Apraglutide
Apraglutide (FE 203799)
Apraglutide is a novel, long-acting synthetic glucagon-like peptide-2 (GLP-2) analog designed for once-weekly subcutaneous dosing, under clinical development for short bowel syndrome with intestinal failure (SBS-IF). A pivotal Phase 3 trial (STARS) has been completed and NDA submission initiated, though peer-reviewed Phase 3 results are not yet published (PMID 32075870; NCT04627025; tavily-regulatory: investor.ironwoodpharma.com).
Last updated: 2026-03-10
Safety Summary
Across the Phase 1/2 and Phase 2 SBS studies, treatment-related adverse events were usually mild to moderate and were dominated by GI/stoma effects and fluid-balance effects, including decreased stoma output, stoma complications, nausea, flatulence, polyuria, edema, abdominal pain, vomiting, and mild injection-site reactions (PMID 35233802; PMID 34287970; PMID 39461299). No treatment-related serious adverse events were reported in the randomized 4-week Phase 2 crossover trial (PMID 34287970). One treatment-related SAE of abdominal pain was reported in the open-label Phase 1/2 study (PMID 35233802). In the 52-week CiC study, 127 AEs were reported, mostly mild to moderate; one severe treatment-related SAE of acute obstructive cholangitis occurred in a patient with pre-existing asymptomatic cholecystolithiasis, requiring ERCP and cholecystectomy (PMID 39461299). The full text of the CiC study notes that GLP-2 has been linked to gallbladder hypomotility contributing to bile stasis, and that liver function test monitoring is warranted during GLP-2 analog therapy (PMID 39461299). A network meta-analysis found no significant safety difference between apraglutide and control groups; catheter-related bloodstream infection was the most common AE across GLP-2 analogs (PMID 38663565). In Phase 1 studies, apraglutide was generally well tolerated with no serious adverse events or immunogenicity observed.
Known Side Effects
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Who Should NOT Use This
One patient in the 52-week CiC study developed severe acute obstructive cholangitis judged treatment-related and had asymptomatic cholecystolithiasis on baseline imaging. GLP-2 has been linked to gallbladder hypomotility contributing to bile stasis and stone formation. Pre-existing biliary disease warrants caution and liver function monitoring (PMID 39461299).
GLP-2 analogs stimulate intestinal cell proliferation and could theoretically promote neoplastic growth. Patients with history of GI cancer, polyps, ulcerative colitis, or Crohn's disease were excluded from clinical trials (NCT03417765 exclusion criteria; PMID 35233802). The 52-week CiC study required colonoscopy or CT colonography screening for neoplastic lesions (PMID 39461299). Colorectal polyps are listed as AEs of special interest in the aGVHD trial (NCT05415410). These remain clinical caution areas rather than formal labeled contraindications, as the drug is not yet approved.
Patients with active pancreatic disease, severe liver disease, or inadequate organ function were excluded from early trials (NCT03417765 exclusion criteria; PMID 35233802). However, later single-dose PK studies found no dose adjustment needed in severe renal impairment (PMID 38465515) or moderate hepatic impairment (PMID 41545784). These were controlled PK studies, not long-term efficacy trials in unstable organ disease.
Pregnant or lactating patients were excluded from all clinical trials (NCT03417765, NCT05415410, NCT05018286 exclusion criteria).
Talk to Your Doctor
Before considering Apraglutide, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-16]
Evidence Assessment
Apraglutide has completed a pivotal Phase 3 randomized controlled trial (STARS; NCT04627025, N=164) for SBS-IF, plus an ongoing Phase 3 open-label extension (STARS extend; NCT05018286, N=158). Multiple Phase 1 and Phase 2 trials have been completed with positive results published in peer-reviewed journals (PMID 34287970, PMID 35233802, PMID 39461299, PMID 37316329). Ironwood Pharmaceuticals has initiated NDA submission (tavily-regulatory: investor.ironwoodpharma.com). Caveat: Peer-reviewed Phase 3 results are not yet published; the Tier 2 assignment is based on trial completion, NDA initiation, and press release data indicating positive outcomes. FDA has indicated a confirmatory Phase 3 trial may be needed for approval. If the tier system strictly requires published peer-reviewed Phase 3 results, Tier 3 would apply. Phase B evaluator rated Tier 3 on this basis.
1Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome.PMID 32075870
Hargrove DM et al. - The Journal of Pharmacology and Experimental Therapeutics (2020) - Preclinical pharmacology (in vitro and animal PK/PD) - Multiple animal models (rats, monkeys, minipigs)
Apraglutide had very low clearance (0.27 mL/kg/min in rats vs 9.9 for teduglutide and 2.8 for glepaglutide), long elimination half-life (159 min in rats vs 19 for teduglutide), and high plasma protein binding. It retained potency and selectivity at GLP-2R comparable to native hGLP-2. Greater intestinotrophic activity than other GLP-2 analogs at less-frequent dosing intervals.
Limitations: Preclinical data only. Manufacturer-funded study (VectivBio/GlyPharma). The comparative finding that glepaglutide was less potent and less selective was contested by the glepaglutide manufacturer (PMID 34039655).
2Novel Long-Acting GLP-2 Analogue, FE 203799 (Apraglutide), Enhances Adaptation and Linear Intestinal Growth in a Neonatal Piglet Model of Short Bowel Syndrome with Total Resection of the Ileum.PMID 30614011
Slim GM et al. - JPEN. Journal of Parenteral and Enteral Nutrition (2019) - Animal study (neonatal piglets) - N=18 piglets (10 saline, 8 apraglutide)
Apraglutide induced unique intestinal lengthening (P = 0.001), greater small intestinal weight (P = 0.004), longer villus height (P = 0.027), and greater crypt depth (P = 0.054) compared to saline. Also reduced fecal fat (P = 0.043) and energy losses (P = 0.043).
Limitations: Small sample size (n=18). Neonatal piglet model may not fully translate to adult human SBS. Short treatment duration (7 days).
3Site-Specific and Temporal Effects of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Receptor Agonist, on Intestinal Growth in Mice.PMID 32144124
Martchenko SE et al. - The Journal of Pharmacology and Experimental Therapeutics (2020) - Animal study (mice) - Male and female mice, 3, 7, and 10 week treatment periods
Apraglutide (3 mg/kg, 3x/week) significantly increased small intestinal weight (P < 0.001) and length (P < 0.001) after 3 weeks. Crypt depth and villus height increased after 3 weeks (P < 0.001). Crypt number and intestinal circumference increased at 7-10 weeks (P < 0.01). Colon weight and length also enhanced (P < 0.001). Time- and location-dependent specificity in intestinotrophic actions.
Limitations: Mouse model; high suprapharmacologic dose. Manufacturer-funded.
4Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers.PMID 37316329
Bolognani F et al. - The Journal of Pharmacology and Experimental Therapeutics (2023) - Phase 1 RCT (healthy volunteers) - N=24 randomized (23 completed)
Mean clearance 16.5-20.7 L/day, volume of distribution 55.4-105.0 L. Dose-dependent citrulline increase: 5 mg and 10 mg induced higher citrulline than 1 mg and placebo. PK/PD analysis showed 5 mg weekly induced maximal citrulline response. Citrulline elevations sustained 10-17 days after final dose.
Limitations: Healthy volunteers, not SBS patients. Small sample size (n=24). Manufacturer-funded (VectivBio).
5Apraglutide, 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.PMID 34287970
Eliasson J et al. - JPEN. Journal of Parenteral and Enteral Nutrition (2022) - Phase 2 RCT (placebo-controlled, double-blind, crossover) - N=8 adults with SBS-IF
Once-weekly 5 mg apraglutide increased urine volume output by 714 mL/day (95% CI: 490-939; P < 0.05) and 10 mg by 795 mL/day (95% CI: 195-1394; P < 0.05) vs placebo. No significant differences between doses. AEs mild to moderate; no SAEs related to treatment.
Limitations: Very small sample size (n=8). Short treatment duration (4 weeks per period). Crossover design limits long-term safety assessment. Manufacturer-funded.
