Introduction

Short bowel syndrome (SBS) is a rare gastrointestinal condition with a high risk of developing intestinal failure (SBS-IF) and need for parenteral support (PS). Glucagon-like peptide-2 (GLP-2) analogs stimulate adaptation of the remaining gut resulting in increased intestinal absorption and reduced PS needs. Extensive literature is available on the effect of teduglutide in patients (pts) without a remaining colon. However, in SBS-IF with a colon-in-continuity (CiC), where there is less dependency on IV fluid compared to calories, the impact of GLP-2 analogs is much less established. Apraglutide (APRA) is a novel, long-acting GLP-2 analog in development for SBS-IF.

Aims & Methods

This multicenter, open-label, phase 2 study in SBS-IF-CiC aims to investigate the safety and efficacy of APRA in reducing PS needs at 52 weeks (wks). STARS Nutrition is a 52-w study in adult pts with SBS-IF-CiC receiving once-weekly subcutaneous APRA injections (5 mg). Metabolic balance studies were performed at baseline and 4 wks with stable PS, followed by a 48-wk PS adjustment period. During monthly 48h fluid balance assessments, oral fluid intake was kept constant by adhering to an individual predefined drinking menu while urine was collected. PS was reduced according to a pre-defined algorithm if an increase in mean daily urinary output of ≥10% was observed. Safety was the primary endpoint. Secondary endpoints included changes in weekly PS volume, energy content, and PS days, and proportion of clinical responders (PS reduction of ≥20%). Data are presented as mean (95% CI) unless specified otherwise. Nominal p-values are calculated using paired T-tests with significance set at 0.05.

Results

Nine pts were included and comprise the full study population. Small bowel length was 19 (range 0-50) cm and 79 (range 43-100) % of the colon was in continuity. Pts had baseline PS needs of 10 (range 4-21) L distributed over 5.2 (range 3 – 7) days/wk. APRA had an acceptable safety profile, consistent with previous data. All pts experienced ≥1 adverse event (AE) after initiating APRA; a total of 127 AEs was reported. Three pts experienced serious AEs. APRA was interrupted for 1 wk in one patient with acute cholangitis; APRA was restarted and successfully continued to study completion. PS-related outcomes are presented in Table 1. Absolute weekly PS volume decreased significantly by -4702 (-6539 – -2865) mL/wk (p=0.0004). Accordingly, PS energy content significantly decreased by -3510 (-4991 – -2029) kcal/wk (p=0.0006). All pts qualified as clinical responders. Seven pts (78%) achieved ≥1 day off PS of whom two pts (22%) reached enteral autonomy. Pts gained an additional 2.1 (0.7 – 3.6) days off per wk. Body weight and daily urine output remained constant despite PS reductions.

Table 1 Parenteral support related outcomes after 24 and 52 weeks of apraglutide treatment; mean (95% CI); * p<0.05.

Conclusion

APRA has an acceptable safety profile and significantly reduces PS needs in pts with SBS-IF-CiC resulting in days without PS. STARS Nutrition is the first study prospectively showing evidence for clinical benefit of a long-acting GLP-2 analog in SBS-IF-CiC.

Disclosure

PBJ has received grants/research support/honoraria or consultation fees from Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast, Ferring, Fresenius Kabi, GLyPharma, Naia Pharma, NPS Pharmaceuticals, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio and Zealand Pharma.
FJ has received grants/research support/honoraria or consultation fees from Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
TV has served on the speaker bureau for Fresenius Kabi, Remedus, Takeda, VectivBio and Zealand Pharma. TV has provided clinical advice to Baxter, Shire, Takeda, VectivBio, Zealand Pharma. TV has received research grants from Takeda and VectivBio.
This research was supported by VectivBio. FB, CL and NNY are employees of VectivBio.