Apraglutide

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.

A high-output stoma (HOS) or fistula is when small bowel output causes water, sodium and often magnesium depletion. This tends to occur when the output is >1.5 -2.0 L/24 hours though varies according to the amount of food/drink taken orally. An HOS occurs in up to 31% of small bowel stomas. A high-output enterocutaneous fistula may, if from the proximal small bowel, behave in the same way and its fluid management will be the same as for an HOS. The clinical assessment consists of excluding causes other than a short bowel and treating them (especially partial or intermittent obstruction). A contrast follow through study gives an approximate measurement of residual small intestinal length (if not known from surgery) and may show the quality of the remaining small bowel. If HOS is due to a short bowel, the first step is to rehydrate the patient so stopping severe thirst. When thirst has resolved and renal function returned to normal, oral hypotonic fluid is restricted and a glucose-saline solution is sipped. Medication to slow transit (loperamide often in high dose) or to reduce secretions (omeprazole for gastric acid) may be helpful. Subcutaneous fluid (usually saline with added magnesium) may be given before intravenous fluids though can take 10-12 hours to infuse. Generally parenteral support is needed when less than 100 cm of functioning jejunum remains. If there is defunctioned bowel in situ, consideration should be given to bringing it back into continuity.

Background: Apraglutide is a novel long-acting glucagon-like peptide-2 (GLP-2) analog designed for once-weekly subcutaneous dosing, with the potential to increase fluid and nutrient absorption by the remnant intestine of patients who have short bowel syndrome (SBS) with intestinal insufficiency (SBS-II) or intestinal failure (SBS-IF). This trial investigated the safety and effects on intestinal absorption of apraglutide in patients with SBS-II and SBS-IF. Methods: In this open-label, phase 1 and 2 trial, adult patients with SBS-II (n = 4) or SBS-IF (n = 4) and a fecal output of ≥1500 g/day received once-weekly subcutaneous 5 mg apraglutide for 4 weeks. Safety was the primary end point. Secondary end points included change from baseline in intestinal absorption of wet weight (indicative of fluid absorption), electrolytes, and energy (by bomb calorimetry) measured by inpatient metabolic balance studies. Results: Common treatment-related adverse events were decreased gastrointestinal (GI) stoma output (n = 6), stoma complications (n = 6), GI stoma complications (n = 5), nausea (n = 5), flatulence (n = 4), abnormal GI stoma output (n = 4), polyuria (n = 3), and abdominal pain (n = 3). The only treatment-related serious adverse event (experienced in one patient) was abdominal pain. Apraglutide significantly increased wet weight and energy absorption by an adjusted mean of 741 g/day (95% CI, 194 to 1287; P = 0.015) and 1095 kJ/day (95% CI, 196 to 1994; P = 0.024), respectively. Sodium and potassium absorption significantly increased by an adjusted mean of 38 mmol/day (95% CI, 3 to 74; P = 0.039) and 18 mmol/day (95% CI, 4 to 32; P = 0.020), respectively. Conclusion: Once-weekly 5 mg apraglutide was well tolerated in patients with SBS-II and SBS-IF and significantly improved the absorption of fluids, electrolytes, and energy.