WO2020020904A1 - Utilisations thérapeutiques d'agonistes de glp-2 - Google Patents

Utilisations thérapeutiques d'agonistes de glp-2 Download PDF

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Publication number
WO2020020904A1
WO2020020904A1 PCT/EP2019/069832 EP2019069832W WO2020020904A1 WO 2020020904 A1 WO2020020904 A1 WO 2020020904A1 EP 2019069832 W EP2019069832 W EP 2019069832W WO 2020020904 A1 WO2020020904 A1 WO 2020020904A1
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bile acid
glp
agonist
intestinal
ala
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PCT/EP2019/069832
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English (en)
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Erik LINDSTRÖM
Jolanta SKARBALIENE
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Zealand Pharma A/S
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Publication of WO2020020904A1 publication Critical patent/WO2020020904A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof

Definitions

  • the present invention relates to the use of GLP-2 agonists to modulate bile acid metabolism.
  • GLP-2 agonists may be capable of inhibiting bile acid synthesis, and so are useful for the treatment of conditions in which inhibition of bile acid synthesis is beneficial. Such conditions include primary and secondary bile acid diarrhea, and conditions which cause or contribute to cholestasis.
  • the invention also relates to the use of FGF19 and C4 as biomarkers to monitor bile acid synthesis and homoeostasis, e.g. in SBS patients.
  • liver biopsy remains the gold standard for assessing liver inflammation and for staging liver fibrosis, its invasive character and potential post-procedure complications limit its use as a preferred surveillance tool.
  • clinical features and current biochemical markers and score systems also tend to fail to properly detect the degree and progression of liver damage (Sasdelli et al. 2018), making it difficult to initiate preventive measures and early therapeutic approaches.
  • TE transient elastography
  • ICG Indocyanine green
  • ICG Indocyanine green elimination
  • ICG is a water-soluble, tricarbocyanine dye which binds completely to albumin and beta-lipoprotein after intravenous injection.
  • ICG is taken up from the plasma almost exclusively by the liver parenchymal cells and is excreted unchanged by the canicular membrane into the bile (Levesque et al 2016).
  • decreased levels of elimination rate reflects impaired parenchymal liver function, liver blood flow and bile excretion (Levesque et al 2016, Mailer et al. 2018).
  • Lipid content in PS and recurrent sepsis may lead to activation of liver macrophages (Kupffer cells) (Cavicchi et al 2000). Since the activation of the Kupffer cells plays an important role in the progressive fibrotic process, circulating macrophage-specific markers are proposed as potential noninvasive biomarkers for the diagnosis and monitoring of liver fibrosis (Cavicchi et al 2000, Andersen et al. 2014). In this regard, soluble CD163 (sCD163) and soluble mannose receptor (sMR) have received special attention. Both sCD163 and sMR are endocytic macrophage surface receptors which are shed by activated Kupffer cells in response to inflammation and can be measured in plasma.
  • sCD163 and sMR are endocytic macrophage surface receptors which are shed by activated Kupffer cells in response to inflammation and can be measured in plasma.
  • GLP-2 glucagon-like peptide-2
  • SBS short bowel syndrome
  • Human GLP-2 (hGLP-2) is a 33-amino-acid peptide with the following sequence: Hy-His-Ala- Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-lle-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-lle-Asn- Trp-Leu-lle-GIn-Thr-Lys-lle-Thr-Asp-OH. It is derived from specific post-translational processing of proglucagon in the enteroendocrine L cells of the intestine and in specific regions of the brainstem.
  • GLP-2 binds to a single G-protein-coupled receptor belonging to the class II glucagon secretin family. GLP-2 has been reported to induce significant growth of the small intestinal mucosal epithelium via the stimulation of stem cell proliferation in the crypts, and by inhibition of apoptosis in the villi (Drucker et al , 1996). GLP-2 also has growth effects on the colon. Furthermore, GLP-2 inhibits gastric emptying and gastric acid secretion (Wojdemann et al., 1999), enhances intestinal barrier function (Benjamin et al., 2000), stimulates intestinal hexose transport via the
  • Native hGLP-2 is not particularly useful in a clinical setting due to its very short half-life in humans of around 7 minutes for full length GLP-2 [1-33] and 27 minutes for truncated GLP-2 [3- 33].
  • the short half-life is due to degradation by the enzyme dipeptidylpeptidase IV (DPP-IV).
  • DPP-IV dipeptidylpeptidase IV
  • GLP-2 receptor agonists with better pharmacokinetic characteristics, in particular to improve the half-life of GLP-2 peptides.
  • GLP-2 analogues with substitutions have been suggested such as e.g.
  • GLP-2 analogues containing Gly substitution at position 2 [hGly2] GLP-2, teduglutide) which increases the half-life from seven minutes (native hGLP-2) to about two hours.
  • Acylation of peptide drugs with fatty acid chains has also proven beneficial for prolonging systemic circulation as well as increasing enzymatic stability without disrupting biological potency.
  • WO 2006/117565 (Zealand Pharma A/S) describes GLP-2 analogues which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and/or improved chemical stability, e.g. as assessed in in vitro stability assays.
  • GLP-2 analogues are described which have substitutions at one or more of positions 8, 16, 24 and/or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 and one or more of positions 3, 5, 7, 10 and 11 , and/or a deletion of one or more of amino acids 31 to 33. These substitutions may also be combined with the addition of a N- terminal or C-terminal stabilizing peptide sequence.
  • glepaglutide ZP1848 which has been designed to be stable in liquid formulations, and is typically administered by daily dosing using an injection pen.
  • Teduglutide which was approved in the EU and the US in 2012, represents the first evidence based peptide hormone for long-term treatment of patients with SBS (SPC R. Revestive:
  • WO 2011/143335 proposes the use of GLP-2 agonists for treatment of liver or kidney dysfunction in individuals experiencing intestinal failure, short bowel syndrome or parenteral nutrition, based on results obtained with teduglutide in SBS patients.
  • NPS Pharmaceuticals, Inc. proposes the use of GLP-2 agonists for treatment of liver or kidney dysfunction in individuals experiencing intestinal failure, short bowel syndrome or parenteral nutrition, based on results obtained with teduglutide in SBS patients.
  • GLP-2 agonists may upregulate or increase FGF19 production, which in turn acts to inhibit bile acid synthesis in the liver.
  • the invention therefore provides a GLP-2 agonist for use in the prophylaxis or treatment of a condition in a human subject in which reduction of bile acid synthesis, liver bile acid content, or intestinal bile acid content is desirable, or contributes to an amelioration of pathology or symptoms.
  • the invention further provides a method of prophylaxis or treatment of a condition in which reduction of bile acid synthesis, liver bile acid content, or intestinal bile acid content is desirable, or contributes to an amelioration of pathology or symptoms, the method comprising
  • the invention further provides the use of a GLP-2 agonist in the preparation of a medicament for the prophylaxis or treatment of a condition in a human subject in which reduction of bile acid synthesis, liver bile acid content, or intestinal bile acid content is desirable, or contributes to an amelioration of pathology or symptoms.
  • the condition may be selected from cholestatic liver disease (or cholestatic liver injury), primary biliary cholangitis (PBC, also known as primary biliary cirrhosis), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), intestinal failure-associated liver disease (IFALD), alcoholic hepatitis, primary bile acid diarrhea, secondary bile acid diarrhea and gallstones.
