 1, Day 8 to Day 14 60 μg, ie, 12U, reached earliest at Week 2, Day 15 to Day 21 Etc. 120 μg, ie 24U, reached earliest at Week 5, Day 36 to Day 42 140 μg, ie 28U, reached earliest at Week 6, Day 43 to Day 49 Etc. 200 μg, ie, 40U, reached earliest at Week 9, Day 64 to Day 70 Dose escalation can be suspended, doses can be reduced and doses can be increased again, depending on the tolerability of study medication. Placebo: patients will be allocated to the same dose increase regimen. After Week 14, Day 99, no further dose adjustments will be made.

(48) At randomization, all patients randomized will start with the 20 μg daily dose step (or corresponding placebo). The dose will be increased in weekly steps of 20 μg as shown above until the targeted dose of 120 μg SC daily or 200 μg SC daily is reached and if no significant tolerability issues (for example, nausea and vomiting) are observed. The dose increase can be stopped, maintained at a tolerable level and can be increased again in weekly 20 μg SC dose steps if no significant tolerability issues (for example, nausea and vomiting) are observed, until the targeted dose levels are reached and tolerated. After Week 14, Day 99, no further dose adjustments will be allowed.

(49) The same dose increase regimen scheme will be conducted for patients assigned to placebo treatment, however with placebo instead of SEQ ID NO.: 1.

(50) After Week 14, Day 99 the maintenance dose level has to be reached and will not be changed for the remainder of the treatment period.

(51) Primary endpoint of the study is the percentage of patients with resolution of NASH, defined as absence of hepatocyte ballooning (ballooning component of NAS=0) without worsening of fibrosis score at Week 52.

(52) Secondary endpoints of the study are, inter alia, Change from baseline to Week 26 and to Week 52 in MRI-PDFF-derived total liver fat, liver volume, and fractional liver fat content Percentage of patients who achieve status of no hepatocyte ballooning with lobular inflammation score of 0 or 1 without worsening of fibrosis score at Week 52 Percentage of patients who achieve an improvement of fibrosis by at least 1 stage without worsening of the hepatocyte ballooning component of NAS at Week 52 Change from baseline to Week 52 in the overall NAS Change from baseline to Week 52 in individual components of NAS (steatosis, hepatocyte ballooning, and lobular inflammation) and in fibrosis score Change from baseline in body weight, waist and hip circumference, and waist to hip ratio and Pharmacokinetic parameters including apparent clearance (CL/F), volume of distribution (V/F), and C.sub.trough levels.

(53) Patients will be assigned to either placebo or one of the two dose cohorts of SEQ ID NO.: 1. There will be an approximately equal number of patients per each of these three treatment arms (placebo, cohort 1 SEQ ID NO.: 1, cohort 2 SEQ ID NO.: 1).

(54) The screening period will last for up to 8 weeks. Efficacy will be assessed at 12 months after randomization by a liver biopsy, for which patients could be hospitalized for up to 48 hours after the biopsy according to local guidelines.

(55) There will be a 28 days posttreatment follow-up period.

(56) Inclusion criteria for the study population are: Male and female patients, aged ≥18 and ≤80 years, with histologically confirmed presence of NASH (within the last 6 months prior to randomization) and FFPE-liver specimen available for re-analysis. Liver biopsy is allowed to be carried out during the screening phase. Histopathologic confirmation of NASH will be done by a central reading laboratory. NAFLD activity score has to be

(57) Patients have to be on diet/exercise and in case of diabetic patients on treatment at a stable dose with metformin and/or sulfonylureas for at least 3 months prior to screening. Signed informed consent is required.

