Glepaglutide: Research & Studies
Scientific evidence, clinical trials, and research findings
๐TL;DR
- โข3 clinical studies cited
- โขOverall evidence level: moderate
- โข6 research gaps identified
Research Studies
Glepaglutide, a Long-Acting Glucagon-like Peptide-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome: A Phase 3 Randomized Controlled Trial
Jeppesen PB, Vanuytsel T, Subramanian S, et al. (2025) โข Gastroenterology
Phase 3 EASE SBS 1 trial evaluating glepaglutide 10 mg twice weekly or once weekly vs placebo over 24 weeks in 106 patients with SBS-IF requiring parenteral support at least 3 days per week.
Key Findings
- Twice-weekly glepaglutide reduced weekly PS volume vs placebo (mean change -5.13 vs -2.85 L/week; P=0.0039)
- Clinical response (at least 20% PS reduction) in 65.7% vs 38.9% (P=0.0243)
- Reduction in PS days of at least 1 day/week in 51.4% vs 19.4% (P=0.0043)
- Complete enteral autonomy achieved in 14% of twice-weekly group vs 0% placebo
- Once-weekly dosing did not reach statistical significance vs placebo
Limitations: Once-weekly arm failed to show significant benefit; FDA CRL requesting additional confirmatory trial; 24-week treatment duration may not capture full intestinal adaptation potential
Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial
Naimi RM, Hvistendahl M, Enevoldsen LH, et al. (2019) โข Lancet Gastroenterology and Hepatology
Phase 2 crossover trial in 18 patients with SBS evaluating three doses of glepaglutide (0.1, 1, and 10 mg daily) for 3 weeks each.
Key Findings
- 10 mg dose reduced adjusted mean fecal output by -833 g/day from baseline (P=0.0002)
- 1 mg dose reduced adjusted mean fecal output by -592 g/day from baseline (P=0.002)
- 0.1 mg dose did not significantly reduce fecal output
- Well tolerated across all dose groups
Limitations: Small sample size (18 patients); short treatment duration (3 weeks per dose); crossover design with potential carryover effects
Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects
Berner-Hansen M, Nielsen TH, Golor G, et al. (2022) โข Clinical Drug Investigation
Phase 1 pharmacokinetic study in healthy subjects evaluating glepaglutide 5 and 10 mg subcutaneously once weekly for 6 weeks, or a single IV infusion of 1 mg.
Key Findings
- Effective half-life of 88.3 hours for 10 mg SC dose (supporting twice-weekly dosing)
- Two main metabolites (M1 and M2) formed by C-terminal proteolytic cleavage at the SC depot
- M2 accounts for approximately 90% of overall exposure at steady state
- Both metabolites retain GLP-2 receptor potency similar to parent drug
- No safety issues identified
Limitations: Healthy volunteer study; pharmacokinetics may differ in SBS patients with altered subcutaneous absorption
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๐Research Gaps & Future Directions
- โขLong-term safety data beyond 52 weeks of treatment
- โขConfirmatory efficacy data at the once-weekly dose
- โขHead-to-head comparison with teduglutide
- โขEffect on intestinal polyp development with chronic use
- โขPediatric SBS population data
- โขEfficacy in SBS subtypes (end-jejunostomy vs colon-in-continuity)
Research Overview#
Glepaglutide (ZP1848) has been evaluated in a clinical development program spanning phase 1 pharmacokinetic studies through a pivotal phase 3 trial for short bowel syndrome with intestinal failure. The evidence demonstrates clinically meaningful reductions in parenteral support requirements with twice-weekly dosing, though the FDA has requested additional confirmatory data before approval.
The evidence level is classified as moderate based on a positive phase 3 trial published in Gastroenterology, supported by phase 2 data in Lancet Gastroenterology & Hepatology, but tempered by the FDA's Complete Response Letter and the failure of the once-weekly dosing arm.
EASE SBS 1 Trial (Phase 3)#
Jeppesen et al., Gastroenterology 2025 (PMID 39708985)#
The EASE SBS 1 trial was an international, placebo-controlled, randomized, parallel-group, double-blind phase 3 trial. Patients with SBS-IF requiring parenteral support at least 3 days per week were randomized 1:1:1 to 24 weeks of glepaglutide 10 mg twice weekly, once weekly, or placebo.
