Long-acting Glucagon-like Peptide-2 Analogue Research Articles

The Long-Acting Glucagon-Like Peptide-2 Analog Apraglutide Enhances Intestinal Protection and Survival After Chemotherapy and Allogeneic Transplantation in Mice.

BACKGROUND The gastrointestinal (GI) barrier can be damaged by chemotherapy or radiation therapy, causing fatigue, malnutrition, sepsis, dose-limiting toxicity, and, occasionally, death. Glucagon-like peptide-2 (GLP-2) promotes mucosal epithelium growth and repair in the GI tract. Here, we examined the GI-protective effects of apraglutide, a long-acting peptide GLP-2 analog, in murine models of chemotherapy, and total body irradiation followed by allogeneic transplantation. MATERIAL AND METHODS The impact of apraglutide on cytarabine or melphalan chemotherapy-induced intestinal damage was assessed in BALB/c mice, and the effect on allogeneic transplantation in BALB/cJ and C57BL/6J mice. Outcomes included survival, and changes in body weight, intestinal function and morphology, including colon length and bacterial composition of the intestinal microbiota. RESULTS Adding apraglutide to chemotherapy significantly improved survival rates and reduced weight loss, with no impact on leukocyte counts (and, therefore, no effect on chemotherapy-induced immunosuppression), compared with chemotherapy alone in mice. These benefits were associated with preservation of the morphological integrity of the GI mucosa, attenuation of the negative impact of cytarabine on the intestinal microbiota, and significant improvement in plasma levels of citrulline. In addition, in a model of irradiation followed by allogeneic transplantation, mice in groups receiving apraglutide had improved survival, reduced weight loss, and increased colon length compared with those that did not. CONCLUSIONS Apraglutide protects intestinal function and improves survival in mice following allogeneic transplantation or chemotherapy with cytarabine or melphalan. The potential effect of apraglutide on chemotherapy efficacy and on engraftment following allogeneic transplantation has been investigated in a parallel manuscript.

Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment.

Glepaglutide is a novel, ready-to-use, long-acting, glucagon-like peptide-2 (GLP-2) analog intended for the treatment of patients with short bowel syndrome (SBS). This study investigated the impact of renal function on the pharmacokinetics and safety of glepaglutide. In this 3-site, non-randomized, open-label study, 16 subjects were enrolled: 4 with severe renal impairment (eGFR 15 to < 30mL/min/1.73m2), 4with end stage renal disease (ESRD) not on dialysis (eGFR < 15mL/min/1.73m2), and 8 matching controls with normal renal function (eGFR ≥ 90mL/min/1.73m2). Blood samples were collected over a 14-day period following a single subcutaneous (SC) dose of glepaglutide 10mg. Safety and tolerability were assessed throughout the study. The primary pharmacokinetic parameters were area under the curve between dosing and 168h (AUC0-168h) and the maximum plasma concentration (Cmax). There was no clinically relevant difference between subjects with severe renal impairment/ESRD and normal renal function with respect to total exposure (AUC0-168h) and peak plasma concentrations (Cmax) of glepaglutide following a single SC dose. A single SC dose of glepaglutide 10mg appeared safe and well tolerated in subjects with normal renal function and subjects with severe renal impairment or ESRD. No serious adverse events were reported, and no safety issues were identified. No difference in glepaglutide pharmacokinetics was seen between renal impaired and normal subjects. Based on this trial, dose adjustment appears not to be warranted in SBS patients with renal impairment. The trial is registered at http://www. gov (NCT04178447) and has the EudraCT number: 2019-001466-15.

HM15912, a Novel Long-Acting Glucagon-Like Peptide-2 Analog, Improves Intestinal Growth and Absorption Capacity in a Male Rat Model of Short Bowel Syndrome.

Extensive bowel resection caused by various diseases that affect the intestines, such as Crohn's disease, volvulus, and cancer, leads to short bowel syndrome (SBS). Teduglutide is the only approved glucagon-like peptide-2 (GLP-2) drug for SBS; however, it requires daily administration. A novel GLP-2 analog with a prolonged duration of action to reduce dosing frequency and promote a greater efficacy may provide patients with a better quality of life. In the present study, the sustained exposure of HM15912 was characterized in normal male rats. The efficacy of HM15912 on intestinal growth and absorption capacity was also evaluated in normal male mice, rats, and SBS rats. HM15912 exhibited a remarkably extended half-life (42.3 hours) compared with teduglutide (0.6 hours) in rats. Despite somewhat lower in vitro potency on GLP-2 receptor than human GLP-2 or teduglutide, this longer-lasting mode of action promotes HM15912 to be more effective in terms of small intestinal growth than existing GLP-2 analogs even with a less frequent dosing interval of as little as once a week in rodents, including SBS rats. Furthermore, the small intestinal weight was approximately doubled, and the D-xylose absorption was significantly increased after pre-treatment of existing GLP-2 analogs on the market or under clinical development followed by HM15912 in rodents. These results indicate that HM15912 possesses a significant small bowel trophic effect driven by continuously increased exposure, supporting that HM15912 may be a novel treatment option with greater efficacy and the longest dosing interval among existing GLP-2 analogs for SBS with intestinal failure. SIGNIFICANCE STATEMENT: HM15912, a novel long-acting glucagon-like peptide-2 (GLP-2) analog, has a significant small bowel hypertrophic effect in rodents with a reduced frequency of administration compared to the existing GLP-2 analogs on the market or currently under clinical development. This study supports the possibility that HM15912 could be administered much less frequently than other long-acting GLP-2 analogs for patients with short bowel syndrome.