(58) Main exclusion criteria are: Any of the individual components of the NAFLD score (steatosis, ballooning, periportal inflammation) being <1 Kleiner fibrosis score of 4 Insulin dependent diabetes HbA1c at screening visit ≥9.0% FPG >270 mg/dL by the central laboratory at screening (Visit 1) and confirmed by a repeat test prior to randomization BMI <25 kg/m.sup.2 or >45.0 kg/m.sup.2 Diagnosis of type 1 diabetes mellitus Treatment (currently or within the 8 weeks prior to Randomization or 5 half-lives of the drug given, whichever is longer) with: Glucose-lowering agent(s) other than metformin or sulfonylureas (eg, GLP-1-agonists, SGLT-2-inhibitors, glitazones, or DPP4-inhibitors) Weight loss drugs, including orlistat Systemic steroids Methotrexate Amiodarone Vitamin E Use of insulin within the last 6 months prior to Randomization, except for episode(s) of short-term treatment (<15 consecutive days) for intercurrent illness Any prior exposure to drugs belonging to the class of GLP-1 receptor agonists or GLP-1 analogs or contraindication(s) to use of GLP-1 agonists Poorly controlled hypertension (a resting systolic blood pressure [SBP]>160 mm Hg and/or diastolic blood pressure [DBP]>95 mm Hg at screening) History of cardiac conduction abnormalities including long QT syndrome History of pancreatitis or pancreatectomy History of weight loss surgery Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC Any prior exposure to drugs belonging to the class of GLP-1 receptor agonists or GLP-1 analogs Contraindications or known hypersensitivity reaction to glucagon Past medical history of liver transplantation, hepatocellular carcinoma (HCC), multiple endocrine neoplasia (MEN) syndrome, malignancy (within last 3 years, exception for treated skin malignancy) Other liver etiologies (i.e. drug-induced, viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, alpha 1 anti-trypsin deficiency, Wilsons disease) Participation in any clinical trial of an investigational therapy or agent within 3 months prior to randomization NAS<4 Liver enzymes >5-fold upper limit of normal Average alcohol consumption per week >21 units (210 g) for males, >14 units (140 g) for females within the last 5 years Significant change (defined as 5% self-reported change) in body weight during the 2 months prior to screening for patients with liver biopsy collected during screening, or significant change (defined as 5% self-reported change in body weight) within 6 months prior to randomization if a pre-existing liver biopsy sample was collected prior to screening Period Known positivity for antibody to human immunodeficiency virus (HIV)

(59) The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

(60) The invention is further characterized by the following items.

(61) Item 1. A compound or salt or solvate thereof having the general formula A His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-X16-X17-X18-Ala-X20-Asp-Phe-Ile-Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-N H2

(62) wherein

(63) X14 is Lys, wherein the —NH.sub.2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea);

(64) X15 is Asp or Glu;

(65) X16 is Ser or Glu;

(66) X17 is Lys, Arg, or Gln;

(67) X18 is Ala, Arg or Leu;

(68) X20 is Gln or Lys; and

(69) X28 is Ala or Asn;

(70) for use in a method of preventing and/or treating metabolic liver disease.

(71) Item 2. The compound or salt or solvate thereof of item 1 for use according to item 1, wherein

(72) X14 is Lys, wherein the —NH.sub.2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea);

(73) X15 is Asp or Glu;

(74) X16 is Ser or Glu;

(75) X17 is Lys or Gln;

(76) X18 is Ala or Leu;

(77) X20 is Gln or Lys; and

(78) X28 is Ala.

(79) Item 3. The compound or salt or solvate thereof of item 1 for use according to item 1, wherein

(80) X14 is Lys, wherein the —NH.sub.2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm);

(81) X15 is Asp or Glu;

(82) X16 is Ser;

(83) X17 is Lys or Arg;

(84) X18 is Ala or Arg;

(85) X20 is Gln; and

(86) X28 is Ala or Asn.

(87) Item 4. The compound or salt or solvate thereof of item 1 for use according to item 1, wherein the compound is SEQ ID NO.: 1 or a salt or solvate thereof.

(88) Item 5. The compound or salt or solvate thereof of item 1 for use according to item 1, wherein the compound is SEQ ID NO.: 2 or a salt or solvate thereof.