6Apraglutide, a novel once-weekly glucagon-like peptide-2 analog, improves intestinal fluid and energy absorption in patients with short bowel syndrome: An open-label phase 1 and 2 metabolic balance trial.PMID 35233802
Eliasson J et al. - JPEN. Journal of Parenteral and Enteral Nutrition (2022) - Phase 1/2 open-label metabolic balance study - N=8 (4 SBS-II, 4 SBS-IF)
5 mg weekly increased wet weight absorption by 741 g/day (P = 0.015), energy absorption by 1095 kJ/day (P = 0.024), sodium by 38 mmol/day (P = 0.039), potassium by 18 mmol/day (P = 0.020). One SAE (abdominal pain). Common AEs: decreased stoma output, stoma complications, nausea, flatulence.
Limitations: Open-label, no placebo control. Very small sample (n=8). Short duration (4 weeks). Manufacturer-funded. Full text reports multiple VectivBio-affiliated investigators.
7Efficacy and safety of apraglutide in short bowel syndrome with intestinal failure and colon-in-continuity: A multicenter, open-label, metabolic balance study.NCT04964986PMID 39461299
Verbiest A et al. - Clinical Nutrition (2024) - Phase 2 open-label metabolic balance study (52 weeks) - N=9 adults with SBS-IF-CiC
PS volume decreased by 4702 mL/week (-52%; P < 0.001) at week 52. 7/9 patients (78%) achieved at least 1 day off PS. Fecal output reduced by 253 g/day at week 4 (P = 0.013). Wet weight absorption increased 316 g/day (P = 0.039), energy absorption 1134 kJ/day (P = 0.041), carbohydrate absorption 56.1 g/day (P = 0.024) at week 48. Small bowel length increased 29.7 to 40.7 cm on MRI (P = 0.012). Dosing: 5 mg (>=50 kg) or 2.5 mg (<50 kg). One severe treatment-related SAE: acute obstructive cholangitis in a patient with pre-existing asymptomatic gallstones.
Limitations: Open-label, no control group. Very small sample (n=9). Single-arm design. Manufacturer-funded (Ironwood/VectivBio).
8Pharmacokinetics and Tolerability of a Single Dose of Apraglutide in Individuals With Impaired Renal Function.NCT04699032PMID 38465515
Greig G et al. - Journal of Clinical Pharmacology (2024) - Phase 1 open-label PK study - N=16 (8 severe renal impairment, 8 normal function)
Patients with severe renal impairment had lower (not higher) apraglutide exposure: Cmax = 36.9 vs 59.5 ng/L, AUCinf = 3100 vs 4470 h*ng/mL. No dose reduction needed for renal impairment. AEs mild or moderate.
Limitations: Small sample (n=16). Single-dose study. Manufacturer-funded (VectivBio).
9Pharmacokinetics and Safety of Single-Dose Apraglutide in Individuals with Normal and Impaired Hepatic Function: A Phase 1, Open-Label Trial.NCT05706623PMID 41545784
Greig G et al. - Clinical Pharmacology in Drug Development (2026) - Phase 1 open-label PK study - N=16 (8 moderate hepatic impairment, 8 normal function)
No increased apraglutide exposure in moderate hepatic impairment. Cmax = 58.7 vs 71.3 ng/mL, AUCinf = 4086 vs 5351 h*ng/mL. No dose alteration needed for mild/moderate hepatic impairment. AEs mild or moderate.
Limitations: Small sample (n=16). Single-dose study. Severe hepatic impairment was not studied. Manufacturer-funded.
10The Long-Acting Glucagon-Like Peptide-2 Analog Apraglutide Enhances Intestinal Protection and Survival After Chemotherapy and Allogeneic Transplantation in Mice.PMID 39497378
Minden MD et al. - Annals of Transplantation (2024) - Animal study (mice, multiple models) - BALB/c and C57BL/6J mice across multiple experiments
Apraglutide + chemotherapy significantly improved survival and reduced weight loss vs chemotherapy alone, with no impact on leukocyte counts. Preserved GI mucosal morphological integrity. Attenuated cytarabine-induced microbiome disruption. Improved citrulline levels. In irradiation + allogeneic transplantation model, improved survival and increased colon length.
