Glepaglutide

Glepaglutide (ZP1848)* is a long-acting, stable and soluble GLP-2 analogue, developed and wholly owned by Zealand Pharma. Glepaglutide is currently in clinical Phase II development for the treatment of short bowel syndrome (SBS).

GLP-2 (glucagon like peptide 2) is a naturally occurring peptide hormone produced primarily by the small intestine. It is secreted together with GLP-1 in response to food ingestion and acts by binding to the GLP-2 receptor, which is predominantly found in the gastrointestinal tract. GLP-2 plays a key role in intestinal growth and formation by promoting regeneration of the epithelial surface of the gut and thus is an obvious therapeutic target in the field of gastrointestinal diseases.

The molecule has been designed to be stable in liquid formulations for easy and convenient daily dosing in an injection pen.

Results from preclinical studies

In preclinical studies, glepaglutide (ZP1848) demonstrated efficacy on small intestine growth and demonstrated the physico-chemical properties of a long-acting, stable and soluble peptide therapeutic with the potential for convenient administration in liquid formulation. Zealand has also investigated glepaglutide in a combined single (SAD) and multiple (MAD) ascending dose Phase I trial. Results from this trial demonstrated that ZP1848 is safe and well tolerated with a supportive effect on bowel function. The attractive potential identified for glepaglutide in SBS and the opportunity for Zealand to initiate a clinical Phase II development program in this specialist care indication is an important step in line with the company’s strategic focus on increasing the value of its proprietary pipeline.

Positive results from the Phase 2 trial

The trial was initiated in 2016 at Rigshospitalet, University of Copenhagen, Denmark, one of the world's leading centers for the treatment of SBS. The aim was to assess the efficacy, safety and tolerability of different doses of glepaglutide in SBS patients. The primary trial objective was the effect of glepaglutide on patients' intestinal absorptive capacity, measured as reduction in wet weight fecal output. In addition, a number of relevant secondary endpoints were evaluated, including increase in energy uptake, change in urine output and changes in absorption of electrolytes and macronutrients.

The trial was a proof-of-concept, double-blind, cross-over, dose-finding trial investigating the effect of three different once-daily doses of glepaglutide (10 mg, 1 mg and 0.1 mg). A total of 16 SBS patients completed the trial, and each patient was treated with two different doses of glepaglutide. The first dose was administered over a three-week period, followed by a washout period of four weeks and then treatment with the second dose for a further three weeks.

Principal Investigator of the Phase 2 trial, Professor Palle Bekker Jeppesen, MD, PhD, Department of Gastroenterology, Rigshospitalet, University of Copenhagen, comments: "This is the most comprehensive Phase 2 trial conducted to date in patients with short bowel syndrome and I am truly impressed with the clinical results seen for glepaglutide in these patients. Short bowel syndrome is a severe chronic condition where patients need better treatments to improve intestinal absorption. The results of this Phase 2 trial suggest the potential of glepaglutide to provide increases in both energy, fluid and electrolyte absorption. I look forward to contributing to the next clinical development phase."

Glepaglutide successfully met the primary study endpoint of reducing fecal wet weight output (ostomy output or diarrhea), with 833 grams/day (P=0.0002) and 593 grams/day (P=0.0021) in the 10 mg and 1 mg dose groups, corresponding to a relative decrease of 30% and 23%, respectively. In addition, glepaglutide also appeared to increase energy absorption (p<0.05) for the combined 10 mg and 1 mg dose group. Pharmacokinetic data confirmed the long half-life of glepaglutide when dosed daily.

Glepaglutide was observed to be safe and well tolerated in the trial. The most frequently reported adverse events were nausea, abdominal pain, abdominal distension, vomiting, stoma complications, dizziness, polyuria, decreased appetite, peripheral edema, cough and injection site reactions. Most of these were mild to moderate.

 

*Glepaglutide is a proposed International Non-proprietary Name (pINN)

Short bowel syndrome

Short bowel syndrome (SBS) is a complex chronic disease characterized by severe or complete loss of bowel function. SBS can result from either physical removal of portions of the small intestine and colon or from loss of function as a result of bowel damage. The primary underlying causes of SBS are Crohn’s disease, ischemia, radiation and colon cancer.

Patients with SBS have reduced intestinal absorption and ability to maintain protein-energy, fluid, electrolyte, or micronutrient balances when on a conventionally accepted, normal diet. Many are therefore dependent on constant parenteral (intravenous) supplements in the form of fluids, salts and nutrition to maintain body homeostasis. Before the 1970s, this group of patients often died because of dehydration and malnutrition. Today, the implementation of parenteral support, including the possibility of home administration, via a catheter placed in a central vein close to the heart, has increased survival and life expectancy for patients with SBS, resulting in high prevalence growth. There are estimated 10-20,000 SBS patients in the US and a similar number in the EU
Patients dependent on regular parenteral support experience a number of serious and life-threatening complications associated with their disease and treatment including shortened life span, high risk of sepsis, blood clots or liver damage, and reduced quality-of-life due to the time required for and consequences of frequent access to an intravenous pump.

Teduglutide (Gattex®/ Revestive®), a GLP-2 receptor agonist, was approved in 2012 and launched in 2014 in both the US and Europe as the first medicine indicated for the treatment of SBS.


About glp-2 agonists

Zealand Pharma has announced positive results from the Phase 2 trial of glepaglutide in adult patients with short bowel syndrome (SBS).

The trial was initiated in 2016 at Rigshospitalet, University of Copenhagen, Denmark, one of the world's leading centers for the treatment of SBS. The aim was to assess the efficacy, safety and tolerability of different doses of glepaglutide in SBS patients. The primary trial objective was the effect of glepaglutide on patients' intestinal absorptive capacity, measured as reduction in wet weight fecal output. In addition, a number of relevant secondary endpoints were evaluated, including increase in energy uptake, change in urine output and changes in absorption of electrolytes and macronutrients.

The trial was a proof-of-concept, double-blind, cross-over, dose-finding trial investigating the effect of three different once-daily doses of glepaglutide (10 mg, 1 mg and 0.1 mg). A total of 16 SBS patients completed the trial, and each patient was treated with two different doses of glepaglutide. The first dose was administered over a three-week period, followed by a washout period of four weeks and then treatment with the second dose for a further three weeks.

Principal Investigator of the Phase 2 trial, Professor Palle Bekker Jeppesen, MD, PhD, Department of Gastroenterology, Rigshospitalet, University of Copenhagen, comments: "This is the most comprehensive Phase 2 trial conducted to date in patients with short bowel syndrome and I am truly impressed with the clinical results seen for glepaglutide in these patients. Short bowel syndrome is a severe chronic condition where patients need better treatments to improve intestinal absorption. The results of this Phase 2 trial suggest the potential of glepaglutide to provide increases in both energy, fluid and electrolyte absorption. I look forward to contributing to the next clinical development phase."

Glepaglutide successfully met the primary study endpoint of reducing fecal wet weight output (ostomy output or diarrhea), with 833 grams/day (P=0.0002) and 593 grams/day (P=0.0021) in the 10 mg and 1 mg dose groups, corresponding to a relative decrease of 30% and 23%, respectively. In addition, glepaglutide also appeared to increase energy absorption (p<0.05) for the combined 10 mg and 1 mg dose group. Pharmacokinetic data confirmed the long half-life of glepaglutide when dosed daily.

Glepaglutide was observed to be safe and well tolerated in the trial. The most frequently reported adverse events were nausea, abdominal pain, abdominal distension, vomiting, stoma complications, dizziness, polyuria, decreased appetite, peripheral edema, cough and injection site reactions. Most of these were mild to moderate.