Glepaglutide vs Apraglutide
Comprehensive side-by-side comparison of mechanisms, dosing, side effects, and research
Also: ZP1848, Zeydovio
Glepaglutide is Zealand Pharma's long-acting GLP-2 analog for short bowel syndrome, built to be injected once or twice a week instead of daily like teduglutide. Its path has been bumpy. The FDA rejected it in December 2024 because the single phase 3 trial only worked at the twice-weekly dose, but Europe went the other way: in September 2026 the EMA's CHMP recommended approval under the name Zeydovio. As of late October 2026 the final European Commission decision is still pending, and the US needs another trial.
Also: FE 203799, Once-weekly GLP-2 analog
Apraglutide is a once-weekly GLP-2 analog for short bowel syndrome, originally from VectivBio and now owned by Ironwood Pharmaceuticals. Its phase 3 STARS trial hit its main goal in 2024, but in April 2025 Ironwood said the FDA wanted a confirmatory trial, partly because patients in STARS got less drug exposure than planned due to how doses were prepared and given. That new trial, STARS-2, started in June 2026, so approval is years away (a submission before end of 2029 has been mentioned).
Key Comparison Insights
- Both peptides belong to the Healing category, suggesting similar primary applications.
Detailed Comparison
| Attribute | Glepaglutide | Apraglutide |
|---|---|---|
| Category | Healing | Healing |
| FDA Status | Not FDA Approved | Not FDA Approved |
| Clinical Status | Pre I II III IV FDA | Pre I II III IV FDA |
| Mechanism of Action | Glepaglutide activates the GLP-2 receptor in the intestine, the same target as teduglutide, which makes the gut lining grow and absorb more fluid and nutrients. What is different is the delivery. After a subcutaneous injection it forms a depot and is slowly released, mostly as two active metabolites rather than the parent molecule. In a healthy-volunteer study the effective half-life was roughly 88 to 124 hours, long enough to make weekly or twice-weekly dosing plausible. The flip side is the same as the rest of the GLP-2 class: anything that makes gut tissue grow raises questions about polyps and tumors over the long run. | Like teduglutide and glepaglutide, apraglutide activates GLP-2 receptors in the gut, signaling the intestinal lining to grow and absorb more. It was engineered for very low clearance and high plasma protein binding, which gives it a much longer half-life. In rat studies its IV half-life was about 159 minutes versus 19 for teduglutide and 16 for glepaglutide, and it kept more gut-growth activity when dosed less often. That is the basis for once-weekly dosing in humans. Same class caveat as the others: long-term stimulation of gut tissue growth carries a theoretical polyp and tumor risk that requires monitoring. |
| Common Dosing | 10 mg twice weekly (trial dose) Twice weekly | 2.5-5 mg once weekly by body weight (trial dose) Once weekly |
| Administration | Subcutaneous injection (prefilled pen in the EU filing) | Subcutaneous injection once weekly |
| Typical Duration | 24 weeks in EASE-1, with longer-term extension studies | 24-week primary endpoint, with treatment continued to week 48 and beyond in STARS |
| Best Time to Take | Same days each week (trial schedule) | Same day each week (trial schedule) |
Possible Side Effects May vary by individual |
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| Research Summary | The main evidence is EASE-1, published in Gastroenterology in April 2025 (Jeppesen and colleagues). It randomized 106 adults with SBS and intestinal failure to glepaglutide 10 mg twice weekly, 10 mg once weekly, or placebo for 24 weeks. Twice weekly cut weekly parenteral support by 5.13 L versus 2.85 L on placebo (p=0.0039), and 65.7% were responders versus 38.9% on placebo. Once weekly (3.13 L) did not reach significance. A handful of patients came off IV support completely, none on placebo. On 19 December 2024 the FDA issued a complete response letter saying there was not enough evidence at the to-be-marketed dose and asked for another trial; Zealand is running EASE-5 to support a US resubmission. Zealand filed in Europe in June 2025 and the CHMP gave a positive opinion on 17 September 2026 for adults with SBS (10 mg prefilled pen). Common side effects listed by the EMA are injection site reactions, abdominal pain, nausea, and vomiting. Bottom line: real phase 3 data, but from a single trial with one of two doses positive, which is exactly why the two regulators disagreed. | STARS (NCT04627025) randomized 164 adults with SBS and intestinal failure 2:1 to weekly apraglutide (2.5 mg or 5 mg by body weight) or placebo. Topline results in February 2024: weekly parenteral support volume fell 25.5% versus 12.5% on placebo at week 24 (p=0.001). In stoma patients the gap was bigger (25.6% vs 7.8%), and 43% vs 27.5% gained at least one day a week off IV support. But the colon-in-continuity endpoints missed, and enteral autonomy at week 48 (12.5% vs 7.4%) was not significant. Discontinuation for side effects was low (3.6% vs 1.9%). While preparing the NDA, Ironwood found exposure in STARS was lower than intended because of dose preparation and administration, and in April 2025 said the FDA required a confirmatory trial. STARS-2 is a 24-week, placebo-controlled trial of about 124 patients (NCT07742735), started June 2026. So: a positive phase 3 on paper, with a dosing problem that undercuts confidence, and no approval in sight before the end of the decade. |
Frequently Asked Questions: Glepaglutide vs Apraglutide
What is the difference between Glepaglutide and Apraglutide?
Glepaglutide is a healing peptide that glepaglutide is zealand pharma's long-acting glp-2 analog for short bowel syndrome, built to be injected once or twice a week instead of daily like teduglutide. its path has been bumpy. the fda rejected it in december 2024 because the single phase 3 trial only worked at the twice-weekly dose, but europe went the other way: in september 2026 the ema's chmp recommended approval under the name zeydovio. as of late october 2026 the final european commission decision is still pending, and the us needs another trial. Apraglutide is a healing peptide that apraglutide is a once-weekly glp-2 analog for short bowel syndrome, originally from vectivbio and now owned by ironwood pharmaceuticals. its phase 3 stars trial hit its main goal in 2024, but in april 2025 ironwood said the fda wanted a confirmatory trial, partly because patients in stars got less drug exposure than planned due to how doses were prepared and given. that new trial, stars-2, started in june 2026, so approval is years away (a submission before end of 2029 has been mentioned). The main differences lie in their mechanisms of action and clinical applications.
Which is better, Glepaglutide or Apraglutide?
Neither is universally "better" - the choice depends on your specific goals. Glepaglutide is typically used for healing purposes, while Apraglutide is used for healing. Always consult with a healthcare provider to determine which may be appropriate for your situation.
Can Glepaglutide and Apraglutide be used together?
Some peptide protocols combine multiple compounds for synergistic effects. However, using Glepaglutide and Apraglutide together should only be considered under medical supervision, as both compounds have their own side effect profiles and potential interactions. Research on their combined use may be limited.