CHMP Backs Zealand Pharma's Zeydovio (glepaglutide) for Short Bowel Syndrome
核心洞察
The EMA's CHMP has recommended marketing authorization for Zeydovio (glepaglutide) in adults with short bowel syndrome (搜索), the first major advance in the indication in Europe in over a decade.
The positive opinion rests on the Phase 3 EASE-1 trial, where twice-weekly glepaglutide cut weekly parenteral support volume by 5.13 L/week versus 2.85 L/week with placebo (p=0.0039).
At 24 weeks, 65.7% of twice-weekly glepaglutide patients achieved at least a 20% reduction in parenteral support volume versus 38.9% on placebo, and 14% weaned off support entirely.
The Committee for Medicinal Products for Human Use (搜索) (CHMP) of the European Medicines Agency (搜索) has issued a positive opinion recommending marketing authorization for Zeydovio (glepaglutide) for the treatment of adults with short bowel syndrome (搜索) (SBS). Zealand Pharma (搜索), which developed the long-acting GLP-2 analogue, said the recommendation represents the first major advance in SBS treatment in Europe in more than a decade.
The opinion will now be reviewed by the European Commission, with a final decision on the Marketing Authorization Application expected within approximately 67 days. Subject to approval, the marketing authorization would be valid in all European Union member states, as well as Iceland, Liechtenstein and Norway.
EASE-1 Efficacy Data
The recommendation is based on the pivotal Phase 3 EASE-1 trial, a randomized, double-blind study in 106 SBS patients with intestinal failure who were dependent on parenteral support for at least three days per week. Patients were evenly randomized to glepaglutide 10 mg once or twice weekly, or placebo. The primary endpoint was the absolute change in weekly parenteral support volume from baseline at 24 weeks.
Glepaglutide administered twice weekly significantly reduced the total weekly volume of parenteral support by 5.13 liters per week compared with 2.85 liters per week in the placebo group (p=0.0039). Clinical efficacy was observed in patients with and without colon-in-continuity.
Among patients receiving glepaglutide twice weekly, 65.7% achieved a clinical response, defined as at least a 20% reduction in weekly parenteral support volume at 24 weeks, versus 38.9% in the placebo group. A reduction in parenteral support days of at least one day per week was achieved by 51.4% of twice-weekly patients versus 19.4% of placebo patients. Nine patients treated with glepaglutide were completely weaned off parenteral support to achieve enteral autonomy, while no placebo-treated patients reached that endpoint; for the twice-weekly dose, 14% (n=5) achieved enteral autonomy. Glepaglutide treatment appeared safe and well tolerated.
In total, 102 of 106 participating patients completed EASE-1, of which 96 continued into the two-year long-term safety and efficacy extension trial, EASE-2.
"The positive opinion for Zeydovio is the first major advancement in short bowel syndrome (搜索) treatment in Europe in more than a decade," said David Kendall, MD, Chief Medical Officer of Zealand Pharma (搜索). "Those living with short bowel syndrome face significant daily burdens and are susceptible to significant health risks from parenteral support, and every day free from it can be life changing."
Supporting and Mechanistic Trials
The CHMP opinion was also supported by interim results from the EASE-2 and EASE-3 extension studies, which ran for up to two years, and by mechanistic findings from EASE-4.
EASE-2 was a randomized, double-blind trial in which patients continued their randomly assigned treatment from EASE-1 at glepaglutide 10 mg once or twice weekly, while patients who received placebo in EASE-1 were re-randomized to glepaglutide. A smaller group of patients not previously treated with glepaglutide was directly randomized to the drug. In an interim analysis after at least six months of treatment, clinical response across the key efficacy endpoints was generally maintained or showed continued improvement, including additional patients on both doses weaning off parenteral support.
Patients completing EASE-2 were eligible for EASE-3, which evaluated glepaglutide administered once weekly using an autoinjector. Both trials were completed in 2026, and remaining patients have rolled over to a new extension trial, EASE-6. Results from EASE-2 and EASE-3 are expected to be presented at scientific meetings in 2027.
EASE-4 was a Phase 3b trial assessing the mechanistic effects of once-weekly glepaglutide on intestinal fluid and energy uptake. Its primary endpoint was absolute change in intestinal wet weight absorption, with secondary endpoints covering changes in energy, electrolyte and macronutrient absorption after 24 weeks, plus changes in parenteral support use, body composition and safety after 52 weeks. At week 24, the mean numerical increase in intestinal wet weight absorption was 398 g/day (p=0.0585) and mean energy absorption was 1038 kJ/day (p=0.0215), with improvements in electrolyte and macronutrient absorption. At week 52, mean parenteral support volume was reduced by 800 mL/day (p=0.0106) and mean parenteral support energy content fell by 866 kJ/day (p=0.0103).
Dosing and U.S. Pathway
Glepaglutide is a long-acting GLP-2 analogue designed to improve intestinal function and reduce or eliminate dependence on parenteral support. Its long half-life and high stability in aqueous solution support twice-weekly subcutaneous administration through a ready-to-use, single-dose autoinjector.
The U.S. Food and Drug Administration (搜索) has granted orphan drug designation to glepaglutide for the treatment of SBS. Zealand Pharma (搜索) is advancing the Phase 3 EASE-5 trial, a randomized, double-blind, placebo-controlled study designed to confirm the efficacy and safety of twice-weekly glepaglutide, followed by a long-term, open-label safety evaluation in SBS patients with intestinal failure. Patient recruitment is progressing well, and the company said the trial is intended to provide further confirmatory evidence for a U.S. regulatory submission. Zealand Pharma added that it is actively engaging in partnership discussions for future global commercialization of glepaglutide in SBS.
Disease Burden
Short bowel syndrome (搜索) is a rare, chronic and severe disease associated with reduced or complete loss of intestinal function, leaving many patients chronically dependent on complex parenteral support. While life-sustaining, parenteral support places significant restrictions on patients' ability to engage in daily activities, and patients are at risk of serious and life-threatening complications including sepsis, blood clots, liver damage and renal impairment.
Zealand Pharma (搜索) is headquartered in Copenhagen, Denmark, with a U.S. presence in Boston, Massachusetts, and focuses on peptide-based medicines for obesity, metabolic and other serious diseases.