Clin Nutr. 2024 Oct 16;43(12):158-166. doi: 10.1016/j.clnu.2024.10.011. Online ahead of print.

Astrid Verbiest ¹, Mark Krogh Hvistendahl ², Federico Bolognani ³, Carrie Li ³, Nader N Youssef ⁴, Susanna Huh ⁴, Alex Menys ⁵, Gauraang Bhatnagar ⁶, Ragna Vanslembrouck ⁷, Ronald Peeters ⁷, Riccardo Sartoris ⁸, Pieter Vermeersch ⁹, Lucas Wauters ¹, Kristin Verbeke ¹⁰, Palle Bekker Jeppesen ², Francisca Joly ¹¹, Tim Vanuytsel ¹²

Author information

¹Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium; Leuven Intestinal Failure and Transplantation Center (LIFT), University Hospitals Leuven, Leuven, Belgium.

²Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

³Ironwood Pharmaceuticals Inc, Basel, Switzerland.

⁴Ironwood Pharmaceuticals Inc, Boston, MA, USA.

⁵Motilent, London, United Kingdom.

⁶Motilent, London, United Kingdom; Frimley Health NHS Foundation Trust, United Kingdom.

⁷Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium.

⁸Medical Imaging Service, Hôpital Beaujon, Clichy, France.

⁹Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.

¹⁰Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.

¹¹Centre for Intestinal Failure, Department of Gastroenterology and Nutritional Support, Hôpital Beaujon, Clichy, France.

¹²Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium; Leuven Intestinal Failure and Transplantation Center (LIFT), University Hospitals Leuven, Leuven, Belgium. Electronic address: tim.vanuytsel@uzleuven.be.

Abstract

Background: Apraglutide is a novel long-acting GLP-2 analog in development for short bowel syndrome with intestinal failure (SBS-IF). This multicenter, open-label, phase 2 study in SBS-IF and colon-in-continuity (CiC) investigates the safety and efficacy of apraglutide.

Methods: This was a 52-week phase 2 metabolic balance study (MBS) in 9 adult patients with SBS-IF-CiC receiving once-weekly subcutaneous apraglutide injections. Safety was the primary endpoint. Secondary endpoints included changes in absorption parameters (MBS at baseline, after 4 weeks with stable parenteral support (PS), and 48 weeks), PS needs (48-week PS adjustment period based on monthly 48-h fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks).

Results: PS volume decreased by -4702 mL/week (-52 %; p < 0.001) at week 52. Seven patients (78 %) achieved ≥1 day off PS at week 52. At 4 weeks, fecal output was reduced by 253 g/day (p = 0.013). At 48 weeks, increases in wet weight absorption by 316 g/day (p = 0.039), energy absorption by 1134 kJ/day (p = 0.041) and carbohydrate absorption by 56.1 g/day (p = 0.024) were observed. Moreover, small bowel length increased from 29.7 to 40.7 cm (p = 0.012), duodenal wall thickness increased by 0.8 mm (p = 0.02) and motility in the proximal colon was reduced (p = 0.031). A total of 127 adverse events was reported, which were mostly mild to moderate.

Conclusion: Apraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC.

Clinicaltrials: gov, Number NCT04964986.