SMALL INTESTINE

Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients

P B Jeppesen¹, E L Sanguinetti², A Buchman³, L Howard⁴, J S Scolapio⁵, T R Ziegler⁶, J Gregory², K A Tappenden⁷, J Holst⁸, P B Mortensen¹

¹ Department of Medicine CA-2121, Section of Gastroenterology, Rigshospitalet, University Hospital of Copenhagen, Denmark
² NPS Pharmaceuticals, Salt Lake City, UT, USA
³ Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
⁴ Division of Gastroenterology and Nutrition, Albany Medical College, Albany, NY, USA
⁵ Mayo Clinic, Jacksonville, FL, USA
⁶ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
⁷ Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA
⁸ Panum Institute, Copenhagen, Denmark

Correspondence to:
Correspondence to:
Dr P Bekker Jeppesen
Department of Medicine CA-2121, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Bekker{at}dadlnet.dk

Background and aims: Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.

Methods: Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with 50% colon in continuity.

Results: Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (–711 (734) g/day; p = 0.001) and faecal energy excretion (–808 (1453) kJ/day (–193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice.

Conclusion: Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.

Abbreviations: GLP-2, glucagon-like peptide 2; SBS, short bowel syndrome; PN, parenteral nutrition; DPP-IV, dipeptidyl peptidase IV; AEs, adverse events

Keywords: glucagon-like peptide 2; intestinal adaptation; intestinal failure; parenteral nutritional; short bowel syndrome; teduglutide

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