  • PBC primary biliary cholangitis
  • PSC primary biliary cholangitis
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • IALD intestinal failure-associated liver disease
  • alcoholic hepatitis alcoholic hepatitis
  • primary bile acid diarrhea or secondary bile acid diarrhea and gallstones.
  • reduction of bile acid synthesis or liver bile acid content may be desirable, or may contribute to an amelioration of pathology or symptoms, and the condition may be selected from cholestatic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), intestinal failure-associated liver disease (IFALD), alcoholic hepatitis and gallstones.
  • PBC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • IALD intestinal failure-associated liver disease
  • alcoholic hepatitis alcoholic hepatitis and gallstones.
  • reduction of bile acid synthesis or intestinal bile acid content may be desirable, or may contribute to an amelioration of pathology or symptoms, and the condition may be selected from primary bile acid diarrhea and secondary bile acid diarrhea.
  • the GLP-2 agonist may be a native (or wild-type) GLP-2 molecule, e.g. native hGLP-2.
  • GLP-2 may be an analogue of GLP-2.
  • the GLP-2 analogue is represented by the formula:
  • R 1 is hydrogen, Ci -4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl;
  • X5 is Ser or Thr
  • X11 is Ala or Ser
  • R 2 is NH 2 or OH
  • Z 1 and Z 2 are independently absent or a peptide sequence of 1-6 amino acid units of Lys;
  • X5 is Thr and/or X11 is Ala.
  • GLP-2 glucagon-like peptide 2
  • glucagon-like peptide 2 (GLP-2) analogues include: ZP1846 H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2
  • ZP1848 (glepaglutide) may be a particularly preferred GLP-2 agonist.
  • a further example of a GLP-2 agonist is [Gly2]hGLP-2, i.e. teduglutide, having the amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITD, and pharmaceutically acceptable salts or derivatives thereof.
  • the invention provides:
  • GLP-2 agonist for use in a method of prophylaxis or treatment of intestinal failure-associated liver disease (IFALD) in a subject affected by SBS, said method comprising administering 5-15 mg of the GLP-2 agonist to the patient once or twice weekly, wherein the GLP-2 agonist is H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 (ZP1848)
  • a method of prophylaxis or treatment of intestinal failure-associated liver disease (IFALD) in a subject affected by SBS comprising administering 5-15 mg of a GLP-2 agonist to the patient once or twice weekly, wherein the GLP-2 agonist is
  • a GLP-2 agonist in the preparation of a medicament for use in a method of prophylaxis or treatment of intestinal failure-associated liver disease (IFALD) in a subject affected by SBS, said method comprising administering 5-15 mg of the GLP-2 agonist to the patient once or twice weekly, wherein the GLP-2 agonist is
  • the method may comprise administering about 10mg of said GLP-2 agonist to the patient once or twice weekly, where“about” signifies +/- 10%.
  • the method may comprise administering the GLP-2 agonist by, subcutaneous injection.
  • the invention further provides the use of FGF19 or C4 as a biomarker for monitoring bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content.
  • the invention further provides a method of monitoring bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content, in a subject, the method comprising determining a level of FGF19 or C4 in the subject, and correlating the level so determined with the state of bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content, in the subject.
  • the method may comprise the step of determining a level of FGF19 or C4 in a biological sample from the subject.
  • the level of FGF19 or C4 may be a fasting level of FGF19 or C4.
  • the sample may be blood, serum or plasma, particularly plasma.
  • the method may comprise the step of obtaining the sample from the subject, or may employ a sample which has previously been obtained from the subject.
  • the level of the biomarker may be compared with a reference level, to determine whether the level is increased or reduced relative to that reference level.
  • the reference level may be a standard value, or range of values.
  • the reference level may have been determined from another subject, or may be representative of a plurality of subjects. Where the subject is affected by a particular condition, such as SBS, the reference value may be determined from “healthy” subjects (e.g. subjects not affected by the relevant condition) or other subjects affected by the same condition. Alternatively the reference level may be a value or range of values previously obtained for the same subject.
  • the biomarkers may be used to monitor the effects of treatment on a subject affected by a condition.
  • the method may comprise determining a level of FGF19 or C4 in a biological sample from the subject, wherein the subject is undergoing treatment for the condition, comparing the level so determined to a reference level previously determined for the same subject, and correlating the result with the effect of the treatment on bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content.
  • the biomarkers may be particularly useful in subjects affected by SBS, i.e. SBS patients. Thus they may be undergoing treatment for SBS, and the biomarkers may be used to monitor the effects of that treatment.
  • the subjects may lack terminal ileum and/or ileocecal valve.
  • Figure 6 a, b Individual serum levels of sCD163 and sMR (sCD206) before and after treatment for each patient
  • INR International Normalized Ratio
  • N number of patients in full analysis set.
  • Table 9 Individual and median baseline demographics from the first treatment period.
  • Total unconjugated primary bile acid CA and CDCA
  • Total conjugated primary bile acid g-CA, g-CDCA, t-CA and t-CDCA
  • Total secondary bile acid lithocholic acid, taurodeoxycholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid and tauroursodeoxycholic acid
  • Table 10 Effects of glepaglutide on alkaline phosphatase, C4, FGF19, FXR gene expression, CCK, individual fecal bile acids and gallbladder motility. Results are calculated as changes from baseline in each treatment dose. Median and interquartile range values are shown. Test for difference is done by the Wilcoxon signed-rank test. Test for dose-response relationship is done by Friedman’s test.
  • a“subject affected by SBS” may equally be regarded as an“SBS patient”. They typically refer to a human, although they may also refer to a non-human animal. Thus, these terms include mammals such as humans, primates, livestock animals (e.g. bovines and porcines), companion animals (e.g. canines and felines) and rodents (e.g. mice and rats).
  • livestock animals e.g. bovines and porcines
  • companion animals e.g. canines and felines
  • rodents e.g. mice and rats.
  • solvate in the context of the present invention refers to a complex of defined .
  • stoichiometry formed between a solute (in casu, a peptide or pharmaceutically acceptable salt thereof according to the invention) and a solvent.
  • the solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid.
  • a solvate is normally referred to as a hydrate.
  • sarcosine Sar
  • norleucine Nle
  • a-aminoisobutyric acid Aib
  • 2,3-diaminopropanoic acid Dap
  • 2,4-diaminobutanoic acid Dab
  • 2,5-diaminopentanoic acid ornithine; Orn
  • 3- aminoproanoic acid b-Ala
  • b-leucine b-Leu, b ⁇ , beta-leucine
  • (3R)-3-Amino-4-methylpentanoic acid 2-naphthylalanine (2Nal; 3-(2-naphthyl)-L-alanine; (S)-2-Amino-3-(naphthalen-2- yl)propanoic acid), and deamino-histidine (daH; imidazolylpropionic acid, 3-(1 H
  • Naturally occurring in this context is meant the 20 amino acids encoded by the standard genetic code, sometimes referred to as proteinogenic amino acids.
  • amino acid residues in peptides of the invention are of the L- configuration.
  • D-configuration amino acids may be incorporated.