Limitations: Animal models only. Manufacturer-funded (Ironwood Pharmaceuticals). May not translate directly to human GvHD outcomes.
11Efficacy and safety of glucagon-like peptide 2 in patients with short bowel syndrome: a systematic review and network meta-analysis.PMID 38663565
Sabra HK et al. - Journal of Gastrointestinal Surgery (2024) - Systematic review and network meta-analysis - 23 clinical trials, 843 patients (teduglutide, apraglutide, glepaglutide)
GLP-2 appears safe and effective in SBS. Teduglutide 0.1 mg/kg/day had highest citrulline increase. No significant safety difference among apraglutide dose groups vs control. Catheter-related bloodstream infection was most common AE across GLP-2 analogs.
Limitations: Small number of patients in included studies. Variable follow-up durations. Indirect comparisons between GLP-2 analogs. Most apraglutide data from early-phase studies.
12Trial to Evaluate Efficacy and Safety of Apraglutide in SBS-IF (STARS)NCT04627025
VectivBio AG (Sponsor) - ClinicalTrials.gov (2024) - Phase 3 RCT (randomized, placebo-controlled) - N=164 enrolled
Pivotal Phase 3 trial completed. Evaluated weekly subcutaneous apraglutide for reducing parenteral support in SBS-IF. Full results not yet published in peer-reviewed literature. Press releases indicate clinically meaningful improvements (tavily-clinical: baybridgebio.com).
Limitations: Registry entry only; no peer-reviewed results available in the source set. Only press release and conference data accessible.
13Open-label Extension Trial to Evaluate the Long-term Safety of Apraglutide in Short Bowel Syndrome (STARS extend)NCT05018286
VectivBio AG (Sponsor) - ClinicalTrials.gov (2021) - Phase 3 open-label extension - N=158 enrolled
Active, not recruiting. Evaluating long-term safety for up to 208 weeks. Extension of STARS and other parent trials. Press release data showed further increase in patients achieving enteral autonomy (tavily-recent: Ironwood press release).
Limitations: Open-label design. No control group. Study ongoing, primary completion estimated October 2027.
14Proof-of-concept Trial of Apraglutide in Acute Graft Versus Host Disease (aGVHD)NCT05415410
VectivBio AG (Sponsor) - ClinicalTrials.gov (2022) - Phase 2 RCT (single-blind) - N=31 enrolled (15 low dose, 15 high dose, 1 standard dose)
Study terminated by company decision. 10 deaths occurred (3 low dose, 6 high dose, 1 standard dose), reflecting severity of underlying condition. Results posted on ClinicalTrials.gov.
Limitations: Terminated early. Small sample. Single-blind. High mortality reflecting disease severity, not necessarily drug-related.
15Intestinal adaptation and rehabilitation in adults with short bowel syndrome.PMID 38963563
Pironi L - Current Opinion in Clinical Nutrition and Metabolic Care (2024) - Review - N/A (narrative review)
Reviews recent data on GLP-2 analogs including apraglutide. Confirms Phase 2 RCTs published for apraglutide and glepaglutide, with Phase 3 RCTs completed. Notes teduglutide real-world data confirms efficacy but raises alert on GI polyp risk.
Limitations: Narrative review, not systematic. Author perspective.
16Positive clinical outcomes associated with use of glucagon-like peptide-2 (GLP-2) analogues in patients with intestinal failure: A systematic review and meta-analysis.PMID 41344401
Bastas A et al. - Clinical Nutrition ESPEN (2026) - Systematic review and meta-analysis - 23 studies included
Teduglutide demonstrated positive and incremental effect: 64% achieved 20%+ PS reduction at 6 months, 73% after 2+ years. Enteral autonomy: 13% at 6 months, 31% after 2+ years. Early reports suggest similar benefits for apraglutide and glepaglutide.
Limitations: Mostly teduglutide data. Apraglutide data described as 'early reports.' Heterogeneous study designs.