(89) Item 6. The compound or salt or solvate thereof of item 1 for use according to item 1, wherein the compound is SEQ ID NO.: 3 or a salt or solvate thereof.

(90) Item 7. The compound or salt or solvate thereof of any one of items 1-6 for use according to any one of items 1-6, wherein said compound has a high solubility at an acidic pH, particularly between 3.5 and 5.5, more particularly about 4.5, and/or a physiological pH, particularly about 7.4, and wherein said solubility at said acidic and/or physiological pH is at least 0.5 mg/ml.

(91) Item 8. A pharmaceutical composition comprising a compound or salt or solvate thereof of any one of items 1-7 as an active agent together with at least one pharmaceutically acceptable carrier, for use according to item 1.

(92) Item 9. The pharmaceutical composition of item 8 for use according to item 1, wherein the pharmaceutical composition is parenterally administered, particularly injected.

(93) Item 10. The pharmaceutical composition of item 8 or 9 for use according to item 1, wherein the pharmaceutical composition is administered in combination with at least one further therapeutically active ingredient.

(94) Item 11. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of preventing and/or treating non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and/or NAFLD-associated liver fibrosis.

(95) Item 12. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of preventing non-alcoholic steatohepatitis (NASH), particularly NASH associated with fibrosis.

(96) Item 13. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating non-alcoholic steatohepatitis (NASH), particularly NASH associated with fibrosis.

(97) Item 14. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating non-alcoholic steatohepatitis (NASH), particularly NASH associated with fibrosis.

(98) Item 15. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating non-alcoholic steatohepatitis (NASH), particularly NASH associated with fibrosis.

(99) Item 16. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating non-alcoholic steatohepatitis (NASH), particularly NASH associated with fibrosis.

(100) Item 17. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of preventing and/or treating sequelae of non-alcoholic steatohepatitis (NASH), particularly NAFLD-related liver cirrhosis and/or NAFLD-related hepatocellular carcinoma.

(101) Item 18. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of preventing and/or treating sequelae of non-alcoholic steatohepatitis (NASH), particularly NAFLD-related liver cirrhosis and/or NAFLD-related hepatocellular carcinoma.

(102) Item 19. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of preventing and/or treating sequelae of non-alcoholic steatohepatitis (NASH), particularly NAFLD-related liver cirrhosis and/or NAFLD-related hepatocellular carcinoma.

(103) Item 20. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of preventing and/or treating sequelae of non-alcoholic steatohepatitis (NASH), particularly NAFLD-related liver cirrhosis and/or NAFLD-related hepatocellular carcinoma.

(104) Item 21. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of simultaneously preventing and/or simultaneously treating NASH and additional pathological conditions or risk factors.

(105) Item 22. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of simultaneously treating NASH and obesity.

(106) Item 23. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and obesity.

(107) Item 24. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and obesity.

(108) Item 25. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and obesity.

(109) Item 26. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of simultaneously treating NASH and type 2 diabetes mellitus.

(110) Item 27. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and type 2 diabetes mellitus.

(111) Item 28. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and type 2 diabetes mellitus.

(112) Item 29. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and type 2 diabetes mellitus.

(113) Item 30. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of simultaneously treating NASH and type 2 diabetes mellitus and obesity.

(114) Item 31. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and type 2 diabetes mellitus and obesity.

(115) Item 32. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and type 2 diabetes mellitus and obesity.

(116) Item 33. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of simultaneously treating NASH and type 2 diabetes mellitus and obesity.

(117) Item 34. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating NASH, wherein a patient, particularly a human patient, is diagnosed as having NASH, if there is a presence of steatosis and hepatocyte ballooning and any degree of inflammation, or, alternatively, steatosis and advanced inflammation (score>1) in the absence of hepatocyte ballooning, with a Kleiner fibrosis score of <4.