  • an amino acid code written with a small letter represents the D-configuration of said amino acid, e.g.“k” represents the D-configuration of lysine (K).
  • the terminal groups present at the N- and C-termini of a peptide backbone are designated R 1 and R 2 respectively.
  • R 1 is bonded to the nitrogen atom of the N-terminal amino group and R 2 is bonded to the C-terminal carbonyl carbon atom.
  • R 1 “Hy-“ (hydrogen) indicates a free primary amino group at the N- terminus. (The other hydrogen atom of the N-terminal amino group is invariant, regardless of the nature of R 1 .)
  • R 1 acetyl (“Ac”) indicates the presence of an N-terminal secondary acetyl amide group.
  • R 2 “-OH” or“-NH2” indicates a C-terminal carboxyl (COOH) or amido (CONH2) group respectively.
  • Percent (%) amino acid sequence identity with respect to a reference polypeptide sequences is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Sequence alignment can be carried out by the skilled person using techniques well known in the art, for example using publicly available software such as BLAST, BLAST2 or Align software. For examples, see Altschul et al. 1996 or Pearson et al. 1997.
  • AE Adverse Event
  • ALAT/ALT Alanine Transaminase
  • ALP Alkaline Phosphatase
  • ANCOVA Analysis of Covariance
  • ASAT/AST Aspartate Transaminase
  • AUC Area Under the Curve
  • BV Baseline Value
  • CAP Controlled Attenuation Parameter
  • CCK Controlled Attenuation Parameter
  • ECG Electrocardiography
  • FGF Fibroblast Growth Factor
  • FXR Farnesoid X Receptor
  • Gl Gastrointestinal
  • GIE gastrointestinal emptying
  • GLP Glucagon-Like Peptide
  • HBsAg Hepatitis B Surface Antigen
  • IBD Inflammatory Bowel Disease
  • ICG Indocyanine Green
  • IFALD Intestinal Failure Associated Liver Disease
  • IF Intestinal Failure
  • II Intestinal Insufficiency
  • LPS Lipopolysaccharide
  • LBP Lipopolysaccharide Binding
  • PDR Plasma Disappearance Rate
  • R15 Retention Rate after 15 Minutes
  • QoL Quality of Life
  • SBS Short Bowel Syndrome
  • SAE Serious Adverse Event
  • sCD163 Soluble CD163
  • sMR Soluble Mannose Receptor
  • SF-36 Short Form 36
  • ULN Upper Limits of Normal
  • TE Transient Elastography
  • Tmax Time to Peak
  • UC ulcerative colitis
  • UK unknown
  • VAS Visual Analog Scale
  • WD withdrew.
  • Bile acids are steroid acids found predominantly in bile.
  • the primary bile acids cholic acid and chenodeoxycholic acid
  • cholic acid and chenodeoxycholic acid are synthesised in liver cells via a multi-step process involving cytochrome P450-mediated oxidation of cholesterol. These are conjugated with glycine or taurine before secretion from the liver.
  • Bacteria process these compounds further, by partial dehydroxylation and removal of the glycine and taurine groups, to form the secondary bile acids deoxycholic acid and lithocholic acid. These can then be taken back up into the liver, conjugated to glycine and taurine, and re-secreted. This process is known as enterohepatic circulation.
  • the main human bile acids are cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and lithocholic acid.
  • the major bile acids found in bile are taurocholic acid, glycocholic acid, taurochenodeoxycholic acid and glycochenodeoxycholic acid, which are present at approximately equal concentrations.
  • bile acids conjugated to glycine and taurine
  • bile salts The forms of bile acids conjugated to glycine and taurine are often referred to as bile salts.
  • the term“bile acids” will be used in this specification to embrace all bile acids, including so-called bile salts.
  • the farnesoid X receptor also known as the bile acid receptor (BAR), or NR1 H4, is a steroid receptor expressed in liver cells (hepatocytes) and intestinal cells (enterocytes). It is capable of binding chenodeoxycholic acid and other bile aids. Having bound ligand, it translocates to the nucleus where (as part of a complex with a heterodimer partner) it binds to hormone response element sequences in genomic DNA, regulating expression of various steroid-sensitive genes.
  • SHP small heterodimer partner
  • CYP7A1 CYP7A1
  • Hepatic CYP7A1 is a rate-limiting enzyme in bile acid production and generates 7a- hydroxycholesterol from cholesterol.
  • 7a-hydroxycholesterol is a precursor of 7a-Hydroxy-4- cholesten-3-one (C4) which serves as a marker for bile acid synthesis.
  • Another gene upregulated by FXR is the gene for FGF19 (fibroblast growth factor 19). FGF19 is expressed in the ileum, and also exerts a negative regulatory effect on bile acid synthesis.
  • FXR farnesoid X receptor
  • GLP-2 agonists especially glepaglutide, may find use in the prophylaxis or treatment of conditions in which reduction of bile acid synthesis, liver bile acid content, or intestinal bile acid content is desirable, or contributes to an amelioration of pathology or symptoms.
  • Such conditions include cholestatic liver disease (or cholestatic liver injury), primary biliary cholangitis (PBC, also known as primary biliary cirrhosis), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), intestinal failure- associated liver disease (IFALD; also known as parenteral nutrition-associated liver disease or PNALD), alcoholic hepatitis, primary bile acid diarrhea, secondary bile acid diarrhea and gallstones.
  • PBC primary biliary cholangitis
  • PSC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • IALD intestinal failure- associated liver disease
  • alcoholic hepatitis alcoholic hepatitis
  • primary bile acid diarrhea secondary bile acid diarrhea and gallstones.
  • conditions which benefit particularly from reduction of bile acid synthesis or liver bile acid content may include cholestatic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease
  • NAFLD nonalcoholic steatohepatitis
  • NASH nonalcoholic steatohepatitis
  • IALD intestinal failure-associated liver disease
  • conditions which benefit particularly from reduction of bile acid synthesis or intestinal bile acid content may include primary bile acid diarrhea and secondary bile acid diarrhea.
  • the trophic effect of glepaglutide on the ileum is believed to increase FGF19 levels in plasma which in turn reduces hepatic bile acid synthesis (reflected by reductions in plasma C4)
  • the reduced bile acid synthesis and the lower amount of bile acids secreted into the intestine is expected to be beneficial in primary and secondary bile acid diarrhea.
  • a reduction in bile acid synthesis may benefit any or all of these conditions, and others.
  • a reduction of bile acid content in liver, intestine, or both may also be beneficial in any or all of these conditions, and others.
  • IFALD may be associated with short bowel syndrome (SBS). That is to say, patients affected by IFALD may also be affected by SBS. SBS, or the administration of parenteral nutrition as a result of SBS, may contribute to the pathogenesis of IFALD.
  • SBS short bowel syndrome
  • the subject to be treated is not receiving parenteral nutrition, or is not receiving total parenteral nutrition (e.g. they are receiving a maximum of 25%, 50%, or 75% of their calorific intake parenteraily). In some embodiments, the subject is not affected by IFALD.
  • the subject to be treated may have resected small bowel, or may have impaired small bowel function.
  • the subject may lack terminal ileum and/or ileocecal valve.
  • the subject may be a SBS patient with end-jejunostomy and no colon, or a SBS patient with colon- in-continuity.
