Apraglutide, a novel glucagon-like peptide-2 analog, improves fluid absorption in patients with short bowel syndrome intestinal failure: Findings from a placebo-controlled, randomized phase 2 trial

Johanna Eliasson, Mark K Hvistendahl, Nanna Freund, Federico Bolognani, Christian Meyer, Palle B Jeppesen, Johanna Eliasson, Mark K Hvistendahl, Nanna Freund, Federico Bolognani, Christian Meyer, Palle B Jeppesen

Abstract

Background: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome-associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF.

Methods: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6-10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period.

Results: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490-939; P < .05) and 795 ml/day (95% CI, 195-1394; P < .05), respectively, compared with placebo, with no significant differences between doses.

Conclusions: Once-weekly apraglutide was well tolerated at both tested doses and significantly increased urine volume output, providing evidence for increased intestinal fluid absorption. A phase 3 trial is underway in adults with SBS-IF.

Trial registration: ClinicalTrials.gov NCT03415594.

Keywords: glucagon-like peptide-2; intestinal adaptation; intestinal failure; parenteral support; short bowel syndrome.

Conflict of interest statement

Palle B. Jeppesen has served as a consultant and speaker for VectivBio AG and was the principal investigator in this study. Johanna Eliasson has served as a consultant for VectivBio AG and was a study investigator. Mark K. Hvistendahl and Nanna Freund were study investigators. Federico Bolognani and Christian Meyer are employees of VectivBio AG.

© 2021 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.

Figures

FIGURE 1
FIGURE 1
Trial design. Screening was performed up to 25 days before the baseline visit. Follow‐up was performed 4–6 weeks after the last dose. The washout period was 6–10 weeks after the last dose in the treatment period
FIGURE 2
FIGURE 2
Individual and mean changes from baseline to the end of treatment in urine volume output. The dashed line represents the mean, and ∆ represents the mean change from baseline (SD). One patient discontinued after the first dose of 10 mg (data excluded graphically). The difference in grayscale shows the individual patients. B, baseline; T, treatment
FIGURE 3
FIGURE 3
Individual and mean changes from baseline to the end of treatment in urinary sodium excretion. The dashed line represents the mean, and ∆ represents the mean change from baseline (SD). One patient discontinued after the first dose of 10 mg, and one patient did not provide a baseline sample for 5 mg (data excluded graphically). The difference in grayscale shows individual patients. B, baseline; T, treatment

