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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Clinical Nutrition |
| Vol/bind | 43 |
| Udgave nummer | 12 |
| Sider (fra-til) | 158-166 |
| Antal sider | 9 |
| ISSN | 0261-5614 |
| DOI | |
| Status | Udgivet - 2024 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:The following inclusion criteria were assessed at screening: adult (\u226518 ys) patients with SBS-IF defined as <200 cm remaining small bowel from duodeno-jejunal flexure, \u226528 % of CiC according to the Cummings Classification [18] without colostomy, last intestinal resection leading to SBS-IF at least 12 months prior to inclusion, PS requirement of \u22652 days per week, stable weight and PS volume and composition in the 3 preceding months. Additional dosing inclusion criteria were assessed after the baseline MBS and included average fecal wet weight excretion \u2265500 g/day to account for a sufficient degree of malabsorption and average urinary volume of \u22650.8L and <2.5 L/day to ensure stable hydration. Key exclusion criteria were a body mass index (BMI) \u226530 kg/m2, major abdominal surgery (>10 % intestinal resection) in the last 6 months, history of cancer (including colon carcinoma) or clinically significant lymphoproliferative disease within 5 years; Child-Pugh score Class C, significantly elevated liver enzymes, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, treatment for a period of >2 weeks with glutamine, growth factors such as growth hormone, somatostatin analogs, GLP-1 or GLP-2 analogs in the previous 6 months. Full inclusion and exclusion criteria are listed in Supplementary Table 1. Patients were recruited in two centers: the Leuven Intestinal Failure and Transplantation Center (LIFT), University Hospitals Leuven, Leuven, Belgium and the Centre for Intestinal Failure, Department of Gastroenterology and Nutritional Support, H\u00F4pital Beaujon, Clichy, France. The study was approved by both local ethics committees (S64949 and CPP2021-01-006-PP). All patients signed informed consent forms prior to inclusion in the study and the study procedures were performed in accordance with the Helsinki Declaration.While oral intake was kept constant at 4 weeks as per protocol, the MBS at 48 weeks revealed that patients spontaneously increased their nutritional intake by 188 g/day without affecting stool output, resulting in an increased absorption. A potential explanation of these data could be that the reduced stool output early on \u2013 as shown in the 4-week MBS \u2013 made patients more confident to increase their oral intake. A synergistic effect of the increased absorption (direct effect) combined with the increased intestinal nutrient passage (indirect effect) most likely explains treatment efficacy, collectively compensating for malabsorption, contributing to a boosted adaptation. This hypothesis is supported by the MBS results: although the increased oral wet weight intake is on the modest side, we observed distinct increases in wet weight absorption of 316 g/day and energy absorption of 1134 kJ/day. Despite increased oral intake, the output remained stable, again supporting improved absorption. Moreover, our study confirms the role of the colon as an energy-absorbing organ through fermentation of carbohydrates [30,31]: despite the severe malabsorption at baseline with only 36.6 % of fat and 30.7 % of protein absorption, carbohydrate absorption was well preserved at 86.7 %. Carbohydrate absorption further increased over time in relation to apraglutide treatment and increased intake. It remains unclear whether this effect on carbohydrate absorption can also be attributed to either the structural changes and/or the functional changes including the decreased motility and the prevalent microbiome with a potentially improved fermentation capacity e.g. resulting in increased short-chain fatty acid generation and absorption.A pre-defined PS reduction algorithm was used to standardize the PS reductions which was based on changes in urinary output as a surrogate marker for intestinal absorption, similar to previous studies with other GLP-2 analogs. Even if there was an option to reduce PS based on the combined opinion of the investigator and an adjudication committee, all PS reductions in this study were based on objective increases in urinary output; arguing against a major placebo response. Nevertheless, reducing PS in patients with a preserved colon comes with a few challenges. In patients with SBS-IF-CiC, the colon has the potential to restore the fluid balance. This explains why patients with SBS-IF-CiC have lower fluid needs compared to patients with an end-jejunostomy, while they are dependent on PS for the energy. This study demonstrates that there is a downside of a PS reduction algorithm based solely on fluid absorption in SBS-IF-CiC. Based on the algorithm significant PS volume (\u221259 %) and PS energy (\u221255 %) reductions were executed, while the energy absorption results from the 48-week MBS show that PS energy reductions (2098 kJ/day) were higher than the gain in intestinal energy absorption (1134 kJ/day). Nevertheless, total and lean body weight remained constant, arguing against a significant energy deficit. Indeed, the absorption as measured during the 72-h MBS in the hospital does not necessarily fully reflect the oral (energy) intake and absorption at home due to factors such as hospital meal menus, hospital kitchen recipes and food item (un)availability. Altogether, our data demonstrate significantly reduced dependency on PS which is supported by MBS, although the extent of boosted intestinal adaptation may have been overestimated by the PS reduction algorithm.TV is supported by Flanders Research Foundation (FWO) through a senior clinical research mandate (1830517N) and a research grant (G059822N).The study was sponsored by VectivBio (Basel, Switzerland), now part of Ironwood Pharmaceuticals, Inc. (Boston, USA). The sponsor was involved in the design of the protocol, but the final decision was made by the three senior authors. The sponsor was not involved in the analysis and collection of the data. The sponsor provided feedback on the manuscript which was drafted by the academic authors (first author and shared senior authors).
Funding Information:
The study was sponsored by VectivBio (Basel, Switzerland), now part of Ironwood Pharmaceuticals , Inc. (Boston, USA ). The sponsor was involved in the design of the protocol, but the final decision was made by the three senior authors. The sponsor was not involved in the analysis and collection of the data. The sponsor provided feedback on the manuscript which was drafted by the academic authors (first author and shared senior authors).
Funding Information:
TV is supported by Flanders Research Foundation (FWO) through a senior clinical research mandate (1830517N) and a research grant (G059822N).
Publisher Copyright:
© 2024 The Author(s)