  • GLP-2 agonists may also be used simply to reduce bile acid synthesis, liver bile acid content, or intestinal bile acid content in subjects affected by SBS.
  • a GLP-2 agonist (which may alternatively be referred to as a“GLP-2 receptor agonist”, or simply a“GLP-2 peptide”) is a peptide having agonist activity at the GLP-2 receptor.
  • Activity at the GLP-2 receptor may be assessed in vitro, e.g. by determining their ability to stimulate intracellular cyclic AMP (cAMP) synthesis in cells expressing the human GLP-2 receptor.
  • cAMP cyclic AMP
  • the cells will have been genetically engineered to express the GLP-2 receptor (e.g. by transfection with an expression vector carrying the gene for the receptor and capable of driving its expression) and equivalent cells lacking the GLP-2 receptor will be used as a negative control.
  • Such assays are described, for example, in WO 2013/164484.
  • GLP-2 agonists have at least one GLP-2 biological activity, in particular in causing growth of the intestine. This can be assessed in in vivo assays, for example as described in WO 2006/117565, in which the mass of the intestine, or a portion thereof is determined after a test animal has been treated or exposed to a GLP-2 agonist.
  • the GLP-2 agonist may be a native (or wild-type) GLP-2 molecule, e.g. native hGLP-2 having the sequence set out above.
  • the GLP-agonist will have one or more amino acid substitutions, deletions, inversions, or additions compared with native GLP-2 and as defined above, and so can be regarded as a GLP-2 analogue.
  • the analogue may additionally have chemical modification of one or more of its amino acid side groups, a-carbon atoms, terminal amino group, or terminal carboxylic acid group.
  • a chemical modification includes, but is not limited to, adding chemical moieties, creating new bonds, and removing chemical moieties.
  • Modifications at amino acid side groups include, without limitation, acylation of lysine e-amino groups, N- alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine.
  • Modifications of the terminal amino include, without limitation, the des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl
  • Modifications of the terminal carboxy group include, without limitation, the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications.
  • lower alkyl is C1 -C4 alkyl.
  • one or more side groups, or terminal groups may be protected by protective groups known to the ordinarily-skilled peptide chemist.
  • the a-carbon of an amino acid may be mono- or di-methylated.
  • the GLP-2 analogue is represented by the formula:
  • R 1 is hydrogen, Ci -4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl;
  • X5 is Ser or Thr
  • X11 is Ala or Ser
  • R 2 is NH 2 or OH
  • Z 1 and Z 2 are independently absent or a peptide sequence of 1-6 amino acid units of Lys;
  • Z 1 and Z 2 are independently present or absent. When present, they each independently represent a peptide sequence of 1-6 amino acid units of Lys, i.e. 1 , 2, 3, 4, 5 or 6 Lys residues.
  • the Lys residues may have either D- or L-configuration, but preferably have an L-configuration.
  • Particularly preferred sequences Z are sequences of four, five or six consecutive lysine residues, and particularly six consecutive lysine residues.
  • Z 1 is absent.
  • Z 2 may be either present or absent.
  • X5 is Thr and/or X11 is Ala.
  • GLP-2 glucagon-like peptide 2
  • glucagon-like peptide 2 (GLP-2) analogues examples include:
  • ZP2242 H-HGEGSFSSELSTILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 9)
  • ZP1848 (glepaglutide) may be a particularly preferred GLP-2 agonist.
  • a further example of a GLP-2 agonist is [Gly2]hGLP-2, i.e. teduglutide, having the amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITD.
  • GLP-2 agonists include FE 203799 (GlyPharma Therapeutic / Ferring Pharmaceuticals), BioChaperone teduglutide (BC GLP-2; Adocia), NB1002 (Naia
  • GLP-2 agonists are described in DaCambra et al. 2000, US 5,789,379; US 5,994,500; US 6,184,201 ; US 6,184,208; WO 97/39031 ; WO 01/41779; WO 02/066511 ; WO 2006/1 17565 and WO 2008/056155. It should be understood that a GLP-2 agonist might also be provided in the form of a salt or other derivative. Salts include pharmaceutically acceptable salts such as acid addition salts and basic salts. Examples of acid addition salts include hydrochloride salts, citrate salts and acetate salts.
  • Examples of basic salts include salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions + N (R 3 ) 3(R 4 ), where R 3 and R 4 independently designates optionally substituted Ci-e-alkyl, optionally substituted C2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium
  • R 3 and R 4 independently designates optionally substituted Ci-e-alkyl, optionally substituted C2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 3 and R 4 independently designates optionally substituted Ci-e-alkyl, optionally substituted C2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl
  • GLP-2 agonists include solvates, coordination complexes with metal ions such as Mn 2+ and Zn 2+ , esters such as in vivo hydrolysable esters, free acids or bases, hydrates, prodrugs or lipids.
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • Derivatives which as prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds. Typically, at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • prodrugs include the use of protecting groups which may be removed in situ releasing active compound or serve to inhibit clearance of the drug in vivo.
  • GLP-2 agonists, or salts or derivatives thereof may be formulated as pharmaceutical compositions prepared for storage or administration, and which comprise a prophylactically or therapeutically effective amount of a GLP-2 agonist, or a salt or derivative thereof, in a pharmaceutically acceptable carrier.
  • the prophylactically or therapeutically effective amount of a GLP-2 agonist will depend on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, but will depend on such factors as weight, diet, concurrent medication and other factors, well known those skilled in the medical arts.
  • Pharmaceutically acceptable salts of the compounds of the invention having an acidic moiety can be formed using organic and inorganic bases. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with
  • salts also may be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
  • Amino acid addition salts can also be formed with amino acids such as lysine, glycine, or phenylalanine.
  • therapeutically effective amount of the peptides or pharmaceutical compositions of the present invention will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, the particular mode of administration and the desired effects and the therapeutic indication. Because these factors and their relationship to determining this amount are well known in the medical arts, the determination of therapeutically effective dosage levels, the amount necessary to achieve the desired result, will be within the ambit of the skilled person.
  • a therapeutically effective amount is one which reduces symptoms of a given condition or pathology, and preferably which normalizes physiological responses in an individual with the condition or pathology. Reduction of symptoms or normalization of physiological responses can be determined using methods routine in the art and may vary with a given condition or pathology.
  • a therapeutically effective amount of a GLP-2 agonist, or a pharmaceutical composition comprising the GLP-2 agonist is an amount which restores a measurable physiological parameter to substantially the same value (preferably to within + 30%, more preferably to within + 20%, and still more preferably, to within 10% of the value) of the parameter in an individual without the condition or pathology.
  • a “prophylactically effective amount” is typically one which inhibits or delays onset, development, or rate of progression, of symptoms or pathology, as compared to onset, development, or progression in the absence of administration. Prophylaxis may be considered as therapy.
  • the chosen GLP-2 agonist is formulated with a carrier that is
  • peripheral parenteral routes include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration.
  • the route of administration is the subcutaneous route or subcutaneous
  • the present pharmaceutical composition comprises a GLP-2 agonist, or a salt or derivative thereof and a pharmaceutically acceptable carrier.
  • Suitable pharmaceutically acceptable carriers are those used conventionally with peptide-based drugs, such as diluents, excipients and the like.
  • Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used.