(118) Item 35. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH, wherein a patient, particularly a human patient, is diagnosed as having NASH, if there is a presence of steatosis and hepatocyte ballooning and any degree of inflammation, or, alternatively, steatosis and advanced inflammation (score>1) in the absence of hepatocyte ballooning, with a Kleiner fibrosis score of <4.

(119) Item 36. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH, wherein a patient, particularly a human patient, is diagnosed as having NASH, if there is a presence of steatosis and hepatocyte ballooning and any degree of inflammation, or, alternatively, steatosis and advanced inflammation (score>1) in the absence of hepatocyte ballooning, with a Kleiner fibrosis score of <4.

(120) Item 37. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH, wherein a patient, particularly a human patient, is diagnosed as having NASH, if there is a presence of steatosis and hepatocyte ballooning and any degree of inflammation, or, alternatively, steatosis and advanced inflammation (score>1) in the absence of hepatocyte ballooning, with a Kleiner fibrosis score of <4.

(121) Item 38. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating NASH in a human patient, wherein the patient is considered as suffering from NASH, when, at the onset of treatment, (i) steatosis and hepatocyte ballooning scores are >0, or, in the absence of hepatocyte ballooning, steatosis score is >0 and inflammation score is >1, and (ii) a Kleiner fibrosis score of >0 and <4 is determined.

(122) Item 39. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH in a human patient, wherein the patient is considered as suffering from NASH, when, at the onset of treatment, (i) steatosis and hepatocyte ballooning scores are each >0, or, in the absence of hepatocyte ballooning, steatosis score is >0 and inflammation score is >1, and (ii) a Kleiner fibrosis score of >0 and <4 is determined.

(123) Item 40. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH in a human patient, wherein the patient is considered as suffering from NASH, when, at the onset of treatment, (i) steatosis and hepatocyte ballooning scores are each >0, or, in the absence of hepatocyte ballooning, steatosis score is >0 and inflammation score is >1, and (ii) a Kleiner fibrosis score of >0 and <4 is determined.

(124) Item 41. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH in a human patient, wherein the patient is considered as suffering from NASH, when, at the onset of treatment, (i) steatosis and hepatocyte ballooning scores are each >0, or, in the absence of hepatocyte ballooning, steatosis score is >0 and inflammation score is >1, and (ii) a Kleiner fibrosis score of >0 and <4 is determined.

(125) Item 42. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating NASH in a human patient suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(126) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(127) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(128) (iii) the BMI is <30.

(129) Item 43. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH in a human patient suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(130) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(131) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(132) (iii) the BMI is <30.

(133) Item 44. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH in a human patient suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(134) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(135) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(136) (iii) the BMI is <30.

(137) Item 45. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH in a human patient suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH, but not suffering from type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(138) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(139) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(140) (iii) the BMI is <30.

(141) Item 46. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating NASH and type 2 diabetes in a human patient suffering from NASH and type 2 diabetes mellitus, but not from obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus, but not from obesity, when, at the onset of treatment,

(142) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(143) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(144) (iii) the BMI is <30.

(145) Item 47. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and type 2 diabetes in a human patient suffering from NASH and type 2 diabetes mellitus, but not from obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus, but not from obesity, when, at the onset of treatment,

(146) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(147) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(148) (iii) the BMI is <30.

(149) Item 48. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and type 2 diabetes in a human patient suffering from NASH and type 2 diabetes mellitus, but not from obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus, but not from obesity, when, at the onset of treatment,

(150) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(151) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(152) (iii) the BMI is <30.

(153) Item 49. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and type 2 diabetes in a human patient suffering from NASH and type 2 diabetes mellitus, but not from obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus, but not from obesity, when, at the onset of treatment,

(154) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(155) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(156) (iii) the BMI is <30.

(157) Item 50. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating NASH and obesity in a human patient suffering from NASH and obesity, but not from type 2 diabetes mellitus, wherein the patient is considered as suffering from NASH and obesity, but not from type 2 diabetes mellitus, when, at the onset of treatment,

(158) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(159) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(160) (iii) the BMI is ≥30.