References

    1. Jeppesen PB. Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr. 2014;38(Suppl 1):8S‐13S.
    1. Pironi L, Arends J, Baxter J, et al. ESPEN endorsed recommendations. Definition and classification of intestinal failure in adults. Clin Nutr. 2015;34(2):171‐180.
    1. Jeppesen PB. The long road to the development of effective therapies for the short gut syndrome: a personal perspective. Dig Dis Sci. 2019;64(10):2717‐2735.
    1. Jeppesen PB, Hartmann B, Hansen BS, et al. Impaired meal stimulated glucagon‐like peptide 2 response in ileal resected short bowel patients with intestinal failure. Gut. 1999;45(4):559‐563.
    1. Jeppesen PB, Hartmann B, Thulesen J, et al. Glucagon‐like peptide 2 improves nutrient absorption and nutritional status in short‐bowel patients with no colon. Gastroenterology. 2001;120(4):806‐815.
    1. Wojdemann M, Wettergren A, Hartmann B, Holst JJ. Glucagon‐like peptide‐2 inhibits centrally induced antral motility in pigs. Scand J Gastroenterol. 1998;33(8):828‐832.
    1. Hvistendahl MK, Naimi RM, Enevoldsen LH, Madsen JL, Fuglsang S, Jeppesen PB. Effect of glepaglutide, a long‐acting glucagon‐like peptide‐2 analog, on gastrointestinal transit time and motility in patients with short bowel syndrome: findings from a randomized trial. JPEN J Parenter Enteral Nutr. 2020;44(8):1535‐1544.
    1. Wojdemann M, Wettergren A, Hartmann B, Hilsted L, Holst JJ. Inhibition of sham feeding‐stimulated human gastric acid secretion by glucagon‐like peptide‐2. J Clin Endocrinol Metab. 1999;84(7):2513‐2517.
    1. Jeppesen PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX‐0600), a dipeptidyl peptidase IV resistant glucagon‐like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54(9):1224‐1231.
    1. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP‐2‐driven improvement of gut permeability. Gut. 2009;58(8):1091‐1103.
    1. Benjamin MA, McKay DM, Yang PC, Cameron H, Perdue MH. Glucagon‐like peptide‐2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse. Gut. 2000;47(1):112‐119.
    1. Bremholm L, Hornum M, Andersen UB, Hartmann B, Holst JJ, Jeppesen PB. The effect of glucagon‐like peptide‐2 on mesenteric blood flow and cardiac parameters in end‐jejunostomy short bowel patients. Regul Pept. 2011;168(1‐3):32‐38.
    1. Marier JF, Beliveau M, Mouksassi MS, et al. Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon‐like peptide‐2 (GLP‐2) analog, following multiple ascending subcutaneous administrations in healthy subjects. J Clin Pharmacol. 2008;48(11):1289‐1299.
    1. Marier JF, Mouksassi MS, Gosselin NH, Beliveau M, Cyran J, Wallens J. Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease. J Clin Pharmacol. 2010;50(1):36‐49.
    1. Jeppesen PB, Pertkiewicz M, Messing B, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012;143(6):1473‐1481.
    1. Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B, SJ O'Keefe. Randomised placebo‐controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut. 2011;60(7):902‐914.
    1. Wisniewski K, Sueiras‐Diaz J, Jiang G, et al. Synthesis and pharmacological characterization of novel glucagon‐like peptide‐2 (GLP‐2) analogues with low systemic clearance. J Med Chem. 2016;59(7):3129‐3139.
    1. Bolognani F, Gal P, Moerland M, et al. The pharmakokinetic and pharmacodynamic relationship between apraglutide and citrulline: a randomized, placebo‐controlled, double‐blind study in healthy volunteers. Clin Nutr ESPEN. 2020;40:413‐414.
    1. Hargrove DM, Alagarsamy S, Croston G, et al. Pharmacological characterization of apraglutide, a novel long‐acting peptidic glucagon‐like peptide‐2 agonist, for the treatment of short bowel syndrome. J Pharmacol Exp Ther. 2020;373(2):193‐203.
    1. Naimi RM, Hvistendahl M, Enevoldsen LH, et al. Glepaglutide, a novel long‐acting glucagon‐like peptide‐2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial. Lancet Gastroenterol Hepatol. 2019;4(5):354‐363.
    1. Crenn P, Coudray‐Lucas C, Thuillier F, Cynober L, Messing B. Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology. 2000;119(6):1496‐1505.
    1. Fuglsang KA, Brandt CF, Scheike T, Jeppesen PB. Hospitalizations in patients with nonmalignant short‐bowel syndrome receiving home parenteral support. Nutr Clin Pract. 2020;35(5):894‐902.
    1. Lauverjat M, Hadj Aissa A, Vanhems P, Bouletreau P, Fouque D, Chambrier C. Chronic dehydration may impair renal function in patients with chronic intestinal failure on long‐term parenteral nutrition. Clin Nutr. 2006;25(1):75‐81.
    1. Ladefoged K, Olgaard K. Sodium homeostasis after small‐bowel resection. Scand J Gastroenterol. 1985;20(3):361‐369.
    1. Messaris E, Sehgal R, Deiling S, et al. Dehydration is the most common indication for readmission after diverting ileostomy creation. Dis Colon Rectum. 2012;55(2):175‐180.
    1. Jeppesen PB, Lund P, Gottschalck IB, et al. Short bowel patients treated for two years with glucagon‐like peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function. Gastroenterol Res Pract. 2009;2009:616054.
    1. Pietrobelli A, Wang Z, Formica C, Heymsfield SB. Dual‐energy X‐ray absorptiometry: fat estimation errors due to variation in soft tissue hydration. Am J Physiol. 1998;274(5):E808‐E816.
    1. Paller MS, Schrier RW. Pathogenesis of sodium and water retention in edematous disorders. Am J Kidney Dis. 1982;2(2):241‐254.
    1. Compher C, Gilroy R, Pertkiewicz M, et al. Maintenance of parenteral nutrition volume reduction, without weight loss, after stopping teduglutide in a subset of patients with short bowel syndrome. JPEN J Parenter Enteral Nutr. 2011;35(5):603‐609.
    1. Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015;372(1):55‐65.
    1. Armstrong LE. Assessing hydration status: the elusive gold standard. J Am Coll Nutr. 2007;26(Suppl 5):575S‐84S.
    1. Weaver CM, Martin BR, McCabe GP, et al. Individual variation in urinary sodium excretion among adolescent girls on a fixed intake. J Hypertens. 2016;34(7):1290‐1297.
    1. Shire. Product information. GATTEX® (teduglutide) instructions for use, revised 05/2019. (accessed Aug 19, 2021)
    1. Chen K, Mu F, Xie J, et al. Impact of teduglutide on quality of life among patients with short bowel syndrome and intestinal failure. JPEN J Parenter Enteral Nutr. 2020;44(1):119‐128.

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