  • pH buffering agents may be phosphate, citrate, acetate, tris/hydroxymethyl)aminomethane (TRIS), N- Tris(hydroxymethyl)methyl -3- aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
  • Preferred buffer ranges are pH 4-8, pH 6.5-8, more preferably pH 7-7.5.
  • Preservatives such as para, meta, and ortho-cresol, methyl- and propylparaben, phenol, benzyl alcohol, sodium benzoate, benzoic acid, benzyl-benzoate, sorbic acid, propanoic acid, esters of p- hydroxybenzoic acid may be provided in the pharmaceutical composition.
  • Stabilizers preventing oxidation, deamidation, isomerisation, racemisation, cyclisation, peptide hydrolysis, such as e.g. ascorbic acid, methionine, tryptophane, EDTA, asparagine, lysine, arginine, glutamine and glycine may be provided in the pharmaceutical composition.
  • Stabilizers, preventing aggregation, fibrillation and precipitation such as Sodium dodecyl sulphate, polyethylene glycol,
  • carboxymethyl cellulose, cyclodextrin may be provided in the pharmaceutical composition.
  • Organic modifiers for solubilization or preventing aggregation such as ethanol, acetic acid or acetate and salts thereof may be provided in the pharmaceutical composition.
  • Isotonicity makers such as salts e.g. sodium chloride or most preferred carbohydrates e.g. dextrose, mannitol, lactose, trehalose, sucrose or mixtures thereof may be provided in the pharmaceutical composition.
  • Detergents such as Tween 20, Tween 80, SDS, Poloxamers e.g. Pluronic F-68, Pluronic F-127, may be provided in the pharmaceutical composition.
  • Dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • a pharmaceutically acceptable acid addition salt of the GLP-2 peptide agonist is provided for. Suspending agents may be used.
  • Organic modifiers such as ethanol, tertiary-buthanol, 2-propanol, ethanol, glycerol, Polyethylene glycol may be provided in the pharmaceutical formulation for lyophilization of a lyophilized product.
  • Bulking agents and isotonicity makers such as salt e.g. sodium chloride, carbohydrates e.g. dextrose, mannitol, lactose, trehalose, sucrose or mixtures thereof, amino acids e.g.
  • glycine, glutamate, or excipients such as cystein, lecithin or human serum albumin, or mixtures thereof may be provided in the pharmaceutical composition for lyophilization.
  • compositions of the present invention may be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration;
  • sterile solutions or sterile powder or suspensions for injectable administration preferably sterile solutions or sterile powder or suspensions for injectable administration; and the like.
  • the dose and method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors, which those skilled in the medical arts will recognize.
  • parenteral such as intravenous, subcutaneous or intramuscular injectable pharmaceutical compositions can be prepared in conventional forms, either as aqueous solutions or suspensions; lyophilized, solid forms suitable for reconstitution
  • Diluents for reconstitution of the lyophilized product may be a suitable buffer from the list above, water, saline, dextrose, mannitol, lactose, trehalose, sucrose, lecithin, albumin, sodium glutamate, cysteine hydrochloride; or water for injection with addition of detergents, such as Tween 20, Tween 80, poloxamers e.g. pluronic F-68 or pluronic F-127, polyethylene glycol, and or with addition of preservatives such as para-, meta-, and ortho-cresol, methyl- and
  • propylparaben phenol, benzyl alcohol, sodium benzoate, benzoic acid, benzyl-benzoate, sorbic acid, propanoic acid, esters of p-hydroxybenzoic acid, and or with addition of an organic modifier such as ethanol, acetic acid, citric acid, lactic acid or salts thereof.
  • the injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances, such as wetting agents, or pH buffering agents.
  • Absorption enhancing preparations e.g., liposomes, detergents and organic acids
  • the compounds are formulated for administration by infusion, e.g., when used as liquid nutritional supplements for patients on total parenteral nutrition therapy (for example neonatals, or patients suffering from cachexia or anorexia), or by injection, for example subcutaneously, intraperitoneal or intravenously, and are accordingly utilized as aqueous solutions in sterile and pyrogen-free form and optionally buffered to physiologically tolerable pH, e.g., a slightly acidic or physiological pH.
  • Formulation for intramuscular administration may be based on solutions or suspensions in plant oil, e.g. canola oil, corn oil or soy bean oil. These oil based formulations may be stabilized by antioxidants e.g. BHA (butylated hydroxianisole) and BHT (butylated hydroxytoluene).
  • plant oil e.g. canola oil, corn oil or soy bean oil.
  • antioxidants e.g. BHA (butylated hydroxianisole) and BHT (butylated hydroxytoluene).
  • the GLP-2 agonist may be formulated in a vehicle, such as distilled water or in saline, phosphate buffered saline, 5% dextrose solutions or oils.
  • a vehicle such as distilled water or in saline, phosphate buffered saline, 5% dextrose solutions or oils.
  • the solubility of the GLP-2 agonist may be enhanced, if desired, by incorporating a solubility enhancer, such as detergents and emulsifiers.
  • aqueous carrier or vehicle can be supplemented for use as injectables with an amount of gelatin that serves to depot the GLP-2 agonist at or near the site of injection, for its slow release to the desired site of action.
  • Gelling agents such as hyaluronic acid, may also be useful as depot agents.
  • a GLP-2 agonist will typically be administered to patients by injection, most typically by subcutaneous injection or intramuscular injection.
  • the GLP-2 agonist may be administered using an injection pen, which allow patients to self-administer the agonist.
  • administration of the GLP-2 agonist causes formation of a subcutaneous depot from which the GLP-2 agonist, or metabolites thereof, are released.
  • the subcutaneous depot may form through the interaction of the GLP-2 agonists, in particular where the agonist is an analogue comprising a lysine tail (i.e. a Z 1 group and/or a Z 2 group), through a reaction between the analogues and with hyaluronic acid in the subcutaneous compartment.
  • the agonist is an analogue comprising a lysine tail (i.e. a Z 1 group and/or a Z 2 group)
  • a reaction between the analogues and with hyaluronic acid in the subcutaneous compartment i.e. a Z 1 group and/or a Z 2 group
  • the GLP-2 agonist may be utilized in the form of a sterile-filled vial or ampoule containing a therapeutic amount of the peptide, in either unit dose or multi-dose amounts.
  • the vial or ampoule may contain the GLP-2 agonist and the desired carrier, as an administration ready formulation.
  • the vial or ampoule may contain the GLP-2 agonist in a form, such as a lyophilized form, suitable for reconstitution in a suitable carrier, such as sterile water or phosphate-buffered saline.
  • a suitable carrier such as sterile water or phosphate-buffered saline.
  • the therapeutic dosing and regimen most appropriate for patient treatment will of course vary with the disease or condition to be treated, and according to the patient parameters. Without wishing to be bound by any particular theory, it is expected that doses, between 0.1 and 25 mg per patient, and shorter or longer duration or frequency of treatment may produce
  • the therapeutic regimen may include the administration of maintenance doses appropriate for preventing recurrence of pathology or symptoms following cessation of initial treatment.
  • the dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in further clinical trials.
  • An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person.
  • a human dose of a GLP-2 peptide may be between about 0.01 mg/kg and 100 mg/kg body weight, such as between about 0.01 mg/kg and 10 mg/kg body weight, for example between 10- 100 pg/kg body weight.
