Glepaglutide for short bowel syndrome

Glepaglutide is being developed as a GLP-2 analog for the treatment of Short Bowel Syndrome (SBS). SBS patients cannot absorb enough nutrients and fluids through the gastrointestinal tract.

Short bowel syndrome is a severe condition with significant therapeutic needs

Short bowel syndrome (SBS) is a life-threatening and complex chronic severe condition associated with reduced or complete loss of intestinal function. The main underlying causes of SBS are major intestinal surgery following Crohn’s disease, ischemia, radiation damage and surgery in adults. In young children, congenital intestinal atresia, necrotizing enteric colitis and intestinal volvulus are the most common causes. In older children and adolescents, SBS is mainly due to volvulus or trauma.

 It is estimated that 20,000-40,000 patients are affected by SBS in the U.S. and Europe. The most severely affected people are dependent on daily parenteral support. This requires them to be connected to infusion lines and pumps, which pose significant restrictions on a patient’s ability to engage in daily activities.

Glepaglutide is a long-acting GLP-2 analog

If people are diagnosed with SBS and also has intestinal failure (IF) then the person is dependent on total parenteral nutrition also called home parenteral nutrition (TPN or HPN). That means that the small intestine cannot absorb nutrition nor fluids and will need to be delivered via bags of nutrition and fluids via a central venous catheter also known as a central line catheter.   If the patient does not have intestinal failure (IF) but is considered intestinal insufficient (also called II) - those patients are not dependent on getting their nutrients via a central catheter. Those II patients may become at risk of becoming an IF patient - if the condition worsens.

Glepaglutide meets primary endpoint in 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.

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.