Gastroenterology. 2024 Dec 19:S00165085(24)057871. doi:10.1053/j.gastro.2024.11.023.Online ahead of print.

Palle B Jeppesen ¹, Tim Vanuytsel ², Sukanya Subramanian ³, Francisca Joly ⁴, Geert Wanten ⁵, Georg Lamprecht ⁶, Marek Kunecki ⁷, Farooq Rahman ⁸, Thor S S Nielsen ⁹, Mark Berner-Hansen ¹⁰, Ulrich-Frank Pape ¹¹, David F Mercer ¹²

Author information

¹Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark. Electronic address: Palle.Bekker.Jeppesen@regionh.dk.

²Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium.

³MedStar Georgetown University Hospital, Washington, DC.

⁴Beaujon Hospital, University of Paris, UMR1149, Paris, France.

⁵Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

⁶Universitätsmedizin, Rostock, Germany.

⁷Pirogov Hospital, Lódz, Poland.

⁸University College London Hospitals, London, United Kingdom.

⁹Zealand Pharma, Denmark.

¹⁰Zealand Pharma, Denmark; Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark.

¹¹Asklepios Klinik St. Georg, Hamburg, Germany.

¹²University of Nebraska Medical Center, Omaha, Nebraska.

Abstract

Background and aims: Glepaglutide is a long-acting GLP-2 analog developed to improve intestinal absorption in short bowel syndrome (SBS) patients. We conducted a trial to establish efficacy and safety of glepaglutide in reducing parenteral support (PS) needs in SBS patients with intestinal failure (IF).

Methods: In an international, placebo-controlled, randomized, parallel-group, double-blind, phase 3 trial, SBS-IF patients requiring PS ≥3 days/week were randomized 1:1:1 to 24 weeks of glepaglutide 10 mg twice-weekly (TW) or once-weekly (OW), or placebo. PS volume was equivalently reduced if average urine volume of a 48-hour balance period exceeded baseline values by >10%.

Results: 106 patients were randomized and dosed. Glepaglutide TW significantly reduced weekly PS volumes from baseline to week 24 versus placebo (mean change of -5.13 vs. -2.85 L/week; P = .0039; primary endpoint). Results were similar across major anatomical subgroups. Glepaglutide TW was also superior to placebo for key secondary endpoints of proportion of patients achieving clinical response defined as ≥20% PS volume reduction from baseline to weeks 20 and 24 (65.7% vs. 38.9%; P = .0243), and patients achieving a reduction in days on PS ≥1 day/week from baseline to week 24 (51.4% vs. 19.4%; P = .0043). Complete PS weaning ("enteral autonomy") was achieved for 5 patients (14%) receiving glepaglutide TW versus 0 for placebo patients. No statistically significant differences were shown for glepaglutide OW versus placebo for primary or key secondary endpoints. Significant glepaglutide benefits on patient-reported outcome (Patient Global Impression of Change) were shown. Glepaglutide was assessed to be safe and well tolerated.

Conclusion: Glepaglutide treatment in SBS-IF patients resulted in clinically relevant reductions in PS requirements and was well tolerated.