  • a human dose (total dose) of a GLP-2 peptide may be from about such as between and including 0.1 mg and 25 mg per patient between and including 0.5 mg and 20 mg per patient, such as between and including 1 mg and 15 mg per patient, such as between and including 1 mg and 10 mg per patient, and between and including 5 mg and 15 mg per patient, once or twice weekly or as a plurality of doses as defined herein separated in time by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 days.
  • a fixed dose of the GLP-2 peptide may be used in accordance with a dosing pattern disclosed herein, i.e. a dose which is the same regardless of the body weight of the patient, given once or twice weekly.
  • the fixed dose may be a dose of about 5 mg, 6 mg, 7 mg, 8 mg, 9, mg, 10 mg, 1 1 mg, 12 mg, 13 mg, 14 mg or 15 mg, e.g. 5 mg, 6 mg, 7 mg, 8 mg, 9, mg, 10 mg,
  • a fixed dose of about 10 mg may be used, e.g. a fixed dose of 10mg, e.g. given once or twice weekly. “About” in this context indicates +/- 10%.
  • the use of fixed dosing has the advantage of increasing compliance and reducing the risk of patient dosing errors, including risks of miscalculating a weight based dose to be
  • Biomarkers The invention further relates to the identification of biomarkers for monitoring bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content.
  • biomarkers may find particular use in subjects affected by SBS (i.e. SBS patients), and particularly in SBS patients lacking terminal ileum and/or ileocecal valve. It is believed that the study described below represents the first time that FGF19 and C4 have been studied in patients without preserved terminal ileum and ileocecal valve. However the invention is not necessarily limited to such subjects.
  • GLP-2 agonists may increase FGF19 production in such patients, which in turn suppresses bile acid synthesis.
  • FGF19 and C4 (7a-hydroxy-4-cholesten-3-one - a marker for bile acid synthesis) have been found to correlate with bile acid synthesis, levels of bile acids in liver and/or intestine, and with fecal bile acid content and composition, demonstrating that they find use as biomarkers for monitoring bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content.
  • the invention provides the use of FGF19 or C4 as a biomarker for monitoring bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content, e.g. in a subject affected by SBS.
  • the invention further provides a method of monitoring bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content, in a subject, the method comprising determining a level of FGF19 or C4 in the subject, and correlating the level so determined with the state of bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content, in the subject.
  • the method may comprise the step of determining a level of FGF19 or C4 in a biological sample from the subject.
  • the level of FGF19 or C4 may be a fasting level of FGF19 or C4.
  • the sample may be blood, serum or plasma, particularly plasma.
  • the method may comprise the step of obtaining the sample from the subject, or may employ a sample which has previously been obtained from the subject.
  • Levels of FGF19 and C4 are inversely correlated.
  • an increased level of FGF19 or a reduced level of C4 typically indicates a reduction in bile acid synthesis, liver bile acid content, or intestinal bile acid content, and thus may indicate an improvement in bile acid homeostasis.
  • a reduced level of FGF19 or an increased level of C4 typically indicates an increase in bile acid synthesis, liver bile acid content, or intestinal bile acid content, and thus may indicate an deterioration in bile acid homeostasis.
  • the level of the biomarker may be compared with a reference level, to determine whether the level is increased or reduced relative to that reference level.
  • the reference level may be a standard value, or range of values.
  • the reference level may have been determined from another subject, or may be representative of a plurality of subjects. Where the subject is affected by a particular condition, the plurality of subjects may be“healthy” subjects (not affected by the relevant condition) or other affected subjects. Alternatively the reference level may be a value or range of values previously obtained for the same subject.
  • an increased level of FGF19 or a reduced level of C4 compared to the reference level may indicate a reduction in bile acid synthesis, liver bile acid content, or intestinal bile acid content, and thus may indicate an improvement in bile acid homeostasis.
  • a reduced level of FGF19 or an increased level of C4 compared to the reference level typically indicates an increase in bile acid synthesis, liver bile acid content, or intestinal bile acid content, and thus may indicate an deterioration in bile acid homeostasis.
  • the biomarkers may be used to monitor the effects of treatment on a subject.
  • the subject may be undergoing treatment for SBS, or for dysregulation of bile acid homeostasis, e.g. with a GLP-2 agonist or other therapy.
  • the method may comprise determining a level of FGF19 or C4 in a biological sample from a subject undergoing treatment for a condition, comparing the level so determined to a reference level previously determined for the same subject (e.g. before treatment, or earlier in the course of treatment), and correlating the result with the effect of the treatment on bile acid homeostasis, bile acid synthesis, liver bile acid content, or intestinal bile acid content.
  • the biomarkers may be particularly useful in a subject affected by SBS, i.e. SBS patients.
  • SBS a subject affected by SBS
  • the subject may be undergoing treatment for SBS, and the biomarkers may be used to monitor the effects of that treatment.
  • the subject may lack terminal ileum and/or ileocecal valve.
  • GLP-2 agonists described herein can be made according to the methods such as solid phase peptide synthesis described in WO 2006/117565, the content of which is expressly incorporated by reference in its entirety.
  • a daily dosing regimen was applied in the trial to obtain near-steady state plasma exposures throughout the duration of the trial.
  • the trial design was optimized to address the limited number of SBS patients available for clinical testing and need for establishing effective and safe plasma exposure-ranges of glepaglutide.
  • a daily injection of 1 mg of glepaglutide was expected to show therapeutic effects comparable to the clinically effective dose of 1 mg/day of native GLP-2 (Jeppesen et al. 2001 ).
  • Injections of 0.1 mg and 10 mg glepaglutide were expected to yield an exposure significantly lower and higher than this level, respectively. Accordingly, the three tested doses were expected to provide clinically relevant efficacy and to cover the potential dose range for daily dosing of SBS patients.
  • a wash-out period of four to eight weeks separated the two treatment periods.
  • the primary endpoint of the trial was the absolute change from baseline in fecal wet weight output measured separately over the two treatment periods.
  • the primary and secondary endpoints as well as exploratory effect parameters were assessed as changes from baseline and were measured during hospitalization for 72-hour metabolic balance studies prior to and at the end of each treatment period.
  • sample size was chosen based on the magnitude of effect of GLP-2 treatment on reductions of fecal output as observed in previous studies (Jeppesen et al. 2001 and Jeppesen et al. 2005), as well as taking the practical and feasible availability of eligible patients with SBS into account. By having the patients serve as their own control in the cross-over design, adequate power was expected regarding the primary endpoint to separate the active doses from the non-active dose.
  • Absolute absorption was calculated as dietary intake minus fecal excretion. Relative absorption was calculated as absolute absorption divided by dietary intake.
  • Renal function was assessed by the urine output and creatinine clearance was calculated by dividing 24-hour urinary creatinine excretion by the plasma creatinine concentration. Hydration level was estimated by body weight, plasma protein, hematocrit, plasma aldosterone, and 24- hour urinary sodium excretion.
  • Body weight was calculated as the mean measurements performed on four consecutive days after an overnight fast using a leveled platform scale every morning after urination and defecation/emptying of the stoma bags.
  • Body composition was measured by Dual-energy X-ray Absorptiometry (Norland XR-36 DXA densitometer, Norland Corp., Fort Atkinson, Wl., USA).