Short- versus long-term, gender and species differences in the intestinotrophic effects of long-acting glucagon-like peptide 2 analog.

Glucagon-like-peptide 2 (GLP-2) is an endogenous enteroendocrine physiological trophic peptide. Glepaglutide is a novel long-acting GLP-2 analog under development for the treatment of patients with Short Bowel Syndrome (SBS). The objective of this work was to compare the small intestinal trophic effects in both genders following short (1 week) versus long-term (26-39 weeks) GLP-2 treatment in Wistar rats and Beagle dogs. Following both short- and long-term treatment with glepaglutide, a significant dose-dependent intestinotrophic effect was seen in both genders and species. At all doses increased length and weight of the small intestine as well as macroscopic thickening and villous hypertrophy were noted in all segments of the small intestine, without any differences between genders. The findings were still present following a 6-week recovery period, indicating long-acting intestinotrophic effects of glepaglutide. These studies demonstrate that a long-acting GLP-2 analogue (glepaglutide) has a fast onset and long duration of intestinotrophic action with similar profile in both genders and species (rat and dog).

Safety and efficacy of apraglutide in patients with short bowel syndrome: an open-label phase 2 metabolic balance trial

Rationale: Treatment with glucagon-like peptide-2 (GLP-2) analogues promotes intestinal adaptation in patients with short bowel syndrome (SBS). Apraglutide is a novel long-acting GLP-2 analogue designed to enable once weekly dosing. This trial investigated the safety and efficacy of once weekly 5 mg apraglutide in patients with SBS intestinal failure (SBS-IF) and intestinal insufficiency (SBS-II).

Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial.

Patients with short bowel syndrome (SBS) and distal-bowel resections lack neuroendocrine feedback regulations, potentially resulting in rapid gastrointestinal (GI) transit. The objective was to assess the efficacy of glepaglutide, a long-acting glucagon-like peptide-2 analog, on GI transit in patients with SBS. In this single-center, double-blind, dose-finding, phase 2 trial, patients with SBS were randomly assigned to 3 treatments (0.1, 1, and 10mg) in a 2-period crossover design. Each treatment period included 3weeks of daily, subcutaneous glepaglutide injections separated by a washout period of 4-8weeks. Endpoints were changes from baseline and included scintigraphy, wireless motility capsule (WMC, SmartPill Given Imaging, Ltd, Yokneam, Israel), and paracetamol absorption test. A total of 18 patients were randomized. In the 10-mg dose group (n = 9), glepaglutide significantly increased time to 10% gastric emptying (GE) of solids by 27 (4-50) minutes (adjusted mean [95% CI]), time to 50%GE of fluids by 40 (1-80) minutes, and time to 10% small bowel-emptying of solids by 21 (1-41) minutes. The WMC transit did not significantly change in any of the dose groups. The maximum paracetamol concentration significantly increased in the 10-mg dose group; however, the area under the curve remained the same. The prolonged GI transit after glepaglutide treatment, along with demonstrated positive effects on intestinal mucosal growth and potential effects on GI hypersecretions, is believed to contribute to the observed beneficial effects on fecal output (primary endpoint) and associated improvement in intestinal absorption.

Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial

BackgroundWith the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage.We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function. MethodsLiver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025. FindingsBetween Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected. InterpretationGlepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies. FundingZealand Pharma.

Su2015 – Effect of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Analog, on Patients with Short Bowel Syndrome and Intestinal Insufficiency: Preliminary Results from an Open-Label Study

Su2015 – Effect of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Analog, on Patients with Short Bowel Syndrome and Intestinal Insufficiency: Preliminary Results from an Open-Label Study

Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial

Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. Zealand Pharma.

