BackgroundApraglutide 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. MethodsThis 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-hour fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks). ResultsPS volume decreased by -4702mL/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. ConclusionApraglutide 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