  • Endoscopy was performed after an overnight fast through the stoma using a thin, flexible sigmoidoscope from Olympus (Tokyo, Japan). This examination was performed only if the patient had separately consented to this procedure. At least two tissue samples were taken approximately 10-20 cm from the stoma nipple using a standard 9 mm biopsy forceps.
  • biopsies were fixed in 10% formalin. At the time of the analyses the biopsies were molded in paraffin and cut into 5 pm slices whereupon they were stained with haematoxylin/eosin and examined with a light microscope. Villus and epithelium height as well as crypt depth were determined using ImagePro plus 9.2 software (Media Cybernetics, USA).
  • hepatic function was assessed by: 1 ) Transient elastography (TE) and controlled attenuation parameter (CAP) by Fibroscan ® 502 touch (Echosens, France) using the FibroScan M probe and: 2) indocyanine green (ICG) disappearance rate and retention.
  • TE Transient elastography
  • CAP controlled attenuation parameter
  • ICG indocyanine green
  • ICG clearance a bolus of ICG (0.25 mg/kg, ICG-pulsion, Pulsion Medical Systems, Feldkirschen, Germany) was injected intravenously followed by flushing with saline (Purcell et al. 2006).
  • Plasma disappearance rate (PDR, %/min) and retention after 15 min (R15, %) were measured by the noninvasive validated pulse spectroscopy device LiMON (Pulsion, Maquet Holding B.V. & Co., Rastatt, Germany) (Cheung et al. 2012, Purcell et al. 2006, Sakka et al. 2000) applied with a near-infrared finger-clip attached to the patient’s index finger.
  • LiMON Pulsion, Maquet Holding B.V. & Co., Rastatt, Germany
  • ICG-PDR and ICG-R15 were measured after injection with glepaglutide. The principles behind the method have been described previously (Levesque et al. 2016).
  • FXR farnesoid X receptor
  • Plasma citrulline was analyzed by high-pressure liquid chromatography (Fjermestad et al. 2017). Fibroblast growth factor (FGF)-19 concentrations were measured using a commercial ELISA kit (cat no. RD191107200R, BioVendor, Brno, Czech Republic). 7a-Hydroxy-4-cholesten-3-one (C4) was analyzed by liquid chromatography-mass spectrometry, i.e. liquid chromatography (Waters Acquity UPLC) connected to a triple quadrupole mass spectrometer (Waters Xevo TQ- S). Details are described in the supplemental information. The methods for determination of GLP-1 (0rskov C et al.
  • sMR soluble mannose receptor
  • LBP lipopolysaccharide binding protein
  • Plasma sCD163 and sMR were analyzed by in-house sandwich enzyme-linked immunosorbent assays (ELISAs) (Moller et al. 2002, Rodgaard-Hansen et al. 2014). LBP was measured using a commercially available ELISA kit (Duoset, R&D Systems, Minneapolis, MN, USA).
  • ELISAs sandwich enzyme-linked immunosorbent assays
  • ALP phosphatase
  • INR international normalized ratio
  • ASAT p-albumin and liver transaminases
  • PK glepaglutide pharmacokinetic
  • ADA anti-glepaglutide antibodies
  • the immunogenicity of glepaglutide was assessed using a direct ELISA-type of assay developed for the DELFIA-platform for the measurement of binding antibodies against glepaglutide.
  • the trial used a 3-treatment (0.1 mg, 1.0 mg, 10 mg), 2-period cross-over design.
  • Six sequences (A, B, C, D, E, F) were used, corresponding to all ordered pairs of three treatments: A ⁇ 10 mg/1 mg, B ⁇ 10 mg/0.1 mg, C ⁇ 1 mg/10 mg, D ⁇ 1 mg/0.1 mg, E-0.1 mg/10 mg and F ⁇ 0.1 mg/1 mg.
  • a sequence label thus uniquely determined the treatments allocated for periods 1 and 2.
  • Five blocks of length 6 were prepared in advance; each block being a random ordering of A:B:C:D:E:F.
  • the trial investigator enrolled patients and assigned them their patient numbers.
  • the randomization process linked the assigned patient numbers to the first available randomization number, each corresponding to a sequence label.
  • the packaging list destined for the drug supplier, included the randomization number, the sequence label, the treatment period and the dosage to be used for each vial.
  • the packaging list was supplied by an independent clinical research organization. Staff involved in randomization had no further involvement with the trial. Trial investigators, patients and other care providers were blinded throughout the trial; i.e. information regarding allocation and its methods were not available until after the final data analysis was performed.
  • RNA isolation kit RNAeasy minikit Qiagen
  • the biopsies were weighed and homogenized in 700 ul lysis buffer with 1 % mercaptoethanol with a TissueLyzer operated at 28Hz in 6 * 60 seconds with intermittent cooling. Lysate was centrifuged and supernatant were added 1 volume of 70% ethanol, mixed and transferred to an RNeasy spin column for on-column washing procedures and DNase treatment. RNA was eluted with RNase free water.
  • Calibrators was produced by adding 7a-Hydroxy-4-cholesten-3-one (Toronto Research
  • Sample preparation Patient serum (50 pL) was added acetonitrile (200 pL) with a deuterated internal standard 7a-Hydroxy-4-cholesten-3-one-d7 (C4-d 7 ) (Toronto Research Chemicals, Toronto, Canada), subsequently, mixed and centrifuged (5000g for 10 min). The supernatant was used for injection (injection volume 2 pL).
  • C4-d 7 deuterated internal standard 7a-Hydroxy-4-cholesten-3-one-d7
  • Mass spectrometry Quantification was based on the positive mass transitions 401.5 > 177.2 for C4 and 408.5 > 177.2 for the deuterated internal standard C4-d (Wojdemann M et al 1999).
  • Figures 1 to 8 and Tables 1 to 8 illustrate the results of an analysis of covariance (ANCOVA), used to assess the effects of the three dose-levels of glepaglutide (0.1 mg, 1 mg or 10 mg) on change-from-baseline over a treatment period of three weeks, using Statistical Analysis
  • the changes were of the same magnitude in patients with SBS-II and SBS- IF, with or without colon in continuity, and reverted to baseline after the drug-free period, thus, no carryover effect was observed.
  • Other significant improvements in hydration level were observed in terms of reduction in plasma albumin, plasma protein, haematocrit and plasma aldosterone in the 1 mg dose group.
  • CAP value was above 248 dB/m (cut-offs for steatosis > SO (Karlas et al. 2012) in 10 out of 16 patients; three out of five (60%) patients with SBS-II and seven out of 1 1 (64%) patients with SBS-IF.
  • ICG-PDR at baseline was 19.4 ⁇ 5.7%/min and mean ICG-R15 was 7.6 ⁇ 6.9%.
  • ICG-PDR was below the lower limits of normal (LLN) in eight patients; among them seven patients had SBS-IF.
  • ICG-R15 was elevated in two patients with SBS-IF at baseline (Levesque et al. 2016).
  • Fasting median plasma C4 concentration was 113 pg/L (45 to 444) Table 9), and 17 out of 18 patients (94%) had fasting C4 concentrations above 50 pg/L indicating increased bile acid loss (Camilleri et al. 2009, Freudenberg et al.