Novel Long‐Acting GLP‐2 Analogue, FE 203799 (Apraglutide), Enhances Adaptation and Linear Intestinal Growth in a Neonatal Piglet Model of Short Bowel Syndrome with Total Resection of the Ileum

Glucagon-like peptide-2 (GLP-2) is an intestinotrophic factor released from L-cells in the ileum, a segment commonly resected or atretic in neonatal short bowel syndrome (SBS). In piglets, ileal resection decreases intestinal adaptation and endogenous GLP-2 production, whereas exogenous replacement promotes adaptation. In this study, we determined the effect of a novel long-acting GLP-2 analogue, FE 203799 (FE; apraglutide), upon intestinal growth, adaptation, and function in neonatal SBS piglets without ileum. Neonatal piglets were randomized to saline (n = 10) vs FE treatment (n = 8). All piglets underwent 75% intestinal resection with jejunocolic anastomosis and were pair-fed parenteral and enteral nutrition. Saline and FE (5mg/kg) treatments were administered subcutaneously on days 0 and 4. On day 6, 24-hour fecal samples were collected for subsequent nutrient analysis. On day 7, small-intestinal length and weight were measured and tissue collected for analyses. On day 7, saline and FE-treated piglets were healthy and gained equivalent weight (P = 0.12). Compared with saline piglets, FE-treated piglets had lower fecal fat (P = 0.043) and energy (P = 0.043) losses and exhibited intestinal lengthening (P = 0.001), greater small-intestinal weight (P = 0.004), longer villus height (P = 0.027), and greater crypt depth (P = 0.054). The subcutaneous GLP-2 analogue, FE, enhanced intestinal adaptation in a neonatal model of SBS without ileum. The observed intestinal lengthening with FE treatment was unique compared with our prior experience with native GLP-2 in this same model and has important clinical implications for treating neonatal SBS. At this developmental stage, growth in the intestine, if augmented, could accelerate weaning from parenteral nutrition.

Glepaglutide, a long-acting glucagon-like peptide-2 analog, alters postprandial intestinal hormone levels but not glucose homeostasis in patients with short bowel syndrome

Rationale: Native glucagon-like peptide (GLP)-2 as well as GLP-2 analogs have been shown to improve intestinal function in patients with short bowel syndrome (SBS). Since the effects of GLP-2 on endogenous meal-stimulated intestinal hormone release and glucose homeostasis are largely unknown, we aimed to elucidate these relationships in patients with SBS treated with glepaglutide, a long-acting GLP-2 analog.

Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on hepatic function as measured by transient elastography and indocyanine green clearance in patients with short bowel syndrome

Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on hepatic function as measured by transient elastography and indocyanine green clearance in patients with short bowel syndrome

755 - Effects of Short-Term Treatment with Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Intestinal Morphology and Citrulline in Patients with Short Bowel Syndrome

755 - Effects of Short-Term Treatment with Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Intestinal Morphology and Citrulline in Patients with Short Bowel Syndrome

794 - Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, Improves Intestinal Absorption of Macronutrients, Body Weight and Lean Body Mass in Patients with Short Bowel Syndrome

794 - Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, Improves Intestinal Absorption of Macronutrients, Body Weight and Lean Body Mass in Patients with Short Bowel Syndrome

Stapled, Long-Acting Glucagon-like Peptide 2 Analog with Efficacy in Dextran Sodium Sulfate Induced Mouse Colitis Models.

Glucagon-like peptide 2 (GLP-2) is a hormone that has been shown to stimulate intestinal growth and attenuate intestinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is hampered by the short half-life in vivo. We now describe a highly potent, stapled long-acting GLP-2 analog, peptide 10, that has a more than 10-fold longer half-life than teduglutide and improved intestinotrophic and anti-inflammatory effects in mouse models of DSS-induced colitis.

Short bowel syndrome: the role of GLP-2 on improving outcome

The medical management of short bowel syndrome frequently requires lifelong parenteral nutrition. Methods of increasing intestinal absorption and reducing parenteral nutrition dependence, by improving postresection intestinal adaptation, are increasingly being explored. Glucagon-like peptide-2 (GLP-2) is an important intestinotrophic growth factor and mediator of intestinal adaptation. This review summarizes our current understanding of GLP-2 physiology and provides an update on clinical trials in short bowel syndrome and related conditions. There is growing understanding how the effects of GLP-2 are mediated by downstream effectors such as insulin-like growth factor-1. In the treatment of short bowel syndrome, GLP-2 and the long-acting GLP-2 analogue teduglutide (Gattex) are effective in improving fluid absorption. A recent multicentre, placebo-controlled study demonstrates that this can translate into meaningful reductions in parenteral nutrition requirements. Treatment dose and timing of treatment initiation might influence the mucosal growth response. Most of the small intestine has to be preserved to facilitate the previously documented benefits of GLP-2 on bone metabolism. Therapeutic uses of GLP-2 in other gastrointestinal conditions are being explored. GLP-2 treatment appears well tolerated, although concerns about the long-term use of this growth-promoting agent remain. GLP-2 therapy holds promise as an adjuvant treatment modality for short bowel syndrome and other gastrointestinal disorders.