Study design:
- 106 patients randomized and dosed
- International, multicenter
- Primary endpoint: change in weekly PS volume from baseline to week 24
Primary endpoint results (twice weekly vs placebo):
- Mean change in weekly PS volume: -5.13 vs -2.85 L/week (P=0.0039)
- Treatment difference: -2.28 L/week
Key secondary endpoints (twice weekly vs placebo):
- Clinical response (at least 20% PS volume reduction at weeks 20-24): 65.7% vs 38.9% (P=0.0243)
- Reduction in PS days of at least 1 day/week: 51.4% vs 19.4% (P=0.0043)
- Complete enteral autonomy: 14% (5 patients) vs 0% (0 patients)
Once-weekly results:
- No statistically significant differences were found for glepaglutide once weekly vs placebo for the primary or key secondary endpoints
Safety in EASE SBS 1#
Glepaglutide was assessed to be safe and well tolerated. The safety profile was consistent with GLP-2 class effects and the SBS patient population.
Phase 2 Trial#
Naimi et al., Lancet Gastroenterology & Hepatology 2019 (PMID 30880176)#
A single-center, double-blind, crossover, randomized phase 2 trial in 18 adults with SBS. Patients received daily subcutaneous injections of three sequential glepaglutide doses (0.1, 1, and 10 mg) for 3 weeks each, with 4-8 week washout periods.
Key results:
- 10 mg: adjusted mean fecal output reduction of -833 g/day (P=0.0002)
- 1 mg: adjusted mean fecal output reduction of -592 g/day (P=0.002)
- 0.1 mg: no significant effect
Intestinal morphology sub-study (PMID 35511704):
- Glepaglutide increased villus height and crypt depth at 1 mg and 10 mg doses
- Increased intestinal blood flow demonstrated by CT angiography
Pharmacokinetic Studies#
Berner-Hansen et al., Clinical Drug Investigation 2022 (PMID 36323988)#
Phase 1 study in 45 healthy subjects characterizing glepaglutide pharmacokinetics:
- Effective half-life: 88.3 hours for 10 mg SC (supporting twice-weekly dosing)
- Two main metabolites (M1 at 35 amino acids, M2 at 34 amino acids) formed by C-terminal proteolytic cleavage
- M2 is the predominant metabolite (~90% of exposure at steady state)
- Both metabolites retain full GLP-2 receptor potency
- Parent drug contributes less than 1% of total exposure
Phase 3b Absorption Study (PMID 40774623)#
Open-label study in 10 SBS patients receiving glepaglutide 10 mg once weekly:
- At week 24: intestinal wet weight absorption increased by 398 g/day (P=0.0585) and energy absorption by 1038 kJ/day (P=0.0215)
- At week 52: PS volume reduced by 800 mL/day (P=0.0106) with corresponding energy content reduction of 866 kJ/day (P=0.0103)
- Improvements in electrolyte and macronutrient absorption
Evidence Quality Assessment#
| Criterion | Assessment | Details |
|---|---|---|
| Study design | Phase 3 RCT + Phase 2 crossover | Double-blind, placebo-controlled (Ph3); crossover (Ph2) |
| Sample size | Moderate (Ph3: 106; Ph2: 18) | Adequate for orphan disease indication |
| Primary endpoint | Met for twice-weekly dosing | PS volume reduction at 24 weeks |
| Secondary endpoints | Met for twice-weekly | Clinical response, PS day reduction, enteral autonomy |
| Once-weekly dosing | Not significant | Failed to meet primary or key secondary endpoints |
| Safety profile | Favorable | Consistent with GLP-2 class; well tolerated |
| Regulatory pathway | CRL issued | FDA requesting additional confirmatory trial |
| Peer-reviewed publication | Yes | Gastroenterology (Ph3), Lancet GH (Ph2) |
Key Research Gaps#
-
Confirmatory efficacy data: The FDA CRL requests an additional trial to confirm efficacy at the to-be-marketed dose, which will need to clarify whether twice-weekly or alternative dosing is optimal.
-
Head-to-head comparison with teduglutide: No direct comparative trial exists. Cross-trial comparisons suggest similar PS reduction magnitudes, but formal comparison would inform clinical decision-making.
-
Long-term intestinal polyp surveillance: GLP-2 analogs stimulate intestinal growth, raising theoretical concerns about polyp or neoplasm promotion. Long-term colonoscopy surveillance data are needed.
-
Pediatric SBS: No pediatric data exist for glepaglutide. Teduglutide has pediatric approval, representing an advantage.
-
SBS subtype analysis: Efficacy may differ between patients with end-jejunostomy (high-output stoma) versus those with colon-in-continuity. Subgroup analyses are limited.
Related Reading#
Frequently Asked Questions About Glepaglutide
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