  • the baseline C4-AUC0-2h was 261 h*pg/L (166 to 1105) (Table 9).
  • Plasma concentrations of FGF19 and C4 were unaffected by meal ingestion in the 120 minutes postprandial period. A linear dose response relationship was observed in changes of
  • Mean sCD163 at baseline was 3.1 ⁇ 1.7 mg/mL, mean sMR was 0.3 ⁇ 0.1 mg/ml_ and mean LBP was 4.8 ⁇ 4.0pg/ml_. Elevated levels (higher than the reference range 97.5 percentile for healthy individuals (Rodgaard-Hansen et al. 2014; Moller, 2012) of sCD163 and sMR were observed in three and two SBS-IF patients, respectively. LBP was below LLN in 13 out of 18 patients.
  • ALP alkaline phosphatase
  • liver transaminases ASAT and ALAT
  • the fasting gallbladder volume was 31 mL (9 to 105, Table 9)
  • EF-AUC0-2h was 60 hx% (-134 to 150, Table 9)
  • the EFmax was 49% (6 to 93, Table 9)
  • the EF-Tmax was 45 min (15 to 120).
  • Short bowel length and PS volume at baseline did not seem to correlate with baseline values nor changes in ICG-PDR and ICG-R15.
  • AEs All patients experienced at least one drug-related AE; most were mild or moderate in severity. The incidence of AEs was equally distributed across the different dose groups. The most common AEs were stoma complications (increased diameter and protrusion of the stoma nipple) and transient injection site reactions (redness, itching, subcutaneous infiltration and pain) which occurred more frequently with increasing dose. Common AEs additionally included peripheral edema and polyuria which tended to occur more frequently in the 1 mg and 10 mg dose groups than in the 0.1 mg dose group. Other AEs included abdominal pain, abdominal distension, nausea, fatigue, dizziness and vomiting, which all occurred during treatment with all three doses and with no definite dose-response relationship.
  • SAE serious AE
  • Glepaglutide was metabolized mainly to its pharmacodynamically active metabolite ZP1848 I-34 -
  • the plasma exposure as observed by both AUC and Cmax increased dose-dependently and the PK profiles were observed to be relatively flat throughout the 24-hour dosing interval.
  • the geometric mean plasma concentrations within the dosing interval were 130 pM, 899 pM, and 5310 pM for the 0- 1, 1 and 10 mg doses, respectively.
  • Glepaglutide in 1 and 10 mg dose groups, tended to prolong liquid-phase intestinal and total Gl emptying and in the 10 mg dose group prolonged liquid-phase gastric emptying as well as solid-phase intestinal and total Gl emptying measured by scintigraphy.
  • significant increase in citrulline and trends towards morphological improvements were observed which indicate increased enterocyte mass and intestinal absorptive surface area.
  • the delayed transit time through the Gl tract combined with the morphological improvements may enhance enzymatic breakdown of macronutrients and facilitate increased enterocyte-solid/liquid exposure, allowing the enterocytes more time for chyme absorption. Effects of glepaglutide on various Gl secretions were not evaluated in this trial.
  • RAAS renin-angiotensin-aldosterone system
  • TE in an adult IF population have only been assessed in one previous study (Gossum et al. 2015), where patients with different pathophysiological etiology of IF were included with liver function ranging from no significant hepatic alterations to overt clinical signs of severe liver disease (Pironi et al 2015). This might explain why the median TE (10.0 (4-24) kPa) in that study was higher than what was found in the present study, where only stable patients with SBS-II and -IF without significant abnormal liver biochemistry were included. Our data do not confirm previous findings concerning the negative correlation between TE and the severity of SBS as indicated by short bowel length and PS volume (Gossum et al. 2015; Hukkinen et al. 2016).
  • ICG elimination probably reflects the increase in portal blood flow. Nevertheless, as evident by the reduction in ALP and total bilirubin, this may also imply that treatment with glepaglutide benefit liver excretory function in patients with SBS.
  • the positive effect of glepaglutide on the liver tests may be mediated indirectly through the improvement in intestinal absorption, allowing a greater portal circulation of fluids and nutrients. This was supported by the positive correlations between changes in ICG-PDR/R15 and changes in wet weight absorption, as well as negative correlations between baseline values of ALP/bilirubin and wet weight absorption.
  • FXR Farnesoid X Receptor
  • FGF19 Fibroblast Growth Factor 19
  • C4 7oHydroxy-4-Cholesten-3- One
  • sCD163 may suggest activation of hepatic macrophages in the 10 mg dose group.
  • the increase is probably unrelated to increased bacterial translocation from the intestines since LBP did not increase following treatment with glepaglutide. It is possible that a sudden increase in the compromised portal blood flow, which is evident by low levels of ICG-PDR at baseline, induces shear stress in the portal system leading to the activation of the liver macrophages, which now need to relate to a new-normal portal flow status. A return to the normal would be expected after long term use of glepaglutide. However, sCD163 did not seem to correlate with either changes in ICG-PDR or the increase in wet weight absorption.
  • GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow.
  • Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology.
  • Jeppesen PB Pertkiewicz M, Messing B, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure [Internet].
  • Jeppesen PB Sanguinetti EL, Buchman A, et al. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients.
  • CAP attenuation parameter
  • Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology.
  • Pattni SS Pattni SS, Brydon WG, Dew T, Walters JRF, Fibroblast Growth Factor 19 and 7a-Hydroxy-4- Cholesten-3-one in the Diagnosis of Patients With Possible Bile Acid Diarrhea.

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Abstract

L'invention concerne l'utilisation d'agonistes de GLP-2 pour moduler le métabolisme des acides biliaires. En particulier, l'on suppose que les agonistes de GLP-2 peuvent être capables d'inhiber la synthèse des acides biliaires, et sont donc utiles pour le traitement d'affections dans lesquelles l'inhibition de la synthèse des acides biliaires est bénéfique. De telles affections comprennent la diarrhée primaire des acides biliaires, la diarrhée secondaire des acides biliaires et des affections qui provoquent ou contribuent à la cholestase. L'invention concerne en outre l'utilisation de FGF19 et de C4 en tant que biomarqueurs pour surveiller la synthèse des acides biliaires et l'homéostasie, par exemple chez des patients SBS.
PCT/EP2019/069832 2018-07-23 2019-07-23 Utilisations thérapeutiques d'agonistes de glp-2 WO2020020904A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2022129142A1 (fr) 2020-12-16 2022-06-23 Zealand Pharma A/S Utilisation d'analogues du glp-2 chez des patients présentant une insuffisance rénale
WO2024068933A1 (fr) 2022-09-30 2024-04-04 Zealand Pharma A/S Analogues du peptide-2 de type glucagon (glp-2) et leurs utilisations médicales pour le traitement du syndrome de l'intestin court (sic)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022129142A1 (fr) 2020-12-16 2022-06-23 Zealand Pharma A/S Utilisation d'analogues du glp-2 chez des patients présentant une insuffisance rénale
WO2024068933A1 (fr) 2022-09-30 2024-04-04 Zealand Pharma A/S Analogues du peptide-2 de type glucagon (glp-2) et leurs utilisations médicales pour le traitement du syndrome de l'intestin court (sic)

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