(161) Item 51. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and obesity in a human patient suffering from NASH and obesity, but not from type 2 diabetes mellitus, wherein the patient is considered as suffering from NASH and obesity, but not from type 2 diabetes mellitus, when, at the onset of treatment,

(162) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(163) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(164) (iii) the BMI is ≥30.

(165) Item 52. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and obesity in a human patient suffering from NASH and obesity, but not from type 2 diabetes mellitus, wherein the patient is considered as suffering from NASH and obesity, but not from type 2 diabetes mellitus, when, at the onset of treatment,

(166) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(167) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(168) (iii) the BMI is ≥30.

(169) Item 53. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and obesity in a human patient suffering from NASH and obesity, but not from type 2 diabetes mellitus, wherein the patient is considered as suffering from NASH and obesity, but not from type 2 diabetes mellitus, when, at the onset of treatment,

(170) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(171) (ii) the fasting plasma glucose concentration is <7 mmol/l and the plasma glucose concentration is <11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load and the HbA1c value is <48 mmol/mol (<6.5%); and

(172) (iii) the BMI is ≥30.

(173) Item 54. The compound or salt or solvate thereof of any one of items 1-7 or the pharmaceutical composition of any one of items 8-10 for use in a method of treating NASH and type 2 diabetes mellitus and obesity in a human patient suffering from NASH and type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(174) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(175) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(176) (iii) the BMI is

(177) Item 55. A compound of SEQ ID NO.: 1 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 1 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and type 2 diabetes mellitus and obesity in a human patient suffering from NASH and type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(178) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(179) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(180) (iii) the BMI is

(181) Item 56. A compound of SEQ ID NO.: 2 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 2 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and type 2 diabetes mellitus and obesity in a human patient suffering from NASH and type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(182) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(183) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(184) (iii) the BMI is ≥30.

(185) Item 57. A compound of SEQ ID NO.: 3 or a salt or solvate thereof or a pharmaceutical composition comprising a compound of SEQ ID NO.: 3 or a salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier, for use in a method of treating NASH and type 2 diabetes mellitus and obesity in a human patient suffering from NASH and type 2 diabetes mellitus and obesity, wherein the patient is considered as suffering from NASH and type 2 diabetes mellitus and obesity, when, at the onset of treatment,

(186) (i) (a) the steatosis and hepatocyte ballooning scores are each >0 and the inflammation score is 0-3, or (b) the steatosis score is >0 and the inflammation score is >1 in the absence of hepatocyte ballooning, wherein according to both (a) and (b) the Kleiner fibrosis score is <4;

(187) (ii) the fasting plasma glucose concentration is ≥7 mmol/l, or/and the plasma glucose concentration is ≥11.1 mmol/l in a glucose tolerance test two hours after an oral 75 g glucose load, or/and the HbA1c value is ≥48 mmol/mol (≥6.5%); and

(188) (iii) the BMI is ≥30.

(189) Item 58. A method of preventing or treating metabolic liver disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt or solvate thereof having the general formula A

(190) TABLE-US-00008 His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser- Lys-Gln-X14-X15-X16-X17-X18-Ala-X20-Asp-Phe-Ile- Glu-Trp-Leu-Lys-X28-Gly-Gly-Pro-Ser-Ser-Gly-Ala- Pro-Pro-Pro-Ser-NH2

(191) wherein

(192) X14 is Lys, wherein the —NH2 side chain group is functionalized by one of the groups selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-(γE-Palm) and (S)-4-Carboxy-4-octadecanoylamino-butyryl-(γE-Stea);

(193) X15 is Asp or Glu;

(194) X16 is Ser or Glu;

(195) X17 is Lys, Arg, or Gln;

(196) X18 is Ala, Arg or Leu;

(197) X20 is Gln or Lys; and

(198) X28 is Ala or Asn.